Eosinophilic Esophagitis

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1 pediatric gastroenterology Board Review Manual Statement of Editorial Purpose The Hospital Physician Pediatric Gastroenterology Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in pediatric gastroenterology. Each manual reviews a topic essential to the current practice of pediatric gastroenterology. PUBLISHING STAFF PRESIDENT, Group PUBLISHER Bruce M. White editorial director Debra Dreger SENIOR EDITOR Robert Litchkofski Associate EDITOR Tricia Faggioli EDITORial assistant Farrawh Charles executive vice president Barbara T. White executive director of operations Jean M. Gaul PRODUCTION Director Suzanne S. Banish PRODUCTION associate Kathryn K. Johnson ADVERTISING/PROJECT manager Patricia Payne Castle sales & marketing manager Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Pediatrics. Endorsed by the Association for Hospital Medical Education Eosinophilic Esophagitis Editor: Elizabeth B. Rand, MD Associate Professor of Pediatrics, University of Pennsylvania School of Medicine; Medical Director, Liver Transplant Program; Director, Fellowship Training Program, Division of Gastroenterology, Hepatology and Nutrition, The Children s Hospital of Philadelphia, Philadelphia, PA Contributor: Chris A. Liacouras, MD Professor of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pennsylvania School of Medicine; Attending Gastroenterologist, The Children s Hospital of Philadelphia, Philadelphia, PA Table of Contents Introduction Etiology Pathophysiology Clinical Presentation and Diagnosis Management Conclusion References Cover Illustration by Christine Armstrong Copyright 2007, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA ,. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of appropriate topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. Pediatric Gastroenterology Volume 1, Part 2

2 Pediatric Gastroenterology Board Review Manual Eosinophilic Esophagitis Chris A. Liacouras, MD INTRODUCTION Over the past 10 years, eosinophilic esophagitis (EoE) has become one of the most discussed diseases among pediatric gastroenterologists and allergists in the United States. EoE is a disease found in children and adults characterized by a severe, isolated eosinophilic infiltration of the esophagus that is unresponsive to acid blockade but instead responds to the removal of dietary allergens. There is historical evidence that EoE has existed for more than 25 years. 1 Prior to 1995, patients with symptoms of gastroesophageal reflux (GER) or dysphagia who had histologic evidence of esophageal eosinophils were usually diagnosed with gastroesophageal reflux disease (GERD). This approach was supported by Winter et al, 2 who showed a correlation between the presence of esophageal eosinophils and reflux esophagitis. 3 In 1995, pediatric gastroenterologists recognized that patients presenting with symptoms of GER and a large number of esophageal eosinophils instead had an alternate disorder, EoE. 4 The majority of these patients were being misdiagnosed with and improperly treated for severe GERD. EoE is an emerging worldwide disease. It has recently been documented in many European countries as well as in Australia, Brazil, and Japan. 5 8 Recent epidemiologic studies suggest a rising incidence in the United States in both children and adults, with at least 1 case occurring in every 10,000 children each year. 9 While pediatric gastroenterologists have been interested in EoE for more than 10 years, awareness among adult gastroenterologists has increased only over the past 3 years. 10 Since EoE was first recognized as a separate entity over 10 years ago, there has been an increasing number of articles in the medical literature relating to the etiology, clinical presentation, and treatment of EoE in both children and adults. This manual reviews the literature on EoE in pediatric patients, with a focus on diagnosis and management. ETIOLOGY The cause of EoE remains controversial. Proposed Hospital Physician Board Review Manual causes include food allergy, environmental allergy, aeroallergens, primary autoimmune disease (ie, a subset of eosinophilic gastroenteritis [EG]), and severe, uncontrolled acid reflux disease. However, it is important to differentiate between the pathologic description of esophageal eosinophilia and the disease process of EoE. Esophageal eosinophilia can occur as a response to any gastrointestinal inflammatory condition, including parasitic disease, GER, autoimmune disease, and inflammatory bowel disease. In contrast, EoE is a unique entity and should be considered whenever a severe, esophageal eosinophilia exists despite the use of acid blockade with proton pump inhibitors (PPIs). 11,12 Since 1982, esophageal acid exposure has been linked to the presence of esophageal eosinophils (usually < 5 eosinophils per high-power field [HPF] [400 ]). 2,3 Rarely, large numbers of esophageal eosinophils have been associated with prolonged acid exposure. 13 In general, however, esophageal eosinophilia caused by GER resolves with the use of PPIs. Several studies over the past 10 years have revealed a persistent esophageal eosinophilia despite aggressive acid blockade or the performance of a Nissen fundoplication. 14 These reports suggest that acid exposure is not the only cause of esophageal eosinophilia. Although aeroallergens have been implicated as a cause of EoE in mouse models and anecdotally in some case reports, there are no clinical studies to show that they play a role in EoE in humans. 15 Some investigators have proposed a nonallergic cause for EoE, 16 suggesting that an underlying autoimmune abnormality may be the basis for the disease. However, no studies or clinical evidence suggests that EoE is a primary autoimmune disorder. In addition, most investigators consider EoE a separate entity from EG, 17 given the lack of consistent resolution of EG with an elimination or elemental diet compared to the excellent response of dietary treatment in patients with EoE. Most cases of EoE appear to be caused by food allergy. Two types of EoE have been proposed: an immediate IgE-mediated and a cell-mediated delayed food allergy. Although a few patients have been shown to have an immediate IgE-mediated food allergy, the preponderance of patients have a cell-mediated, delayed food allergy in Pediatric Gastroenterology Volume 1, Part 2

