Eosinophilic Esophagitis: Diagnosis and Treatment

Introduction

Eosinophilic esophagitis (EoE) is a localized chronic inflammatory disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophilic inflammation of the esophageal mucosa. This eosinophilic inflammation is triggered by a T helper type 2 (Th2) lymphocyte-mediated response to food allergens that come into contact with the esophageal mucosa. The disease is diagnosed through a comprehensive assessment of demographic, clinical, endoscopic, and histological findings. Unfortunately, no single clinical feature is specific to EoE [1].

EoE is a relatively recently recognized disease. The first case was described in 1978 and was initially interpreted as achalasia [2]. In the early 1980s, cases of esophageal eosinophilia were observed, although at that time eosinophilia was considered a diagnostic criterion for reflux disease [3]. It took another two decades to establish that EoE was a distinct disease characterized by symptoms of esophageal dysfunction and eosinophilic infiltration [4].

EoE was found to be particularly prevalent among younger atopic males, with endoscopic findings differing from those observed in gastroesophageal reflux disease (GERD). Initially considered rare, EoE was soon recognized as a condition with rapidly increasing incidence and prevalence [5].

Population-based studies conducted in the United States and Europe demonstrated that this increase reflected a genuine rise in disease incidence rather than simply greater clinical awareness and recognition [6, 7].

According to recent meta-analyses, the prevalence of EoE is 32.5 cases per 100,000 adults and 30.9 cases per 100,000 children. In other words, approximately one in 3,000 people in Western countries lives with EoE [8]. The disease is most frequently diagnosed between the ages of 20 and 40 years, although it can occur at any age [9].

Previously, to differentiate EoE from GERD, patients were recommended to undergo a two-month course of proton pump inhibitors (PPIs) at twice the standard dose, based on the assumption that the response to treatment would help distinguish between the two conditions [10].

However, it was subsequently observed that some patients experienced improvements in both symptoms and histological findings following PPI treatment, even in the absence of evidence of GERD [11].

Consequently, a PPI-responsive subphenotype of EoE was identified, and the use of PPI treatment as a diagnostic trial was abandoned [12].

Therefore, reliably distinguishing EoE from GERD remains challenging. Furthermore, several other conditions may also cause eosinophilic infiltration of the esophageal mucosa, including eosinophilic gastroenteritis, celiac disease, Crohn's disease, achalasia, and drug-induced hypersensitivity reactions [1].

Symptoms

The clinical manifestations of EoE tend to follow an age-related progression from early childhood into adulthood (Table 1).

Diffuse inflammation of the esophageal mucosa is believed to persist for many years before causing esophageal remodeling and fibrotic changes.

In childhood, symptoms are diverse and may include impaired growth, feeding difficulties, nausea, vomiting, and abdominal pain.

In older children, symptoms become more specifically esophageal, including heartburn, chest pain, and early manifestations of dysphagia, such as slow and selective eating.

In adolescents and adults, symptoms associated with esophageal narrowing develop and become increasingly pronounced. These include dysphagia with solid foods and food impaction, which may lead to esophageal perforation (Boerhaave syndrome) [1].

However, as more information about the disease becomes available, it is becoming clear that this progression does not occur in every patient.

For example, chest pain and heartburn may be among the predominant symptoms in adults, whereas school-aged children may present with dysphagia [14].

Table 1. Symptoms of Eosinophilic Esophagitis in Children and Adults [1]

Children	Adults
Growth impairment	Dysphagia
Feeding difficulties	Slow eating
Nausea and vomiting	Avoidance of solid foods
Abdominal pain	Avoidance of eating in public
Heartburn	Chest pain
Selective eating	Heartburn

Thus, symptoms may be directly related to the disease or may manifest as compensatory behaviors and habits that allow patients to live with the condition.

In addition, EoE is associated with other atopic diseases, including allergic rhinitis, asthma, atopic dermatitis, and IgE-mediated food allergy [15, 16].

Disease Activity Assessment Systems

To document symptom severity, frequency, and duration, evaluate treatment effectiveness, and monitor changes in the disease over time, various disease assessment scales and questionnaires have been developed.

One such tool is the EoE Activity Index. By assessing this system, disease activity can be evaluated in adults over periods of 7 and 30 days. The score is based on dysphagia severity and can reliably document the frequency, intensity, and duration of dysphagia episodes, the frequency of food impaction, the time required to finish a meal, and the frequency of eating.

This symptom assessment system also evaluates compensatory behaviors, including slow eating, avoidance of solid foods, and vomiting. The score correlates well with histological and endoscopic findings [1, 13].

Other assessment systems have also been developed, including the Mayo Clinic Dysphagia Questionnaire and the Cincinnati University EoE Symptom Assessment System [1].

Most of these tools are too complicated for routine clinical practice, but they are useful in clinical trials. For example, the Dysphagia Symptom Questionnaire consists of only three questions and is completed daily for 30 days: Did you eat solid food yesterday? Did food get stuck or move slowly? Did you have to take any action to make the food pass more easily? [17].

Questionnaires should be used to monitor disease progression.

