Treating eosinophilic esophagitis in children

Eosinophilic esophagitis (EE) is an emerging disease in children and adults. Despite the publication of consensus guidelines, this disease is often misdiagnosed as gastroesophageal reflux, diagnosed late, or may go undiagnosed altogether. The objective of this review is to familiarize pediatricians with the presenting signs and symptoms of EE and to review current management strategies.

Background

Eosinophilic esophagitis was first described in 1995 in a group of 10 children presenting with long-term gastrointestinal (GI) symptoms that failed to improve with antireflux therapies but that ultimately responded to an elemental diet.¹ In 2007, the first set of

consensus guidelines for the diagnosis and treatment of EE was published by a multidisciplinary task force.² The consensus recommendations were updated in 2011 to reflect advances in the understanding of disease epidemiology, pathophysiology, and treatment. The definition of EE was altered to include the concept of “a chronic, immune/antigen-mediated” condition.³

According to current consensus guidelines, EE is a clinicopathologic diagnosis defined by upper GI symptoms suggestive of esophageal dysfunction; defined histopathology with eosinophil-predominant inflammation; lack of response to acid suppression with high-dose proton-pump inhibitor (PPI) therapy for 6 to 8 weeks; and exclusion of other causes of esophageal eosinophilia. Esophageal biopsy must demonstrate at least 15 eosinophils/high-power field (eos/hpf [x400]) in at least 1 area and normal mucosa in the stomach and duodenum (Table 1).³

Pathophysiology

Eosinophilic esophagitis is hypothesized to result from a T-helper (Th)2-mediated inflammatory response to food and/or environmental allergens.⁴ The Th2 cytokines interleukin-4, interleukin-5, and interleukin-13 have been implicated in disease pathogenesis as has eotaxin-3, a chemokine that attracts eosinophils to sites of inflammation. Chronic esophageal inflammation results in eventual fibrotic changes referred to as esophageal remodeling.⁵

Epidemiology

Eosinophilic esophagitis has been described in patients ranging in age from 1 year to 98 years.⁶ Three-quarters of all cases are seen in men.² Although more common in Caucasians, EE has also been described in all ethnicities and on 6 continents.⁶ Familial cases of EE have been described with 7% of patients reporting a positive family history. Most likely, there is a genetic susceptibility predisposing individuals to EE.² Current incidence rates of pediatric EE are 10 per 100,000 children per year, with a prevalence rate of 43 per 100,000. Increasing prevalence rates have been reported in the past 2 decades.⁷ In the past, EE was probably underdiagnosed or misdiagnosed as gastroesophageal reflux disease (GERD). Recent heightened awareness of this disorder may also account for observed increased prevalence rates.⁶

Clinical presentation

Young children often present with feeding refusal or failure to thrive. Recurrent vomiting and abdominal pain may occur in school-aged children. Older children and adolescents often present with dysphagia, choking, and food impaction. A detailed dietary history may reveal chewing and swallowing abnormalities, including prolonged mealtimes, compensatory mechanisms (cutting food in small pieces or requiring liquids to swallow solid foods), or avoidance of specific foods such as meat.³ Seasonal variation of symptoms may correlate with aeroallergen exposure. Many patients lack findings on physical examination and have normal growth parameters, which may lead to a delay in diagnosis.⁶

Allergic disorders are seen in 50% to 80% of patients with EE.² Asthma occurs in 14% to 70%, allergic rhinitis in 40% to 75%, and immunoglobulin E (IgE)-mediated food allergies are reported in 15% to 43% of children.³

Differential diagnosis

Other disorders that must be excluded from EE include GERD, infection, autoimmune disease, inflammatory bowel disease, and other systemic/GI processes. Differentiating EE from GERD may be difficult because both entities may present with similar symptoms (dysphagia, odynophagia, heartburn, chest pain, feeding disturbances), as well as esophageal eosinophilia. The degree of esophageal eosinophilia, however, is generally milder in GERD⁷ because GERD more typically involves the distal esophagus, whereas EE occurs more diffusely throughout the esophagus. In addition, GERD may be excluded by lack of response to acid suppression (6–8 week course high-dose PPI), or by demonstration of normal pH monitoring study of the distal esophagus.² It is possible that EE and GERD may coexist. Esophageal inflammation in EE may enhance esophageal sensitivity to physiologic acid exposure, causing secondary GERD, or alternatively, GERD may develop secondary to esophageal dysmotility caused by EE. Other causes of esophageal eosinophilia include eosinophilic gastroenteritis, hypereosinophilic syndrome, infection, achalasia, drug hypersensitivity, Crohn disease, celiac disease, autoimmune disease, and PPI-responsive esophageal eosinophilia (PPI-REE),⁴ in which patients present with symptoms similar to those of EE and display moderate esophageal eosinophilia, but respond to PPI therapy.⁸

Endoscopic findings

Esophageal biopsy is required for diagnosis of EE. Esophageal abnormalities are frequently visualized on endoscopy, although the esophageal mucosa may appear normal in up to a third of patients.³ Many of the endoscopic findings are nonspecific and include a granular or corrugated appearance of the mucosa, or loss of vascular markings.² More highly suggestive findings include a ring-like appearance of the esophagus, vertical linear furrows, or scattered areas of white papular exudate that contain numerous eosinophils (Figure). This exudate may be mistaken for Candida esophagitis and can occur anywhere within the esophagus. Strictures may be present as can a diffuse narrowing of the esophagus known as small-caliber esophagus.