3 which symptoms do not develop immediately after the allergen is ingested. Instead, esophageal inflammation may take several days to develop, and it may take several more days for any symptoms to develop. Thus, it is often impossible for the patient to specifically identify which food(s) caused the problem. Additionally, because a severe esophageal eosinophilic inflammation occurs, symptoms may continue for days to weeks after the suspected food(s) are withdrawn (until the inflammation resolves). PATHOPHYSIOLOGY Eosinophils are not found in the normal esophageal squamous epithelium; instead, they migrate to the esophagus as a response to esophageal inflammation. There are 2 ways in which eosinophils may migrate to the esophagus in EoE. First, in persons who are sensitized to a specific allergen, IgE interacting with food allergens and aeroallergens may degranulate mast cells, causing the release of histamine, interleukins (IL), chemokines, eosinophilic chemotactic factor, and plateletactivating factor, all of which may attract eosinophils to the affected site. 18,19 Second, patients who have a cellmediated allergy produce chemokines in response to inflammation. Many inflammatory mediators have been linked to the regulation of eosinophil production, migration, and activation. These markers consist of but are not limited to eotaxin, IL-3, IL-4, IL-5, IL-13, and granulocyte-macrophage colony-stimulating factor. Eosinophils respond to ILs such as IL-13 and IL-5, which promote tissue inflammation and may play a role in the recruitment of eosinophils to the esophagus. In both cases, eosinophils are recruited from the bone marrow and migrate to the esophagus, where they are activated and release toxic substances. Eosinophils contain cationic proteins such as eosinophil-derived major basic protein and eosinophil peroxidase, which can damage the intestinal mucosa. In patients with chronic EoE, linear furrowing and the formation of esophageal rings may occur due to the release of histamine, which activates acetylcholine, causing a contraction of the esophageal muscularis mucosa. Narrowing of these muscle fibers deforms the mucosal layer, resulting in the formation of esophageal rings. Initially, these rings may be transient and reversible; however, it has been speculated that continuous contraction of the muscle fibers, hypertrophy and thickening of the muscle layers of the mucosa, and chronic eosinophilic infiltration may lead to permanent scar formation. Straumann et al 20 characterized the differences between populations of eosinophils normally found in the gut and eosinophils abnormally found in the esophagus by comparing the expression of proinflammatory proteins by these tissue-dwelling eosinophils in patients with EoE and controls with functional dyspepsia. 20,21 In controls, a small but significant proportion of intestinal eosinophils expressed CD25 and IL-13, suggesting activation; however, patients with EoE demonstrated strong evidence of activation of eosinophils infiltrating the esophagus and intestines with increased expression of CD-25, IL-4, and IL-13. Straumann et al concluded that tissue-dwelling eosinophils demonstrated different and distinct cytokine expression patterns in patients with EoE when compared with controls. Although various other cytokines and ILs were also identified in the esophagus, intestine, and blood in both controls and patients with EoE, none of them were specific to EoE. CLINICAL PRESENTATION AND DIAGNOSIS CASE PRESENTATION A 12-year-old boy presents to his physician s office with an intermittent history of difficulty swallowing and choking on food. Past medical history is significant for regurgitation and vomiting as an infant and young child. At that time, he was initially treated with a histamine 2 blocker, which seemed to improve his symptoms. However, he continued to have episodes of epigastric pain, nausea, and occasional vomiting. At age 10 years, his medication was changed to a PPI, which seemed to improve his symptoms somewhat. However, over the past 2 years he began to experience intermittent episodes of dysphagia. Otherwise, he has no weight loss, diarrhea, joint pain, rash, gastrointestinal bleeding, or mouth sores. He did have asthma as a child. His weight and height are at the 50th percentile, and his physical examination is normal. What are the clinical features of EoE? CLINICAL FEATURES The cause of chronic vomiting and dysphagia should always be sought (Table 1 and Table 2). GER is the most common cause of vomiting in infants and young children, but vomiting may be a prominent sign of many other disorders (Table 3). The approach to vomiting in infants is determined by the age of the baby and by the presence of worrisome symptoms, such as failure to thrive, pain, problems with feeding, or gastrointestinal bleeding. Prior to 1995, most children and adolescents who presented with dysphagia were diagnosed with either achalasia or GERD. Presently, pediatric patients Hospital Physician Board Review Manual

