**4.4 Eosinophilic esophagitis**

Eosinophilic esophagitis (EoE) is an immune-mediated condition in which eosinophils infiltrate into the esophageal mucosa and lead to symptoms of esophageal dysfunction [119]. In the absence of secondary causes, the disease is considered to belong to the spectrum of eosinophilic gastrointestinal disorders [120]. In the absence of treatment, EoE can lead to esophageal fibrosis, the formation of strictures, and esophageal narrowing leading to esophageal dysfunction [119, 121]. Throughout the world, the health care systems are burdened by EoE, a major factor in upper gastrointestinal morbidity [122, 123]. The US healthcare system is estimated to spend \$350 to \$947 million burden annually on EoE [122]. It has been found that the EoE disease prevalence has been associated with Single Nucleotide Polymorphisms (SNP) in the Thymic stromal lymphopoietin (TSLP) and TSLP-Rwhich is correlated with increase in the TSLP levels [124]. There are several environmental allergens implicated. One of these allergens is food. Food allergens trigger EoE and the disease can be put into

remission by removal of specific foods, either via elimination diets or hypoallergenic elemental formulas [125–127]. It is commonly accepted that EoE, is due to a Th2 inflammation driven by TSLP secreted by esophageal epithelial cells and is under the influence of genetic predisposition [124, 128–130]. EoE Th2 inflammation with a non-IgE-mediated trigger has been found to be triggered by certain foods [131]. It was reported that food that causes vomiting and abdominal pain is soy, wheat, egg, and milk [132, 133]. An elimination diet known as the six-food elimination diet (SFED) refers to the removal from the diet of EoE patients of wheat, milk, eggs, nuts, soy, fish, and shellfish that are considered to be allergens [134]. Th2 cytokines result in an increased Th2 response from T cells, basophils, Invariant natural killer T iNKTs, and mast cells in EoE. Th2 cytokines also enhance eosinophil survival and activation, thus resulting in fibrotic modification [135]. It has been reported that IL-4 enhances eotaxin-3 secretion by epithelial cells, which is responsible for the increased migration of eosinophils. IL-4 also causes fibroblasts to release periostin, collagen, and B-actin, promoting local fibrosis [136]. Eosinophils are mainly differentiated, recruited, and survived by cytokine IL-5 [137]. The cytokine TSLP is primarily produced by epithelial cells at barrier surfaces such as skin, gut, and lungs because of danger signals, infectious agents, cytokines produced by atopic cytokines (IL-4, IL-13, TNFα), and environmental allergens [138]. The Th2 inflammation observed in EoE is most likely caused by TSLP. EoE prevalence estimates vary with location. The highest incidence occurs in western countries where EoE is more easily diagnosed and has an estimated prevalence of 56 per 100,000 people [139] in some statistics. However, several estimates place the prevalence of EoE at between 0.5 and 1 case per 1000 individuals, yet the disease is detected in between 2.4% and 6.6% of patients undergoing endoscopy for any reason [140–144]. The primary symptoms of EoE in adolescents and adults is dysphagia, which affects 60−100% of patients, food impaction can affect more than 25%, and 30−60% of patients report heartburn and 44% report noncardiac chest pain [145–150]. Diagnostic criteria must include both clinical and histological features: symptoms of esophageal dysfunction, the presence of at least 15 eosinophils in a high-power field, and exclusion of alternative causes of eosinophilia in the esophagus [119, 151].
