Current Advances in Diagnosis, Therapeutics, and Surgical Interventions for the Management of Refractory Gastroesophageal Reflux Disease (GERD): An Update.

Gastroesophageal reflux disease (GERD) is a chronic illness characterized by complications arising from the reflux of stomach contents, which significantly lower the quality of life, increase morbidity, and increase medical expenses associated with treating the condition. The main goal of treatment in GERD is symptomatic relief, relapse prevention, and healing of erosive esophagitis. The treatment mainly involves lifestyle changes to control acid production and proton pump inhibitors (PPIs) as the first line of treatment. Endoscopic interventions or anti-reflux surgery may be beneficial in relieving symptoms in people whose symptoms are triggered by reflux. In this review, we discuss the pathophysiology and newer diagnostic and treatment modalities including available surgical management options to manage refractory GERD.

Clinical features of gastroesophageal reflux disease and erosive esophagitis: Insights from patients undergoing esophagogastroduodenoscopy in resource-limited Ethiopia.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common disease worldwide with varying clinical presentations and risk factors. Prevalence data for Africa is lacking, but an increasing trend is expected due to demographic and epidemiological transitions. Although endoscopic studies for general gastrointestinal disorders have shown some patients with erosive esophagitis (EE), no studies in Ethiopia have investigated the clinical characteristics, risk factors, and severity of GERD using esophagogastroduodenoscopy (EGD). AIM: To assess the clinical features of GERD in Ethiopian patients who underwent EGD and determine the severity and risk factors of EE. METHODS: We conducted a multicenter, retrospective cross-sectional study of 221 patients diagnosed with GERD and endoscopic findings of EE at Trauma Associated Severe Hemorrhage and Amniotic Membrane Stem Cell between January 2019 and August 2022. Data were collected from electronic medical records and phone call interviews. We used descriptive statistics and binary logistic regression analysis with SPSS version 26 to identify the association between variables with a statistical significance set at P value < 0.05. RESULTS: The mean ± SD age of the patients was 44.8 (± 15.9) years, with a male-to-female ratio of 1.6:1. The most commonly reported symptom was epigastric pain (80.5%), followed by heartburn (43%). Los Angeles (LA)-A EE was diagnosed in 71.1% of patients, followed by LA-B (14.9%), LA-C (7.7%), and LA-D (5.9%). Multivariate analysis showed that age 50 or above, presence of bleeding, and endoscopic findings of duodenitis/duodenopathy were significantly associated with severe EE (P < 0.05). Stricture and Barrett's esophagus were observed in 4.5% and 1.36% of patients with EE, respectively. CONCLUSION: Most of the patients had milder EE with fewer complications. However, severe EE was more prevalent in older patients and those with duodenitis/duodenopathy.

Herpes Simplex Virus Esophagitis in an Immunocompetent Patient: A Case Report.

Even though it is rare, herpes simplex virus (HSV) esophagitis has a significant adverse impact on immunocompromised people, such as those with HIV, cancer patients receiving chemotherapy or radiation to the neck, and recipients of transplants receiving immunosuppressive treatments. This makes a high level of clinical suspicion necessary for a precise diagnosis and successful treatment. Although rare, its occurrence in immunocompetent patients poses unique challenges for diagnosis and therapy. A 68-year-old woman with HSV esophagitis presented with severe symptoms, including odynophagia and hematemesis. Endoscopy revealed "volcano-like" ulcers; after confirmation of HSV-1 infection, treatment with acyclovir, esomeprazole, and sucralfate led to symptom resolution within a week and complete healing in three months. This case underscores the importance of considering HSV esophagitis in the differential diagnosis of esophageal ulcers in immunocompetent patients, emphasizing the need for early diagnosis and antiviral therapy for effective treatment.

Granulomatous hyperinflammatory state induced by dupilumab treatment for eosinophilic esophagitis.