4 Table 1. Causes of Vomiting Gastroesophageal reflux Anatomic malformations (gastric outlet obstruction, pyloric stenosis, volvulus, malrotation, esophageal atresia, enteral duplications) Intussusception Duodenal/gastric ulcer Eosinophilic esophagitis Milk/soy allergy Celiac disease Bezoar Nonspecific food allergy Infections (viral gastroenteritis, Helicobacter pylori, parasites) Meconium ileus Inspissated milk syndrome Neurologic abnormalities (meningitis/encephalitis, intracranial injury, tumor) Metabolic disorders (phenylketonuria, galactosemia) Adrenal hyperplasia Renal disease (uremia, kidney stones, urinary tract infection) Drug reaction Feeding disorder (bulimia) Caustic ingestions Overfeeding who present with either dysphagia or a food impaction increasingly are being diagnosed with EoE. Often, clues to the presence of EoE can be determined through a careful history, physical examination, and noninvasive diagnostic testing. Clinically, EoE presents in a variety of ways, and the presentation can vary by age-group. Infants and young children commonly present with symptoms indistinguishable from those seen in GER, including vomiting, regurgitation, epigastric pain, and irritability. Older children typically present with heartburn, water brash, or dysphagia. Despite having chronic intermittent symptoms, many adolescents with EoE often are seen for the first time by a physician because they experience an esophageal food impaction. 22 Approximately 50% of affected children exhibit other allergic signs and symptoms, including bronchospasm, rhinitis, and eczema. 23,24 Patients with EoE also may have other food allergies such as oral allergy syndrome, anaphylaxis, or reactions that cause urticaria or diarrhea. Finally, these patients frequently have aeroallergen sensitization 25 and a strong family history of food allergies or other allergic disorders. Males appear to develop EoE more frequently than females. 26 Uncommon symptoms include food refusal, growth failure, hematemesis, and globus. The clinical Table 2. Causes of Dysphagia Eosinophilic esophagitis Achalasia Gastroesophageal reflux Foreign body Caustic ingestion Anatomic abnormalities (web, diverticulum, strictures) Zenker s diverticulum Esophageal spasm Neuromuscular disorders (myasthenia gravis, muscular dystrophy) Multiple sclerosis Autoimmune disease Globus hystericus features of EoE may evolve over years. Symptoms such as abdominal pain and heartburn occur regularly, while patients with vomiting or dysphagia may display these symptoms sporadically, complaining only once per month. Although the use of acid suppression medication often improves the patient s symptoms, it does not eliminate the symptoms nor change the abnormal esophageal histology. EoE also occurs in adults. Adults present with symptoms similar to those seen in children, but dysphagia occurs much more commonly and is often associated with esophageal strictures. 27 No studies have evaluated the long-term effects of untreated EoE in children. Additionally, there has been no documentation that untreated pediatric EoE leads to ongoing adult EoE; however, it has been hypothesized that the change in symptomatology from toddlers to adolescents to adults represents disease progression with ongoing fullthickness eosinophilic esophageal tissue inflammation, which may lead to the development of dysphagia and esophageal strictures. 28 How is the diagnosis of EoE made? Because patients who present with symptoms of EoE such as vomiting, regurgitation, epigastric pain, or dysphagia may have multiple underlying causes, several tests may be used to make the correct diagnosis. Unfortunately, no single test has the ability to make the correct diagnosis all of the time; therefore, it is important to know the usefulness and limitations of each test. DIAGNOSTIC TESTING Upper Gastrointestinal Series A barium-contrast upper gastrointestinal (UGI) series can be useful in identifying anatomic abnormalities Pediatric Gastroenterology Volume 1, Part 2

5 Table 3. Clues for Causes of Vomiting Suggested Cause History Fever Bilious emesis Mental retardation Nausea after meals Dysphagia Intermittent lethargy Headache/weakness Right upper quadrant abdominal pain Right/left-sided mid-abdominal pain Travel history Physical examination Heme-positive stool Visible bowel loops, borborygmi Absent bowel sounds Jaundice Unusual stool odor Tense anterior fontanelle Muscle weakness Infectious etiology Obstruction Pica/bezoar Gastroesophageal reflux/ulcer Achalasia, eosinophilic esophagitis, stricture Intussusception Central nervous system disorder Gallbladder disease Renal disease Parasite Esophagitis, gastritis, ulcer Intestinal obstruction Ileus Gallbladder/liver disease Metabolic disease Central nervous system disorder Central nervous system disorder Laboratory Elevated ttg autoantibody titer Anemia Electrolyte disturbance Elevated ALT/gamma glutamyl transpeptidase/bilirubin Elevated uric acid/bun/creatinine Elevated amylase/lipase Celiac disease Intestinal mucosal disease (Crohn s, ulcer, celiac disease) Pyloric stenosis/metabolic disorders Liver/gallbladder disease Renal disease Pancreatitis ALT = alanine aminotransferase; BUN = blood urea nitrogen; ttg = tissue transglutaminase. of EoE in adolescents and adults, particularly esophageal rings (Figure 1), strictures, or small-caliber esophagus. 29 A UGI series also is useful for evaluating other lesions of the esophagus, gastroesophageal junction, stomach, and duodenum. Examining the gastrointestinal tract with this study to the ligament of Treitz provides important information about the presence of malrotation, esophageal and duodenal webs, pyloric stenosis, esophageal strictures, hiatal hernias, duplication cysts, and large ulcers. It is important to note that the sensitivity of a UGI series for Figure 1. A barium study revealing multiple rings ( trachealization ) of the esophagus in a patient with eosinophilic esophagitis. many mucosal lesions such as EoE, reflux esophagitis, gastritis, and small ulcers is very low. This test should not be used to document GER as it can often provide both false-positive and false-negative results. 