Eosinophilic esophagitis

How can I be sure that the patient has eosinophilic esophagitis?

Signs and symptoms

In adults, symptoms of EoE are dominated by dysphagia and food impaction and less commonly heartburn or atypical chest pain. In children, symptoms of EoE include abdominal pain, nausea, vomiting, anorexia and dysphagia.

Usual constellation of clinical features

Eosinophilic esophagitis (EoE) should be suspected in patients presenting with chronic symptoms of dysphagia and food impaction. Most patients have had symptoms for several years prior to diagnosis. Furthermore, some patients may have been previously diagnosed with gastroesophageal reflux disease (GERD) or idiopathic esophageal strictures since EoE is a relatively recently recognized disorder. Less commonly, patients may complain of atypical chest pain. Demographic characteristics for EoE include younger age, male gender, and a past or current history of atopic disorders (asthma, eczema, allergic rhinitis).

Physical examination in patients with EoE is typically normal, although signs of concomitant atopy may be present (e.g., eczematous rash, wheezing). Laboratory testing in adults with EoE demonstrate peripheral eosinophilia in the minority. Very high degrees of peripheral eosinophilia are unusual in EoE and should prompt investigation for secondary causes of esophageal eosinophilia.

Endoscopic features that are characteristic but not pathognomonic for EoE include rings, longitudinal furrows, and exudates within the esophagus (Figure 1). While the presence of one or more of these esophageal mucosal abnormalities on endoscopy are present in most cases, none are required for the diagnosis of EoE. Nevertheless, endoscopic features have reasonable accuracy and should increase clinical suspicion for eosinophilic esophagitis.

Figure 1.

A 2011 consensus recommendation statement by 33 adult and pediatric physicians with expertise in allergy/immunology, gastroenterology, and pathology defined EoE as a clinicopathologic diagnosis. Clinically, EoE requires the presence of symptoms of esophageal dysfunction, dominated by dysphagia in adults. Pathologically, at least one biopsy should demonstrate eosinophil predominant inflammation that is characterized by a peak concentration of greater than or equal to 15 eosinophils per high power microscopic field (Figure 2). Additional histologic features include basal cell hyperplasia, rete peg elongation, eosinophil microabscess formation, surface layering of eosinophils within the squamous epithelium, extracellular eosinophil protein, dilated intercellular spaces, and lamina propria fibrosis. Other causes of esophageal eosinophilia need to be excluded before the diagnosis of EoE is established.

Figure 2.

A tabular or chart listing of features and signs and symptoms

Symptoms

– Dysphagia

– Food impaction

– Chest pain

– Heartburn

– Nausea/vomiting*

– Abdominal pain*

– Anorexia*

– Early satiety*

* Manifestations reported in children and uncommonly in adults.

Endoscopically visualized esophageal features

– Fixed rings (“trachealization” or corrugated esophagus)

– Linear furrows (vertical lines)

– White exudates (plaques)

– Reduced vascular markings (pallor, edema)

– Focal stricture (proximal or distal)

– Narrow or small caliber esophagus

– Mucosal fragility (“crepe paper esophagus”)

Histologic features

– Increased esophageal eosinophilia (≥15 eosinophils per high power field)

– Eosinophilic microabscesses

– Surface layering of eosinophils

– Extracellular eosinophil granules

– Basal cell hyperplasia

– Dilated intercellular spaces

– Lamina propria fibrosis

Pathognomonic or characteristic features

At this time, there is no pathognomonic feature for EoE. The symptom presentation can mimic that seen with other esophageal disorders, including (GERD), Schatzki’s ring, and a number of esophageal inflammatory disorders and motor disorders.

Furthermore, the histologic features of eosinophil-predominant inflammation have been described with a number of diseases, most importantly (GERD) and eosinophilic gastroenteritis. Nevertheless, the combination of clinical and demographic features, discussed above, in combination with histopathology is characteristic for EoE in the absence of evidence of secondary causes of esophageal eosinophilia.

