Gastroenterology Hepatology

Eosinophilic esophagitis

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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.

Endoscopic, esophageal abnormalities in eosinophilic esophagitis: A, esophageal rings; B, rings with focal stricture; C, exudates; D, longitudinal furrows.

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.

Histopathology of eosinophilic esophagitis.

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.

Management of eosinophilic esophagitis.

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.

Table I.

Treatment options for eosinophilic esophagitis, including advantages and disadvantages
Treatment Advantages Disadvantages
Medications
Topical steroids (fluticasone, budesonide) Ease of administration.High degree of efficacy in randomized controlled trials. Candidiasis, Recurrent disease activity after cessation of topical steroids
Systemic steroids High degree of effectiveness.Ease of administration Toxicities of systemic steroidRecurrent disease after cessation
Antihistamines Ease of administration Limited data to support effectiveness
Leukotriene antagonist Symptom improvement in uncontrolled studies Higher doses may be needed for effectNo change in esophageal eosinophiliaSide effects of nausea and myalgias
Immunomodulator (azathioprine, 6 mercaptopurine) Steroid sparing agent ImmunosuppressionSide effect profileLimited data (3 patients) to support use
Anti-TNF therapy (infliximab) Rationale based on increased tissue expression of TNF No clinical improvement in a small uncontrolled trial
Anti-IL-5 therapy Rationale based on role of IL-5 in systemic eosinophilic disorders Conflicting data to support efficacy
Cromolyn sodium Rationale based on asthma model Limited pediatric data does not support effectiveness
Diet
Elemental High degree of effectivenessSimplified initial formula dietAvoidance of long-term use of medications Poor palatabilityRequires prolonged period of foodReintroductionNeed for repeated EGD and biopsies to identify allergen
Directed elimination High degree of effectivenessTheoretical advantage of more selective dietAvoidance of long-term use of medications Skin prick test with poor predictive valueAtopy patch testing not standardizedNeed for repeated EGD and biopsies to identify allergen
Empiric elimination High degree of effectivenessAvoidance of long-term use of medications Need for repeated EGD and biopsy to identify allergenHigh degree of vigilance to avoid contamination
Dilation
High degree of effectivenessProlonged symptom response without medications Reports of esophageal laceration causing significant painReports of esophageal perforation and hospitalization

What is the most effective initial therapy?

The most effective therapies for EoE include topical corticosteroids, elimination or elemental dietary therapy, and esophageal dilation. Of these options, only topical steroids have been supported with randomized controlled trials at this time. There have not been controlled trials comparing alternative therapies to know which treatment is superior. Moreover, the primary treatment outcome utilized in the medical and dietary therapies has been a reduction in esophageal eosinophilia. While central to disease diagnosis, it is uncertain that esophageal eosinophilia alone correlates with symptom improvement.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

What therapy is best if initial therapy fails?

If therapy with topical corticosteroids fails, it is important to examine the reason for failure. If the patient has histologic resolution of esophageal eosinophilia but remains symptomatic, esophageal strictures may need to be addressed by means of esophageal dilation. If the patient has both symptoms and histologic activity, the dose of topical steroids can be increased. Alternatively, an elimination diet could be initiated, recognizing that there is no controlled data to support the effectiveness of diet for steroid refractory patients.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Advantages and disadvantages of second-line therapies are listed in Table I.

Listing of these, including any guidelines for monitoring side effects

See Figure 3 for a therapeutic algorithm.

How should I monitor the patient with eosinophilic esophagitis?

How should I monitor complications of eosinophilic esophagitis?

Complications of esophageal strictures can be monitored by means of symptom assessment, upper endoscopy or barium esophagram. Esophageal perforation can be detected by barium esophagram or chest CT scan.

Monitoring recommendations

Disease activity can be subdivided into inflammatory activity or fibrostenotic complications. Inflammatory activity is best assessed by means of symptom assessment and esophageal histology. Fibrostenotic complications can be assessed by means of symptom assessment, barium esophagram or upper endoscopy.

It is not clear that either form of disease activity needs to be monitored for all patients with EoE. Symptom improvement is often used to guide decisions regarding the need for additional therapy. However, patients may have sporadic symptoms or may modify their dietary habits to compensate for disease activity. In such circumstances, the patient may still be at considerable risk for recurrent food impaction.

What's the evidence?

Dellon, ES, Gonsalves, N, Hirano, I. "ACG Clinical Guideline: Evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE)". Am J Gastroenterol. vol. 108. 2013. pp. 679-692.

Dellon, ES.. "Epidemiology of eosinophilic esophagitis". Gastroenterol Clin North Am. vol. 43. 2014. pp. 201-218.

Liacouras, CA, Furuta, GT, Hirano, I. "Eosinophilic esophagitis: updated consensus recommendations for children and adults". J Allergy Clin Immunol. vol. 128. 2011. pp. 3-20.

Furuta, GT, Liacouras, CA, Collins, MH. "Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment". Gastroenterology. vol. 133. 2007. pp. 1342-63.

Hirano, I.. "Eosinophilic esophagitis". American Journal of Gastroenterology. 2016.

Spechler, SJ, Genta, RM, Souza, RF.. "Thoughts on the complex relationship between gastroesophageal reflux disease and eosinophilic esophagitis". Am J Gastroenterol. vol. 102. 2007. pp. 1301-6.

Schoepfer, AM, Gonsalves, N, Bussmann, C. "Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation". Am J Gastroenterol. vol. 105. 2010. pp. 1062-70.

Dohil, R, Newbury, R, Fox, L. "Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial". Gastroenterology. vol. 139. 2010. pp. 418-29.

Hirano, I, Moy, N, Heckman, MG, Thomas, CS, Gonsalves, N, Achem, SR.. "Endoscopic Assessment of the Esophageal Features of Eosinophilic Esophagitis: Validation of a Novel Classification and Grading System". Gut. vol. 62. 2013. pp. 489-95.

Straumann, A, Conus, S, Degen, L. "Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis". Gastroenterology. vol. 139. 2010. pp. 1526-37.

Schaefer, ET, Fitzgerald, JF, Molleston, JP. "Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children". Clin Gastroenterol Hepatol. vol. 6. 2008. pp. 165-73.

Spergel, JM, Andrews, T, Brown-Whitehorn, TF. "Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests". Ann Allergy Asthma Immunol. vol. 95. 2005. pp. 336-43.

Kagalwalla, AF, Sentongo, TA, Ritz, S. "Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis". Clin Gastroenterol Hepatol. vol. 4. 2006. pp. 1097-102.

Gonsalves, N, Yang, GY, Doerfler, B, Ritz, S, Ditto, AM, Hirano, I.. "Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors". Gastroenterology. vol. 142. 2012. pp. 1451-9.e1.

Attwood, SE, Lewis, CJ, Bronder, CS. "Eosinophilic oesophagitis: a novel treatment using Montelukast". Gut. vol. 52. 2003. pp. 181-5.

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