30 Esophageal ph Monitoring In the past, a 24-hour ph probe was considered to be the gold standard for the diagnosis of GER. Although ph monitoring has been shown to be less efficacious than previously thought, it is still a reasonably reliable method for determining the presence of gastric acid in the esophagus. 31 This test can usually be performed in an outpatient setting and provides physiologic readings in several phases of activity: prandial, postprandial, during exercise, and during sleep. It is sometimes useful to perform a dual gastric-esophageal ph probe in order to measure both gastric acid production and esophageal acid exposure. This is often done while the patient is on acid-blocking medication in order to determine Hospital Physician Board Review Manual

6 the efficacy of the medication. Since patients with GERD demonstrate markedly abnormal ph probe results, the probes were initially used to differentiate GER from EoE in patients who were not on acid blockade; however, because PPIs are often prescribed to treat possible GER prior to endoscopy, ph probes are no longer routinely ordered. Their use is limited to those patients in whom the diagnosis remains uncertain. Esophageal Manometry Esophageal manometry provides multiple direct pressure measurements of the esophageal body and the upper and lower esophageal sphincter. 32 Manometry determines the coordination of peristalsis and the tone and the relaxation of the sphincters and is the definitive test for many motility disorders, especially achalasia. However, it is important to remember that any disease that causes mucosal inflammation can contribute to the development of altered esophageal motility. Thus, patients with EoE may have secondary dysmotility. Upper Endoscopy with Biopsy Currently, the diagnosis of EoE is based on the use of upper endoscopy and esophageal biopsy. The diagnosis of EoE often is immediately suspected during endoscopy based on visual findings that include multiple small, white, raised specks on the esophageal mucosa (Figure 2), trachealization or ring-like formation of the esophagus (Figure 3), and esophageal linear furrows or railroad tracks (Figure 4). 29,33,34 However, approximately one third of children may have a normal-looking esophagus on visual evaluation despite having histologic evidence of EoE. Thus, biopsy of both the upper and lower esophagus is essential when making the diagnosis of EoE. In either location, more than 20 eosinophils per HPF [400 ] in a patient who is on a PPI establishes the diagnosis of EoE (Figure 5). Often a severe basal cell hyperplasia also exists. Patients must also have normal biopsies of the gastric antrum and duodenum. Patients who present primarily with dysphagia have significantly more esophageal eosinophils than those who present with symptoms of GER, and in general, both groups demonstrate a significantly greater number of eosinophils in the distal esophagus than in the mid or upper esophagus. Because the histology of EoE can be very sporadic, most advocate taking at least 2 biopsies from both the distal and mid esophagus. If 20 or more eosinophils are found in any single microscopic field, then EoE should be considered as a primary diagnosis. 35 Because many disorders can present with varying degrees of esophageal eosinophilia, it is extremely important for the pathologist to state the degree of eosinophilia by counting the eosinophils in addition to making any comments relating to a specific diagnosis such as reflux esophagitis. To be sure that GERD is not causing the esophageal eosinophilia, the biopsy must be performed while the patient is on acid blockade with a PPI (Table 4). If the esophagus normalizes with acid blockade, then EoE is not the cause. On the other hand, if a severe esophageal eosinophilia exists despite the use of an aggressive acid blockade, EoE is the most likely diagnosis. What is the role of allergy testing in patients with EoE? ALLERGY TESTING Although noninvasive allergy testing (eg, skin prick test [SPT] and radioallergosorbent test [RAST]) is useful in identifying food allergens that cause immediate hypersensitivity reactions, these tests typically do not identify the food allergens that cause EoE. 36 SPT and RAST often are not very useful in patients with EoE, who can have non IgE-mediated allergies or a mix of IgE- and non IgE-mediated allergies. Recently, skin patch testing has been used. Originally described in the early 1900s, this test was difficult to use because of the lack of standardization; however, over the past 10 years its use has increased mainly to identify non IgE-mediated food reactions contributing to atopic dermatitis. Skin patch testing used in combination with SPT has been reported to identify allergic foods in up to 50% of patients with EoE. 37 MANAGEMENT CASE CONTINUED The patient undergoes a UGI series, which shows no esophageal abnormalities and no evidence of hiatal hernia, ulcer disease, or malrotation. An upper endoscopy evaluation is performed and reveals multiple rings and white plaques in the distal esophagus. Esophageal biopsy reveals clusters of eosinophils and eosinophil abscesses at the surface of the squamous epithelium. What treatments are available for EoE? PRINCIPLES OF MANAGEMENT Patients with EoE may present in 4 different ways, and the presentation determines the management approach taken. First is the patient who presents with Pediatric Gastroenterology Volume 1, Part 2

