Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation, whose incidence is rising. It significantly affects patients’ quality of life and, if left untreated, results in fibrotic complications. Although broad consensus has been achieved on first-line therapy, a subset of patients remains non-responder to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This review provides a comprehensive description of the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins and transcription factors) that could represent present and future therapeutic targets, while summarizing previous therapeutic approaches in literature.

Eosinophilic esophagitis (EoE) is a chronic immune-mediated inflammatory disorder and represents the leading cause of food impaction. The pathogenesis of EoE is the result of an interplay between genetic, environmental and host immune system factors. New therapeutic approaches for EoE have been proposed. In this manuscript we review the current evidence regarding EoE management in pediatric age, with a particular focus on new findings related to the efficacy and safety of monoclonal antibodies.

Conventional therapies have failed in treating some patients with EoE, which then requires aggressive procedures such as esophageal dilatation. The most effective available medical therapy for EoE is swallowed topic corticosteroids (fluticasone propionate and budesonide), which have two main drawbacks: they are related to well-known adverse effects (especially in the paediatric population), and there are not enough long-term data to confirm that they are able to reverse the remodelling process of the esophageal mucosa, which is the major cause of EoE symptoms (including dysphagia, abdominal pain, nausea, obstruction, perforation and vomiting). The monoclonal antibodies appear to be an interesting therapeutic approach. However, the studies conducted until now have shown substantial histological improvement not coupled with significant clinical improvements and no significant relationship between a decreasing number of eosinophils and clinical symptoms, highlighting the importance in the pathogenesis of EoE of cells such as T-helper cells, mast cells, B cells, epithelial cells and natural killer cells.

Monoclonal antibodies targeting a signal involved in the pathogenesis of EoE may not break the complex self-propagating inflammatory activation responsible for perpetuation of the inflammatory response and the development of symptoms and complications. We speculate that combined biological therapies targeting more than one molecule or cell may provide better results, with conventional therapies potentially enhancing the effects of antibodies. However, further studies should aim to find the best therapeutic approach to target the cells involved in the remodelling process and to reverse the histological changes in this complex clinical condition.

• Autoimmunity
• Dysphagia
• Eosinophilic esophagitis
• Esophageal symptoms
• Food allergy
• Monoclonal antibody

• Eosinophilic esophagitis
• Eosinophilic gastrointestinal disease

• Adrenal Cortex Hormones/therapeutic use
• Biological Products/therapeutic use
• Cytokines/antagonists & inhibitors
• Enteritis/diagnosis
• Enteritis/therapy
• Eosinophilia/diagnosis
• Eosinophilia/therapy
• Eosinophilic Esophagitis/diagnosis
• Eosinophilic Esophagitis/therapy
• Eosinophils/immunology
• Esophageal Stenosis/prevention & control
• Esophagus/immunology
• Esophagus/pathology
• Gastritis/diagnosis
• Gastritis/therapy
• Humans
• Inflammation/immunology
• Intestinal Mucosa/immunology
• Proton Pump Inhibitors/therapeutic use
• Th2 Cells/immunology

• R01 DK101856 NIDDK NIH HHS
• U54 AI117804 NIAID NIH HHS

Elemental diets, dietary elimination, and steroid therapies are the most common therapies in the clinical trials for eosinophilic esophagitis (EoE). Histological findings (usually reported as eosinophils per microscopic high‐powered field [hpf]) remain the most common end‐point used to define response. Yet, the threshold for defining “response” and “remission” are ill‐defined among consensus guidelines and may vary from study to study. We conducted a systematic literature review of articles on eosinophilic esophagitis, published between January 2007 and November 2017, considering histological remission as the primary outcome. We abstracted treatment information and definitions of histological remission or response. A comparison of definitions of histological remission across and within institutions was performed. A total of 61 articles were included in this review, with approximately 60% of the studies published from centers in the United States. Histological definitions of remission of EoE ranged from 0 to ≤20 eosinophils/hpf. The most stringent criteria, ranging from 0 to ≤5 eosinophils/hpf, were commonly used in interventional trial studies that examined the effects of new treatments. We found remarkable variability in definitions between studies, treatment types, and regions. Age or epidemiological distribution of study subjects did not influence the criteria for histological remission. Clinical and histological improvements are important measures of the effects of treatment. Histological findings, the most objective measure of treatment, should provide an optimal method for comparing the effectiveness of various treatments. Yet, our findings suggest a lack of consistent remission criteria in published studies. Considering these inconsistencies, it is difficult to compare the effectiveness of various treatments.

