In Europe and the United States, eosinophilic esophagitis (EoE) is a common disease causing feeding disorders in children and dysphagia and food impaction in adults.
Definition and differential diagnosis
The initial view was that esophageal eosinophilia was the pathologic manifestation of gastroesophageal reflux disease (GERD). However, in the mid-1990s, experienced clinicians discovered that esophageal eosinophilia could also be seen in patients with other symptoms than reflux, and that acid-suppressant or anti-reflux therapy did not improve the clinical symptoms or histologic abnormalities in these patients, leading to the inference that these patients might have a separate disease from GERD. However, there are no clear diagnostic criteria for EoE.
Recent studies suggest that EoE is an immune-mediated or antibody-mediated chronic esophageal disease characterized by symptoms associated with esophageal dysfunction and eosinophil-dominated inflammation. The primary antigens mediating EoE are currently thought to be of food origin.
The clinical diagnosis of EoE consists of three main aspects.
1. symptoms including but not limited to: feeding disorders, vomiting and abdominal pain occurring in the pediatric population and dysphagia and food impaction occurring in the adolescent or adult population.
2. >15 eosinophils/HPF in the esophageal mucosa.
3. other diseases that can lead to the above clinical manifestations and histological changes (GERD, parasitic infections, allergic vasculitis, esophageal smooth muscle tumors and esophageal Crohn’s disease) need to be excluded. The main thing is to differentiate it from GERD, which is difficult to exclude because there is no test that can clearly identify GERD from EoE.
Pathogenesis
Through years of research, it has been found that EoE is a disease in which the function of the esophageal barrier is altered by environmental factors acting on patients with genetic susceptibility and producing a series of immunological changes, as follows.
1. Environmental factors: Caesarean section, prematurity, use of antibacterial drugs during infancy, food allergies, lack of breastfeeding and living in areas with low population density.
2. Gender: The incidence of EoE is significantly higher in males than in females. In addition, EoE is also significantly associated with genetics, and genome-wide association analysis found it to be associated with three genes.
3, Patients with EoE have dilated esophageal epithelial space, altered barrier function, downregulation of barrier-related proteins and adhesion molecules; altered esophageal permeability, increased opportunity for esophageal mucosal antigen presentation, and increased chemotactic eosinophils.
4. EoE is mediated by Th2 cells and induced mainly by food antigens; the main allergic reactions leading to the development of EoE are non-IgE-related allergic reactions, and it has been found that food-specific IgG4 is present in the esophageal epithelium and that the four most common food antigens are responded to in EoE patients.
Clinical features
1. Epidemiology
EoE affects people of all ages, but predominantly affects white males, with a prevalence of approximately 0.01% to 0.05% in Europe and the United States and an increasing trend in Asia. In addition, people with a personal or family history of atopic diseases such as asthma, eczema, allergic rhinitis, and food allergies are more likely to develop the disease.
2. Clinical manifestations
Pediatric patients may have a variety of nonspecific symptoms, including feeding difficulties, nausea, vomiting, heartburn, and growth disturbances. In contrast, adolescent and adult patients often present with dysphagia and partial food impaction. In addition, patients of different ages may have common symptoms (e.g., chronic reflux symptoms).
Patients may gradually adapt to dysphagia by changing their habits (e.g., eating slowly, using sauces to lubricate food, drinking water with food, and avoiding pills and foods that can cause dysphagia), in which case physicians may underestimate the severity of symptoms. In some rare cases, patients with EoE may experience intense vomiting and spontaneous esophageal rupture after food impaction. 30% of adult patients experience heartburn after drinking alcohol.
3. Imaging manifestations
Endoscopy and radiography are important adjuncts to assess the status of the esophagus in patients with EoE. The most common endoscopic manifestations in patients with EoE are leukoplakia (representing eosinophilic exudate), mucosal edema, linear fissures, esophageal rings, and esophageal strictures. Recently, a validated endoscopic scoring system (EFERFS) has been introduced that standardizes the scoring of EoE signs (edema, esophageal rings, exudates, fissures, and strictures).
The increasing understanding of the disease has facilitated the use of barium contrast in patients with dysphagia. Unlike the limited distal esophageal strictures found in GERD patients, the esophageal strictures in EoE patients are tapered and more extensive. It is important to note that the signs of esophageal stricture in EoE patients are not obvious on endoscopy but are very obvious on barium contrast.
4. Histological features
The most characteristic histologic manifestation of EoE is a marked increase in the number of eosinophils in the esophageal mucosa (Figure 1), with a threshold of at least 15 eosinophils per high-powered view being used to diagnose EoE with nearly 100% sensitivity and 96% specificity, although studies have also described patients with EoE with lower levels of eosinophils and phenotypic features.