7 Figure 2. Visual appearance of multiple esophageal white plaques during an upper endoscopy evaluation in a child with eosinophilic esophagitis. Figure 3. Visual appearance of multiple esophageal rings, or trachealization, during an upper endoscopy evaluation in an adolescent with eosinophilic esophagitis. Figure 4. Visual appearance of linear furrows during an upper endoscopy evaluation in a child with eosinophilic esophagitis. Figure 5. Abnormal histology in a patient with eosinophilic esophagitis. Note the increased number of eosinophils throughout the esophageal tissue as well as the presence of an eosinophilic abscess at the surface of the epithelium. acute, emergent symptoms such as severe dysphagia, food impaction, or uncontrolled vomiting. While such cases are rare, these patients need immediate attention and are often evaluated in an emergency department setting, with decisions regarding the need to perform an urgent endoscopy (dilatation) or hospitalize the patient made subsequently. Second is the patient who has chronic, daily symptoms but is not in extremis. These patients typically present with symptoms similar to GER, such as chronic vomiting, regurgitation, and epigastric pain. The third type of EoE patient has intermittent symptoms occurring once every few weeks or months. This group commonly includes older children, adolescents, and young adults who complain of dysphagia. When evaluated, these patients often have esophageal rings, strictures, or abnormal esophageal motility. The second and third groups of patients frequently do not have to be seen emergently but should undergo routine evaluation and treatment for EoE. The fourth group consists of patients who have severe EoE but do not have clinical symptoms. EoE is diagnosed in these patients after an upper endoscopy Hospital Physician Board Review Manual

8 Table 4. Comparison of Features of Eosinophilic Esophagitis (EoE) and Gastroesophageal Reflux Disease (GERD) Table 5. Pharmacologic Treatment Regimens for Eosinophilic Esophagitis Feature EoE GERD Treatment Dose Vomiting/regurgitation Common Frequent Dysphagia Common Infrequent Clinical symptoms Intermittent Frequent ph probe Usually normal Abnormal Eosinophils > 20/HPF < 5/HPF Acid blockade Unresponsive Responsive White plaques Yes No Esophageal rings Yes No Erosions No Yes HPF = high-power field. with biopsy is performed for a different reason, such as screening for celiac disease. These patients pose a dilemma because the long-term consequences of chronic esophageal eosinophilia without clinical symptoms are unclear, and many physicians are unsure whether these patients should be treated to improve their esophageal histologic abnormalities or instead simply be followed until they develop clinical symptoms. MECHANICAL THERAPY Esophageal Dilatation Esophageal dilatation is useful for EoE patients who present with food impaction due to an esophageal stricture. 38 Although several reports have documented relief of dysphagia with esophageal dilatation using rigid esophageal dilators, symptoms and esophageal strictures recur in the majority patients. In addition, there have been reports of esophageal tearing during esophageal dilatation or with the simple introduction of the endoscope, especially in those with a small-caliber esophagus. 39 Thus, one should be extremely careful whenever considering dilating the esophagus of an EoE patient as perforation is a distinct possibility. When possible, medical or dietary therapy should be instituted prior to performing esophageal dilatation. Fundoplication Surgical procedures designed to tighten the lower esophageal sphincter to prevent the reflux of gastric contents into more proximal areas of the esophagus have been used to treat patients with severe GERD. Several studies have demonstrated that fundoplication does not alter either the symptoms or the esophageal eosinophilia in patients with EoE. 4,14 Therefore, because EoE is not the Proton pump inhibitors 1 2 mg/kg daily (maximum, mg/day) Systemic corticosteroids (eg, prednisone) Topical corticosteroids (eg, fluticasone) Leukotriene receptor antagonists 1 2 mg/kg daily (maximum, 60 mg/day) µg twice daily (metereddose inhaler) Initial, 100 mg/day; maintenance, 10 mg/day result of prolonged esophageal acid exposure, antireflux surgery is not a recommended treatment for EoE. PHARMACOLOGIC THERAPY Proton Pump Inhibitors Currently, most investigators believe that PPI therapy is essential in patients who have clinical symptoms of EoE (Table 5). First, PPIs are used to ensure that GERD is not a cause of esophageal eosinophilia, as discussed earlier. Second, patients with EoE may demonstrate a partial clinical response to acid blockade, most likely because secondary reflux is occurring as a result of esophageal damage and inflammation caused by EoE. Thus, PPIs should be used to ensure that GERD is not occurring and as an adjunct therapy until EoE is successfully treated. 26 Corticosteroids Systemic corticosteroids have been shown to produce rapid, complete normalization of esophageal tissue and symptomatic improvement in patients with EoE. 40 Unfortunately, the chronic use of systemic corticosteroids has been associated with significant side effects. Additionally, when corticosteroids are discontinued, EoE recurs because the underlying problem (food allergy in most cases) has not been addressed. Systemic corticosteroids are useful in acute situations where patients with EoE present with severe dysphagia, food impaction, esophageal strictures, or severe symptoms of GER mandating acute hospitalization because of the patients inability to eat. Steroids are used to rapidly halt esophageal inflammation but should only be used as a short-term solution while other therapies are being instituted. They should not be used as a longterm treatment of EoE. Studies have demonstrated successful treatment of EoE with topical corticosteroids as an alternative to Pediatric Gastroenterology Volume 1, Part 2

