Pediatric Annals

CME 

Practical Management of Eosinophilic Esophagitis

Carla M. Davis, MD

Abstract

CME Educational Objectives

1.Determine the clinical presentation and diagnostic criteria for eosinophilic esophagitis in children.

Discuss the three major treatment strategies for eosinophilic esophagitis.

Provide key strategies for practical identification and management of eosinophilic esophagitis in children and adolescents.

Eosinophilic esophagitis (EoE) is a recently discovered disease that affects patients worldwide. The conceptual definition of EoE is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. As a chronic, antigen-mediated disease causing eosinophilic inflammation in the esophagus, EoE symptoms are similar to gastroesophageal reflux disease (GERD) and it results in significant morbidity.

Abstract

CME Educational Objectives

1.Determine the clinical presentation and diagnostic criteria for eosinophilic esophagitis in children.

Discuss the three major treatment strategies for eosinophilic esophagitis.

Provide key strategies for practical identification and management of eosinophilic esophagitis in children and adolescents.

Eosinophilic esophagitis (EoE) is a recently discovered disease that affects patients worldwide. The conceptual definition of EoE is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. As a chronic, antigen-mediated disease causing eosinophilic inflammation in the esophagus, EoE symptoms are similar to gastroesophageal reflux disease (GERD) and it results in significant morbidity.

Eosinophilic esophagitis (EoE) is a recently discovered disease that affects patients worldwide. The conceptual definition of EoE is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.1 As a chronic, antigen mediated disease causing eosinophilic inflammation in the esophagus, EoE symptoms are similar to gastroesophageal reflux disease (GERD) and results in significant morbidity.

The incidence and prevalence of EoE has increased over the past 10 years, making it the leading cause of upper gastroesophageal symptoms.2 Hence, all clinicians should be aware of its clinical presentation. EoE affects all age groups and has been reported in patients from 1 year to 98 years. It has a male predominance of approximately three to one.

EoE specifically affects the esophagus, although it frequently presents with eosinophilic infiltration in the lower gastrointestinal tract. Lower eosinophilic gastrointestinal diseases (EGIDs) have a different pathogenesis and will not be addressed in this article. Given the increased recognition of EoE, it is important for pediatricians to be familiar with EoE and best practices for diagnosis and treatment.

Clinical Presentation

Symptoms of EoE include abdominal pain, vomiting, nausea, poor weight gain, failure to thrive, food aversion, fussiness, regurgitation, dysphagia, and food impaction. Infants, toddlers and children typically present with symptoms indistinguishable from GERD with varied presentation based on age group (see Sidebar 1). Small infants and toddlers typically present with feeding disorders. Older children tend to present with abdominal pain and vomiting.4,5

Sidebar 1.

Typical Eosinophilic Esophagitis Symptoms in Children

  • Poor weight gain
  • Fussiness
  • Slow eater /sipper
  • Inability to swallow solid foods
  • Pocketing food
  • Nausea
  • Vomiting
  • Failure to thrive
  • Heartburn
  • Regurgitation
  • Abdominal Pain
  • Avoidance of foods
  • Chest pain
  • Food impaction

Typical Eosinophilic Esophagitis Symptoms in Children

Adolescent and adult patients typically present most commonly with dysphagia, food impaction, heartburn, and chest pain; up to 50% of cases of food impaction in emergency room visits are due to EoE. Adolescents describe food getting “stuck” and needing a method to help food pass into the stomach. This may include adding sauces or butter to food to help it pass or drinking large amounts of water or beverages to move the foods into the stomach. Length of mealtimes can be prolonged because patients with EoE have to chew food to reduce it to small pieces before it will pass through a narrow caliber esophagus. Pediatricians should have a low threshold for evaluation for EoE after a food impaction episode.

