History

Esophageal eosinophilia was first reported in an adult patient in 1975. For the next 20 years, sporadic cases and small case reports were noted in the literature. In 1995 Kelly described ten patients with isolated esophageal eosinophilia unresponsive to acid blockade who improved with an elemental formula. This report was the first to suggest that EoE was a distinct entity. It also introduced food allergy as an etiology. Since 1995, there has been a dramatic rise in the number of patients diagnosed and the number of articles written on EoE. In 2006, the first Japanese case of EoE was reported. EoE has now been reported to occur in every continent except for Africa.

Several reports on pediatric patients and adults have suggested that the prevalence of EoE is increasing. Noel described an incidence of EoE of 1 in 10,000 children along with a fourfold increase in prevalence from 2000 to 2003. Straumann illustrated similar findings in adults by reporting an incidence of 6 in 100,000 with an increasing prevalence. Liacouras described an increase in newly diagnosed EoE cases, from 2 cases in 1994 to 72 cases in 2003. Markowitz found that 8% to 10% of pediatric patients unresponsive to reflux therapy had EoE. Fox found that 6% of his adult patients with esophagitis had EoE. A pediatric gastrointestinal clinic in Western Australia found an 18-fold increase of EoE cases from 1995 until 2004.

Pathophysiology

Initially, several factors were considered as the etiology of EoE. At the start, severe gastroesophageal reflux was blamed; however, after discovering that aggressive acid blockade as well as antireflux surgery was unsuccessful, other causes were proposed. Laboratory models suggested that aeroallergens may be responsible for the disease. Although inhaled antigens may have a role, they have not yet been directly implicated as the primary cause in patients with EoE. In contrast, food antigens have been directly linked to the disorder. Several studies have demonstrated resolution of clinical symptoms and normalization of esophageal tissue when patients are placed on a strict amino acid–based diet.

Recent research conducted in Madrid evaluated 35 adult patients with EoE using immunohistochemistry and stereology (observing cells three-dimensionally) and compared them with patients with GERD and normal controls. The density of eosinophils in the esophagus was 300 times greater in EoE patients when compared with controls. In addition, the eosinophils were activated (based on the presence of major basic protein). Although T cells and mast cells were found in increased numbers in patients with GERD, they were present in much higher levels in patients with EoE. Intraepithelial plasma cells were observed only in patients with EoE. The binding of IgE to antigen is thought to initiate the allergic cascade. When patients were treated with swallowed fluticasone, the number of T cells decreased (but not to normal), and the number of mast cells decreased (by one third). The investigators proposed that, in GERD, eosinophils may act as regulatory cells. In contrast, in EoE, these cells are effector cells responding to allergens and, in turn, leading to epithelial damage.

Increased levels of eosinophil active TH ₂ (“allergic”) cytokines are found in the esophagus of patients with EoE. These cytokines include IL-5, IL-13, and IL-4. IL-5 has been found to up-regulate proliferation, recruitment, and survival of eosinophils. Mishra found that one can experimentally induce EoE in wild-type mice. When anti–IL-5 was given to wild-type mice, they developed a blunted esophageal eosinophilia. IL-13–deficient mice also demonstrated an impaired EoE response to allergens. A recent report looked at in vitro allergen-specific responses (to food and aeroallergens) in peripheral blood mononuclear cells from 15 patients with EoE compared with 9 healthy controls. IL-5 production was increased with milk, soy, peanut, dust, and ragweed, although not with egg, wheat, or mold; IL-13 was up-regulated with dust in a comparison with normal controls.

In 2007 Aceves demonstrated that children with EoE undergo significant esophageal remodeling. Quantitative immunohistochemical analysis was performed and several chemokines were studied in patients with EoE, patients with GERD, and normal controls. Esophageal biopsies in EoE revealed increased levels of subepithelial fibrosis, increased expression of TGF-beta and its signaling molecule phosphor-SMAD2/3, and an increased vascular density and vascular adhesion molecule. These findings suggest that these features may lead to esophageal narrowing and stricture formation.

