Key points

Introduction

Our understanding of eosinophilic esophagitis (EoE) has evolved over the past 30 years from isolated case reports of patients with prominent esophageal eosinophilia (often misclassified as gastroesophageal reflux [GERD]) to a well-defined clinical disorder. In the past, EoE was described differently, including allergic esophagitis, primary EoE, or idiopathic EoE. We now know that EoE is a distinct disease. It is defined as a clinicopathologic diagnosis characterized by a localized eosinophilic inflammation of the esophagus (with no other gastrointestinal involvement), symptoms of esophageal dysfunction, the presence of 15 or more eosinophils in the most severely involved high-powered field (HPF) isolated to the esophagus, and failure to respond to adequate proton-pump inhibitor (PPI) therapy. Other recognized causes of esophageal eosinophilia should be excluded before making the diagnosis ( Box 1 ).

Introduction

Our understanding of eosinophilic esophagitis (EoE) has evolved over the past 30 years from isolated case reports of patients with prominent esophageal eosinophilia (often misclassified as gastroesophageal reflux [GERD]) to a well-defined clinical disorder. In the past, EoE was described differently, including allergic esophagitis, primary EoE, or idiopathic EoE. We now know that EoE is a distinct disease. It is defined as a clinicopathologic diagnosis characterized by a localized eosinophilic inflammation of the esophagus (with no other gastrointestinal involvement), symptoms of esophageal dysfunction, the presence of 15 or more eosinophils in the most severely involved high-powered field (HPF) isolated to the esophagus, and failure to respond to adequate proton-pump inhibitor (PPI) therapy. Other recognized causes of esophageal eosinophilia should be excluded before making the diagnosis ( Box 1 ).

Demographics

EoE is characterized by eosinophilia of the esophagus, an organ typically devoid of eosinophils, without infiltration in other parts of the gastrointestinal tract. First described in 1993, EoE has been increasing in incidence and prevalence in Western nations with an estimated annual incidence equal to Crohn disease. The increase in EoE mirrors the increased prevalence of allergic diseases (asthma, allergic rhinitis, atopic dermatitis, and food allergy) over the last few decades. Data from the CDC National Health Information Survey (NHIS) confirm the increase in all atopic diseases. The reported prevalence of asthma increased from 3% in 1990% to 7.7% in 2007. An estimated 25% to 30% of the population in industrialized countries has atopic dermatitis, food allergy, or allergic rhinitis. EoE has now been reported in every continent. Five to 10% of pediatric patients and 6% of adult patients with poorly controlled GERD are thought to have EoE. In our cohort at The Children’s Hospital of Philadelphia, the authors have seen a 70-fold increase, from 1994 to 2011. In Olten Country, Switzerland, this increase has also been observed in the adult population with increased prevalence from 2 per 100,000 in 1989 to 23 per 100,000 in 2004. Patients who have EoE typically are male (by a 3:1 ratio) and 75% have a personal history of atopy. Like other atopic diseases, such as asthma and eczema, EoE is a chronic disease. Most patients will continue to have the disease into adulthood. In a 12-year study of adults, no patients had remission. In a 14-year study of pediatric patients, only 2% had remission of disease.

Clinical presentation: general considerations

EoE should be suspected in patients describing symptoms consistent with GERD but not responding to adequate reflux medications. Presentation in children varies depending on the age of the child. Characteristic symptoms in infants and young children are feeding difficulties, failure to thrive, and classic GERD symptoms. In contrast, school-aged children are more likely to present with vomiting, abdominal pain, and regurgitation. Dysphagia and food impaction are more prevalent in adolescents and adults. One study looked at age of presenting symptoms over a 14-year span and found feeding difficulties or failure to thrive in young children (median age 2.8 years), vomiting and GERD symptoms in older children (median age 5.1 years), abdominal pain in young adolescents (median age 9.0 years), and dysphagia and food impaction (median age 11.1 years) in older adolescents. Food impaction can be a presenting symptom especially if dysphagia is intermittent and mild in nature. In adults, the percent of patients who present with dysphagia and who are diagnosed with EoE has risen by 15% from 1999 to 2009. In addition, adult reports have also suggested that the probability of developing fibrostenosis increases over time (especially when not properly treated). It is easy to postulate that chronic untreated inflammation in children may lead to the esophageal dysfunction and dysphagia seen in older adolescents and adults. In addition, a select cohort of patients with abdominal pain on initial presentation who refused therapy all returned 6 years later with symptoms changed to dysphagia. Mechanical obstruction can be the cause for dysphagia. It is unclear whether variable presentations represent different disease phenotypes or the natural history of the untreated disease.

Vomiting and pain

Vomiting is a common symptom in younger children. It can be mistaken for GERD but, unlike GERD, vomiting associated with EoE usually is not diagnosed before 6 months of life. It can be sporadic in occurrence and not associated with meals. If occurring after ingestion of particular foods, vomiting can be mistaken for food protein-induced enterocolitis or IgE-mediated food allergy especially in children with other food allergies. Although vomiting can present early on in infancy, especially in a highly atopic child, it is more likely after the introduction of solid food into the diet. Some children may induce vomiting if they have dysphagia and feel something is stuck in their throat.

Children may complain of abdominal pain, in particular localizing to the epigastrium despite only having esophageal disease. Adolescents and adults are more likely to localize pain to the chest or complain of heartburn. The pain, which is spasmodic, can be severe enough to lead patients to seek emergency evaluation and lead to cardiac evaluation.

