Eosinophilic Esophagitis (Clinical Gastroenterology)

CLINICAL GASTROENTEROLOGY

Series Editor George Y. Wu University of Connecticut Health Center, Farmington, CT, USA

For further volumes: http://www.springer.com/series/7672

Chris A. Liacouras

L

Jonathan E. Markowitz

Editors

Eosinophilic Esophagitis

Editors Chris A. Liacouras, MD Professor of Pediatrics The University of Pennsylvania School of Medicine Co-Director Center for Pediatric Eosinophilic Disorders The Children’s Hospital of Philadelphia Philadelphia, PA, USA [email protected]

Jonathan E. Markowitz, MD, MSCE Medical Director Pediatric Gastroenterology and Nutrition Greenville Hospital System University Medical Center Greenville, SC, USA [email protected]

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Preface

Eosinophilic esophagitis (EoE) is a disease that has gained increasing interest over the last decade. First appreciated in 1995, EoE is now one of the most talked about disorders among pediatric and adult gastroenterologists, allergists, and pathologists. Over the past decade, the disease has seen impressive advances with regard to the clinical recognition of patients, basic research, allergy testing, and genetic identification. In 2007, the first consensus recommendations on EoE were published in Gastroenterology. Because of the significant increase in the number of publications on the subject, an update of the consensus recommendations were recently published in the Journal of Allergy and Clinical Immunology (July 2011). As part of this update, a conceptual definition was generated that states, “Eosinophilic esophagitis represents a chronic, immune/antigen mediated, esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.” In addition, the diagnostic guideline was adjusted and now defines the disease as follows: “EoE is a clinico-pathological disease. Clinically, EoE is characterized by symptoms related to esophageal dysfunction. Pathologically, one or more biopsies must show eosinophil predominant inflammation. With few exceptions, 15 eosinophils/hpf (peak value) is considered a minimum threshold for a diagnosis of EoE. The disease is isolated to the esophagus and other causes of esophageal eosinophilia should be excluded, specifically PPIresponsive esophageal eosinophilia. The disease should remit with treatments of dietary exclusion and/or topical corticosteroids. EoE should be diagnosed by clinicians taking into consideration all clinical and pathologic information; neither of these parameters should be interpreted in isolation.” The contributing authors have been selected because of their expertise not only from their clinical and research experience, but also from their long-standing interest, dedication, and efforts to increase the knowledge of EoE worldwide. They have written informative chapters providing up-to-date knowledge on both pediatric and adult manifestations of EoE. We hope that the readers will use the information presented to increase their knowledge of EoE and to aid them in the diagnosis, management, and treatment of individual patients.

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As editors, we would like to thank all contributing authors for their hard work and interest in this project. Their commitment and excellence in patient care, research, and education is much appreciated and readily apparent. Philadelphia, PA Greenville, SC

Chris A. Liacouras Jonathan E. Markowitz

Contents

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A History of Eosinophilic Esophagitis.................................................. Chris A. Liacouras and Jonathan E. Markowitz

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Epidemiology, Incidence, and Prevalence of EoE in Children........... Richard J. Noel

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Epidemiology of Eosinophilic Esophagitis in Adults .......................... Petr Hruz and Alex Straumann

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Eosinophil Biology in the Pathogenesis of Eosinophilic Disorders ...................................................................... Steven J. Ackerman

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Role of Lymphocytes and Mast Cells in Eosinophilic Esophagitis ................................................................... Mirna Chehade and Hugh A. Sampson

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Esophageal Remodeling in Eosinophilic Esophagitis ......................... Louanne M. Tourangeau and Seema S. Aceves

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The Genetic Basis of Eosinophilic Esophagitis.................................... Joseph D. Sherrill and Marc E. Rothenberg

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Relationships Between Eosinophilic Esophagitis and Eosinophilic Gastroenteritis .......................................................... Dan Atkins and Glenn T. Furuta

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Clinical Manifestations of Eosinophilic Esophagitis in Children .............................................................................................. Philip E. Putnam

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Clinical Presentation of Eosinophilic Esophagitis in Adults .............. Nirmala Gonsalves

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Relationship of Eosinophilic Esophagitis to Gastroesophageal Reflux  Edaire Cheng, Harland S. Winter, and Stuart Spechler

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Radiographic Diagnosis of Eosinophilic Esophagitis.......................... Marc S. Levine and David A. Katzka

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Endoscopic Features of Eosinophilic Esophagitis ............................... David A. Leiman and Gary W. Falk

