The esophagus physiologically lacks eosinophils, and when present, the condition is considered to be pathologic. Eosinophilic esophagitis was once thought to be a component of gastroesophageal reflux disease (GERD). However, it is now known to be a separate entity as we understand more about the esophagus being an active immunogenic organ. Eosinophils can be found in the esophagus in response to various stimuli or antigen. Eosinophilic esophagitis (EoE) is a chronic immune or antigen-mediated process. Clinically, it presents with various esophageal dysfunction, and pathologically, there is mucosal inflammation predominantly with eosinophils, which is confined to the esophagus only. Diseases which can cause eosinophilia should be ruled out before diagnosing a patient with EoE.
The exact etiology of EoE is unknown; however, it is thought to be a result of the interactions of environmental, genetic, and host immune factors. A food allergy may trigger EoE, but food anaphylaxis is a rare phenomenon among these patients. There is a strong correlation between atopy and EoE, with patients commonly reporting a history of chronic seasonal allergy, asthma, atopic dermatitis, or other allergic/immunologic conditions.
EoE is common in both pediatric and adult populations. Epidemiologic studies have reported EoE cases in many countries on all continents except Africa. Based on many population studies, the reported incidence of EoE is between 0.1/10,000 to 1.2/10,000 worldwide. In the pediatric population, EoE is more common among boys. In the adult population, Caucasian and non-Hispanic white men are more likely to have EoE than women of respective races, 76% compared to 48%. EoE can occur in all age groups; however, it is most common in men during their 20s and 30s, and the mean age of diagnosis is 34.
EoE occurs as a result of an immunogenic reaction to various antigens which are commonly found in food and air. There is a strong genetic component involved in the pathogenesis of EoE and a high concordance reported for EoE among family members. The pioneer study that described the genetic basis for EoE was a study of genome-wide microarray expression profile analysis. This study reported that the gene responsible for EoE was TSLP (thymic stromal lymphopoietin) which is located in the 5q22 region of male X chromosome. TSLP stimulates Th2 cells and induces eotaxin-3. The stimulated Th2 cells activate various proinflammatory cytokines such as IL5, IL13, and IL15, which recruit eosinophils. Eotaxin-3 is overexpressed in the esophageal mucosa in EoE patients. Overall, this immunogenic process starts as an allergic response to various environmental antigens, food, or aeroallergens and leads to the inflammation of esophageal mucosa.
The other important cytokine involved in the pathogenesis is TGF-B (transforming growth factor-beta), which is released by eosinophils and mast cells recruited after immune activation. TGF-B is responsible for remodeling of esophageal mucosa and smooth muscle dysfunction. The remodeling of inflamed mucosa can occur with repeated exposure to the antigens, leading to remodeling and fibrosis which clinically manifests as various esophageal dysfunction that includes dysphagia, epigastric pain, dyspepsia, chest pain, and food impaction. It has been reported that a single exposure to airway antigen challenge and cutaneous antigen exposure may lead to recruitment of eosinophils in the esophagus leading to EoE.
For patients suspect for EoE, esophageal biopsies usually should be taken from the proximal, mid, and distal esophagus. During the endoscopy, biopsies also should be taken from the antrum and duodenum to rule out other possible causes of eosinophilia.
Histopathology is an important aspect of making a diagnosis of EoE. The histopathology reveals extensive eosinophils infiltrated esophageal mucosa, in addition to mast cells, basophils, basal cell hyperplasia, elongated papillae, superficial layering of eosinophils, extracellular eosinophilic granules, and fibrosis of sub-epithelium.
History is very important when considering a diagnosis of EoE as there are many overlapping symptoms of EoE that coincide with gastroesophageal reflux (GERD). The most common manifestation in adults is dysphagia to solid food. An emergency department visit due to food impaction has been the most common presenting symptom in patients with EoE. Other symptoms such as chest pain or heartburn are common as well. Pediatric patients can present with nausea, vomiting, food intolerance, abdominal pain, and weight loss. A history of various atopic conditions such as asthma, atopic dermatitis, seasonal allergy, food allergy, allergic rhinitis, and eczema may be present as well.
A physical exam is less useful than the history in making the diagnosis of EoE. The most common finding is tenderness to palpation of the abdomen without signs of peritonitis.
Clinicians should arrive at the diagnosis of EoE only after positive findings on clinical, endoscopic, and histopathologic examinations. Patients who present with food impaction, dysphagia, and history of atopy should undergo an upper endoscopy evaluation with esophageal biopsy to diagnose EoE.
Upper endoscopy with esophageal biopsy also should be done on patients with a presumed diagnosis of GERD who are resistant to optimal proton pump inhibitor (PPI) dose (20 to 40 mg orally twice daily) and duration (8 to 12 weeks). Esophageal biopsies normally should be taken from the proximal, mid, and distal esophagus. During the endoscopy, biopsies also should be taken from the antrum and duodenum to rule out other possible causes of eosinophilia.