Dysphagia and food impaction

Dysphagia associated with EoE is intermittent and some patients may experience it for more than 2 years before presentation. How patients report dysphagia varies, as can be expected, especially in different age groups. Patients may describe difficultly initiating swallowing, food going down the esophagus too slowly, or food being stuck in the throat. Food impaction can lead to patient anxiety. Patients gradually learn techniques for compensating for dysphagia, including taking small bites, eating slowly with excessive chewing, and drinking fluids after each bite. Some may even jump up and down to help food pass. Patients may also avoid certain food textures or types (eg, meat) due to difficulty swallowing these in the past. In younger children and infants, it is unclear if symptoms such as gagging, choking, feeding difficulties, and food aversions are secondary to current dysphagia and the associated pain or due to previous negative feeding experiences and the related anxiety toward eating. In adolescents, patients with EoE have been misdiagnosed with eating disorders because of symptoms of food-related anxiety, vomiting, and food aversion. Barium radiographic studies are extremely useful in patients who complain of dysphagia. These studies can demonstrate fixed strictures, small caliber esophagus, transient or fixed rings, or a normal esophagus (suggesting that dysphagia is due to secondary esophageal dysmotility). These findings are especially important for the gastroenterologist before an endoscopy is performed.

EoE patients with dysphagia may have a mechanical obstruction. Strictures can be seen, even in infants. Strictures are, however, less common in children who usually do not have radiographic evidence of obvious mechanical obstruction. One study found that 8 out of 18 children found to have Schatzki rings via radiographic images had EoE. Those having EoE did not have rings on endoscopy but, most likely, had a focal spasm at time of imaging. In contrast, strictures, rings, narrowing of the esophagus, and Schatzki rings have all been described in adults with EoE and dysphagia. A biopsy should be performed on patients with mechanical obstruction, including foreign bodies (eg, food, coins), to rule out EoE.

One active area of research in EoE, as well as other atopic conditions, is tissue remodeling. In atopic dermatitis, skin can become lichenified and thick over time. In poorly controlled asthmatics, a permanent decline in lung function may occur. Patients with EoE can have narrowing of the esophagus or stricture formation secondary to untreated EoE. However, narrowing occurs in only a very small percentage of adult patients because strictures are only seen in 5% to 15% of adult series and these are usually only in patients with longstanding untreated disease. This progression of complications is attributed to fibrous remodeling associated with the natural history of untreated EoE. Delayed diagnosis of EoE is associated with an increased risk of stricture formation in a time-dependent manner. Children with untreated EoE have basement membrane thickening and increased vascular activation, similar to changes seen in airway remodeling with increased SMAD2/3 and transforming growth factor (TGF)-β.

Correlation of symptoms with endoscopy and histology

The appearance of mucosal rings, furrowing, strictures, and white plaques are often seen on visual inspection. However, up to one-third of patients with active EoE may have a normal appearing esophagus. There is poor correlation between biopsies and symptoms. Patients can have normal biopsies and still have symptoms and the converse. For example, in the largest clinical trial for EoE with 240 subjects, there was no correlation between symptoms and eosinophils found on esophageal biopsies. Subjects on placebo had symptom resolution without improvement in esophageal eosinophilia. Currently, serial endoscopies of the esophagus are unavoidable for EoE because there are no other available testing options. One study followed 330 subjects with at least 1 year of clinical follow-up (average 3.2 years). These subjects had 2526 total biopsies with an average of 4.5 esophagogastroduodenoscopies (EGDs) per subject. At time of presentation, 144 subjects also required lower endoscopies. Disease burden, including financial, would be eased if there was a reliable, easily obtainable (eg, blood, stool) biomarker for EoE that would lessen the frequency of EGDs.

Other clinical presentations

In children with asthma, chest pain and cough may be mistaken for an asthma exacerbation; however when these patients do not respond to aggressive asthma treatment, after asking a careful history, EoE should be considered. The diagnosis of EoE has also been made in children with airway anomalies such as subglottic stenosis and laryngeal cleft.

Eosinophilic gastroenteritis is eosinophilic inflammation at extraesophageal gastrointestinal sites. This entity usually does not respond to dietary therapies and it is treated with corticosteroids. EoE has also been described in conjunction with other gastrointestinal disorders such as Crohn disease and celiac disease. The prevalence of EoE in children with confirmed celiac disease is 1% to 4%. In general, EoE is not typically in remission with removal of gluten-containing foods alone.

Connective tissue disorders (CTDs) have been recently associated with a greater risk for EoE. A recent retrospective study noted an eightfold increase in EoE (1.3% prevalence) in patients with CTDs at their institution. This included patients with Marfan syndrome, Ehlers-Danlos syndrome, joint hypermobility syndrome, and Loeys-Dietz syndrome. Patients had dysmorphic scaphocephalic facial features, hypermobility of hands and large joints, and high rate of atopic diseases. Esophageal biopsies from EoE patients with CTDs were indistinguishable from those without CTDs but this cohort was more likely to have significant eosinophilic gastrointestinal inflammatory disease affecting other sites such as stomach, duodenum, and colon. On a molecular level, the EoE transcriptome for EoE-CTD was not unique. However, two genes (CD200R1 and SAMSN1) had higher expression and two genes (PTGFRN and COL8A2) had lower expression in this group. This association may further support that TGF-β signaling plays a role in EoE pathogenesis and help target future pharmacotherapies.

EoE has been described in neurologic disorders such as seizure disorders, cerebral palsy, migraines, and Chiari malformation. Certain antiepileptic drugs have been linked to the development of EoE in the setting of a hypersensitivity reaction involving other organ systems. There is no evidence for a causal relationship between EoE and neurodevelopmental disorders such as pervasive developmental delays or sensory integration disorders.