Increasing evidence suggests that genetics may have a role in the etiology of EoE. A genome-wide, micro-array expression analysis performed on patients with EoE found that the gene encoding eotaxin 3 (one of many chemokines important for trafficking of eosinophils) was highly induced, and that a single nucleotide polymorphism was associated with increased susceptibility to EoE. More work on the genetics and underlying pathophysiology is currently being pursued.

Pathophysiology

Initially, several factors were considered as the etiology of EoE. At the start, severe gastroesophageal reflux was blamed; however, after discovering that aggressive acid blockade as well as antireflux surgery was unsuccessful, other causes were proposed. Laboratory models suggested that aeroallergens may be responsible for the disease. Although inhaled antigens may have a role, they have not yet been directly implicated as the primary cause in patients with EoE. In contrast, food antigens have been directly linked to the disorder. Several studies have demonstrated resolution of clinical symptoms and normalization of esophageal tissue when patients are placed on a strict amino acid–based diet.

Recent research conducted in Madrid evaluated 35 adult patients with EoE using immunohistochemistry and stereology (observing cells three-dimensionally) and compared them with patients with GERD and normal controls. The density of eosinophils in the esophagus was 300 times greater in EoE patients when compared with controls. In addition, the eosinophils were activated (based on the presence of major basic protein). Although T cells and mast cells were found in increased numbers in patients with GERD, they were present in much higher levels in patients with EoE. Intraepithelial plasma cells were observed only in patients with EoE. The binding of IgE to antigen is thought to initiate the allergic cascade. When patients were treated with swallowed fluticasone, the number of T cells decreased (but not to normal), and the number of mast cells decreased (by one third). The investigators proposed that, in GERD, eosinophils may act as regulatory cells. In contrast, in EoE, these cells are effector cells responding to allergens and, in turn, leading to epithelial damage.

Increased levels of eosinophil active TH ₂ (“allergic”) cytokines are found in the esophagus of patients with EoE. These cytokines include IL-5, IL-13, and IL-4. IL-5 has been found to up-regulate proliferation, recruitment, and survival of eosinophils. Mishra found that one can experimentally induce EoE in wild-type mice. When anti–IL-5 was given to wild-type mice, they developed a blunted esophageal eosinophilia. IL-13–deficient mice also demonstrated an impaired EoE response to allergens. A recent report looked at in vitro allergen-specific responses (to food and aeroallergens) in peripheral blood mononuclear cells from 15 patients with EoE compared with 9 healthy controls. IL-5 production was increased with milk, soy, peanut, dust, and ragweed, although not with egg, wheat, or mold; IL-13 was up-regulated with dust in a comparison with normal controls.

In 2007 Aceves demonstrated that children with EoE undergo significant esophageal remodeling. Quantitative immunohistochemical analysis was performed and several chemokines were studied in patients with EoE, patients with GERD, and normal controls. Esophageal biopsies in EoE revealed increased levels of subepithelial fibrosis, increased expression of TGF-beta and its signaling molecule phosphor-SMAD2/3, and an increased vascular density and vascular adhesion molecule. These findings suggest that these features may lead to esophageal narrowing and stricture formation.

Increasing evidence suggests that genetics may have a role in the etiology of EoE. A genome-wide, micro-array expression analysis performed on patients with EoE found that the gene encoding eotaxin 3 (one of many chemokines important for trafficking of eosinophils) was highly induced, and that a single nucleotide polymorphism was associated with increased susceptibility to EoE. More work on the genetics and underlying pathophysiology is currently being pursued.