Less common clinical presentations

In adults, less common presentations of EoE include atypical chest pain and refractory reflux disease. Pediatric manifestations of abdominal pain, nausea, vomiting, anorexia, and early satiety are unusual in adults.

Other diseases and conditions that might mimic the signs, symptoms, or clinical features of eosinophilic esophagitis

GERD. Symptoms dominated by heartburn, refluxate, and regurgitation. Endoscopic features include esophageal erosions, peptic strictures, and Barrett’s esophagus. Clinical response to acid suppression is expected.

Eosinophilic gastroenteritis. Symptoms dependent on affected region of the gastrointestinal tract. Eosinophilic gastritis typically presents with abdominal pain, nausea, and vomiting. Eosinophilic enteritis typically presents with diarrhea, malabsorption, and abdominal pain. Muscular or transmural forms of eosinophilic gastroenteritis may present with symptoms and signs of bowel obstruction. Peripheral eosinophil counts are elevated in most cases of eosinophilic gastroenteritis. Mucosal biopsies demonstrate increased eosinophilia in the mucosal but may miss the muscular or serosal forms of disease.

Celiac disease. Symptoms are dominated by diarrhea and weight loss. Laboratory testing demonstrates evidence of malabsorption, including iron deficiency and loss of fat soluble vitamins. Osteopenia is a complication of vitamin D deficiency. Esophageal symptoms of dysphagia and food impaction are distinctly uncommon.

Crohn’s disease. Symptom manifestations are dominated by distal small bowel and colonic disease and include nausea, vomiting, abdominal pain, and diarrhea. Symptomatic esophageal involvement is uncommon in Crohn’s disease.

Infectious esophagitis. Fungal and viral esophagitis typically presents in immunocompromised individuals with symptoms that include both dysphagia and odynophagia. The time course for presentation is acute in contrast to the chronic nature of EoE. Endoscopic appearances of infectious esophagitis are distinct from EoE with the exception of candida esophagitis, where white exudates can be seen in both diseases. Biopsies in infectious esophagitis should identify the causative pathogen although special stains may be required.

Hypereosinophilic syndrome. A rare condition that may, in some cases, have significant overlap with eosinophilic gastrointestinal disorders. However, the degree of peripheral eosinophilia in HES is usually significantly more elevated (>1,500) in HES.

Achalasia. The clinical presentation of achalasia includes progressive dysphagia for both liquids and solids. Liquid dysphagia is distinctly uncommon in EoE. Eosinophils may be identified in the esophageal mucosa and muscularis propria in achalasia. Esophageal manometry in EoE is most commonly normal, although increased esophageal pressurization can be seen in a minority of patients and could be confused with achalasia in some circumstances. Esophageal peristalsis is typically preserved in EoE, although impaired deglutitive opening of the lower esophageal sphincter may be observed, presumably the result of restricted distensibility of the esophagogastric junction.

Drug hypersensitivity. Drug hypersensitivity could manifest with esophageal eosinophilia and should be considered in patients with other manifestations and an acute history temporally associated with medication exposure.

Pemphigoid vegetans. Bullous skin disease can present with dysphagia and proximal esophageal strictures. Skin manifestations are typically present.

Connective tissue disease. Extra esophageal symptoms and signs typically dominate in the presentation of connective tissue disorders. An exception is scleroderma, where esophageal reflux manifestations may occur early in the course of disease and be associated with esophageal eosinophilia.

Graft-versus-host disease. GVHD should be suspected in the appropriate, post-transplant setting. The presentation is typically subacute, compared with the chronic manifestations of EoE.

How can I confirm the diagnosis?

What tests should be ordered first?