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Histologic Features of Eosinophilic Esophagitis ................................. Margaret H. Collins

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Complications Associated with Eosinophilic Esophagitis .................. Stephen E. Attwood and Glenn T. Furuta

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IgE- and Non-IgE-Mediated Food Allergy .......................................... Scott H. Sicherer

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Allergic and Atopic Features of Children with Eosinophilic Esophagitis ............................................................... Janet L. Beausoleil and Terri Brown-Whitehorn

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Atopic and Allergic Features of Adults with Eosinophilic Esophagitis ............................................................... Javed Sheikh and Katherine N. Cahill

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Allergy Testing in Eosinophilic Esophagitis ........................................ Antonella Cianferoni and Jonathan Spergel

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Esophageal Dilation for Eosinophilic Esophagitis .............................. Matthew Bohm and Joel E. Richter

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Steroid Therapy of EoE in Children .................................................... Paola De Angelis and Luigi Dall’Oglio

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Medical Treatment for Pediatric Eosinophilic Esophagitis................ James P. Franciosi

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Corticosteroid Treatment of Eosinophilic Esophagitis in Adults .................................................................................................. Karthik Ravi and Amindra S. Arora

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Dietary Treatment of Eosinophilic Esophagitis................................... Amir F. Kagalwalla and Sally Ritz

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Nutritional Management of Eosinophilic Esophagitis in Pediatric Patients ............................................................................... Mimi Girten, Elizabeth Goldberg, and Michele Shuker

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Oral Tolerance and Eosinophilic Esophagitis ..................................... Pooja Varshney and A. Wesley Burks

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Treatment of Eosinophilic Esophagitis with Biological Agents ......... Kathryn A. Peterson, Molly O’Gorman, W. Daniel Jackson, and Gerald J. Gleich

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Feeding Disorders and Eosinophilic Esophagitis ................................ Asim Maqbool and Colleen Lukens

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Psychological Perspectives on Pediatric Eosinophilic Esophagitis........................................................................ Mary Klinnert

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Eosinophilic Esophagitis: Treatment Approach in Adults ................. Ikuo Hirano

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Eosinophilic Esophagitis: Treatment Approach in Children ............. Jonathan E. Markowitz and Chris A. Liacouras

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Index ................................................................................................................

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Contributors

Seema S. Aceves, MD, PhD Division of Allergy, Immunology, Departments of Pediatrics and Medicine, University of California, Rady’s Children’s Hospital, San Diego, CA, USA Steven J. Ackerman, PhD Department of Biochemistry and Molecular Genetics (M/C 669), and Sections of Hematology-Oncology and Pulmonary, Critical Care, Sleep and Allergy, The University of Illinois at Chicago College of Medicine, Chicago, IL, USA Paola De Angelis, MD Digestive Surgery and Endoscopy Unit, Pediatric Hospital Bambino Gesú, Rome, Italy Amindra S. Arora, MBBChir, FRCP Department of GIH, Mayo Clinic, Rochester, MN, USA Dan Atkins, MD Professor of Pediatrics, Associate Professor of Pediatrics, Co-Director, National Jewish Health, University of Colorado Denver School of Medicine, The Children’s Hospital Denver, Denver, CO, USA Gastrointestinal Eosinophilic Diseases Program, The Children’s Hospital Colorado, National Jewish Health, University of Colorado Denver School of Medicine, Aurora, CO, USA Stephen E. Attwood, FRCS, FRCSI, MCh, BA Mod Physiol Department of Surgery, Northumbria Healthcare, Tyne + Wear, UK Janet L. Beausoleil, MD Department of Pediatrics, Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Terri Brown-Whitehorn, MD Assistant Professor of Clinical Pediatrics, Department of Allergy and Immunology, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Matthew Bohm, DO Clinical Instructor of Medicine, Department of Medicine, Temple University Hospital, Philadelphia, PA, USA xi