Clinical characteristics

Although most reported patients who are diagnosed with EoE are young, Caucasian (>90%), and male (>65%), EoE can occur at any age and in either sex. Patients affected typically present with one or more of the following symptoms: vomiting, regurgitation, nausea, epigastric abdominal pain or chest pain, dysphagia, water brash, globus, or decreased appetite. Less common symptoms include growth failure, hematemesis, and esophageal dysmotility. Symptoms can be frequent and severe in some patients while extremely intermittent and mild in others. Most young children and infants experience vomiting, chronic nausea, or regurgitation, whereas older children and adolescents experience heartburn, epigastric pain, or episodes of dysphagia. More than 50% of patients have concomitant atopic disorders including asthma, eczema, or allergic rhinitis. Furthermore, as many as 50% of patients have one or more parents with a history of allergy. EoE should be strongly considered in patients who have severe or refractory symptoms of gastroesophageal reflux despite the use of acid suppression medication. Family history, job-related contacts, and links to other immunologic diseases have also been reported.

Although most of the early literature was related to children and adolescents, recent reports have described the clinical features in adults. As is true in pediatrics, EoE predominately occurs in males, and there is an increased prevalence of other atopic disorders (asthma, allergic rhinitis, eczema) in the patient and other family members. In adults, the peak age incidence occurs between the fourth and sixth decades of life. Clinical symptoms vary from subtle intermittent symptoms that may mimic gastroesophageal reflux to severe symptoms such as chronic dysphagia or acute food impaction. Currently, most adults with EoE are diagnosed as a result of the emergent presentation of a patient with an esophageal food impaction; however, as more gastroenterologists become aware of this disorder, other symptoms previously thought to be unrelated to EoE (heartburn, water brash, epigastric pain) may be seen in patients with EoE.

Reports from other subspecialties are also emerging. Three patients with subglottic stenosis and laryngeal edema refractory to reflux treatment were also found to have EoE. Occupational exposure may have had a role in the development of EoE in two adult patients. One adult was a baker with wheat sensitivity and the other a horse trainer with sensitivity to hay. Family history is also of importance and should be taken into consideration. A recent series of 17 patients with dysphagia, eosinophilia, or Schatzki’s ring were described from seven families in which both younger and older generations had EoE across as many as three generations. A recent case report described a 7-year-old black male with poorly controlled asthma, eczema, and type 1 diabetes who had abdominal pain and positive celiac serology. Endoscopy revealed significant esophageal eosinophilia and villous blunting, all of which responded to dietary modification, including his other atopic conditions.

Diagnosis

The diagnosis of EoE always begins with the recognition of symptoms; however, the severity and chronicity of EoE symptoms often go overlooked. In a pediatric study, there was a 3-year lag between symptoms and first endoscopy. In a recent retrospective German study of mostly adults, there was a 4-year lag between symptoms and diagnosis. Food impaction has been a primary presentation of EoE in many adults. Esophageal food impaction occurs with an estimated frequency of 13 cases per 100,000 in adults. Two recent studies found that a significant number of patients who presented with food impaction had underlying EoE. Anytime a food impaction or severe dysphagia occurs in adults, EoE should be considered, and, along with the removal of the impaction, an upper endoscopy with biopsy should be performed.

The most important part of diagnosis is upper endoscopy with biopsy. Visual inspection is not sufficient because even a normal appearing esophagus can have significant esophageal eosinophilia. As many as one third of patients with EoE may have a normal appearing esophagus. Other findings include esophageal furrows, strictures, mucosal rings (trachealization), and white plaques. Esophageal tissue from patients who have EoE may also demonstrate thickened mucosa with basal layer hyperplasia and papillary lengthening. Because there is definite variability in histology within the same patient, multiple esophageal biopsy specimens should be obtained. Gonsalves found that the sensitivity and specificity of making the diagnosis of EoE increased by the number of biopsies. Muller reiterated that multiple biopsies are essential for diagnosis. Baxi and colleagues set out to characterize whether the number of eosinophils correlated with the degree of symptoms and found that only dysphagia correlated with higher eosinophil counts. They were unable to find statistical differences in age, gender, or other symptoms in patients with low levels of eosinophils (1 to 5 cells/hpf), moderate levels of esophageal eosinophils (6 to 14 cells/hpf), or higher levels of eosinophils (>15 cells/hpf).