Management of Eosinophilic Esophagitis

EoE is a chronic disease that requires long-term treatment. The goals of treatment are to:

Decrease eosinophilic inflammation
Alleviate symptoms
Prevent disease progression
Prevent disease complications (malnutrition, suboptimal growth))
Support normal development and psychological adjustment

Treating children with EoE involves diet therapy and/or medical therapy. Children with strictures and food impaction that do not improve with medical and/or diet therapy may require dilation.

A multi-center, retrospective study drawing from a European database of patients with EoE (adults and children) demonstrated that clinical and histologic remission or response occurred in 82% of patients taking topical steroids, 69% of patients taking proton pump inhibitors, and 42% of patients on empirical elimination diets.

The choice of treatment depends on the clinical picture, as well as family circumstance and preferences.

EoE is a condition that is highly variable in its presentation, severity and response to treatment. As such, each patient and family should participate in a shared decision-making discussion so they fully understand risks, benefits and expected outcomes associated with all treatment options.
Recent guidelines promote shared decision making and individualized approaches towards management. For example, one patient/family may place high value on not restricting their diet as much as possible whereas another may wish to avoid medications.

Dietary Therapy

For many children, EoE is a non-IgE-mediated allergic disease, thus removal of relevant food allergens can cause remission of the disease.

It is important to acknowledge that elimination diets can be difficult to adhere to and can decrease quality of life and possibly promote disordered eating.
Early research demonstrated highest rates of remission with complete elemental diets followed by six-food elimination diets (see below) but these are also often unsustainable for long periods of time.
Early research also evaluated the use of IgE skin prick or serologic tests to guide specific food elimination diets, but this is now considered outdated due to false positive results and inconsistency in identification of food triggers.

Dietary therapy has 3 main approaches:

Elemental diet
Empirical food elimination (four or six-food elimination)
Milk elimination

Elemental diet

The elemental diet is a highly restrictive diet that consists of a liquid amino acid–based formula, which does not induce an allergic response. It has been shown to be more than 90% effective in causing histological remission of EoE symptoms. However, this diet needs to be carefully considered alongside the needs of the child and family because of the following issues:

Cost
Poor palatability
Need for careful monitoring to ensure that nutritional needs are met
Potential interference with food acceptance in young children
Potential interference with development of oral feeding skills
Use of a gastrostomy tube may be necessary to deliver adequate quantities of the formula

Modifying the elemental diet can help to avoid some of the difficulties:

Palatability of the formula can be enhanced by adding flavorings (eg, simple syrup
The diet can include one or two foods prepared in a variety of ways (mashed, pureed, cubed) to avoid the development of texture aversion and to improve oral skill development.

Although the elemental diet is a useful method to achieve remission, its use in chronic therapy is limited because of the difficulty in maintaining the diet.

Empirical food elimination

A six-food elimination diet (SFED) has been shown to cause a histologic remission rate of approximately 73% in children. Parents are asked to eliminate the following from the child’s diet:

Milk
Wheat
Egg
Soy
Peanut/tree nuts
Fish/shellfish

Variations of the diet include the 4-food elimination diet (typically empirical removal of milk, wheat, soy and egg) or elimination of milk alone.

The SFED relies on eliminating the most frequent allergic triggers, of which milk is the most common trigger (61%). Implementing the diet requires motivation and involves understanding several factors and procedures:

Assess the child for nutritional risks to address the risks of limiting food intake during childhood.
Conduct a psychosocial assessment to solicit information on potential barriers to diet
- Social support systems, including alternate caregivers and school settings
- Financial resources—Prepared food that is free from all triggers may be difficult to find and expensive to purchase.
- Patient and parent motivation
- Family lifestyle
Once remission is achieved with the diet, the child can add in one food over the course of several weeks, after which time biopsy can be used to determine whether remission is maintained.
- Adding foods back in sequentially ensures that only the food that is causing the allergic response is eliminated, which is crucial in facilitating long-term adherence to the diet.
The diet is not easy to maintain, and care must be taken to control the child’s food exposures in all settings, including:
- Child care
- School
- Extended family settings and nonfamilial caregiver settings
- Parties or friends’ houses
- Restaurants

Milk elimination diet

Milk is now recognized as the most common food trigger and patients/families who opt for starting with an initial food elimination diet may focus on milk avoidance as a first approach. This reduces hardships associated with avoidance of multiple foods but still requires monitoring as stated above.

The overall effectiveness of empirical milk-only elimination diets has been reported to be 68% in one small study (n = 17).

The typical initial duration of all elimination diets is 6 to 8 weeks, after which endoscopy and biopsy are repeated to determine histologic response.

