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: 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.

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 With Predominance of CD4 T Cells and Expansion of Th1 Cells Is Associated With Achalasia.

OBJECTIVES: Although histologic features in biopsies suggesting a possibility of achalasia would be helpful diagnostically, such features remain unknown. The goal of this study was to explore the prevalence, histologic features, and immunophenotype of lymphocytic esophagitis (LyE) in achalasia biopsies. METHODS: The study group consisted of 57 patients with achalasia. Controls comprised 52 patients with severe gastroesophageal reflux disease (GERD) and normal esophageal motility. CD4/CD8 immunophenotype of lymphocytes was analyzed by immunohistochemistry. RESULTS: LyE was identified in 30% (17/57) of patients with achalasia and 6% (3/52) of patients with GERD, indicating a strong association with achalasia (odds ratio, 6.94; 95% confidence interval, 1.90-25.38). LyE was focal in 59% (10/17) of the cases and diffuse in 41% (7/17). CD4 T-cell predominance over CD8 T cells was observed in 88% of patients with achalasia and LyE. T helper 1 (Th1) cells, but not T helper 2 cells, were expanded in CD4 T cells; in the absence of evident infection, this was compatible with the role of Th1 cells in organ-specific autoimmunity. CONCLUSIONS: Achalasia should be considered in the differential diagnosis of clinical entities associated with CD4-predominant LyE. Additional studies to explore the significance of Th1 cells in achalasia-associated LyE are warranted.

CD8 T-Cell-Predominant Lymphocytic Esophagitis is One of the Major Patterns of Lymphocytic Inflammation in Gastroesophageal Reflux Disease.

CONTEXT.­: Published reports have suggested an association of lymphocytic esophagitis (LyE) with gastroesophageal reflux disease (GERD) and primary motility disorders and have also shown that GERD and motility disorders frequently overlap. These findings make it difficult to determine the true relationship between LyE and GERD, which may be confounded by the presence of motility disorders with LyE. OBJECTIVE.­: To characterize patterns of lymphocytic inflammation in patients with GERD who have no motility abnormalities. DESIGN.­: We identified 161 patients seen at our institution from 1998 to 2014 who were diagnosed with GERD, had normal esophageal motility, and available esophageal biopsies. LyE was defined as peripapillary lymphocytosis with rare or absent granulocytes. CD4 and CD8 immunophenotype of lymphocytes was evaluated using immunohistochemistry. RESULTS.­: We found increased intraepithelial lymphocytes in 13.7% of patients with GERD. Two major patterns and 1 minor pattern of lymphocytic inflammation were observed as follows: (1) LyE (in 6.8% [11 of 161] of patients and typically focal), (2) dispersed lymphocytes in an area of reflux esophagitis (in 5.6% [9 of 161] and typically diffuse), and (3) peripapillary lymphocytes in an area of reflux esophagitis (in 1.2% [2 of 161]). CD8 T cells significantly outnumbered CD4 T cells in 91% of patients with lymphocytic esophagitis and 100% of patients with dispersed lymphocytes (9 of 9) or peripapillary lymphocytes (2 of 2) in the area of reflux esophagitis. CONCLUSIONS.­: These findings suggest that LyE is one of the major patterns of lymphocytic inflammation in GERD. CD8 T-cell-predominant immunophenotype may be useful as a marker of GERD in the differential diagnosis of LyE.

Lymphocyte-predominant Esophagitis: A Distinct and Likely Immune-mediated Disorder Encompassing Lymphocytic and Lichenoid Esophagitis.