We present the first case of a dupilumab-induced hyperinflammatory state in the setting of underlying eosinophilic esophagitis characterized by multisystem granulomatous inflammation. Although clinical trial data and subsequent real-world experience support dupilumab as a highly effective therapy for eosinophilic esophagitis, close monitoring for development of adverse symptoms following initiation remains paramount.

Successful novel use of dupilumab for gastrointestinal involvement of idiopathic hypereosinophilic syndrome: case report and review of the literature.

Hypereosinophilic syndrome (HES) is characterized by blood and tissue hypereosinophilia leading to organ damage. Gastrointestinal involvement is the third most common manifestation. We present a patient with idiopathic HES with secondary eosinophilic esophagitis (EoE), gastritis, and enteritis, corticosteroids-dependent, azathioprine- and mepolizumab-refractory. The patient achieved clinical and histopathologic remission following dupilumab treatment. A 28 year-old female presented with chronic episodic nausea and emesis since childhood and initial diagnosis of primary eosinophilic gastrointestinal disease (EGID), improved with corticosteroids, refractory to azathioprine. She was found to have peripheral eosinophilia and multifactorial anemia, with iron, B12, and folate deficiencies. Esophageal, gastric, duodenal, and terminal ileum biopsies showed significant eosinophilic infiltrate. Bone marrow biopsy at age 31 confirmed HES diagnosis. By age 32, she became total parental nutrition (TPN)-dependent. She failed trials of benralizumab and mepolizumab [anti-interleukin (IL)-5 inhibitors], and cromolyn (mast-cell stabilizer). After developing new esophageal stricture, we initiated dupilumab (IL-4/13 inhibitor), recently FDA-approved for EoE. After 9 weeks, esophageal stricture, gut tissue eosinophilia, and prior intestinal ulcerations resolved. She ceased TPN and is tolerating a non-restricted diet, with complete symptom resolution. Our patient's complete remission with dupilumab shows promise for broadening its use in treating GI involvement in HES, along with primary EGIDs.

A Cricopharyngeal Bar as an Underrecognized Finding in an Adolescent with Eosinophilic Esophagitis.

A 16-year-old Caucasian male with previously diagnosed eosinophilic esophagitis (EoE) 4 years before his initial visit to an allergist-immunologist, scheduled due to severe dysphagia and recurrent food impaction. He had been off EoE therapy for 1 year. After resuming inhaled fluticasone and a proton pump inhibitor (PPI), esophagogastroduodenoscopy (EGD) was immediately scheduled. The dates of the original EGD procedures with the histological summary and EoE therapy are reported in the Table 1. The fourth endoscopy revealed near normal histology, with rare candida staining (Table 1). He was continued on daily PPI and the fluticasone was discontinued. Three weeks of Fluconazole failed to resolve his dysphagia. A repeat barium swallow confirmed a pre-existing cricopharyngeal bar, and he was referred to an otolaryngology for further care. [Table: see text].

Increased expression of proton pump and allergic inflammation genes predicts PPI failure in pediatric eosinophilic esophagitis.

Proton pump inhibitors (PPIs) are one of the standards of care of eosinophilic esophagitis (EoE) treatment, though PPI response rates are variable ranging from 23 to 63% in pediatric studies. We sought to determine if expression of select genes in esophageal mucosa can predict PPI responsiveness in EoE. Children with a new diagnosis of EoE (15 or more eosinophils/hpf on esophageal biopsy) were prospectively treated with 8 weeks of PPI therapy before follow-up esophagogastroduodenoscopy (EGD). Children with <15 eosinophils/hpf on follow-up were classified as having PPI-Responsive EoE (PPI-R) and ≥ 15 eosinophils/hpf as PPI-Nonresponsive EoE (PPI-NR). Using the Nanostring nCounter Analysis System, mRNA expression of a custom panel of genes was measured in esophageal biopsies. Immunohistochemical staining of biopsies was performed. Among children with EoE, 32% (8/25) had PPI-R EoE. ATP12A, ATP4A, tryptase-beta 2 (TPSB2), CLC and IL13 had higher expression in PPI-NR EoE compared to PPI-R EoE or controls. Immunohistochemical staining of ATP12A was higher among PPI-R EoE and PPI-NR EoE, compared to non-EoE controls. In this study, PPI-NR EoE had significantly higher baseline gene expression of mast cell, cytokine, proton pump, and eosinophil genes compared to PPI-R EoE. PPIs may be involved in an inflammatory cascade of mast cell activation that stimulates IL-13 release, which upregulates ATP12A and ATP4A that leads to eosinophil recruitment. Histologic PPI failure may occur when increased gene expression of these components is high and cannot be overcome pharmacologically, especially in the case of proton pump genes.