Childhood and adult EoE have a similar pathogenesis and clinical features which occur along a continuum. Although definitive prospective long-term natural history studies have not been performed, 14-year clinical follow-up of children and adults show that the disease does not remit after removal of treatment.7,8 Upon withdrawal of treatment, eosinophilic inflammation consistently persists. Current consensus is that eosinophilic inflammatory mucosal infiltrate in children does not resolve1,7 and may develop over time into chronic fibrotic change. However, this fibrosis is not irreversible because topical steroid treatment can reverse this change.9 Since no childhood cohort has been followed into adulthood, the true natural history of childhood EoE is still unknown. There is no evidence that EoE is associated with esophageal malignant transformation or Barrett’s esophagus.8

Diagnostic Criteria

This disease cannot be diagnosed by a pathologist alone. A clinician must evaluate each patient to make the diagnosis.1 Given the need for expert consensus and guidelines for the diagnosis and treatment of EoE, in 2007, 33 experts convened to define the disease and the diagnostic criteria. As several other diseases can result in eosinophils in the esophagus (see Sidebar 2), a decision was made to require both clinical and pathologic criteria for proper diagnosis. Therefore, a patient must meet both clinical and histologic criteria to be diagnosed with EoE. Typical symptoms must be present, along with non-responsiveness to GERD treatment and a peak eosinophil number of at least 15 per high-powered field with one or more biopsy specimens showing eosinophil-predominant inflammation. A minimum of two to four biopsy specimens should be obtained from both the proximal and distal esophagus for optimal evaluation.

Sidebar 2.

Diseases Associated with Eosinophilic Esophagitis

  • Gastroesophageal reflux disease
  • Eosinophilic esophagitis
  • Eosinophilic gastrointestinal diseases
  • Celiac disease
  • Crohn’s disease
  • Infection
  • Hypereosinophilic syndrome
  • Achalasia
  • Drug hypersensitivity
  • Vasculitis
  • Pemphigoid vegetans
  • Connective tissue disease
  • Graft-versus-host disease

Diseases Associated with Eosinophilic Esophagitis

In 2011, the consensus guidelines were updated to include the exclusion of a recently defined condition called proton pump inhibitor (PPI)-responsive esophageal eosinophilia. These patients have typical EoE symptoms, esophageal eosinophilia greater than 15 eosinophils per high-powered field, and clinical and pathologic treatment response to PPIs. Treatment of GERD with PPIs was added to the diagnostic criteria to exclude PPI responsive esophageal eosinophilia (see Sidebar 3).1

Sidebar 3.

Diagnostic Criteria for the Diagnosis of Eosinophilic Esophagitis

  • Clinical symptoms of esophageal dysfunction
  • Peak count of >15 eosinophils in 1 high-power field
  • Lack of responsiveness to high-dose proton pump inhibition (up to 2 mg/kg/day) or normal pH monitoring of the distal esophagus

Diagnostic Criteria for the Diagnosis of Eosinophilic Esophagitis

Physical Exam

Children with EoE frequently have normal examinations but may have epigastric tenderness, or findings consistent with allergic rhinitis, asthma or eczema including allergic shiners, wheezing, or eczematous skin findings.5, 9 Other manifestations of atopic disease should be identified on physical exam and growth parameters should be evaluated because poor weight gain can be a prominent feature in small children.5,6,9 To date, characteristic oral or pharyngeal findings have not been described, even with dysphonia as a presenting clinical feature.1

Endoscopic and Histologic Data

Endoscopic findings in EoE vary from normal to significantly abnormal gross appearance. Edema, linear furrows, white plaques or exudates that represent micro-abscesses of eosinophils, mucosal rings also called “trachealization,” strictures and a small caliber esophagus are evidence of esophageal inflammation in EoE.1 None of these features are pathognomonic for EoE, thus histologic evaluation is essential for diagnosis.