Lymphocytic esophagitis is a well-known manifestation of Crohn disease among children but is not considered to be an immune-mediated mucositis in adults. We hypothesize that adult-onset lymphocyte-predominant esophagitis is also an immune-mediated inflammatory pattern, the nature of which has been masked by other conditions that feature esophageal lymphocytosis and occur in older patients. We performed this study to consolidate diagnostic criteria for lymphocyte-predominant esophagitis and determine its clinical significance. We identified 61 patients with lymphocyte-rich inflammation in the mid or proximal esophagus, none of whom had another explanation for esophageal lymphocytosis. Affected patients were usually older adults and 72% were women. Most (56%) presented with dysphagia and 34% had eosinophilic esophagitis-like changes with rings, exudates, and/or edematous mucosa and linear furrows. Intraepithelial lymphocytosis was accompanied by mucosal injury featuring edema, basal zone hyperplasia, and scattered dyskeratotic cells. Some cases displayed occasional neutrophils or even superficial microabscesses; eosinophils were consistently infrequent. Most (67%) patients had at least 1 systemic immune-mediated disorder, particularly Crohn disease (30%) and connective tissue diseases (23%); only 1 had mucocutaneous lichen planus. We conclude that mild mucosal lymphocytosis (ie, ≥20 lymphocytes/HPF) alone is a frequent and nonspecific finding; criteria for lymphocyte-predominant esophagitis should include evidence of mucosal injury and allow for more than the occasional neutrophil. When this diagnosis is limited to cases that feature lymphocytosis unattributed to acid reflux, motility disorders, or infection, lymphocyte-predominant esophagitis may represent an immune-mediated disorder with characteristic clinical manifestations and a predilection for middle-aged women.

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.

The spectrum of therapeutic activity of mepolizumab.

Introduction: The basis of the development of the anti-interleukin-5 monoclonal antibody mepolizumab was the acknowledgment of the crucial importance of this cytokine in promoting eosinophils production, activation, and survival, which is associated with the eosinophilic asthma phenotype, as well as with other disorders characterized by high levels of eosinophils. Areas covered: All the available literature on the outcomes treatment with mepolizumab in eosinophilic disorders are reviewed, including asthma, chronic rhinosinusitis, esophagitis, granulomatosis with polyangiitis, eosinophilic chronic obstructive pulmonary disease, hypereosinophilic syndrome, and allergic bronchopulmonary aspergillosis. Expert opinion: The efficacy of mepolizumab in eosinophilic asthma is clearly demonstrated by a number of controlled trials and by meta-analyses. Among other eosinophilic disorders, controlled trials are available for chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic chronic obstructive pulmonary disease. Allergic bronchopulmonary aspergillosis, as well as other minor eosinophilic disorders, are backed only by case reports and are waiting controlled trials to verify the therapeutic role of mepolizumab.

Upper gastrointestinal tract involvement of pediatric inflammatory bowel disease: A pathological review.

Upper gastrointestinal (UGI) tract involvement of inflammatory bowel disease (IBD) is commonly seen in pediatric patients. Upper endoscopy is included in the routine workup of children with suspected IBD to enhance the diagnosis and management of these patients. Currently, childhood IBD is classified into ulcerative colitis (UC), atypical UC, Crohn's disease (CD) and IBD unclassified. Histologic confirmation of UGI tract involvement, in particular the presence of epithelioid (non-caseating) granulomas, is helpful in confirming the diagnosis of IBD and its classification. Herein, we reviewed selected IBD-associated UGI tract manifestations in children. Lymphocytic esophagitis, seen predominantly in CD, is histologically characterized by increased intraepithelial lymphocytes (> 20 in one high-power field) in a background of mucosal injury with absence of granulocytes. Focally enhanced gastritis is a form of gastric inflammation in pediatric IBD marked by a focal lymphohistiocytic pit inflammation with or without granulocytes and plasma cells in a relatively normal background gastric mucosa. Duodenal inflammation seen in children with IBD includes cryptitis, villous flattening, increased intraepithelial lymphocytes, and lamina propria eosinophilia. Finally, epithelioid granulomas not associated with ruptured gland/crypt are a diagnostic feature of CD. The clinicopathologic correlation and differential diagnosis of each microscopic finding are discussed. Clinicians and pathologists should be cognizant of the utility and limitations of these histologic features.

An uncommon case of herpetic esophagitis in a small child with allergic rhinitis: A case report and literature review (CARE compliant).