Endoscopy

Patients with EoE often require repeated endoscopic examinations. During endoscopy, characteristic signs of chronic inflammation, including mucosal edema, white exudates, and longitudinal furrows, as well as remodeling changes such as rings and strictures, may be observed.

In addition, biopsies of the esophageal mucosa are obtained during endoscopy.

Approximately 5% of patients have an endoscopically normal-appearing esophagus [18].

Typical findings in children and adults differ. As mentioned earlier, children more frequently exhibit inflammatory changes, whereas adults more commonly present with mixed inflammatory and fibrotic changes, including rings and strictures [19–21].

To standardize endoscopic findings when monitoring disease activity, an endoscopic scoring system has been developed [18].

Unfortunately, endoscopic findings are neither sensitive nor specific for the disease.

Radiology

Contrast esophagography using a barium suspension is an additional diagnostic examination, particularly in adolescents and adults.

This examination can identify esophageal strictures and is more sensitive than endoscopy for detecting them.

It helps determine the cause of dysphagia in patients whose endoscopic findings are nearly normal.

Barium esophagography can also help identify esophageal rings and facilitate the planning of endoscopic examinations and dilation procedures, particularly in patients with narrow proximal strictures or a small-caliber esophagus [1].

The use of barium radiography in children is limited. However, in one study involving 22 children, strictures were identified by contrast esophagography rather than endoscopy in approximately half of the patients [22].

Histology

The diagnosis of EoE is confirmed by histological examination.

During endoscopy, 6–8 biopsy specimens should be obtained from the distal and middle and/or proximal portions of the esophagus [23].

Histological examination of the biopsy specimens must demonstrate more than 15 eosinophils per high-power field in the esophageal mucosa. This is a sine qua non criterion for diagnosing active EoE [5].

Multiple biopsies are necessary because eosinophilic inflammation is unevenly distributed throughout the esophagus, even in patients with active disease.

In addition to eosinophilia, other histological features may be observed, including spongiosis (dilation of intercellular spaces), increased numbers of mast cells and lymphocytes, and basal zone hyperplasia [24, 25].

A histological scoring system for EoE has been developed [25].

Eight parameters are assessed: eosinophil density, basal zone hyperplasia, eosinophilic abscesses, eosinophilic surface layering, dilation of intercellular spaces, epithelial damage, epithelial dyskeratosis, and lamina propria fibrosis.

The diversity of histological findings demonstrates the considerable variation in morphological responses to inflammation.

New Diagnostic Methods

The cost of endoscopic and histological examinations, the discomfort associated with these procedures, and the risks of repeated examinations have prompted the search for new, less expensive and/or less invasive methods for monitoring disease progression.

The following methods are being investigated:

• Transnasal endoscopy, which does not require sedation, allows adequate visualization of the mucosa, and enables collection of sufficient biopsy material [26].
• Esophageal impedance measurement, based on the principle that dilation of intercellular spaces due to the accumulation of fluids and electrolytes increases epithelial electrical conductivity [27].
• Impedance planimetry, which measures changes in the pressure of an inflated balloon pulled through the esophageal lumen, allowing assessment of esophageal mucosal thickening and changes caused by fibrotic processes [28].

The need for repeated biopsies could potentially be reduced by using the Cytosponge technique.

During this procedure, the patient swallows a gelatin capsule attached to a string and containing a compressed mesh.

Within five minutes, the capsule dissolves, allowing the mesh to expand into a sphere approximately 3 cm in diameter.

As the device is withdrawn, it brushes against the esophageal mucosa and collects sufficient material for histological or immunohistochemical examination.

Eosinophil counts obtained using this method correlate well with those obtained during endoscopy, and patients tolerate the procedure considerably better [29].

Blood Biomarkers

Numerous substances are known to be elevated in patients with EoE, including eotaxin-3, IL-4, IL-5, IL-6, IL-9, IL-13, transforming growth factor beta, and others.

However, none of these biomarkers is currently suitable for differentiating EoE from other diseases or monitoring disease activity [1].

Urinary Biomarkers

Levels of 3-bromotyrosine, a chemical marker of EoE activity formed when eosinophil peroxidase halogenates tyrosine residues, have been found to be 93 times higher than those in nonallergic controls and 13 times higher than those in atopic individuals.

This parameter is a potential biomarker for distinguishing active from inactive EoE [30].

Allergy Evaluation

There is general agreement that EoE is an allergic disease triggered by various foods. Therefore, identifying the responsible allergen is an important part of the diagnostic process and may enable effective nonpharmacological treatment [1].

Unfortunately, all currently available diagnostic methods based on detecting IgE sensitization have minimal value in identifying the food allergen responsible for the disease [10, 31].

At present, the only reliable and effective approach to identifying a causative food allergen is to initiate an elimination diet, which is itself a form of treatment, and confirm histological changes after each food is introduced or removed [31].

Nevertheless, allergy evaluation remains necessary in these patients because of the association between EoE and IgE-mediated allergic diseases.

For example, many patients experience EoE exacerbations during periods of high airborne allergen concentrations, and a substantial proportion had allergic rhinitis before developing EoE [15].

Cases of EoE onset and exacerbation during allergen-specific immunotherapy have also been reported [32].

