Toll-like receptor 3 (TLR3) variant and NLRP12 mutation confer susceptibility to a complex clinical presentation.

Genetic aberrations in the toll-like receptor (TLR)3 pathway are associated with increased susceptibility to herpes simplex virus (HSV) infections. Leucine-rich repeat and PYD-containing protein (NLRP)12 is a component of the inflammasome apparatus, which is critical to an immediate innate inflammatory response. Aberrations in NLRP12 have been shown to mediate auto-inflammation. In this study, we present a 44-year old patient with severe HSV esophagitis and Crohn's disease. An immune and genetic investigation confirmed two coinciding genetic mutations in TLR3 and NLRP12. Our findings support conducting laboratory workup that targets TLR3 pathway in the immunocompetent host developing recurrent HSV infections.

Variations in the Clinical Course of Patients with Herpes Simplex Virus Esophagitis Based on Immunocompetence and Presence of Underlying Esophageal Disease.

BACKGROUND AND AIMS: Herpes simplex esophagitis (HSE) is the second most common cause of infectious esophagitis and occurs in both immunocompetent and immunocompromised patients. The aim of this study was to reappraise the clinical course of HSE in different patient populations based on degree of immunocompetence and the presence or absence of underlying esophageal disease. METHODS: Patients with histopathologically confirmed HSE identified from the Mayo Clinic pathology database from 2006 to 2016 were included in this study. Relevant demographic, clinical, and endoscopic data were retrospectively reviewed and compared between two cohorts: (a) immunocompromised and immunocompetent patients and (b) patients with and without underlying esophageal disorders. RESULTS: Forty-six patients were included in the study. The most common presenting symptoms were odynophagia (34.8%) and dysphagia (30.4%). Thirty-three (71.7%) patients were immunocompromised, and these patients who experienced longer duration of symptoms (25.5 ± 23.4 days vs. 7.0 ± 5.5 days, p = 0.04) were more likely to require an extension of treatment course (38.1% vs. 8.3%, p = 0.05) compared to their immunocompetent counterparts. Seventeen (37%) patients had underlying esophageal disease, and these patients were more likely to have concomitant esophageal candidiasis (41.2% vs. 10.3%, respectively; p = 0.01). CONCLUSION: Herpes simplex virus causes esophagitis in both immunocompetent and immunocompromised patients. While the disease course appears to be self-limited for all patient populations, clinical and endoscopic differences in the disease presentation and clinical course based on immune status and the presence or absence of underlying esophageal disease exist.

Modeling Esophagitis Using Human Three-Dimensional Organotypic Culture System.

Esophagitis, whether caused by acid reflux, allergic responses, graft-versus-host disease, drugs, or infections, is a common condition of the gastrointestinal tract affecting nearly 20% of the US population. The instigating agent typically triggers an inflammatory response. The resulting inflammation is a risk factor for the development of esophageal strictures, Barrett esophagus, and esophageal adenocarcinoma. Research into the pathophysiology of these conditions has been limited by the availability of animal and human model systems. Three-dimensional organotypic tissue culture (OTC) is an innovative three-dimensional multicellular in vitro platform that recapitulates normal esophageal epithelial stratification and differentiation. We hypothesized that this platform can be used to model esophagitis to better understand the interactions between immune cells and the esophageal epithelium. We found that human immune cells remain viable and respond to cytokines when cultured under OTC conditions. The acute inflammatory environment induced in the OTC significantly affected the overlying epithelium, inducing a regenerative response marked by increased cell proliferation and epithelial hyperplasia. Moreover, oxidative stress from the acute inflammation induced DNA damage and strand breaks in epithelial cells, which could be reversed by antioxidant treatment. These findings support the importance of immune cell-mediated esophageal injury in esophagitis and confirms the utility of the OTC platform to characterize the underlying molecular events in esophagitis.

Esophageal mucosa in HIV infection: A"deeper" look at this little spoken organ.

