Eosinophilic Esophagitis in Children

From The Child's Doctor, Fall 2005

Amir F. Kagalwalla, MD

Attending physician, Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago; Associate professor of Pediatrics, Northwestern University Feinberg School of Medicine

Disclosure: Dr. Kagalwalla has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.

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Summary

Eosinophilic esophagitis (EE) is a newly recognized clinicopathological disorder. It is the fastest rising diagnosis in pediatric gastroenterology practice at Children’s Memorial Hospital. This disorder is frequently misdiagnosed and treated as severe gastroesophageal reflux disease (GERD). Clinicians should suspect EE when GERD symptoms fail to respond to aggressive acid suppression treatment. Symptoms dramatically improve, however, with elimination diet or with corticosteroid treatment. Prompt referral by primary care physician is essential to establishing the correct diagnosis and instituting appropriate treatment expediently to relieve symptoms and prevent complications.

EE is a chronic inflammatory disorder that is characterized by dense infiltration of the esophageal epithelium. This condition is categorized as a food hypersensitivity disorder. Generally, food hypersensitivity disorders are subdivided into:

• Type 1 immediate or immunoglobulin E (IgE)-mediated disorders diagnosed with radioallergosorbent (RAST) test or skin prick tests

• Type 4 delayed or cell-mediated disorders identified with skin patch test

EE may be classified either as IgE-mediated or cell-mediated condition, or both, depending on the operative mechanism.

The dramatic rise in the number of children diagnosed with this condition, all over the country, is partly explained by increased awareness and partly by a true increase in prevalence. At Children’s Memorial the number of children newly diagnosed with EE has progressively risen from only 1 case in 2000 to more than 50 in 2004.

Etiology

Support for an allergic etiology of EE is provided by:

• Improvement of clinical symptoms and histology with elimination of the offending food allergen(s) or with corticosteroid treatment

• Associated atopic manifestations, such as reactive airway disease, allergic rhinitis and eczema, which are present in 50% of children with this disorder

• Family history of atopic disease obtained in up to 45% of children with EE

• Environmental allergies suggested by animal experimental data

Genetic predisposition is supported by findings that 10% of patients have an immediate family member affected with EE.

Clinical characteristics

This disorder is seen in all races, with a male to female ratio of 4:1. Two peaks at 1 to 4 years of age and 10 to 14 years of age have been identified. In addition to other atopic conditions, history of food allergies and peripheral eosinophilia is often present.

In younger children, symptoms are similar to those seen with GERD and include vomiting, dysphagia, abdominal pain, chest pain, and failure to thrive. These symptoms do not completely resolve with acid suppression treatment and these patients are referred to gastroenterologist for refractory GERD or to a surgeon for fundoplication. We have also encountered toddlers with EE presenting with significant food aversion as the primary manifestation. In adolescents, intermittent episodes of distress causing food impaction that leads to emergency room visits to have food dislodged is not an uncommon presentation.

Diagnosis

Endoscopy images of the normal esophagus and a case with GERD (Figures 1, 2) differ significantly from the several distinctive appearances of the esophagus that suggest EE (Figures 3-6):

• Multiple white plaques in the esophagus

• Furrowing: longitudinal linear creases or folds along the long axis of the esophagus

• Granular esophagus with multiple tiny nodules

• Trachealization or ringed esophagus, which is when the esophagus has the appearance of the trachea

• Tubular esophagus with a long mid-esophageal stricture

FIGURE 1: Normal esophagus

FIGURE 2: GERD

FIGURE 3: White plaques

FIGURE 4: Furrowing

FIGURE 5: Granular

FIGURE 6: Ringed

Ringed or tubular esophagus is commonly seen in adolescents and adults with EE. By contrast in GERD, erythema, erosions or ulcerations are seen.

Endoscopy findings are not diagnostic of EE, however. The gold standard for the diagnosis of EE is the dense infiltration of eosinophils, with at least 20 eosinophils per high power field (hpf ) in the esophageal biopsies. In GERD, eosinophilic inflammation is also present, but the eosinophil count rarely exceeds 7 to 10 eosinophils per hpf. Other findings, such as basal cell hyperplasia and increased papillary length are seen in both EE and GERD, but eosinophilic abscesses (4 or more eosinophils in superficial clusters) are typically seen only in EE and distinguish EE from GERD. The differences between EE and GERD are summarized in Table 1.

Complications

Since it is now only 10 years since the description of the first pediatric case series of EE, the natural history of this disorder in children is unknown and remains to be defined. Since 4% to 6% of children with EE present with stricture of the esophagus, it is felt to be a complication of persistent esophageal inflammation. Although links between EE and dysplasia have not been described, concerns about this possibility remain, since long term follow-up data is currently unavailable.

Investigations

A 24-hour pH probe study is helpful to exclude GERD, particularly in the younger children with reflux-type symptoms. A number of studies have utilized results of positive RAST, skin prick tests, and skin patch tests to eliminate the specific incriminating food allergen(s) from the diet. Elimination of food antigen based on the results of RAST and skin prick tests, however, has failed to improve symptoms, suggesting that the food allergy is not primarily IgE-mediated. A recent study of food elimination based on positive response to a combination of skin prick and skin patch tests reported significant clinical and histological improvement in all EE patients. The mechanism responsible for causing allergen induced esophageal inflammation appears to be cell-mediated hypersensitivity from this study.