IMAGE CREDIT / AUTHOR SUPPLIED

Histopathology

Diagnosis of EE requires the documentation of esophageal eosinophilia. The peak eosinophil count/hpf is recorded from histologic examination of hematoxylin-eosin-stained esophageal tissue sections at 400x magnification. Multiple biopsy specimens from the proximal and distal esophagus should be obtained even if the mucosa appears normal, as eosinophilic inflammation may be patchy.² Ongoing inflammation may result in lamina propria fibrosis.³ In children, biopsy of the gastric antrum and duodenum is necessary to exclude other GI disorders.

Laboratory evaluation

An estimated 50% to 80% of children with EE are atopic, and have concurrent atopic dermatitis, asthma, and/or allergic rhinitis.² Allergy evaluation should be undertaken in all patients with EE to determine relevant aeroallergens and food allergens. Laboratory evaluation may consist of complete blood count with differential to determine the presence of peripheral blood eosinophilia (absolute eosinophil count >300-350/mm³), which is seen in 40% to 50% of patients. Serum IgE may be elevated (>114 kU/L) but may reflect the presence of other allergic diatheses such as atopic dermatitis.⁶ Prick puncture skin tests (PST) or serum IgE tests may be helpful in determining the presence of specific IgE antibodies to environmental or food allergens.² Many patients will have positive PST to more than 1 food. The most common PST-positive foods in EE include milk, egg, soy, peanut, chicken, wheat, beef, peas, corn, potato, and rice.⁹ Milk is the most common food allergen associated with EE, followed by wheat and egg, but there is a high incidence of false-negative PST to milk.⁶ Atopy patch tests (APTs) to foods have also been used to evaluate delayed non-IgE-mediated food reactions in EE, but these tests are not standardized.¹⁰ The most common APT-positive foods in EE include corn, soy, wheat, milk, rice, chicken, beef, potato, egg, and peas.⁹

Radiograph studies such as a barium swallow should be considered prior to endoscopy in patients with EE presenting with dysphagia to alert the endoscopist to potential structural abnormalities such as strictures or small-caliber esophagus.² Esophageal manometry may be required to examine dysmotility if suspected clinically.

Treatment

Objectives of EE therapy include improvement in histology and quality of life, reduction in clinical symptoms, and prevention of complications such as food impaction or long-term sequelae such as strictures or small-caliber esophagus. Current treatment modalities include dietary modification and pharmacotherapy.

Dietary management. According to current consensus guidelines, dietary modification should be considered for all children and some adults with EE because food allergens are strongly implicated in disease pathogenesis.³ The 3 dietary strategies used include elemental diet administration, empiric dietary elimination, and targeted food elimination (Table 2).²

Use of an elemental diet consisting of an amino acid-based formula remains the most-effective and accepted dietary intervention for EE.^1,9 These formulations are unpalatable, however, and compliance may be poor in children and adults. Formula administration may require nasogastric or gastrostomy feedings that may negatively impact quality of life.

A second dietary strategy used in the treatment of EE is empiric dietary elimination of allergenic foods.¹¹ A 2006 study retrospectively compared the efficacy of empiric dietary elimination versus elemental formula administration in children with EE.¹² Six allergenic foods (milk, soy, egg, wheat, peanut/tree nuts, fish/shellfish) were removed from the diet of these children for 6 weeks. Histopathologic improvement occurred in 74% of those receiving the 6-food elimination diet (SFED), compared with 88% of those receiving the elemental diet. Currently, many clinicians will recommend initiation of the SFED, followed by stepwise reintroduction of single foods into the diet, to identify specific food triggers of EE. Strict food avoidance may be difficult, however, and consultation with a dietitian may be needed to ensure that a nutritious diet is provided. There is also a potential risk of IgE-mediated reactions on food reintroduction.⁸

The third dietary treatment strategy used in EE is targeted food elimination, based on allergy testing. Patients undergo PST and/or APT to identify food triggers and eliminate them from the diet. Eventual food reintroduction is then utilized to identify causative foods. Investigators reported histologic resolution of EE in more than 75% of children after removal of food antigens identified by PST and APT.⁹

Other researchers retrospectively compared use of an elemental diet, the SFED, and targeted food elimination, based on PST and APT, in pediatric EE treatment.¹⁰ Histologic remission was observed in 96% of patients receiving an elemental diet, compared with 81% remission rates in SFED recipients and 65% in targeted diet recipients. The researchers concluded that the low negative predictive values of PST did not support their use in dietary planning.