Herpes Simplex Virus Esophagitis in a Patient Receiving Long-Term Nasal Corticosteroids: A Rare Case.

Herpetic esophagitis (HE), primarily caused by the herpes simplex virus (HSV)-1, is most commonly encountered in immunocompromised hosts, although it has been occasionally observed in immunocompetent patients. In the immunocompromised setting, it is typically correlated with human immunodeficiency virus (HIV) infection, malignancy, chemotherapy and radiotherapy, solid organ transplant, as well as the use of systemic corticosteroids and other immunosuppressive agents. We present the case of a 35-year-old patient on hemodialysis due to diabetic nephropathy who, after having received intranasal corticosteroids for three weeks, developed nausea, vomiting, and epigastric pain. Gastroscopy and subsequent biopsy revealed ulcerative esophagitis compatible with herpetic infection. Immunohistochemistry was negative for cytomegalovirus (CMV), while subsequent quantitative polymerase chain reaction (PCR) testing was positive for HSV-1, establishing the diagnosis of HSV esophagitis. After a 14-day course of valacyclovir, complete relief of symptoms was achieved. Herpetic esophagitis may occur in immunocompetent persons, whereas intranasal corticosteroids cannot be ruled out as potential contributors. Symptoms such as odynophagia, dysphagia, and fever in that setting warrant further investigation.

Correlation of gastrointestinal symptom rating scale and frequency scale for the symptoms of gastroesophageal reflux disease with endoscopic findings.

BACKGROUND: Gastroesophageal Reflux Disease (GERD) is caused by the reflux of gastric contents into the esophagus and has a 13% global prevalence that is increasing. GERD symptoms negatively impact physical, social, and emotional quality of life. The Frequency Scale for the Symptoms of GERD (FSSG) and the Gastrointestinal Symptom Rating Scale (GSRS) determine the efficacy of treatment but may not correlate with endoscopically estimated esophageal mucosal injury severity. We aimed to probe the correlation between FSSG, GSRS, and esophageal injury severity to evaluate whether these scores can predict GERD severity. METHODS: A total of 2962 patients who underwent physical examinations, including upper gastrointestinal endoscopy, at the Kyoto Kuramaguchi Medical Center, Japan, were enrolled in this study. Upper gastrointestinal endoscopy was used to diagnose fundic mucosal atrophy, reflux esophagitis based on the Los Angeles (LA) classification, gastroesophageal flap value function (GEFV) based on Hill's classification, and Barrett's esophagus. Endoscopic diagnoses were examined for correlations with FSSG and GSRS scores. RESULTS: In reflux esophagitis, FSSG and GSRS scores correlated with LA-B and LA-C endoscopic diagnosis but not with LA-M and LA-A endoscopic findings. Multiple regression analysis results were similar. FSSG scores reflected advanced fundic gland mucosal atrophy, while GSRS scores associated with high grade of GEFV. CONCLUSIONS: This is the first report to examine the correlation between FSSG and GSRS scores and endoscopic findings in a relatively large patient population. Our findings suggest that these scores can diagnose the severity of reflux esophagitis.