Two-thirds of patients have gross findings on endoscopy and one-third of patients have normal gross appearance but histologic findings diagnostic for EoE. It is a patchy disease and an increased number of biopsies improves diagnostic accuracy.1,10 Because GERD can also cause mild mucosal eosinophilia in the distal esophagus, eosinophilic inflammation in the proximal esophagus are most characteristic of EoE.11,12

Although there are increased eosinophils in the esophageal mucosa, no correlation has been noted with mucosal and peripheral eosinophilia.1,13,14 Approximately 50% to 60% of the time, patients with elevated esophageal mucosal eosinophils have a normal eosinophil count in the blood.1

The pathophysiology of EoE is characterized by many features common to other atopic diseases such as asthma and eczema, and is inflammatory in nature. EoE is a Th2-driven disease with IL-5 production causing the production of eosinophils, which infiltrate the esophageal mucosa, and IL-13, resulting in the production of immunoglobulin-E (IgE) from B cells. There is an upregulation of eotaxin-3, which is an important chemokine for eosinophil recruitment from the bone marrow. Eosinophils produce TGF-beta, which stimulate fibroblasts to make extracellular matrix proteins.

An immune-mediated response to allergens similar to foods and pollen in a genetically predisposed host causes several changes in the esophageal mucosa. These changes can be seen histologically and include eosinophil micro-abscesses, basal cell hyperplasia, papillar elongation, fibrosis with a thickened epithelial mucosal layer. Multiple cells contribute to the inflammatory response, including CD4 and CD8 T cells, mast cells, eosinophils, dendritic cells, and B cells. Histologic local IgE production by B cells is consistent with an atopic component to this disease.1,5,15

Gene-wide association studies in families with EoE have revealed a single nucleotide polymorphism on 5q22, which is also associated with other atopic diseases like asthma.16 This polymorphism is associated with the gene encoding thymic stromal lymphopoeitin (TSLP), which is also involved with the development of fibrosis in asthma.16 There is an increased incidence of atopic disease in EoE patients, implicating a shared pathogenic mechanism of disease. MicroRNA evaluation of mucosal biopsies shows specific patterns of expression for EoE samples versus normal controls, which may lead to better biomarkers for diagnosis.17

Risk Factors for EoE

Approximately 10% of patients with EoE have family members with the disease.18 It is found in all racial and ethnic groups but is more common in Caucasian males. Frequently, young boys’ families will report a father, paternal grandfather, and paternal great grandfather with the need for frequent dilations. In these cases, the child is considered at increased risk for development of strictures in adulthood.18 atopic disease with eczema, allergic rhinitis, and asthma are associated with EoE in up to approximately 90% of patients.1,8

Management of EoE

There are three major treatment strategies used in EoE management referred to frequently as “diet, drugs and dilation.”5 The latter is typically used only in older adolescents and adults because of the risk of perforation in young children. Although dietary change and medication treatment have not been directly compared in prospective studies, both are considered highly effective.1 Discordance between symptoms and histologic inflammation in EoE patients is the reason endoscopy with biopsy is recommended to determine treatment efficacy.14 Given the chronicity of disease and gradual response to therapy, 6 to 12 weeks between biopsies are typical to allow the treatment to be effective.19–22

Nutritional Therapy

There are three main effective diets in treatment plans for EoE patients: elemental diet (amino acids alone);19,23 empiric elimination diet (avoidance of specific foods);24  and targeted elimination diet (avoidance of foods positive with allergy testing)25 (see Table 1). When implementing these diets, it is very important that a certified dietician be consulted and involved in counseling the family because vitamin and micronutrient deficiencies have been reported with dietary elimination in EoE. If the gastroenterologist is treating a patient with dietary avoidance therapy, communication with the pediatrician is essential so both physicians can help the family work through the complexities of dietary change.