Reintroduction of food and follow-up endoscopy are performed sequentially.
Repeated general sedation is a drawback of elimination diet monitoring; less invasive esophageal sampling may be a solution.
Dietary restrictions are well known to reduce quality of life; however, a multidisciplinary approach available in an EoE clinic can anticipate and address these aspects.

Test-directed elimination diet

Both IgE skin prick tests and atopy patch tests have previously been used to try and identify specific foods for removal from the diet in treatment of EoE. However, given the inaccuracy of these approaches combined with known benefits of either empiric food elimination diets or medical therapy, both skin prick and atopy patch tests have very limited utility in the evaluation of children for EoE for purposes of food elimination.

Medical Therapy

Proton pump inhibitors (PPIs)

In consensus guidelines, the failure to respond to PPIs has been removed as a criterion for ruling out a diagnosis of EoE because some patients with EoE improve with PPI therapy.

PPIs may be considered first-line therapy for EoE, before elimination diets are recommended and before topical steroids are considered.

Given that PPIs have a well-known safety profile and are easy to administer in relation to other therapies, PPIs are a reasonable first therapeutic step.
A subset of patients with EoE respond to PPI therapy alone. Although the exact proportion of this population is difficult to ascertain, it is approximately 50%.
- Trials of 8 to 12 weeks are common.

Swallowed topical steroids

Swallowed topical glucocorticoids taken in a small amount of liquid or a puff from an inhaler are the mainstay treatment option to medically treat inflammation; remission rates are high with this method. The US Food and Drug Administration (FDA) approved the first oral therapy for EoE in 2024. Eohilia (budesonide oral suspension) is approved for patients 11 years and older. No mixing is required for this medication, which improves standardization of the dose.

Additional options (off-label) are

Budesonide (swallowed slurry)
Fluticasone (swallowed puff) (Brand name Flovent was discontinued in 2023; the generic version is poorly covered by insurers.)
Mometasone (oral viscous) (may be considered if the budesonide and fluticasone do not achieve remission)

In general, swallowed topical steroids are well tolerated and have a good safety profile.

The chief side effect is Candida esophagitis (occurring in approximately 9% of cases), which can be managed with antifungal treatment while continuing the steroid.
Five percent to 16% of children who use topical steroids for EoE develop adrenal insufficiency with a low serum cortisol level.
Long-term maintenance treatment of EoE with these medications, particularly at lower doses than those needed to induce remission, is advisable, given the chronic fibrosing characteristic of EoE (see the Long-Term Considerations section). Monitor the patient for possible side effects, such as candidiasis, bone density decrease, and adrenal suppression, particularly if the child is receiving topical corticosteroid therapy for a concomitant atopic condition (Table 3).

Table 3. Comorbid Conditions Often Treated With Topical Corticosteroids That May Require Additional Monitoring for Adverse Effects

Biologic

Dupilumab, a monoclonal antibody to IL-4 receptor alpha, is the first biologic treatment for EoE approved by the FDA.

It is approved for EoE in children 1 year and older who weigh at least 15 kg (33 lb) with EoE. See Table 4 for indications.
Phase 3 trials of dupilumab showed that 60% of patients reached histologic end points and showed clinically relevant improvement in dysphagia.
In 2017, dupilumab was approved for moderate to severe atopic dermatitis in infants and children older than 6 months.
In 2022, dupilumab was approved for treatment of EoE in children and teens 12 years and older.
The treatment is administered on an ongoing basis via weekly or biweekly subcutaneous injection.
It can be used safely in patients who have previously used swallowed topical steroids.
Live vaccines (eg, yellow fever, measles-mumps-rubella, varicella) are currently contraindicated for anyone receiving treatment with dupilumab.
Dupilumab is contraindicated in patients with known hypersensitivity to dupilumab or any excipients in Dupixent.

Table 4. Clinical Scenarios Indicating the Use of Dupilumab for Eosinophilic Esophagitis

Type of Dupilumab Use	Clinical Scenario
Consider for First Line Use	Patients with multiple comorbid atopic conditions that include
	· Moderate, persistent, or difficult to control asthma
	· Moderate, persistent, or difficult to control atopic dermatitis
	· Difficult to control chronic sinusitis with nasal polyps
	Patients with a strong preference to avoid dietary restriction or topical swallowed steroids
Consider as step-up therapy	EoE that is difficult to treat
	Patients with failure to thrive, poor growth or significant weight loss due to EoE
	Patient with frequent use of rescue therapies
	· Oral systemic steroids
	· Esophageal dilations
	Patients with severe diet restriction or requiring amino acid formula
	Patients with clinically significant esophageal strictures or narrow caliber esophagus
	Patients refractory to current therapy
	· Due to continued symptoms
	· Due to persistent abnormal esophageal inflammation
	· Due to adverse effects of current therapy
	· Due to intolerance of current therapy
	· Due to inability to adhere to current therapy
	Patients with adverse effects to current therapy

From Aceves SS, Dellon ES, Greenhawt M, Hirano I, Liacouras CA. Clinical guidance for the use of dupilumab in eosinophilic esophagitis: a yardstick. Ann Allergy Asthma Immunol. 2023;130(3):371-378.