Plant pollen allergens share similar antigenic epitopes with those found in foods. Therefore, patients with respiratory allergies and EoE may experience cross-reactive responses to plant-derived food allergens.

There is currently no evidence that controlling extraesophageal allergic diseases reduces EoE activity [1].

Treatment Options: Medications, Diet, and Dilation

EoE shares characteristics with two groups of diseases: allergic respiratory diseases, because of its Th2 lymphocyte-mediated immune response, and GERD.

Consequently, medications commonly used to treat bronchial asthma and reflux disease have also been investigated for the treatment of EoE [1].

Corticosteroids

In 1998, the effectiveness of systemic corticosteroids (CS) in treating pediatric EoE was demonstrated.

Just a few months later, researchers found that EoE could also be effectively treated with swallowed topical corticosteroids.

Only 10 years later did prospective controlled studies demonstrate that topical fluticasone was safer than systemic corticosteroids and equally effective in achieving histological and symptomatic remission [33–35].

Metered-dose aerosol inhalers containing budesonide or fluticasone may be used, but it is important to remember that the medication must be swallowed rather than inhaled.

Administering an adequate dose is essential.

For example, the following fluticasone doses have been used:

• Children aged 1–4 years: 176 µg/day.
• Children aged 5–10 years: 440 µg/day.
• Children aged 11 years and older: 880–1,760 µg/day.

Higher doses have also been investigated, including 1,760 µg/day in children aged three years and older [36, 37].

Budesonide dosing has been described as follows:

• Children younger than 10 years: 1 mg once daily.
• Children aged 10 years and older: 1 mg twice daily [38].

In adults, initial treatment may consist of budesonide 1 mg or fluticasone 800 µg twice daily [1].

Patients are advised not to eat or drink for 30 minutes after taking the medication.

Treatment with topical corticosteroids is more effective when viscous oral formulations are used, for example, by mixing the contents of budesonide respules with a thickening agent such as sucralose, honey, agave nectar, or another suitable substance [38].

EoE is a chronic disease, and relapse may occur within a few weeks after discontinuation of corticosteroid treatment [39]. Therefore, most patients require long-term therapy.

Few studies have evaluated the effectiveness of long-term treatment.

When low-dose budesonide (0.25 mg twice daily) is administered, complete histological remission can be maintained for one year in 35.7% of patients [41].

Long-term treatment is recommended for certain patient groups (Table 2) [1].

Table 2. Indications for Long-Term Pharmacological Treatment

Indications
Small-caliber esophagus
Symptoms of esophageal narrowing and objective signs of progression
Rapid recurrence of symptoms after discontinuation of treatment
Recurrent food impaction
Life-threatening conditions that increase the risks associated with endoscopic and dilation procedures
Spontaneous perforation or perforation caused by a dilation procedure
Travel to locations where food impaction could pose a risk of death

Proton Pump Inhibitors (PPIs)

There are at least two reasons why proton pump inhibitor (PPI) therapy should be considered in patients with EoE.

First, because both gastroesophageal reflux disease (GERD) and EoE are relatively common, many patients have both conditions [14].

Second, the esophageal mucosa of patients with EoE is considerably more sensitive, meaning that acidic gastric contents can cause more severe pain [40]. Reducing gastric acidity may therefore alleviate EoE symptoms.

Studies have demonstrated that PPI monotherapy can be effective in some patients, both children and adults, who exhibit typical features of EoE despite GERD having been excluded [11].

Biological Therapy

Mepolizumab and reslizumab, selective humanized monoclonal antibodies targeting interleukin-5 (IL-5), could theoretically be effective in treating eosinophilic diseases [1].

Controlled studies involving children and adults demonstrated that anti-IL-5 therapy reduced peripheral blood eosinophilia and was generally safe. However, the clinical benefits were minimal, and noneosinophilic inflammatory cells remained in esophageal tissues.

Consequently, mepolizumab and reslizumab are not recommended for routine EoE treatment [42, 43].

Infliximab, an anti-tumor necrosis factor (anti-TNF) agent, does not reduce eosinophilic infiltration or improve symptoms [44].

Omalizumab has also been investigated, but anti-IgE treatment was no more effective than placebo, further supporting the conclusion that EoE is not an IgE-mediated disease [10].

Interleukin-13 (IL-13) is a cytokine secreted by Th2 lymphocytes.

In clinical trials investigating anti-IL-13 therapy, three infusions administered over eight weeks reduced esophageal eosinophilia by 60%.

The reduction in eosinophil counts and improvement in symptoms persisted for six months [45].

Available efficacy and safety data suggest that new biological therapies targeting IL-13 may be effective in patients with severe EoE [45, 46].

Immunomodulators

In one small study involving three patients with steroid-resistant EoE, treatment with azathioprine and 6-mercaptopurine induced and maintained symptomatic remission [47].

However, no controlled studies have been conducted.

Kęstutis Černiauskas, MD, Allergist and Clinical Immunologist

Clinic of Chest Diseases, Immunology and Allergology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University

Continued in Internistas, supplement Allergy. Asthma. Immunology, 2018.