 
Dietary Therapies

Table 1. Dietary Therapies

Elemental Diet

The first report that an elemental diet was helpful in a small number of patients with esophageal eosinophilia was performed by Kelly and colleagues in 1995.19 They showed that the mucosal eosinophil counts of patients dropped significantly after a 6-week course of an elemental formula. Then Liacouris et al26 reported an elemental diet improved 98% of children with EoE. No other diet to date has been shown as effective, in both children and adults, as an elemental diet, which is administered as a liquid with exclusion of all solid food.26, 27 the implementation of this diet in infancy is relatively simple because infants typically only need formula and elemental formulas and solid foods for infants are commercially available. However, in older children, frequently the unpleasant taste of the formula prohibits oral administration. In these cases, gastrostomy tubes can be placed to administer the formula. This strategy has been used successfully to treat EoE. Elemental therapy alone becomes more difficult as children age and want to participate in social interaction around meals.

Empiric Elimination

Kagawalla et al identified six foods (milk, egg, soy, wheat, nuts, seafood) most commonly associated with EoE and which, upon avoidance, caused resolution of disease in 74% of pediatric patients.21 However, in a very recent large cohort in Philadelphia, this diet only improved 53% of pediatric patients.22 This diet is called the “six food elimination diet” (SFED) and was recently found to be effective in adults.21 This diet is not as effective as the elemental diet, but it allows some oral ingestion of food and patients are not as socially restricted. More recently, in a small group of patients, 65% responded to milk avoidance alone.28

Targeted Elimination

Targeted elimination diets are used when allergy testing is available through an allergist. The foods identified as positive on immediate hypersensitivity skin prick testing (IHST) and/or atopy patch testing are removed from the diet. This diet has been reported to be effective in up to 77% of patients in one center using both IHST and patch testing, with more than 70% of patients avoiding three or more foods.22

Limitations to this diet include the necessity for allergy testing and lack of standardization of atopy patch testing. It should be noted that current evidence for the effectiveness of both elimination diets are retrospective. Prospective studies will be needed in the future to accurately assess these diets.

Role of Allergy Testing

The methods used to test IgE-mediated hypersensitivity include the measurement of specific IgE in serum and skin prick testing, which involves placing a small amount of allergen in the skin epidermis causing a mast cell mediated histamine wheal and flare response. The determination of specific IgE in IgE-mediated atopic disease can be helpful when used with a clinical history to guide environmental and food avoidance.29

Therefore, for EoE patients with concomitant atopic disease, allergy testing may be helpful to control other allergic disease. There is anecdotal evidence that well-controlled allergic rhinitis with nasal steroid mediation contributes to improvement in EoE proximally. For EoE, only skin prick testing is recommended to be used to detect IgE mediated allergy because there are no studies evaluating the use of serum specific IgE for food avoidance treatment.1

Atopy patch tests (APT) have been combined with skin prick tests to guide food avoidance and reintroduction therapy in EoE. APT is performed by placing fresh food in a Finn chamber and attaching the chamber to the skin under an adhesive patch with the food touching the epidermis for 48 hours. The patches are then removed and observed for erythema, induration, and vesicular rash at 72 hours.22

Although the addition of the APT intuitively seems beneficial because EoE is a Th2 cell-mediated disease, there have been no studies to correlate reactions on skin with esophageal inflammation and the food materials used for these tests are non-standardized, making reliability of results questionable.30 Currently, this is considered an optional method for determining causative foods in EoE.1

The four most common foods that correlate with esophageal inflammation based on removal and reintroduction trials are milk, egg, soy, and wheat.20–24 Although children with IgE-mediated food allergy to milk, egg, soy and/or wheat typically have resolution of their allergy by the time they enter adulthood,29 there is no evidence to date that children with EoE have resolution of allergic response to these foods if they have positive tests.