Characteristic but non-diagnostic pathologic features include eosinophil aggregates, microabscesses, and eosinophil distribution along the luminal surface. Other pathologic changes include enlarged interstitial spaces, prolonged pegs, and basal cell proliferation (Figure 1). In addition, there was an increase in the number of other inflammatory cells (including lymphocytes, mast cells, and basophils) on the epithelial surface of the lesion.
5. Associated complications and diseases
Complications associated with EoE include esophageal stricture, food impaction, perforation, and malnutrition, but no carcinogenesis occurs. In addition, disease states associated with EoE include connective tissue disease, celiac disease, and Crohn’s disease.
Treatment
The severity of clinical presentation and histologic manifestations in patients with EoE may not be consistent, making multiple assessments of disease activity particularly important. Therefore, short-term treatment goals include symptom relief, control of inflammation, and restoration of esophageal function. There are three treatment options to achieve these goals: diet, medications, and dilatation. When conditions permit, treatment can be focused on multidisciplinary expert opinion, including gastroenterologists, allergists, and nutritionists.
1. Dietary therapy
As early as 1995, a small study of 10 children with EoE treated with an amino acid-only diet showed significant improvement in clinical symptoms and histological abnormalities, but the disease recurred when the normal diet was resumed. Subsequent larger, similar studies have shown almost complete response to this therapy, and as a result, diet has now become a routine treatment for EoE.
However, the high cost and poor taste of the elemental diet have contributed to the development of two other dietary therapies (Table 1). Allergists use skin prick tests, patch tests, and serum-specific IgE assays for targeted food elimination, and this method has achieved satisfactory results in pediatric patients. However, recent studies have found that this approach fails to achieve the desired results, with only 45% of patients consistently responding.
Empirical dietary elimination therapy does not rely on food allergy testing, but rather treats by eliminating the six most common food allergens (wheat, milk, soy, nuts, eggs and seafood). Studies have shown that this therapy improves clinical symptoms and histological abnormalities by 74% and 64% in children and adult patients, respectively, within 6 weeks.
Although dietary therapy has been clinically successful, some problems remain. For example, endoscopic biopsy is the only reliable method to date to assess histologic response, so multiple endoscopies are required to identify the food allergens that cause patients to develop EoE. In addition, food elimination therapy can lead to increased food costs, poor patient compliance, and malnutrition.
2. Drug therapy
(1) Proton pump inhibitors
Proton pump inhibitors may play a role in the diagnostic evaluation of patients with suspected EoE and in the treatment of the disease.
First, whether or not a patient with EoE responds to a proton pump inhibitor is the only criterion for differentiating GERD from EoE. Secondly, patients with a clear diagnosis of EoE who were treated with a proton pump inhibitor for concurrent symptomatic GERD also showed a response, which improved the patient’s symptoms. Finally, in vitro studies have shown that proton pump inhibitors reduce cytokine secretion from the esophageal epithelium and that this effect is independent of their acid-suppressive mechanism, suggesting that proton pump inhibitors may have an anti-inflammatory effect.
(2) Topical glucocorticoids
Glucocorticoids act on the main pathogenesis of EoE. First, glucocorticoids may reduce esophageal fibrosis by reducing inflammatory cells. In addition, glucocorticoid treatment can reverse elevated IL-13 mRNA levels. Although FDA has not approved glucocorticoids as a treatment for EoE, oral fluticasone has become the main clinical treatment for EoE.
Topical glucocorticoid therapy has been shown to provide 53% to 95% improvement in clinical symptoms and histologic abnormalities over 2 to 12 weeks, and may reduce the incidence of symptoms such as food impaction. Potential side effects of glucocorticoids include local fungal infections, adrenal cortical axis suppression, osteoporosis, and growth retardation.
3. Esophageal dilation
Esophageal dilatation is commonly used to relieve esophageal strictures caused by EoE in both the older pediatric and adult populations. Although early reports suggested that esophageal dilatation was associated with an increased incidence of various complications, a comprehensive study of large case reports found a perforation rate of less than 1% after esophageal dilatation. Although esophageal dilatation may improve the symptoms of EoE patients, it does not stop the progression of the disease.
4. Long-term maintenance therapy
Since EoE is not precancerous and does not affect the life expectancy of patients, the need for long-term maintenance therapy is still controversial. For most patients, EoE is a chronic disease, and when treatment is stopped, symptoms can reappear and affect the patient’s quality of life, and even complications can occur. Therefore, patients with EoE may require long-term maintenance therapy.
Summary
Since the identification of EoE as a separate disease more than 20 years ago, years of clinical practice and research have led to a mature understanding of the clinical manifestations, basic pathogenesis, and effective treatment of EoE. Further research on the molecular features of EoE is needed to develop new treatment strategies and to evaluate the effectiveness and safety of long-term maintenance therapy.