The diagnostic evaluation of a patient with suspected eosinophilic esophagitis begins with an upper endoscopy with esophageal biopsies. The endoscopist should identify characteristic esophageal features of rings, furrows, exudates, mucosal pallor and strictures. Because the mucosal inflammation may be patchy, multiple mucosal biopsies should be obtained. Two to 4 proximal and 2 to 4 distal esophageal biopsies are recommended to maximize the diagnostic yield. The presence of distal only eosinophilia raises the possibility of GERD, whereas more diffuse esophageal eosinophilia is supportive of EoE. However, the sensitivity and specificity of biopsy location in distinguishing EoE from GERD has not been established in prospective studies.

What tests should be used to confirm the initial tests?

The diagnosis of EoE can be strongly suspected in the presence of characteristic clinical symptoms and esophageal eosinophil-predominant inflammation. GERD can be difficult to distinguish from EoE. Ambulatory pH testing or an 8-week trial of proton pump inhibitor (PPI) therapy has been recommended in patients with suspected EoE to exclude possible GERD. However, patients with characteristic symptoms, endoscopic signs, and histopathologic features who respond to PPI therapy may have a PPI responsive form of EoE, and not necessarily typical GERD.

What tests are useful if the diagnosis is still in doubt?

Currently, the diagnosis of EoE relies on the presence of both characteristic symptoms and pathology in the absence of identifiable secondary causes of esophageal eosinophilia. No single diagnostic test can accurately “rule in” the diagnosis of EoE. Response to topical steroids or an elimination diet that removes dietary allergens supports the diagnosis. Biomarkers such as eotaxin-3 and specific proteins expressed by eosinophils, as well as genetic testing for a susceptibility locus on chromosome 5q22, are being investigated for their role in the diagnosis of EoE.

An empiric trial of (PPI) therapy or diagnostic testing for GERD are recommended, given the overlap between GERD and EoE.

A diagnostic algorithm

For a diagnostic algorithm, see Figure 3.

Figure 3.

Diagnostic testing for EoE

Endoscopy. Necessary to obtain esophageal biopsies. Characteristic esophageal abnormalities on endoscopy listed above.

Histology. Necessary for the diagnosis of EoE. Features listed above.

Barium esophagram. May to useful to define presence and extent of esophageal strictures and complications of esophageal perforation.

Allergic Testing. Serum IgE testing and/or skin prick testing for immediate type hypersensitivity reactions to foods may help identify food allergic disease in patients with EoE. However, current studies have reported significant limitations to both the sensitivity and specificity of allergy testing in predicting food triggers in EoE.

Esophageal manometry. Clinical utility of manometry in the evaluation of EoE has not been determined. Nonspecific or normal patterns demonstrated in the majority of patients with EoE. Abnormal esophageal pressurization patterns identified in a subset of patients.

Ambulatory pH testing. pH testing is useful to determine the presence of increased esophageal acid exposure. However, the utility of increased acid exposure in identifying GERD as a cause of suspected EoE or predicting response to proton pump inhibition has not been determined.

Impedance planimetry. Investigational technique to measure distensibility of the esophagus in EoE.

Endoscopic ultrasonography. Limited studies have demonstrated increased thickness of the mucosa, submucosa, and muscularis in EoE. The clinical utility of EUS in EoE has not been determined.

What other diseases, conditions, or complications should I look for in patients with eosinophilic esophagitis?

Risk factors

Risk factors for EoE include male gender, younger age, and presence of atopy (allergic rhinitis, asthma, eczema or food allergy).

Diseases that may occur with eosinophilic esophagitis

Atopic disorders including asthma, allergic rhinitis, and atopic dermatitis are found more commonly in patients with EoE. To date, eosinophilic esophagitis has not been associated with esophageal cancer or progression to eosinophilic gastroenteritis.

Complications of eosinophilic esophagitis

– Esophageal stricture

– Narrow caliber esophagus

– Food impaction

– Esophageal perforation

– Gastrointestinal bleeding

– Malnutrition

– Impaired quality of life

What is the right therapy for the patient with eosinophilic esophagitis?

Effective treatment options for EoE include topical corticosteroids, systemic corticosteroids, elimination diets, and esophageal dilation. See Table I.