Proton pump inhibitors (PPIs)

In consensus guidelines, the failure to respond to PPIs has been removed as a criterion for ruling out a diagnosis of EoE because some patients with EoE improve with PPI therapy.

PPIs may be considered first-line therapy for EoE, before elimination diets are recommended and before topical steroids are considered.

Given that PPIs have a well-known safety profile and are easy to administer in relation to other therapies, PPIs are a reasonable first therapeutic step.
A subset of patients with EoE respond to PPI therapy alone. Although the exact proportion of this population is difficult to ascertain, it is approximately 50%.
- Trials of 8 to 12 weeks are common.

Swallowed topical steroids

Swallowed topical glucocorticosteroids taken in a small amount of liquid or a puff from an inhaler are the mainstay treatment option to medically treat inflammation; remission rates are high with this method. Options (off-label) are:

Budesonide (swallowed slurry)
Fluticasone (swallowed puff)
Mometasone (oral viscous)—may be considered if the budesonide and fluticasone do not achieve remission

In general, swallowed topical steroids are well-tolerated and have a good safety profile.

The chief side effect is candida esophagitis (occurring in approximately 9% of cases), which can be managed with antifungal treatment while continuing the steroid.
Clinical trials with topical steroids for EoE treatment have not shown relevant changes in cortisol levels or systemic cortisol side effects, regardless of length of treatment.
Long-term maintenance treatment of EoE with these medications, particularly at lower doses than those needed to induce remission, is advisable, given the chronic fibrosing characteristic of EoE (see Long-Term Considerations).
- Monitor the patient for possible side effects, such as candidiasis, bone density decrease, and adrenal suppression, particularly if the child is receiving topical corticosteroid therapy for a concomitant atopic condition (see Table 3).

Table 3. Comorbid Conditions Often Treated With Topical Corticosteroids That May Require Additional Monitoring for Adverse Effects

Condition	Form of Delivery
Allergic conjunctivitis	Ophthalmic drops
Allergic rhinitis	Intranasal
Asthma	Inhaled
Atopic dermatitis	Topical ointments

Biological

Dupilumab, a monoclonal antibody to IL-4 receptor alpha, is the first biologic treatment for EoE approved by the Food and Drug Administration.

It is approved for EoE in children 12 years and older who weigh at least 40 kg (88 pounds). See Table 4 for indications.
Phase III trials of dupilumab showed that 60% of patients reached histologic end points and showed clinically relevant improvement in dysphagia.
In 2017, dupilumab was approved for moderate to severe atopic dermatitis in children older than 6 months of age.
The treatment is administered on an ongoing basis via weekly subcutaneous injection.
It can be used safely in patients who have previously used swallowed topical steroids.
Live vaccines (eg, yellow fever, measles-mumps-rubella, varicella) are currently contraindicated for anyone receiving treatment with dupilumab.

Table 4. Clinical Scenarios Indicating the Use of Dupilumab for Eosinophilic Esophagitis

Type of Dupilumab Use

Clinical Scenario

Consider for First Line Use

Patients with multiple comorbid atopic conditions that include

Moderate, persistent, or difficult to control asthma
Moderate, persistent, or difficult to control atopic dermatitis
Difficult to control chronic sinusitis with nasal polyps

Patients with a strong preference to avoid dietary restriction or topical swallowed steroids

Consider as step-up therapy

EoE that is difficult to treat

Patients with failure to thrive, poor growth or significant weight loss due to EoE

Patient with frequent use of rescue therapies

Oral systemic steroids
Esophageal dilations

Patients with severe diet restriction or requiring amino acid formula

Patients with clinically significant esophageal strictures or narrow caliber esophagus

Patients refractory to current therapy

Due to continued symptoms
Due to persistent abnormal esophageal inflammation
Due to adverse effects of current therapy
Due to intolerance of current therapy
Due to inability to adhere to current therapy

Patients with adverse effects to current therapy

From Aceves SS, Dellon ES, Greenhawt M, Hirano I, Liacouras CA. Clinical guidance for the use of dupilumab in eosinophilic esophagitis: a yardstick. Ann Allergy Asthma Immunol. 2023;130(3):371-378.