BACKGROUND AND AIM: Although the esophagus is a common site of opportunistic infection in AIDS patients, little is known about the impact of HIV as well as opportunistic infection in the esophageal mucosa. Our aim is to analyze the esophageal immune profile in HIV+ patients with different immunological status with and without the opportunistic Candida infection. METHODS: Immunohistochemistry to CD4+ and CD8+ T-cells, γ-interferon, transforming growth factor-ß, interleukin (IL)-4, IL-6, IL-13, and IL-17 was performed in esophageal samples of 40 chronically HIV+ patients under highly active antiretroviral therapy (16 with Candida esophagitis, 12 virologically non-supressed with blood CD4 count < 500, and 12 virologically suppressed with blood CD4 count > 500; the latter two groups without esophageal candidiasis). The controls were 12 HIV-negative healthy individuals. RESULTS: Esophageal CD4+ T-cell expression in HIV+ patients did not differ from the control group (P = 0.50). Mucosal CD8+ T-cell expression was significantly increased in HIV+ patients (P = 0.0018). Candida esophagitis and virologically non-supressed HIV+ patients with CD4 < 500 showed an increased expression of IL-17 and IL-6 with fewer expressions of γ-interferon, more attenuated in the latter group. Transforming growth factor-ß was increased only in virologically suppressed HIV+ patients with CD4 > 500. IL-4 and IL-13 were similar to the control group. CONCLUSION: In contrast to CD8+ T-cell expression, esophageal CD4+ T-cell expression does not reflect the HIV+ patient's immunological status. T-helper 17 (Th17) response seems to play a role in the esophageal mucosa of virologically non-supressed HIV+ patients with blood CD4 < 500. Candida esophagitis showed a Th1/Th17 response but seems to be dominantly regulated by the Th17 pathway.

IgG4-related disease involving the esophagus: a clinicopathological study.

Immunoglobulin G4 (IgG4)-related disease is a recently coined systemic disease characterized by specific histopathologic findings of an intense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis in the presence of predominant IgG4-positive plasma cells. Although IgG4-related disease has been described in many organs, involvement of the esophagus is very rare. In this study, we describe the clinicopathologic characteristics of eight patients with IgG4-related esophagitis. We evaluated chronic esophagitis specimens with lymphoplasmacytic infiltrate obtained over the past 6 years (from January 2011 to February 2017) using a chart review, pathologic examination, and IgG4 immunohistochemical staining. The diagnoses of the specimens were either confirmed as IgG4-related esophagitis (IgG4-RE) or chronic esophagitis, not otherwise specified (CENOS), and the clinicopathologic data from each group were compared. Eight patients were diagnosed with IgG4-RE and 10 controls were identified and diagnosed with CENOS. In the IgG4-RE group, esophageal strictures were identified in three patients, two patients had postmyotomy treated achalasia, one patient had erosive esophagitis and another presented with an esophageal nodule. Only one patient had an unremarkable mucosa on endoscopy. In the CENOS group, four patients had esophageal strictures, six had erosive esophagitis, one patient had mild esophagitis. The IgG4-RE group had significantly higher numbers of IgG4-positive plasma cells (66.9 ± 21.9 vs. 4.7 ± 2.4 per high power field; P< 0.001) and a greater IgG4: IgG ratio 0.76 ± 0.13 vs. 0.06 ± 0.05; P< 0.001) when compared to CENOS patients. Two of the patients with recurrent esophageal strictures in the IgG4-RE group showed initial response to steroid therapy and are currently on immunosuppressive therapy which has significantly reduced the need for multiple esophageal dilatations. The presentation of IgG4-related esophageal disease can vary and the key to diagnosis is dependent on histopathology. These observations highlight the need for IgG4 immunohistochemical staining of esophageal biopsies especially in patients with mucosal ulceration, chronic inflammation, and plasmacytosis on biopsy. This will prevent unwarranted esophagectomies and failed medical treatment due to lack of recognition of this entity.

Esophageal infections: an update.

PURPOSE OF REVIEW: Infectious esophagitis generally occurs in patients with impaired immunity. Although methods to suppress the immune system evolve, the potential infectious consequences are poorly understood. The purpose of this article is to review the risk factors, diagnosis, and treatment of infectious esophagitis. RECENT FINDINGS: Minimal pediatric data, including a few case reports and series, involve infectious esophagitis. Esophageal infections are usually caused by the following microbes, in order starting with the most common: Candida albicans, herpes simplex virus, and cytomegalovirus. Uncommon risk factors in these and other reports include epidural triamcinolone and oral budesonide in addition to more common risk factors such as HIV infection, chemotherapeutic agents, and transplant immunosuppressive medications. Rare reports involve immunocompetent patients and treatment of these patients is controversial. SUMMARY: Understanding of infectious esophagitis is growing, and risk factors, diagnosis, and treatments are evolving.

