Emerging Management Concepts for Eosinophilic Esophagitis in Children

Authors and Disclosures

Ralf G Heine,*,^†,‡,§ Mark Nethercote,*,^‡ Jeremy Rosenbaum* and Katrina J Allen*,^†,‡,§

*Department of Gastroenterology and Clinical Nutrition and Royal Children's Hospital, and ^†Department of Allergy and Immunology, Royal Children's Hospital, and ^‡Murdoch Childrens Research Institute, and ^§Department of Paediatrics, The University of Melbourne, Melbourne, Australia

Correspondence
Associate Professor Katrina J Allen, Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Melbourne, Parkville, Vic. 3052, Australia. Email: katie.allen@org.au

Sidebar 1

Case Study 1 A 12-month-old girl (birthweight 3.25 kg) was referred with a history of unsettled behavior, feeding difficulties and failure to thrive. She was breast-fed until 8 months of age, and solids were introduced from 5 months. She initially presented with minor regurgitation after feeds but no overt vomiting. An empirical trial of ranitidine at 2 months of age for suspected GERD did not improve her symptoms. She also had persistent low-grade diarrhea with four to six loose bowel motions daily, but without visible blood. From 4 months of age, her growth velocity slowed significantly and supplemental soy formula was started by her parents. At the time of first review by a pediatric allergist at 12 months, she was generally well but had ongoing diarrhea. Her weight had fallen to well below the 3^rd weight-for-age percentile. On examination, she had a distended abdomen with significant loss of subcutaneous tissue. Bloods tests revealed a mild microcytic anemia. The tissue transglutaminase IgA antibody was negative (normal total serum IgA) while receiving wheat in her diet. SPTs were negative to cow's milk 0 mm, egg 0 mm, soy 0 mm and wheat 0 mm. The APT was positive for cow's milk and soy, and negative for egg and wheat. A gastroscopy at the age of 15 months revealed longitudinal furrowing and white plaques in the esophagus; stomach and duodenum were macroscopically normal. Histological examination of esophageal biopsies was in keeping with a diagnosis of EoE, with 42 eosinophils/HPF in the upper, 38/HPF in the middle and 28/HPF in the lower esophagus. Basal cell proliferation occupying more than 50% of the epithelial thickness was demonstrated. Biopsies from stomach and duodenum were normal, thus excluding celiac disease. A diagnosis of likely non-IgE-mediated cow's milk allergy and EoE was made and the patient treated with an amino AAF. A cow's milk and soy protein-free diet was implemented with the help of a dietician. Within 2–4 weeks of commencing AAF, her irritability and aversive feeding behaviors settled, the diarrhea resolved, and her weight gain gradually improved over the following months. The cause of the diarrhea was not clear in this case but may have been related to an underlying food allergy. Duodenal biopsies were normal, which ruled out celiac disease or other enteropathy. A repeat gastroscopy at 26 months of age found no abnormalities in esophagus, stomach and duodenum (esophageal mucosal eosinophil count 0/HPF). Following the gastroscopy, cow's milk was reintroduced and a further gastroscopy performed while she remained on a soy-free diet. At that stage, the patient had regained weight to the 3^rd weight-for-age percentile. A subsequent gastroscopy at 3 years after introduction of soy was also normal, including normal esophageal histology. At age 5 years the patient had no further clinical evidence of EoE while eating an unrestricted diet.

Learning Points: EoE in infancy may be part of the extended spectrum of cow's milk protein allergy. Infants with EoE typically present with unsettled behavior, feeding aversion, frequent regurgitation and/or poor weight gain. The differential diagnosis of gastrointestinal cow's milk allergy in infancy includes celiac disease, which in this case was excluded on duodenal histology (while on a wheat-containing diet). In infancy, treatment of EoE commonly relies on an amino acid-based formula while strictly avoiding cow's milk and soy protein. The prognosis in this age group may be better than for older children and adults as infantile EoE can resolve after the development of immunological tolerance to cow's milk protein.