VINDICATE-P: A Mnemonic for the Many Comorbidities of Atopic Dermatitis.

Patients with atopic dermatitis (AD) are at increased risk of atopic and non-atopic comorbidities. In fact, the Hanifin and Rajka criteria include allergic and infectious comorbidities as a minor criterion. Despite the well-recognized list of comorbidities, the past 15 years greatly expanded the list of recognized comorbidities of AD. This narrative review focuses on comorbidities of AD using a mnemonic, VINDICATE-P: vascular/cardiovascular, infectious, neoplastic and neurologic, degenerative, iatrogenic, congenital, atopic and autoimmune, traumatic, endocrine/metabolic, and psychiatric. The comorbidities of AD vary by age. More research is needed into the mechanisms of comorbidities and optimal screening strategies in AD patients.

Coexistent Eosinophilic Esophagitis and Dysplastic Barrett's Esophagus With Rapid Eosinophilic Infiltration of Neosquamous Mucosa After Radiofrequency Ablation.

The coexistence of eosinophilic esophagitis (EoE) and Barrett's esophagus (BE) is rare despite the known association of gastroesophageal reflux disease with both conditions. Radiofrequency ablation is an effective endoscopic eradication therapy in patients with dysplastic BE. However, the efficacy and outcomes of radiofrequency ablation in patients with concomitant EoE and BE are not well known. We report a case of rapid eosinophilic infiltration of the neosquamous mucosa after the complete eradication of long-segment dysplastic BE in a patient with coexisting BE and EoE.

Radiation-induced Esophagitis in Breast Cancer Patients Treated With Supraclavicular Field Irradiation.

BACKGROUND/AIM: The objective of this research was to assess the frequency and intensity of radiation-induced esophagitis in breast cancer patients treated with supraclavicular radiotherapy field irradiation. PATIENTS AND METHODS: This study involved 100 patients with positive lymph nodes receiving radiotherapy to the breast or chest wall along with supraclavicular field irradiation, with toxicity levels assessed weekly. Treatment utilized the 3D conformal technique, and variables, such as mean and maximum dose to the cervical esophagus, mean dose to the entire esophagus, and length of the esophagus within the treated area were recorded. RESULTS: The occurrence of grade 2 or higher esophagitis was 48%, with patients facing the risk of developing such esophagitis at an average dose of 13 Gy. The probability of grade 2 esophagitis occurring at doses exceeding 13 Gy was statistically significantly higher (p<0.001) with an odds ratio of 24.4. CONCLUSION: Limiting the mean cervical esophagus dose to <13 Gy could help reduce the frequency and severity of grade 2 or higher toxicity.

[Eosinophilic esophagitis (EoE) in adults in Icelandic and international context].

Eosinophilic esophagitis (EoE) is a common cause of swallowing difficulties in both children and adults. The incidence of EoE has been increasing over the past decades, which cannot be solely attributed to improved diagnostic techniques. EoE is more common in adults than in children. The diagnosis is confirmed by a biopsy from the esophageal mucosa showing a significant infiltration of eosinophils. Many patients respond to treatment with proton pump inhibitors, but those with severe EoE may require dietary modifications, topical steroids, and/or dilation of esophageal strictures. This review covers the incidence, risk factors, natural course, diagnosis, and treatment options for EoE, both within the Icelandic healthcare system andi n a broader context.

Distal esophageal spasm and gastroesophageal reflux disease: re-examining the association.