It is not known if patients will react to baked goods with milk and egg if they have unbaked milk and egg as a trigger for EoE symptoms. Other commonly identified foods implicated in EoE are beef, chicken, pork, oat, rice, corn, potato, and nuts.22,25 Environmental allergens such as birch pollen have been reported recently as clinically relevant in adult patients. Food allergens remain the predominant trigger in both children and adults with EoE.1,5

Pharmacotherapy

Steroids

In EoE, the pathologic changes are striking in the esophageal mucosa and, therefore, medication targeted to the mucosa improves inflammation and chronic fibrosis and remodeling.1,11 Both topical and systemic steroids are effective in reducing inflammation and resolving symptoms in the majority of children with EoE. However, topical steroids are recommended over the use of systemic steroids except in the case of resistant disease.1

The two most commonly used topical steroid medications used in EoE are fluticasone and budesonide.31–35 In a head-to-head comparison with oral prednisone, topical fluticasone was just as effective as the systemic steroid32 (see Table 2). Patients like the ease of carrying the inhaler but can sometimes experience confusion with the use of fluticasone for both asthma and EoE because the administration method is so vastly different for the two diseases. Fluticasone is swallowed to treat EoE, but is inhaled to treat asthma.

 
Corticosteroid Therapies*

Table 2. Corticosteroid Therapies

Budesonide as used for treatment in EoE is a slurry mixture to allow for slower esophageal transit.32,33 This steroid can be difficult to mix and requires more preparation time than fluticasone, but is extremely useful in infants and toddlers who cannot swallow on demand. Both budesonide and fluticasone have beneficial effects on chronic remodeling and fibrosis.11,35

To date, the reported side effects of steroids in EoE reported include thrush, hoarseness, and candidal esophagitis.1,36 No studies have systematically evaluated side effects of long-term use of topical steroid medication in EoE. It is unknown if adrenal suppression, growth delay, osteopenia, increased bruising, mood swings or hirsuitism will be problems in patients with long-term use of topical steroids. Ciclesonide, a steroid parent compound converted by epithelial esterases to form the biologically potent desisobutyryl-ciclesonide (des-CIC), has been successfully used to treat four patients with EoE with minimal side effects.37 Montelukast was shown to be ineffective in lowering mucosal eosinophil counts in EoE.38

Immunomodulators

Newer biologic agents have been used unsuccessfully in EoE probably secondary to the heterogeneity of pathogenic cellular responses. Anti-IL5 agents like mepolizumab were successful in decreasing esophageal eosinophilic infiltration, but had minimal effectiveness on patient symptoms.39–41 Anti-IgE (omalizumab) was not effective in EoE.42 Anti-IL13 agents are currently under investigation and may be useful for specific subgroups of EoE patients, but widespread use of these agents is not indicated at this time. The effect of immunotherapy or “allergy shots” on EoE disease is unknown and needs further study.

Dilation

Dilation improves symptoms in about 80% of patients, and has a relatively low risk for complications in adults (approximately 7%). Younger age and more dilation procedures are associated with an increased risk of complications. These include mucosal rents, chest pain and perforations.43

Practical Disease Identification and Management

When a child presents with typical signs (ie, poor weight gain, failure to thrive) and symptoms (ie, abdominal pain, vomiting) of EoE or GERD, the initial step for a clinician is to treat GERD with a PPI for 8 weeks to exclude both reflux as a cause of the symptoms and PPI-responsive esophageal eosinophilia. A history should be obtained for atopic dermatitis, allergic rhinitis, asthma in the child and family along with a family history of gastrointestinal diseases to determine the child’s risk of development of EoE and other atopic and/or gastrointestinal disease.

Concomitant diseases should be treated appropriately and other causes of eosinophilia excluded. If the signs and symptoms do not resolve with a 2-month trial of PPI treatment, referral to a gastroenterologist for endoscopic evaluation of the esophagus is appropriate. The gastroenterologist should obtain at least two specimens in the proximal and distal esophagus to ensure diagnostic accuracy. This gastroenterologist should ideally have a relationship with a pathologist familiar with EoE who will comment on the characteristic histologic features of the disease.

If the features of EoE grossly and/or histologically meet the diagnostic criteria and other diseases have been excluded, further treatment is warranted with dietary avoidance or topical medication with individualized therapy based on the family’s needs and desires.