9 systemic corticosteroids. 41 Metered-dose inhalers using fluticasone were shown to be effective for EoE after patients were instructed to swallow the normally inhaled preparation. Although this treatment significantly improved patient s symptoms, there was incomplete resolution of esophageal tissue histology. Recently, larger doses have been shown to result in almost complete esophageal healing. 8,42 The benefit of using topical steroid therapy instead of systemic therapy includes decreased side effects and their ability to be used for maintenance therapy. Unfortunately, like systemic corticosteroids, this therapy cannot be discontinued because interruption in therapy almost always results in recurrence of disease. Concerns with the chronic use of topical corticosteroids have been raised, with recent reports of oral and esophageal candidiasis and the possibility of altered adrenal hormone production. 43 Leukotriene Receptor Antagonists The use of leukotriene receptor antagonists has only recently been studied. Several studies have reported that EoE patients had a clinical improvement in symptoms after being placed on these medications. 44,45 The benefits of using a leukotriene receptor antagonist include ease of administration and minimal side effects. On the other hand, the same studies demonstrated no improvement in esophageal histology, and these medications also must be used chronically to avoid recurrence of symptoms. Mast Cell Stabilizers Cromolyn sodium has been employed for mast cell disorders. Although cromolyn has little or no side effects, the advantage of using this medication in patients with EoE is minimal. Specifically, one study 26 demonstrated that when used alone, cromolyn had no significant effect on esophageal histology or clinical symptoms. Monoclonal Antibodies Recently, the use of biologic agents, such as anti- IL-5, in patients with eosinophilic disorders has been entertained. IL-5 is involved in many eosinophil functions, including production, activation, and tissue recruitment. Thus, it has been hypothesized that this cytokine may be involved in the pathogenesis of hypereosinophilic syndromes, a group of diverse disorders characterized by sustained peripheral blood and/or tissue eosinophilia. In a study involving 4 patients with hypereosinophilic syndrome, administration of anti- IL-5 resulted in significant symptom improvement in all patients, including 1 patient who had severe dysphagia. 46 These medications are currently undergoing further investigation. DIETARY THERAPY The diagnosis of allergic EoE cannot be made until an isolated, severe histologic esophagitis (unresponsive to aggressive acid blockade) associated with symptoms similar to those seen in GERD responds both clinically and histologically to the elimination of a specific food(s). The use of dietary therapy for EoE was first reported by Kelly and colleagues in In this study, 10 children previously diagnosed with GERD received an elemental diet using an amino-acid based formula for at least 6 weeks; in all cases, the clinical symptoms and histologic esophageal eosinophilia improved dramatically. Since then, 2 dietary approaches have been used: (1) an elimination diet removing specific foods from the diet based on clinical symptoms, historical data, or noninvasive allergy testing; or (2) an elemental diet removing all foods from the diet except for the administration of an amino-acid based formula. 26,47 Although the elemental diet has been proven to be the gold standard in evaluating whether food allergy is the cause of EoE, various elimination diets also have been successful. Because food allergy is responsible for most EoE cases, dietary therapy should be considered a priority in the management of these patients. Elimination Diet The use of an elimination diet in food-allergic patients is based upon the principle of removing specific, isolated foods from the diet. In the past, the removal of these foods was based on either the association of clinical symptoms with specific food(s) or as a response to abnormal allergy testing (SPT, RAST). In several early reports conducted after EoE became more prevalent, EoE patients were reported as not responding to an elimination diet, which led investigators to believe that food allergy was not the cause of EoE. 21,42 However, because patients with EoE often fail to experience an immediate reaction when exposed to an allergic food and because SPT and RAST testing usually demonstrate poor results, these studies did not prove that food allergy was not the cause of EoE. Recently, skin patch testing has been introduced as a complement to SPT. This combination of skin prick and patch testing has been shown to identify more than 50% of patients who have specific food allergies. 48 There are several steps in initiating an elimination diet. First, since foods that cause patients to experience clinical symptoms shortly after their ingestion may cause EoE, they should be removed from the diet. Second, 10 Hospital Physician Board Review Manual