Distal esophageal spasm (DES) is a rare motility disorder presenting with dysphagia or chest pain. Although studies suggest a link between DES and gastroesophageal reflux disease (GERD), data supporting a distinct GERD-related phenotype are limited. This study aims to investigate demographic, symptomatic, and physiologic differences between DES subjects with and without GERD. A retrospective cohort analysis of DES patients determined by high resolution manometry (HRM) was conducted between February 2020 and January 2023. Demographics, medications, symptoms, and quantitative reflux testing data were collected. DES subjects with reflux (R-DES) were defined by presence of Los Angeles Grade B/C/D esophagitis, Barrett's metaplasia, or abnormal pH testing. DES subjects without reflux (NR-DES) had normal parameters. Statistical analysis employed two-sided or Wilcoxon Rank-Sum, Chi-squared, or Fisher's exact tests, and multivariate logistic regression. Of 69 DES subjects, 32 (46.3%) had GERD. R-DES and NR-DES patients had similar demographic variables except for higher BMI in R-DES (30.41 vs. 26.88, P = 0.01). R-DES and NR-DES shared similar symptom profiles (heartburn P = 0.67, dysphagia P = 0.448, chest pain P = 0.32). Proton pump inhibitor use was similar between groups (78.1% vs. 91.9%, P = 0.202). HRM metrics were comparable except for basal LES tone (20.7 mmHg vs. 32.99 mmHg, P = 0.03) and median IRP 11.82 mmHg versus 17.20 mmHg, P = 0.017). This study found no distinguishing clinical or physiologic differences between DES patients with and without GERD, challenging the historical emphasis of GERD in DES pathogenesis. The impact of GERD management on the natural history of DES remains uncertain.

From Pathogenesis to Treatment: Targeting Type-2 Inflammation in Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. EoE shares a common pathogenetic mechanism with other chronic disorders pertaining to the type 2 inflammatory spectrum, such as atopic dermatitis (AD), allergic rhinitis (AR), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). The recent advancements in EoE pathogenesis understanding have unveiled new molecular targets implied within the "atopic march" picture as well as specific to EoE. These discoveries have led to the clinical evaluation of several novel drugs (monoclonal antibodies and immune modulators), specifically aimed at the modulation of Th2 inflammation. In this comprehensive review, we have focused on the subtle mechanisms of type 2 inflammatory disorders, highlighting the similarities and differences with EoE, taking a deeper look into the evolving field of biologic therapies, already approved or under current investigation.

Esophageal lymphocytosis: exploring the knowns and unknowns of this pattern of esophageal injury.

INTRODUCTION: Lymphocyte-rich inflammation of the esophageal mucosa has gained increased awareness among pathologists and clinicians recently. Patients usually present with symptoms of esophageal dysfunction, including dysphagia and food bolus impaction. Endoscopy may show changes similar to eosinophilic esophagitis but may also be entirely normal ('microscopic esophagitis'). Three morphological subtypes or variant forms have been described which include lymphocytic, lichenoid and lymphocyte-predominant esophagitis. These need to be discriminated against other distinct causes of esophageal lymphocytosis, such as gastro-esophageal reflux disease and Candida infection. AREAS COVERED: This review provides an overview of diagnostic criteria and clinical associations of the disorder and presents an algorithmic approach to diagnosis. A comprehensive literature review was conducted using PubMed, Medline and Google Scholar databases to identify articles related to lymphocyte-rich esophageal inflammation, published up to March 2024. EXPERT OPINION: Lymphocyte-rich inflammation needs to be included in the differential diagnosis and clinical work-up of patients with esophageal dysfunction. There is currently considerable morphological overlap among published subtypes or variant forms. Follow-up studies of affected individuals are needed to formalize diagnostic parameters and identify the clinical course of disease in order to optimize treatment modalities.

Modeling Epithelial Homeostasis and Perturbation in Three-Dimensional Human Esophageal Organoids.