Sidebar 2

Case Study 2 An 8-year-old boy presented with a 12-month history of recurrent abdominal pain, odynophagia, lethargy and occasional regurgitation/vomiting. There was no history of food bolus impaction, change in bowel habits or loss of weight. His mother had a history of allergic rhinitis, and his father had been recently diagnosed as suffering from celiac disease. A gastroscopy was performed and revealed evidence of longitudinal furrowing of the esophageal mucosa. Esophageal histology showed increased intraepithelial eosinophils (52/HPF in the upper, 46/HPF in the middle and 62/HPF in the lower esophagus) and basal cell proliferation of greater than 50% of the total epithelial thickness. Biopsies from stomach and duodenum were normal. Initial management by the treating gastroenterologist involved empirical dietary cow's milk elimination. On review 3 months later, the patient reported a significant improvement in abdominal pain and reflux symptoms. A follow-up gastroscopy was performed 12 months later. Despite symptomatic improvement, esophageal biopsies revealed persistent eosinophilic infiltration with 92 eosinophils/HPF in the upper and 145/HPF in the lower esophagus. The patient was subsequently reviewed by a pediatric allergist. Skin prick tests were negative to all food allergens tested, i.e. cow's milk, soy, egg white, wheat, peanut, several tree nuts, cod fish, shrimp, beef, chicken, lamb, pork, oats, corn and rice. House dust mite tested positive (8 mm), and rye grass was borderline positive (2 mm). A broad-based elimination diet (cow's milk, soy, eggs, nuts, wheat, fish, shellfish, rye, barley, oats, chicken, lamb and beef) was instituted after dietetics review and maintained for 8 weeks. A calcium supplement of 1000 mg daily was prescribed. A follow-up gastroscopy demonstrated histological remission of EoE (four eosinophils/HPF in the upper, and three eosinophils/HPF in the middle and lower esophagus). Soy and oats were then introduced, and a repeat gastroscopy 3 months later revealed no histological relapse. Liberation of the diet to egg, tuna, and other fish then followed, with a fourth gastroscopy at 10 years of age demonstrating ongoing histological remission. Nuts and meats were then introduced, with a further normal endoscopy 6 months later. At 11 years of age the patient was only avoiding cow's milk and wheat. A repeat gastroscopy after re-introduction of cow's milk demonstrated a recurrence of esophageal inflammation (45 eosinophils/HPF in upper, 68/HPF in middle and 34/HPF in the lower esophagus). Cow's milk was subsequently eliminated, and normal histology demonstrated on a repeat gastroscopy 6 months later. The dietary trial for the reintroduction of wheat is pending. The patient was instructed to avoid cow's milk in the long-term.

Learning Points: Despite negative skin prick tests, the patient responded to dietary restriction of food allergens. While the single elimination of cow's milk failed initially, the patient responded to a more broad-based elimination diet. Over the following 3 years, most avoided food allergens could step-wise be reintroduced, followed by a normal gastroscopy. A relapse of EoE was demonstrated after the reintroduction of cow's milk, confirming ongoing cow's milk sensitivity. Subsequent elimination of cow's milk was followed by remission of EoE. This case illustrates the need for gradual liberalization of diet after formal elimination periods and step-wise food challenges, followed by gastroscopy and biopsy. This process is complex, resource consuming and sometimes not conclusive. Confounding factors include the unrecognized aggravation of EoE during the pollen season or use of inhaled steroids for treatment of asthma. Non-invasive markers to assess the effects of oral food challenges on EoE are urgently needed.

Sidebar 3

Case Study 3 A 12-year-old boy presented to the emergency department with an acute food bolus obstruction after eating chicken. In the weeks leading up to the episode he had experienced occasional episodes of retrosternal pain, acid regurgitation and food sticking during meals. On the morning of the bolus obstruction he had been moving hay bales. He has a past history of asthma in early childhood, which has resolved. He suffers from moderate seasonal allergic rhinitis in Spring. He has no known food allergies. On presentation, he complained of retrosternal pain and is unable to swallow liquids or his own saliva. Attempts to free the bolus by sips of clear fluids were unsuccessful. After an observation period of 3 h the patient underwent a gastroscopy for endoscopic disimpaction. A chicken piece was found wedged in the upper esophagus and removed without difficulty. The mucosa of the entire esophagus appeared erythematous and thickened, with longitudinal furrowing. No stricture was demonstrated. Biopsies were taken from the upper and lower esophagus. Histological examination revealed active EoE with up to 125 eosinophils/HPF in the upper and 68/HPF in the lower esophageal biopsies. The patient was treated with a short course of prednisolone (1 mg/kg once daily) for 3 days and then commenced on omeprazole 20 mg daily, as well as swallowed aerosolized fluticasone, 500 mcg (two puffs) twice daily for 2 weeks. Instructions were given to take the medications after meals and to avoid eating and drinking for 1 h, as well as rinsing out his mouth after the application. The patient was then referred for investigation of possible underlying food or inhalant allergies. SPTs were negative (0 mm) to all food allergens tested. He was moderately sensitized to house dust mite (5 mm), and highly sensitized to rye grass (22 mm) and Bermuda grass (7 mm). The patient remained on ongoing treatment with omeprazole and intermittent short courses of swallowed fluticasone aerosol during symptomatic periods. A repeat gastroscopy 6 months later revealed a macroscopically normal esophageal appearance. However, on histological examination he had mildly active EoE with 21 eosinophils/HPF in the lower, and 14/HPF in the upper esophagus.

Learning Points: Inhalant sensitization is common in adolescents and young adults with EoE. These patients often have a clinical history of asthma or allergic rhinoconjunctivitis. Food allergies are less common in this age group. Dysphagia and food bolus obstruction are the classic clinical presentations in this age group and reflect an eosinophil-induced esophageal dysmotility disorder. In the present case, exposure to large amounts of inhaled or swallowed grass pollen while moving hay bales may have triggered acute eosinophilic inflammation and food bolus obstruction. After endoscopic disimpaction treatment usually relies on topical corticosteroids rather than dietary interventions. Case reports have suggested a seasonal variation of EoE, particularly in older children and adolescents. Although there is anecdotal evidence that immunotherapy to grasses may ameliorate the course of EoE in grass pollen sensitized individuals, this has never been formally studied.