RATIONALE: Herpetic esophagitis (HE) is a common condition in immunosuppressed patients, but a rare entity in immunocompetent patients affecting especially male teenagers and young adults. PATIENT CONCERNS: We report the case of a 5-year-old male patient, with a history of allergic rhinitis admitted in our clinic for acute onset fever refractory to antipyretics, chest pain, anorexia, refusal of solid food, accepting only small amounts of fluids, odynophagia, and epigastric pain. The clinical exam revealed severe malaise, pallor, decreased skin turgor, abdominal epigastric tenderness, heartburn at palpation within the epigastric area. The laboratory tests showed leukocytosis, monocytosis, hypoglycaemia, and elevated inflammatory biomarkers. DIAGNOSES: The serology tests for human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV) were negative, except for immunoglobulin G (IgG) anti-EBV which was positive. The chest radiography was normal, and the abdominal ultrasound showed abdominal bloating. The upper digestive endoscopy revealed friable esophageal mucosa, with multiple ulceration on the entire esophagus, and whitish exudates especially on the middle and lower part of the esophagus suggesting a possible eosinophilic esophagitis or caused by Candida. Despite the empirical initiated treatment, the patient's evolution was only slowly favorable. The histological exam established the diagnosis of HE. INTERVENTIONS: We initiated acyclovir therapy with an outstandingly favorable evolution. OUTCOMES: After 1 month, we detected the seroconversion of IgG anti-HSV. The patient's follow-up revealed no additional complaints. LESSONS: Despite its rarity in immunocompetent individuals, HE must be taken into account even in otherwise healthy small children. Allergic conditions might represent a predisposing factor for HE.

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.

Acute Esophageal Necrosis in an Immunosuppressed Kidney Transplant Recipient: A Case Report.

Acute esophageal necrosis (AEN) is rare and characterized endoscopically by distal esophageal ulceration, blackening, and necrosis. It typically arises in patients with multiple comorbidities who have significant systemic disease and frailty. Specific precipitating events are variable. Evidence suggests a multifactorial etiology likely involving esophageal ischemia in the setting of corrosive injury from gastric contents and impaired tissue repair mechanisms. In the transplant setting, immunosuppression likely plays a substantial role. We report a case of AEN in a 70-year-old man following a renal transplant.

Lymphocytic esophagitis: an update on histologic diagnosis, endoscopic findings, and natural history.

Lymphocytic esophagitis is a histologic pattern of injury characterized by increased intraepithelial lymphocytes (>20/high-power field) with rare, or absent granulocytes. Lymphocytes tend to be more numerous in the peripapillary epithelium, and are often associated with evidence of mucosal injury, edema, and scattered dyskeratotic cells. More than a decade following its original description, lymphocytic esophagitis remains an enigmatic entity with variable clinical presentations, associated disorders, etiologies, treatment, and natural history. Most of the confusion regarding the clinical significance of this disorder stems from its diagnostic criteria: lymphocytic esophagitis is currently defined based entirely on histologic criteria, despite the common occurrence of lymphocytosis in a variety of unrelated inflammatory conditions of the esophagus. The goal of this review is to summarize the literature regarding lymphocytic esophagitis and focus on key clinicopathologic features that distinguish it from other esophageal disorders that can show increased numbers of intraepithelial lymphocytes.

A model combining age, equivalent uniform dose and IL-8 may predict radiation esophagitis in patients with non-small cell lung cancer.

BACKGROUND AND PURPOSE: To study whether cytokine markers may improve predictive accuracy of radiation esophagitis (RE) in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: A total of 129 patients with stage I-III NSCLC treated with radiotherapy (RT) from prospective studies were included. Thirty inflammatory cytokines were measured in platelet-poor plasma samples. Logistic regression was performed to evaluate the risk factors of RE. Stepwise Akaike information criterion (AIC) and likelihood ratio test were used to assess model predictions. RESULTS: Forty-nine of 129 patients (38.0%) developed grade ≥2 RE. Univariate analysis showed that age, stage, concurrent chemotherapy, and eight dosimetric parameters were significantly associated with grade ≥2 RE (p < 0.05). IL-4, IL-5, IL-8, IL-13, IL-15, IL-1α, TGFα and eotaxin were also associated with grade ≥2 RE (p < 0.1). Age, esophagus generalized equivalent uniform dose (EUD), and baseline IL-8 were independently associated grade ≥2 RE. The combination of these three factors had significantly higher predictive power than any single factor alone. Addition of IL-8 to toxicity model significantly improves RE predictive accuracy (p = 0.019). CONCLUSIONS: Combining baseline level of IL-8, age and esophagus EUD may predict RE more accurately. Refinement of this model with larger sample sizes and validation from multicenter database are warranted.