Background: Esophageal organoids from a variety of pathologies including cancer are grown in Advanced Dulbecco's Modified Eagle Medium-Nutrient Mixture F12 (hereafter ADF). However, the currently available ADF-based formulations are suboptimal for normal human esophageal organoids, limiting the ability to compare normal esophageal organoids with those representing a given disease state. Methods: We have utilized immortalized normal human esophageal epithelial cell (keratinocyte) lines EPC1 and EPC2 and endoscopic normal esophageal biopsies to generate three-dimensional (3D) organoids. To optimize the ADF-based medium, we evaluated the requirement of exogenous epidermal growth factor (EGF) and inhibition of transforming growth factor-(TGF)-ß receptor-mediated signaling, both key regulators of the proliferation of human esophageal keratinocytes. We have modeled human esophageal epithelial pathology by stimulating esophageal 3D organoids with interleukin (IL)-13, an inflammatory cytokine, or UAB30, a novel pharmacological activator of retinoic acid signaling. Results: The formation of normal human esophageal 3D organoids was limited by excessive EGF and intrinsic TGFß-receptor-mediated signaling. Optimized HOME0 improved normal human esophageal organoid formation. In the HOME0-grown organoids, IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis. Conclusions: HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media.

Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.

BACKGROUND: Investigating the contributory role that epithelial cell metabolism plays in allergic inflammation is a key factor to understanding what influences dysfunction and the pathogenesis of the allergic disease eosinophilic esophagitis (EoE). We previously highlighted that the absence of hypoxia signaling through hypoxia-inducible factor (HIF)-1α in EoE contributes to esophageal epithelial dysfunction. However, metabolic regulation by HIF-1α has not been explored in esophageal allergy. OBJECTIVES: We sought to define the role of HIF-1α-mediated metabolic dysfunction in esophageal epithelial differentiation processes and barrier function in EoE. METHODS: In RNA sequencing of EoE patient biopsy samples, we observed the expression pattern of key genes involved in mitochondrial metabolism/oxidative phosphorylation (OXPHOS) and glycolysis. Seahorse bioenergetics analysis was performed on EPC2-hTERT cells to decipher the metabolic processes involved in epithelial differentiation processes. In addition, air-liquid interface cultures were used to delineate metabolic dependency mechanisms required for epithelial differentiation. RESULTS: Transcriptomic analysis identified an increase in genes associated with OXPHOS in patients with EoE. Epithelial origin of this signature was confirmed by complex V immunofluorescence of patient biopsy samples. Bioenergetic analysis in vitro revealed that differentiated epithelium was less reliant on OXPHOS compared with undifferentiated epithelium. Increased OXPHOS potential and reduced glycolytic capacity was mirrored in HIF1A-knockdown EPC2-hTERT cells that exhibited a significant absence of terminal markers of epithelial differentiation, including involucrin. Pharmacologic glucose transport inhibition phenocopied this, while rescue of the HIF-1α-deficient phenotype using the pan-prolyl hydroxylase inhibitor dimethyloxalylglycine resulted in restored expression of epithelial differentiation markers. CONCLUSIONS: An OXPHOS-dominated metabolic pattern in EoE patients, brought about largely by the absence of HIF-1α-mediated glycolysis, is linked with the deficit in esophageal epithelial differentiation.

POEM in the esophagus - How to deal with the post-POEM reflux.

Reflux after peroral endoscopic myotomy (POEM) is arguably one of the greatest concerns related to the procedure. The exact incidence is difficult to establish as reflux symptoms, esophagitis, and abnormal acid exposure correlate poorly, warranting thorough diagnostic investigation. The incidence is, however, higher than after Heller myotomy or pneumatic dilatation across all these three parameters. Although PPI are effective in the resolution of symptoms and healing of esophagitis, refractory patients exist. Esophageal hypersensitivity and acidic fermentation/esophageal stasis are most likely causes and could be diagnosed by manual analysis of pH metry tracings. Long-term complications like peptic stricture and Barrett's esophagus are rare and reported sporadically. Modifications of POEM procedure aiming to decrease post-POEM reflux led to no conclusive preferred technique. Modern investigations like endoluminal functional lumen imaging probe might help to personalize myotomy to the desired distensibility of the lower esophageal sphincter and decrease reflux.