Endoscopic findings of EoE include corrugated mucosa, longitudinal mucosal furrows, fixed esophageal rings or trachealization, whitish mucosal plaque or exudate, stricture, superficial mucosa tear upon passing endoscope, diffusely narrow lumen, and mucosal friability giving the appearance of crepe paper. Clinicians also should note that some patients may have normal esophagus in upper endoscopy.
The pathological diagnosis of EoE is made when eosinophils are present greater than or equal to 15 per high power field (HPF). Other histological findings suggestive of EoE include basal cell hyperplasia, elongation of papillae, superficial layering of eosinophils, extracellular eosinophilic granules, and fibrosis of sub-epithelium.
There is no diagnostic laboratory test available for EoE, but a mildly elevated serum IgE level is present in patients with EoE. Another common nonspecific finding would be a barium swallow study. Findings can show different types of strictures or a ringed esophagus that could be caused by EoE.
An allergist and immunologist should evaluate patients with a history of atopy or food allergy and a diagnosis of EoE.
The goal of EoE treatment is to control the symptoms by decreasing the number of eosinophils in the esophagus and, subsequently, reducing the esophageal inflammation. Management consists of dietary, pharmacological, and endoscopic treatment.
Patients with a history of atopy to food generally respond well to dietary therapy. The approach to dietary therapy is to avoid the specific food if present. If no specific allergenic food or agent is present, a trial of the six food elimination diet (SFED) can be pursued. The six most common allergenic food that should be avoided in EoE patients are cow's milk, wheat, peanut/tree nut, egg, soy, and seafood/shellfish. Alternative options to SFED is elemental diet, which is an amino acid based diet. Patient on elemental diet sometimes require gastrostomy tube placement for adequate caloric intake. Research has shown that elemental diet is superior to SFED or modified SFED (avoidance of food detected by allergic skin test plus SFED). It is also recommended, although the evidence is low, that the clinical response should be measured based on esophageal symptom control and endoscopically with esophageal biopsy to ascertain that the numbers of eosinophils have decreased or not. Upper endoscopy with esophageal biopsy should be done whenever food is reintroduced or removed from the dietary regimen to assess the success of therapy.
In patients diagnosed with EoE, trial of PPI 20 mg to 40 mg oral daily or twice daily as a first line therapy is a reasonable option. Those who respond to PPI therapy with symptomatic improvement, endoscopy with esophageal biopsy should be repeated. If no eosinophils present in repeat biopsy, the diagnosis is either acid mediated GERD with eosinophilia or non GERD PPI responsive EoE with unknown mechanism. If both symptoms and eosinophils persists after treatment with PPI, the diagnosis is immune mediated EoE. In case of immune mediated EoE, the American College of Gastroenterology (ACG) highly recommend to use topical (swallowed not inhaled) steroids for total 8 weeks. Oral suspension of fluticasone 880-1760 mcg per day or budesonide 1 mg to 2 mg per day is available options in the United States. Patients who do not respond to topical steroid, systemic steroid, Prednisone 2 mg per Kg per day (maximum 60 mg per day), may be used. Patients who initially respond but symptom recur, longer duration of topical steroid or systemic steroid may be used in addition to elemental diet or SFED.
Patients who present with food impaction, flexible upper endoscopy is recommended to remove impacted food. Dilation is deferred in EoE until patients are adequately treated with pharmacological or dietary therapy, and the result of a response to therapy is available.The goals of therapy for treating EoE is to improve the patient’s symptoms as well as a reduction in the eosinophils on biopsy. The initial treatment is started after failure to improve after 2 months of PPI therapy to make the diagnosis of EoE.
Patient with persistent symptoms of dysphagia even after treatment with dietary elimination and medical therapy, endoscopic dilation is performed. Esophageal strictures and rings can be safely dilated in EoE. It is recommended to use a graduated balloon catheter for gradual dilation. The patient should be informed that after dilation they might experience chest pain and in addition risk of esophageal perforation and bleeding.
Due to the strong association of EoE with allergies, it is also suggested that all patients with diagnosed EoE undergo evaluation by an allergist or immunologist.
The challenge in diagnosing EoE is the differential of GERD as there is much overlap between the two diseases. GERD also can have eosinophils in the esophagus on pathology. The major difference between the diseases is the response to a PPI. Due to this difference, endoscopy with biopsy should be done at least two months after a trial of PPI therapy.
Other disease conditions that can have esophageal eosinophilia should be excluded before diagnosing a patient with EoE. Some of the diseases that have esophageal eosinophilia are gastroesophageal (GI) reflux disease, eosinophilic GI disease, PPI-responsive esophageal eosinophilia, Celiac disease, Crohn disease, infection, Achalasia, drug hypersensitivity, vasculitis, connective tissues disorders, and the use of a PPI.