Eosinophilic esophagitis (EoE) is a chronic inflammatory [1, 2],relapsing[3] and recently recognized immune/antigen-mediated condition [4, 5] characterized by basal cell hyperplasia, microabscesses, degranulation, dilated intercellular spaces [6, 7] and predominant eosinophilic infiltration in the esophagus [8-11]. Allergists and gastroenterologists are seeing many more patients with EoE, this is due to an increase in the frequency of EoE in children and adults and greater physician awareness [1, 5, 12, 13].
In eosinophilic esophagitis, the lining of the esophagus becomes inflamed and examination of the lining shows a high cell count of the white blood cell eosinophils are builds up in the epithelial lining of the esophagus [14]. This buildup, which is a reaction to foods, allergens or acid reflux, can inflame or injure the esophageal tissue. and damaged esophageal tissue can lead to fibrosis and strictures [4, 15]which causes dysphagia and food get caught in the mid-esophagus when you swallow [2, 16-19].
EoE can occur at any age and most commonly occurs in Caucasian males[20-22] and has a strong hereditary component with large sibling risk ratio [23]. The symptoms of EoE vary with age [24], In infants and toddlers symptoms are nausea,emesis,abdominal pain and they refuse their food or are not growing properly (failure to thrive) [22, 25-29]. School-age children often have recurrent abdominal pain or vomiting [30], teenagers and adults most often have difficulty swallowing, heartburn and regurgitation [8, 24, 26, 31, 32].
A very latest retrospective study highlighted that EoE strongly linked to chronic rhinosinusitis (CRS) [33]. Peripheral eosinophilia and elevated serum IgE levels are usually found in 50 and 75% of patients, respectively [31, 34],and there’s no phenotypically difference in adult EoE with IgE mediated food sensitivity and non-food sensitive patients [35]. In one prospective study shown predominant IgG4-associated plasma cells up to180-300/hpf in the deep lamina propria in adult EoE, and not an IgE-induced allergy [36, 37].
The majority of patients with EoE are atopic [2, 29, 38, 39], An atopic person is someone who has a family history of allergies or asthma and symptoms of one or more allergic disorders [40]. These include asthma, allergic rhinitis, atopic dermatitis and food allergy [24]. Environmental factors such as aeroallergens: dust mites, animals, pollen and molds can play a role in EoE and more prone to strictures [13, 35]. For some patients, it may seem like their EoE is worse during pollen seasons (spring and fall )or living in a cold or dry climate [41].
The pathogenesis of EoE is relatively poorly understood [42],Increasing evidence suggests a strong genetic [38],immunologic and environmental factors involvement ,some studies says that cesarean birth, premature delivery, antibiotic exposure during infancy, food allergy, lack of breast-feeding, and lack of early exposure to microbes are associated with EoE [14, 43, 44] . Esophageal microbiome may play vital role in EoE especially Haemophilus [45], Corynebacterium , Neisseria [46],and an inverse relationship between H. pylori and the development of EoE [44].
The esophagus is unique from the rest of gastrointestinal tract ,normally there are no eosinophils in the esophagus[15]. The mechanism of dysphagia in EoE is multifactorial ,including mucosal stickness ,esophageal fibrosis,strictures and ring formation [4]. Eosinophils produce and release many proteins and mediators,particularly major basic protein(MBP),eosinophilic cationic protein(ECP),eosinophil-derived neurotoxin (EDN) and eosinophilic peroxidase play major role in tissue damage and remodling [8, 47], serum analysis of absolute eosinophil count (AEC) ECP, and EDN were higher in EoE subjects in one prospective cohort study .
Moreover AEC predicted post-treatment eosinophilia, suggesting a potential role in monitoring EoE disease activity [48]. Bone morphogenetic protein (BMP)[49] promotes squamous differentiation of basal progenitor calls upon their activation in adults esophagus, and basal cell hyperplasia is associated with high levels of follistatin on biopsies sample [6]. The important inflammatory mediators Th2-type cytokines IL-4 , IL-5, IL-13 [1, 16, 20, 38, 39, 50-53] are involved in trafficking eosinophils into esophageal tissue[9, 30].