Pharmacotherapy. Pharmacotherapy of EE usually consists of PPIs and topical swallowed corticosteroids (Table 3).^2,3 Proton-pump inhibitors are used for acid suppression, although EE is resistant to PPI therapy. Oral corticosteroids are effective, but prolonged use is associated with systemic adverse effects. Systemic corticosteroids are reserved for severe cases of EE in which patients require hospital admission for severe dysphagia or weight loss.³

Topical delivery of corticosteroids directly to the esophageal mucosa was first proposed by researchers in 1998.¹³ This involved swallowing, rather than inhaling, aerosolized corticosteroid preparations used for asthma treatment. Patients were advised to spray the medication directly into the mouth, swallow without rinsing, and to avoid intake of food or drink for at least 30 minutes afterward. Topical swallowed corticosteroids are now considered first-line agents for EE, although these drugs are not FDA approved for this use and there are few randomized, controlled trials of their efficacy.

Use of topical swallowed corticosteroids is preferred over oral corticosteroids because adverse effects are lessened and medications are delivered directly to the inflamed esophageal mucosa. Reduction in clinical symptoms and decreases in esophageal eosinophilia are seen. Topical corticosteroids are safe and effective, but only for as long as the duration of treatment, which is generally 6 to 8 weeks. Few adverse effects are seen but treatment may be complicated by dysphonia, oral thrush (in 20% of children), herpes, and Candida esophagitis. Other adverse effects of long-term topical corticosteroid use include reduction in growth velocity, cataracts, and adrenal suppression.^2,3 There are no studies of maintenance therapy in pediatric EE.

Three corticosteroid preparations have been studied in EE therapy: fluticasone propionate, budesonide, and ciclesonide. In 2002, investigators treated a small group of children with swallowed fluticasone propionate and found a significant reduction in esophageal eosinophilia and clinical symptoms after a 2-month course of treatment.¹⁴ Topical corticosteroid therapy was more effective than dietary restriction of food allergens identified by PST or radioallergosorbent test.² A subsequent double-blind, placebo-controlled trial of swallowed fluticasone propionate for pediatric EE found that half of children treated with swallowed fluticasone achieved histologic remission compared with 9% of placebo recipients.¹⁵

To increase palatability, improve coating of the esophagus, and overcome swallowing difficulties that may occur in young or developmentally delayed children, researchers formulated a slurry of oral viscous budesonide.¹⁶ Budesonide, another asthma medication usually administered via nebulizer, was mixed with sucralose to form a viscous liquid to be administered once daily. In 2010, a randomized, double-blind, placebo-controlled trial of oral viscous budesonide demonstrated histologic remission and clinical improvement in the majority of pediatric EE patients studied.⁷

A third topical corticosteroid preparation, ciclesonide, was recently used successfully for treatment in a small group of children with EE that had proved refractory to topical fluticasone propionate and dietary modification.¹⁷

Medications that have no proven utility in treating EE include leukotriene receptor antagonists, mast cell stabilizers, and immunosuppressive medications.^3,6 Biologic agents such as anti-interleukin-5 (mepolizumab and reslizumab) have been studied but clinical improvement did not accompany histologic improvement.⁶ Omalizumab and anti-tumor necrosis factor (TNF) agents have no efficacy in EE treatment.³ Therapies in development for EE include antagonists to interleukin-13, eotaxin-3, and CRTH2, a prostaglandin D2 receptor.¹⁸

Other treatment. Esophageal dilation has been recommended in cases of dysphagia caused by esophageal narrowing or strictures. This may be complicated, however, by chest pain, esophageal tears, and perforation.^3,6,8

Natural history

Although there are few longitudinal studies reporting outcomes, EE appears to be a chronic disease with long-term persistence of esophageal inflammation from childhood into adulthood.^10,19 Disease evolution is related to esophageal remodeling.⁶

Children with EE should be followed regularly by a pediatric gastroenterologist and/or allergist. Periodic endoscopy is usually recommended to monitor disease status because noninvasive biomarkers have not been identified. Clinical and histologic response to therapy and growth parameters should be closely followed.

Conclusion

Eosinophilic esophagitis is an increasingly recognized condition in children and adults that may present with symptoms suggestive of GERD that do not respond to acid suppression. Isolated esophageal eosinophilia is seen on biopsy. Treatment focuses on dietary modification and topical corticosteroids. Complications include strictures and small-caliber esophagus, leading to dysphagia and/or food impaction. Future studies are needed to better define the natural history of EE and to identify effective therapies for children and adults alike.

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DR SCHUVAL is chief, Division of Allergy/Immunology, and associate professor, clinical pediatrics, Stony Brook Children’s Hospital, Stony Brook, New York. DR GOLD is attending physician and associate professor, clinical pediatrics, New York College of Osteopathic Medicine, Old Westbury. The authors have nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.