Long-Term Follow-Up

Families with children with EoE may have a difficult time coping with the stresses of a chronic disease and dietary limitations. Therefore, the pediatrician has an essential role in walking the patient and family through the implications of diagnosis and daily living. Concerns of parents and children may be different but include feelings of being different than family and peers, diet and medication adherence, difficulties with eating, and worry about symptoms and illness.44  After the initial treatment is proven effective in controlling esophageal inflammation with a repeat biopsy 6 to 12 weeks after initiation of therapy, annual follow-up with the gastroenterologist and allergist is a reasonable plan.

Conclusion

EoE is a chronic clinico-pathologic disease that is antigen driven and successfully treated with dietary avoidance and/or topical steroid medication. A multidisciplinary approach is necessary to optimally treat children with EoE. Since children are significantly affected, pediatricians should be aware of the signs, symptoms, risk factors, diagnostic criteria and treatment. Pediatricians will be the first physician to identify the symptoms and refer to the correct specialists to facilitate diagnosis. Collaboration between the gastroenterologist, allergist, dietician and pediatrician are essential to identify children with EoE early and provide optimal care.

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Dietary Therapies


Elemental Six Food Elimination Test Directed Cow’s Milk Elimination
Description Amino acid-based formula is the only source of nutrition Foods containing milk, egg, soy, wheat, nuts, and sea-food are excluded from diet Foods positive on skin prick and patch testing are excluded from diet Foods containing dairy ingredients are excluded from diet
Percent of patients with clinical and histologic remission 98% 26 53%–81% 21,23,24 65%–77%22,23 65%28
 

Corticosteroid Therapies*


Budesonide Fluticasone Prednisone
Dose 10 years or younger: 0.5 mg twice daily Older than 10 years: 1 mg twice daily Children: 88–440 mcg 2 to 4 times daily Adults: 440–880 mcg twice daily 1 mg/kg to 2 mg/kg daily
Administration Instructions Mix 1 respule with 0.5 mg with 5 g (5 packets) of sucralose (Splenda) to make ∼ 1.5 and 2.5 teaspoons of a viscous solution. Do not eat or drink for 30 minutes after administration. Use the metered dose inhaler without a spacer, swallow the medicine, and do not eat or drink for 30 minutes after administration. Take oral tablet or liquid daily
Efficacy 72%–80%33,34 50%–94%31,32 94%32
 

Sidebar 1.

Typical Eosinophilic Esophagitis Symptoms in Children

  • Poor weight gain
  • Fussiness
  • Slow eater /sipper
  • Inability to swallow solid foods
  • Pocketing food
  • Nausea
  • Vomiting
  • Failure to thrive
  • Heartburn
  • Regurgitation
  • Abdominal Pain
  • Avoidance of foods
  • Chest pain
  • Food impaction

Sidebar 2.

Diseases Associated with Eosinophilic Esophagitis

  • Gastroesophageal reflux disease
  • Eosinophilic esophagitis
  • Eosinophilic gastrointestinal diseases
  • Celiac disease
  • Crohn’s disease
  • Infection
  • Hypereosinophilic syndrome
  • Achalasia
  • Drug hypersensitivity
  • Vasculitis
  • Pemphigoid vegetans
  • Connective tissue disease
  • Graft-versus-host disease

Sidebar 3.

Diagnostic Criteria for the Diagnosis of Eosinophilic Esophagitis

  • Clinical symptoms of esophageal dysfunction
  • Peak count of >15 eosinophils in 1 high-power field
  • Lack of responsiveness to high-dose proton pump inhibition (up to 2 mg/kg/day) or normal pH monitoring of the distal esophagus
 
Authors

Carla M. Davis, MD, is Assistant Professor of Pediatrics, Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital.

Address correspondence to: Carla M. Davis, MD, is Assistant Professor of Pediatrics, Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, 1102 Bates Avenue, MC 330.01, Houston, TX 77030; email: cmdavis@texaschildrens.org.

Disclosure: The author has no relevant financial relationships to disclose.

10.3928/00904481-20130619-10

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