• eosinophilic esophagitis
• histological
• improvement
• remission
• response
• treatment
• trial

• Diet therapy
• Dilation
• Disease management
• Drug therapy
• Eosinophilic esophagitis
• Glucocorticoids
• Proton pump inhibitors

• Adolescent
• Adult
• Algorithms
• Child
• Diet Therapy/methods
• Dilatation/methods
• Disease Management
• Eosinophilic Esophagitis/therapy
• Esophagoscopy/methods
• Esophagus/pathology
• Evidence-Based Medicine/methods
• Glucocorticoids/therapeutic use
• Humans
• Practice Guidelines as Topic
• Proton Pump Inhibitors/therapeutic use
• Young Adult

• ALOX15
• CCL26
• Eosinophilic esophagitis
• Gene expression
• Proton pump inhibitor
• RTNLB

• Anti-Inflammatory Agents/therapeutic use
• Eosinophilic Esophagitis/diagnosis
• Eosinophilic Esophagitis/drug therapy
• Esophagoscopy
• Fluticasone/therapeutic use
• Humans
• Patient Compliance
• Proton Pump Inhibitors/therapeutic use
• Recurrence

• R01 DK101856 NIDDK NIH HHS
• U54 AI117804 NIAID NIH HHS

• Eosinophilic gastrointestinal disorders
• eosinophilia
• eosinophilic colitis
• eosinophilic esophagitis
• eosinophilic gastritis
• eosinophilic gastroenteritis
• pharmacological treatment
• therapeutic management

• Animals
• Colitis/drug therapy
• Colitis/physiopathology
• Drug Design
• Dyspepsia/etiology
• Enteritis/drug therapy
• Enteritis/physiopathology
• Eosinophilia/drug therapy
• Eosinophilia/pathology
• Eosinophilia/physiopathology
• Eosinophilic Esophagitis/drug therapy
• Eosinophilic Esophagitis/physiopathology
• Gastritis/drug therapy
• Gastritis/physiopathology
• Gastrointestinal Agents/adverse effects
• Gastrointestinal Agents/therapeutic use
• Gastrointestinal Tract/physiopathology
• Humans

Eosinophilic esophagitis (EoE) is a chronic immune disease, characterized by a dense eosinophilic infiltrate in the esophagus, leading to bolus impaction and reflux-like symptoms. Traditionally considered a pediatric disease, the number of adult patients with EoE is continuously increasing, with a relatively higher incidence in western countries. Dysphagia and food impaction represent the main symptoms complained by patients, but gastroesophageal reflux-like symptoms may also be present. Esophageal biopsies are mandatory for the diagnosis of EoE, though clinical manifestations and proton pump inhibitors responsiveness must be taken into consideration. The higher prevalence of EoE in patients suffering from atopic diseases suggests a common background with allergy, however both the etiology and pathophysiology are not completely understood. Elimination diets are considered the first-line therapy in children, but this approach appears less effective in adults patients, who often require steroids; despite medical treatments, EoE is complicated in some cases by esophageal stricture and stenosis, that require additional endoscopic treatments. This review summarizes the evidence on EoE pathophysiology and illustrates the safety and efficacy of the most recent medical and endoscopic treatments.

• Eosinophilic esophagitis
• Eotaxin
• Immune system
• Proton pump inhibitors-responsive eosinophilia
• Endoscopic dilation

• Biologicals
• Corticosteroids
• Food impaction
• Immunosuppressants
• Indications for treatment
• Natural history
• Oesophageal remodelling
• Unmet needs

• Biomarkers
• Corticosteroids
• Eosinophilic Esophagitis
• Refractory
• Therapy

• Diagnosis
• Endoscopy
• Management Algorithm
• Treatment

• Adrenal Cortex Hormones/therapeutic use
• Algorithms
• Anti-Inflammatory Agents/therapeutic use
• Eosinophilic Esophagitis/diet therapy
• Eosinophilic Esophagitis/drug therapy
• Eosinophilic Esophagitis/pathology
• Humans
• Proton Pump Inhibitors/therapeutic use

• K23 DK090073 NIDDK NIH HHS
• K23DK090073 NIDDK NIH HHS