10 SPT and skin patch testing can be performed in an attempt to identify both IgE and non IgE-mediated allergy that may cause EoE. Again, foods that cause symptoms should be removed from the diet. Finally, because both the clinical history and allergy testing are unreliable in at least 50% of EoE patients, some investigators have chosen to immediately remove the 6 most common food allergens from the diet of a suspected EoE patient: milk, soy, eggs, wheat, nuts, and shellfish. Because clinical symptoms can be intermittent, a repeat upper endoscopy with biopsy must be used to determine if EoE has resolved in the follow-up of patients treated with an elimination diet. In cases where EoE has not resolved, an elemental diet should be considered. Elemental Diet Since the initial study by Kelly and colleagues, 4 most investigators agree that dietary antigens are the main cause of EoE. In addition, it has been shown that the removal of the offending agent results in symptom resolution and histologic normalization of the esophagus without the need for medication. 26 While an elimination diet is often attempted, many patients continue to be either symptomatic or have ongoing esophageal eosinophilia. Thus, an aggressive dietary approach using an amino-acid based formula must often be initiated. Because of the poor palatability of the formula, this diet may require the use of a nasogastric tube. Typically, both clinical symptoms and esophageal histology completely resolve within 2 to 4 weeks after beginning an elemental diet, although the diet may be needed for several months. More than 95% of EoE patients respond to this therapy, 26 suggesting that EoE is primarily caused by food allergens. 26 In rare cases when the esophageal biopsy remains abnormal despite the use of an amino-acid based formula, noncompliance, environmental allergens, and EG should be strongly considered. Although an elemental diet prevents the long-term use of medication and can specifically identify the foods that cause EoE, strict use of an amino-acid based formula is often difficult for the family and patient to accept. After the initiation of an elemental diet, 75% of EoE patients can tolerate enough foods to discontinue the formula within 5 months. Approximately 25% of EoE patients can be classified as extremely allergic and often cannot tolerate the reintroduction of any foods. Thus, they must remain on an amino-acid based formula for a prolonged period of time. Therapeutic Approach When a patient with clinical symptoms is diagnosed with EoE, an allergy consultation should be conducted. Subsequently, a decision should be made regarding the use of dietary therapy or the use of medications (topical corticosteroids). In either case, a repeat upper endoscopy with biopsy should be performed 4 to 6 weeks after initiating treatment. Patients given medical therapy almost always require prolonged therapy, while those prescribed a special diet must remain off the foods that cause EoE for an extended period of time. A small number of patients with EoE may be asymptomatic despite an aggressive histologic EoE, and the argument has been made that these patients do not require treatment. The no treatment approach has been suggested because of the potential side effects of medication, the difficult social aspects of being on a limited diet, and the lack of information regarding the effects of chronic eosinophilic inflammation on the esophagus. In contrast, many physicians argue that by not treating this disease, patients will eventually have increased mucosal disease, contributing to dysphagia and the development of esophageal strictures. In addition, one of the histologic features of EoE is severe hyperplasia of the basic cell layer. In general, significant cell turnover is often considered a prelude to tissue dysplasia. CASE RESOLUTION The patient is referred to an allergy specialist. He undergoes both SPT and skin patch testing, which identify several foods that are removed from the diet. However, the patient continues to have intermittent symptoms, and repeat upper endoscopy with biopsy continues to demonstrate a severe isolated EoE. Next, milk, soy, eggs, wheat, nuts, and shellfish are eliminated from the patient s diet. Again, the symptoms continue and upper endoscopy remains abnormal. Finally, the patient is placed on a strict amino-acid based elemental diet. Repeat endoscopy with biopsy performed after 4 weeks of dietary therapy was started shows complete normalization of the esophagus with resolution of symptoms. Over the next 5 months, multiple foods are reintroduced without a recurrence of symptoms. The patient remains off the foods to which he is allergic for several years. CONCLUSION The diagnosis of EoE has been receiving a great deal of attention recently. Argument still exists regarding the etiology, diagnosis, and treatment of EoE. Clinicians need to differentiate patients with EoE from Pediatric Gastroenterology Volume 1, Part 2 11

11 patients with GERD because the 2 conditions present with similar symptoms. The diagnosis of EoE is based on the presence of a significant, isolated esophageal eosinophilia (> 20 eosinophils per HPF) despite the use of acid blockade. On the other hand, either the finding of a small number of esophageal eosinophils (< 5 per HPF) or a large number of eosinophils that resolve with PPI therapy suggests GERD. The diagnosis is equivocal when an esophageal biopsy reveals 5 to 20 eosinophils per HPF. Once the diagnosis of EoE is made, various treatments including medical and dietary therapy can be instituted. References 1. Landres RT, Kuster GG, Strum WB. Eosinophilic esophagitis in a patient with vigorous achalasia. Gastroenterology 1978;74: Winter HS, Madara JL, Stafford RJ, et al. Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology 1982;83: Tummala V, Barwick KW, Sontag SJ, et al. The significance of intraepithelial eosinophils in the histologic diagnosis of gastroesophageal reflux. Am J Clin Pathol 1987;87: Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995;109: Straumann A, Spichtin HP, Grize L, et al. Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology 2003;125: Horiki N, Maruyama M, Fujita Y, Yonekura T. [A case of idiopathic eosinophilic esophagitis with CT findings showing marked thickening of the esophageal wall.] [Article in Japanese.] Nippon Shokakibyo Gakkai Zasshi 1998;95: Bory F, Vazquez E, Forcada P, et al. [Eosinophilic esophagitis as a cause of dysphagia with a 10-year history.] [Article in Spanish.] Gastroenterol Hepatol 1998;21: Remedios M, Campbell C, Jones DM, Kerlin P. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointest Endosc 2006;63: Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis [letter]. N Engl J Med 2004;351: Potter JW, Saeian K, Staff D, et al. Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features. Gastrointest Endosc 2004;59: Noel RJ, Tipnis NA. Eosinophilic esophagitis a mimic of GERD. Int J Pediatr Otorhinolaryngol 2006;70: Fass R, Shapiro M. Proton pump inhibitor failure in gastro-oesphageal reflux disease what about eosinophilic oesophagitis? Authors reply. Aliment Pharmacol Ther 2006;23: Ngo P, Furuta GT, Antonioli DA, Fox VL. Eosinophils in the esophagus peptic or allergic eosinophilic esophagitis? Case series of three patients with esophageal eosinophilia. Am J Gastroenterol 2006;101: Liacouras CA. Failed Nissen fundoplication in two patients who had persistent vomiting and eosinophilic esophagitis. J Pediatr Surg 1997;32: Mishra A, Hogan SP, Brandt EB, Rothenberg ME. An etiological role for aeroallergens and eosinophils in experimental esophagitis. J Clin Invest 2001;107: Noel RJ, Rothenberg ME. Eosinophilic esophagitis. Curr Opin Pediatr 2005;17: Liacouras CA, Markowitz JE. Eosinophilic esophagitis: a subset of eosinophilic gastroenteritis. Curr Gastroenterol Rep 1999;1: Sampson HA. Immunological approaches to the treatment of food allergy. Pediatr Allergy Immunol 2001;12 Suppl 14: Sampson HA. Food-induced anaphylaxis. Novartis Found Symp 2004;257:161 76, , Straumann A, Kristl J, Conus S, et al. Cytokine expression in healthy and inflamed mucosa: probing the role of eosinophils in the digestive tract. Inflamm Bowel Dis 2005;11: Teitelbaum JE, Fox VL, Twarog FJ, et al. Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate. Gastroenterology 2002;122: Desai T, Goldstein N, Stecevic V, et al. Esophageal eosinophilia is common among adults with esophageal food impaction. Gastroenterology 2002;122:M Orenstein SR, Shalaby TM, Di Lorenzo C, et al. The spectrum of pediatric eosinophilic esophagitis beyond infancy: a clinical series of 30 children [published erratum appears in Am J Gastroenterol 2001;96:2290]. Am J Gastroenterol 2000;95: Liacouras CA, Ruchelli E. Eosinophilic esophagitis. Curr Opin Pediatr 2004;16: Rothenberg ME, Mishra A, Collins MH, Putnam PE. Pathogenesis and clinical features of eosinophilic esophagitis [editorial]. J Allergy Clin Immunol 2001;108: Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol 2005;3: Khan S, Orenstein SR, Di Lorenzo C, et al. Eosinophilic esophagitis: strictures, impactions, dysphagia. Dig Dis Sci 2003;48: Fox VL, Nurko S, Teitelbaum JE, et al. High-resolution EUS in children with eosinophilic allergic esophagitis. 12 Hospital Physician Board Review Manual

12 Gastrointest Endosc 2003;57: Zimmerman SL, Levine MS, Rubesin SE, et al. Idiopathic eosinophilic esophagitis in adults: the ringed esophagus. Radiology 2005;236: Meyers WF, Roberts CC, Johnson DG, Herbst JJ. Value of tests for evaluation of gastroesophageal reflux in children. J Pediatr Surg 1985;20: Sondheimer JM. Continuous monitoring of distal esophageal ph: a diagnostic test for gastroesophageal reflux in infants. J Pediatr 1980;96: Garabedian M. Uses of esophageal manometry and acid perfusion in the study of gastroesophageal reflux and hiatal hernia. Surg Clin North Am 1971;51: Gupta SK, Fitzgerald JF, Chong SK, et al. Vertical lines in distal esophageal mucosa (VLEM): a true endoscopic manifestation of esophagitis in children? Gastrointest Endosc 1997;45: Sundaram S, Sunku B, Nelson SP, et al. Adherent white plaques: an endoscopic finding in eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 2004;38: Ruchelli E, Wenner W, Voytek T, et al. Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy. Pediatr Dev Pathol 1999; 2: Sicherer SH, Sampson HA. 9. Food allergy. J Allergy Clin Immunol 2006;117(2 Suppl Mini-Primer):S Spergel JM, Beausoleil 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: Nostrant TT. Esophageal dilation/dilators. Curr Treat Options Gastroenterol 2005;8: Kaplan M, Mutlu EA, Jakate S, et al. Endoscopy in eosinophilic esophagitis: feline esophagus and perforation risk. Clin Gastroenterol Hepatol 2003;1: Liacouras CA, Wenner WJ, Brown K, Ruchelli E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998;26: Faubion Wa Jr, Perrault J, Burgart LJ, et al. Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr 1998;27: Noel RJ, Putnam PE, Collins MH, et al. Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis. Clin Gastroenterol Hepatol 2004; 2: Shuto H, Nagata M, Terashi Y, et al. [Esophageal candidiasis as complication of inhaled steroid therapy.] [Article in Japanese.] Arerugi 2003;52: Sinharay R. Eosinophilic oesophagitis: treatment using Montelukast [letter]. Gut 2003;52: Attwood SE, Lewis CJ, Bronder CS, et al. Eosinophilic oesophagitis: a novel treatment using Montelukast. Gut 2003;52: Garrett JK, Jameson SC, Thomson B, et al. Antiinterleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol 2004;113: Kagalwalla AF, Sentongo TS, Ritz S, et al. Effect of six-food elimination diet on clinical and histological outcome in eosinophilic esophagitis. Clin Gastroenterol Hepatol. In press. 48. Spergel JM, Andrews T, Brown-Whitehorn TF, et al. Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests. Ann Allergy Asthma Immunol 2005;95: Copyright 2007 by Turner White Communications Inc., Wayne, PA. All rights reserved. Pediatric Gastroenterology Volume 1, Part 2 13