Gastroesophageal reflux in young children and adolescents: Is there a relation between symptom severity and esophageal histological grade?

BACKGROUND: The pediatric literature about the correlation between symptoms and histological lesions in patients investigated for gastroesophageal reflux disease is scarce and inconclusive. The primary aim of the present study was to assess the relation between the complained symptom severity and the esophageal histological grade, through the use of validated and reliable scores. METHODS: All children ages between 2 and 17 years referred to perform upper gastrointestinal endoscopy because of gastroesophageal reflux disease symptoms were asked to complete the Pediatric Gastroesophageal Symptom and Quality of Life validated questionnaire, investigating the main symptoms complained and their impact on daily life and school activities. Esophageal mucosal samples taken during the procedure were analyzed and scored according to the Yerian-Fiocca classification. RESULTS: A total of 164 children were included in the study. No significant association was found between symptomatic score and histological score (r(s): 0.05, P: 0.49). Even when focusing only on adolescents with heartburn or chest pain, no correlation between symptom severity and esophageal lesions was found (r(s): -0.18, P: 0.264). Intercellular space diameter values did not mirror symptom severity. CONCLUSIONS: The main finding of this study on children with reflux symptoms is the lack of correlation between symptom severity and esophageal histological grade. The magnitude of intercellular spaces was found not to be related with the clinical score as well.

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.

Dupilumab Leads to Clinical Improvements including the Acquisition of Tolerance to Causative Foods in Non-Eosinophilic Esophagitis Eosinophilic Gastrointestinal Disorders.

A recent report showed that most pediatric cases of non-eosinophilic esophagitis (EoE) eosinophilic gastrointestinal disorders (EGIDs) (non-EoE EGIDs) are persistent and severe compared with those of EoE, thus requiring further effective therapeutic approaches. In this study, we present the first case based on a systematic search of non-EoE EGID for which tolerance to causative foods and histological and symptomatic improvements were achieved following dupilumab administration, after elimination diets and omalizumab and mepolizumab treatments. Driven by this case, we investigated the efficacies of biological treatments in non-EoE EGID cases based on the patient studied herein, and other patients identified in the conducted systematic review. Seven articles, including five different biologics, were reviewed. Both clinical efficacies and impact differences among the targeted molecules are demonstrated in this study. Our findings show that dupilumab may affect mechanisms that can suppress symptoms induced by offending foods that are different from those induced by other biologics as identified in the conducted systematic review. Additional studies are required to address the unmet needs of non-EoE EGID treatments.

Lymphocytic esophagitis: a diagnosis of increasing frequency.

BACKGROUND: Despite being found with increasing frequency on esophageal biopsies, the clinical significance of lymphocytic esophagitis (LE) remains poorly understood. GOALS: The primary aim of our study was to characterize the clinical presentation and natural history of LE among adult patients. STUDY: We retrospectively reviewed records for all 81 adult patients at the University of Michigan Medical Center who had a histopathologic diagnosis of LE between January 1998 and November 2009. Patient demographics, clinical history, laboratory data, and imaging results from the time of diagnosis were obtained through review of computerized medical records. A telephone survey was conducted to collect natural history data. RESULTS: The number of LE diagnoses increased over time, with 81.5% (n=66) of patients being diagnosed in the last 3 years. The most frequent symptoms at the time of presentation were dysphagia (n=54), chest/abdominal pain (n=36), and heartburn (n=38). The majority (58.6%) of patients reported improvement in their initial gastrointestinal symptoms-most commonly associated with initiation of a proton pump inhibitor. Upon follow-up, most patients reported a good quality of life and satisfaction with their current health status. CONCLUSIONS: LE is a new clinical entity with an increasing incidence. LE seems to have a benign natural history, with most patients reporting an improvement in symptoms and satisfaction with their health-related quality of life. Prospective studies are needed to better characterize the natural history and potential treatments for this clinical entity.

IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R alpha 2-inhibited pathway.

Eosinophilic esophagitis (EE) is an emerging disease associated with both food and respiratory allergy characterized by extensive esophageal tissue remodeling and abnormal esophageal gene expression, including increased IL-13. We investigated the ability of increased airway IL-13 to induce EE-like changes. Mice with pulmonary (but not esophageal) overexpression of IL-13 evidenced esophageal IL-13 accumulation and developed prominent esophageal remodeling with epithelial hyperplasia, angiogenesis, collagen deposition, and increased circumference. IL-13 induced notable changes in esophageal transcripts that overlapped with the human EE esophageal transcriptome. IL-13-induced esophageal eosinophilia was dependent on eotaxin-1 (but not eotaxin-2). However, remodeling occurred independent of eosinophils as demonstrated by eosinophil lineage-deficient, IL-13 transgenic mice. IL-13-induced remodeling was significantly enhanced by IL-13Ralpha2 deletion, indicating an inhibitory effect of IL-13Ralpha2. In the murine system, there was partial overlap between IL-13-induced genes in the lung and esophagus, yet the transcriptomes were divergent at the tissue level. In human esophagus, IL-13 levels correlated with the magnitude of the EE transcriptome. In conclusion, inducible airway expression of IL-13 results in a pattern of esophageal gene expression and extensive tissue remodeling that resembles human EE. Notably, we identified a pathway that induces EE-like changes and is IL-13-driven, eosinophil-independent, and suppressed by IL-13Ralpha2.

Interferon-α exerts proinflammatory properties in experimental radiation-induced esophagitis: Possible involvement of plasmacytoid dendritic cells.

AIMS: Radiation-induced esophagitis, experienced during radiation therapy for lung cancer and head and neck cancer, is a major dose-limiting side effect of the treatment. This study aimed to elucidate the role of interferon-α (IFN-α) in radiation-induced esophagitis. MAIN METHODS: C57BL/6 mice were exposed to 10 and 25Gy of single thoracic irradiation. Esophageal mucosal damage and inflammatory reactions were assessed for 5 days after irradiation. KEY FINDINGS: Irradiation induced esophagitis, characterized by reduction in the thickness of epithelial layer, upregulation of proinflammatory cytokines and chemokines, infiltration of inflammatory cells into the esophageal mucosa, and apoptosis of epithelial cells. Irradiation upregulated the level of gene expression for IFN-α in the esophageal tissue, and the neutralizing antibody against IFN-α ameliorated radiation-induced esophageal mucosal damage, while administration of IFN-α receptor agonist (RO8191) had an inverse effect. Depletion of plasmacytoid dendritic cells (pDCs) by anti-CD317 antibody or pharmacological inactivation with bortezomib suppressed radiation-induced mucosal inflammation and damage, accompanied by decrease in IFN-α expression level. SIGNIFICANCE: These findings suggest that IFN-α and pDCs exert proinflammatory properties in the pathophysiology of radiation-induced esophagitis.

Lymphocytic Esophagitis: Current Understanding and Controversy.

This review summarizes our current understanding of lymphocytic esophagitis (LE), a novel form of chronic esophagitis that incorporates distinctive histologic, clinical, and endoscopic features. First described as a histologic entity, a diagnosis of LE requires intraepithelial lymphocytosis without significant granulocytic inflammation and some evidence of epithelial damage; the rationale for and studies supportive of these histologic criteria are discussed within. Clinically, the majority of patients who present with histologically confirmed LE are older women or patients with underlying immunologic abnormalities, such as Crohn disease, rheumatologic disorders, or common variable immunodeficiency. The most common presenting symptom of LE is dysphagia, and the endoscopic findings can vary from normal mucosa to mucosal changes that resemble eosinophilic esophagitis: edema, rings, furrows, and plaques. The incidence of luminal strictures and the persistent dysphagia and/or lymphocytosis present in some patients provide evidence that LE is a chronic inflammatory disorder, at least within a subset of individuals. Several histologic mimics of LE are examined, as are disagreements surrounding the LE diagnosis.