Management

Treatment of EE is challenging to the physician and difficult for the patient and family. The goals of treatment include resolution of symptoms and of the esophageal inflammation, and prevention of complications, such as strictures.

The most commonly utilized dietary approach eliminates all intact protein by administering an amino acid-based formula. This approach is highly effective, although compliance difficulties related to poor taste are overcome, in a majority of patients, with either nasogastric or gastrostomy tube feeding. Furthermore, these elemental formulas are quite expensive, and the prospect of eliminating all solid foods from the child’s diet is distressing to families.

At Children’s Memorial, we have developed a new dietary approach that eliminates the 6 most common foods responsible for food allergies. These include milk protein, soy, wheat, egg, peanut (and all tree nuts), and all sea food. We have recently demonstrated that both symptom resolution and mucosal healing with elimination diet are comparable to that with amino acid-based elemental diet. The evident advantages include ability to eat solid foods, lack of tube feeding, and lower cost. The limitation of this approach is that it requires participation of an experienced dietitian to counsel families on proper diet implementation and prevention of repeated contamination due to the ubiquitous use of these food proteins in processed foods. Once the esophageal inflammation resolves, foods are re-introduced singly every 6 weeks until the offending food allergens are identified and excluded permanently. (Figures 7, 8 show the change in eosinophilic infiltration before and after the elimination diet.)

FIGURE 7: Pre-elimination diet biopsy

FIGURE 8: Post-elimination diet biopsy

Biopsy images courtesy of Hector Melin-Aldano, MD, Pathology

Corticosteroids, swallowed or systemic, are also effective, but both symptoms and inflammation recur once treatment is discontinued. Since long term steroid use is associated with potential side effects, including candidiasis and suppressed linear growth, and because steroids are only palliative, at Children’s Memorial we prefer the dietary approach, reserving corticosteroids for cases that are resistant to elimination of food allergens.

Resources for families of children with EE

For EE information and support resources, families can be referred to the American Partnership for Eosinophilic Disorders (www.apfed.org) and the Food Allergy Network (www.foodallergy.org).

Also, the Food Allergen and Consumer Protection Act, which goes into effect January 2006, will require manufacturers of all foods, flavorings and spices to identify on the label 8 food antigens – milk protein, egg, soy, peanut, tree nut, wheat, seafood, and shell fish. This law will make it extremely easy for patients with EE to know whether these allergens are present in products and avoid the restricted food antigens.

Summary

A high index of suspicion of EE is necessary to identify children with refractory GERD symptoms resistant to acid suppression treatment, male toddlers with food aversion, or adolescents presenting with food impaction. These children should be referred to pediatric gastroenterologist for endoscopy and esophageal biopsies. History of food allergies and atopic disease, such as asthma, allergic rhinitis, and eczema, as well as unexplained peripheral eosinophilia, are additional risk factors that should heighten suspicion of EE. GERD is the main differential diagnostic consideration and should be excluded. Treatment is challenging, and the dietary elimination/ reintroduction approach is preferred.

FOR FURTHER READING

[1.] Fox VL, Nurko S, Furuta GT. Eosinophilic esophagitis: It’s not just kid’s stuff. Gastrointestinal Endos 2002;56:260-270.

[2.] Orenstein SR, Shalaby TM, Di Lorenzo C, et al. The spectrum of pediatric eosinophilic esophagitis beyond infancy: A clinical series of 30 children. Am J Gastro 2000;95:1422-1430.

[3.] Markowitz JE, Liacouras CA. Eosinophilic esophagitis. Gastroenterol Clin North Am 2003;32:949-966.

[4.] Kumar R, Sentongo T, Nelson SP, et al. Eosinophilic esophagitis in children: A review. Clin Applied Immunol Rev 2003;4:173-188.

[5.] Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113:805-819.

[6.] Faubion WA, Perrault J, Burgart LJ, et al. Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr 1998;27:90-93.

[7.] Liacouras CA, Wenner WJ, Brown K, Ruchelli E. Primary eosinophilic esophagitis in children: Successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998;26:380-385.

[8.] Tietelbaum JE, Fox VL, Twarog FJ, et al. Eosinophilic esophagitis in children: Immunopathological analysis and response to fluticasone propionate. Gastroenterology 2002;122:1216-1225.

[9.] Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: Improvement with amino acid-based formula. Gastroenterology 1995;109:1503-1512.

[10.] Markowitz JE, Spergel JM, Ruchelli E, Liacouras CA. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol 2003;98:777-782.

[11.] Noel RJ, Putnam PE, Collins MH, et al. Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis. Clin Gastroenterol Hep 2004;2:568-575.

[12.] Spergel JM, Beausolell JL, Mascarenhas M, Liacouras CA. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol 2002;109:363-368.

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