Activation of STAT6 by IL-4 and IL13 to mediate the pathogenesis of allergic disorders [38, 54], epithelial cells have been recognized as major effectors in initiating EoE, both through their recruitment of iNKT cells towards the esophageal epithelium, the thymic stromal lymphpoeitin (TSLP) gene and its receptor appear to be a risk factors for EoE, as they do polymorphisms in the eotaxin-3 [55-57] and other chemoattractants [51]. Finally, activated eosinophil- and mast cell-derived TGF ? 1 secretion is crucial in EoE-associated tissue remodeling [58, 59],also Phospholamban (PLN) an integral membrane protein is an important player n TGF? 1-mediated esophageal SM cell and myofibroblast contraction in pediatric population [60].
In recent years a major breakthrough occurred in understanding eosinophils and mast cells in EoE [61, 62],also Histamine-producing cells including mast cells and basophils [63-65] play very important role in bringing eosinophils into esophageal epithelium, these cells respond very well to topical steroids and food elimination diet [64]. One recent study shown higher number of stimulated CD3+CD8+ T cells in the EoE-New/Active group that secreted TNF-? and interferon (IFN)-? compared with the EoE-Remission and Control groups [66].
Endoscopic features of children with EoE having either a normal-appearing esophagus or findings of plaques or edema [27],where’s adults EoE shows, esophageal rings,white exudates or plaques, longitudinal furrows [22], diffuse esophageal narrowing [27], and mucosal fragility, may help the diagnosis,but histological identification of predominant eosinophilic-inflammation, more than 15 eosinophils per high power field(HPF) is the diagnostic criterion [3, 8, 18, 20, 28, 52, 67], obtaining at least 3 or more biopsies from (proximal and distal esophagus) may provide adequate diagnostic yield respectively [68][24, 49, 56, 66, 69, 70] and persisting after an 8 week PPI trial (20-40) mg twice daily of any of the available agents excluding other causes of EE [71-73].
Sometimes coexistence of EoE and lymphocytic esophagitis(LyE) called overlapping phenotype with similar endoscopic features as EoE when more than 40 intraepithelial lymphocytes/hpf are present [74]. Literature by Garcia-Rojo M et al. says that an automatic analysis of CD3, CD4 and CD8 markers can be used to differentiate between EoE from GERD patients on biopsies slides [65].
Immunostaining (IHC) for arachidonate-15 lipooxygenase (ALOX15) has been demonstrated to be a sensitive marker for EoE in children in rare situations with strong clinical suspicion where no fragments reach 15 IEEs/HPF [75]. The number of desmosome was significantly reduced in active EoE epithelia compared with normal epithelia ,which may improve following treatment [76]. EoE is transmural disease [51],involving all layers of esophagus [25]. Endoscopic Ultrasound (EUS) demonstrates transmural esophageal thickness of (all layers) in both children and adult EoE [26, 50]. Adverse immune responses to food are the main cause of EoE in a large number of patients[30]. However the relationship between food allergy and EoE is complex.
In many types of food allergy, the triggers are easily diagnosed by a history of a severe allergic reaction like hives after ingestion of the food. In EoE, it is more difficult to establish the role of foods since the reactions are slower and so a single food is hard to pinpoint as the trigger. it is important to have allergy testing. Allergists may do a series of different allergy tests to identify the foods causing EoE. Foods such as dairy products, egg, soy and wheat can cause non-IgE mediated allergic disorder [39] and are the main causes of EoE. However allergies to these foods often cannot be easily proven by conventional allergy tests (skin tests, patch tests or blood tests). Once a food has been removed from a person’s diet, symptoms generally improve in a few weeks.