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A. Wesley Burks, MD Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC, USA Katherine N. Cahill, MD Clinical Fellow in Allergy and Immunology, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA Mirna Chehade, MD, MPH Mount Sinai center for Eosinophilic Disorders, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, New York, NY, USA Edaire Cheng, MD Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA Antonella Cianferoni, MD, PhD Assistant Professor of Pediatrics, Department of Allergy, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Margaret H. Collins, MD Department of Pathology, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Luigi Dall’Oglio, MD Department of Digestive Endoscopy and Surgery Unit, Bambino Gesú Children’s Hospital IRCCS, Rome, Italy Gary W. Falk, MD, MS Department of Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA James P. Franciosi, MD, MS, MSCE Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Glenn T. Furuta, MD National Jewish Health, University of Colorado Denver School of Medicine, The Children’s Hospital Denver, Denver, CO, USA Gastrointestinal Eosinophilic Diseases Program, Children’s Hospital Colorado, National Jewish Health, University of Colorado Denver School of Medicine, Aurora, CO, USA Mimi Girten, BS, RD, LDN Pediatric Dietician, Department of Clinical Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Gerald J. Gleich, MD Department of Dermatology, University of Utah Hospital, Salt Lake City, UT, USA Elizabeth Goldberg, RN, MSN, CRNP Advance Practice Nurse, Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

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Nirmala Gonsalves, MD Department of Medicine, Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Ikuo Hirano, MD Department of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Petr Hruz, MD, PhD Department of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland W. Daniel Jackson, MD Clinical Professor of Pediatrics, Department of Pediatric Gastroenterology and Nutrition, University of Utah School of Medicine, Salt Lake City, UT, USA Amir F. Kagalwalla, MBBS Division of Gastroenterology, Hepatology, and Nutrition, Northwestern University Feinberg School of Medicine, Children’s Memorial Hospital, John H. Stroger Hospital of Cook County, Chicago, IL, USA David A. Katzka, MD Department of Medicine, Mayo Clinic, Rochester, MN, USA Mary Klinnert, PhD Department of Pediatrics, National Jewish Health, Denver, CO, USA Department of Psychiatry, School of Medicine, University of Colorado, Aurora, CO, USA David A. Leiman, MD Medical Resident, Department of Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA Marc S. Levine, MD Professor of Radiology and Advisory Dean, Chief of Gastrointestinal Radiology, Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Hospital of the University of Pennsylvania, Philadelphia, PA, USA Chris A. Liacouras, MD Co-Director, Center for Pediatric Eosinophilic Disorders, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Professor of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Colleen Lukens, PhD Psychologist, Department of Child and Adolescent Psychiatry and the Behavioral Sciences, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Asim Maqbool, MD Pediatric Gastroenterology, Hepatology, and Nutrition, University of Pennsylvania School of Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

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Jonathan E. Markowitz, MD, MSCE Department of Pediatrics, Pediatric Gastroenterology and Nutrition, Greenville Hospital System University Medical Center, Greenville, SC, USA Richard J. Noel, MD, PhD Division of Gastroenterology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA Molly O’Gorman, MD Associate Professor of Pediatrics, Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Primary Children’s Medical Center and University of Utah Hospital, Salt Lake City, UT, USA Kathryn A. Peterson, MD, MSci (Epid) Assistant Professor of Medicine, Department of Gastroenterology, University of Utah Hospital, Salt Lake City, UT, USA Philip E. Putnam, MD Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Cincinnati Center for Eosinophilic Disorders, Cincinnati, OH, USA Karthik Ravi, MD GI Fellow Department of GIH, Mayo Clinic, Rochester, MN, USA Joel E. Richter, MD, FACP, MACG Department of Medicine, Section of Gastroenterology, Temple University School of Medicine, Philadelphia, PA, USA Sally Ritz, RD, CSP, LDN Certified Specialist in Pediatric Nutrition, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Memorial Hospital, Chicago, IL, USA Marc E. Rothenberg, MD, PhD Department of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA Hugh A. Sampson, MD Professor of Pediatrics, Dean, Translational Biomedical Sciences, Director, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, New York, NY, USA Javed Sheikh, MD Center for Eosinophilic Disorders, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, MA, USA Joseph D. Sherrill, PhD Department of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Michele Shuker, MS, RD, CSP, LDN Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Scott H. Sicherer, MD Department of Pediatrics, Mount Sinai School of Medicine, Jaffe Food Allergy Institute, New York, NY, USA

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Stuart Spechler, MD Chief, Department of Medicine, VA North Texas Healthcare System and the University of Texas Southwestern Medical Center, Dallas, TX, USA Jonathan Spergel, MD, PhD Department of Pediatrics, Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Alex Straumann, MD Department of Gastroenterology, University Hospital Basel, Basel, Switzerland Swiss EoE Research Group, Olten, Switzerland Louanne M. Tourangeau, MD Allergy and Immunology, Department of Medicine, University of California, San Diego, CA, USA Pooja Varshney, MD Fellow-in-Training, Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC, USA Harland S. Winter, MD Associate Professor of Pediatrics, Department of Pediatric Gastroenterology, Harvard Medical School, MassGeneral Hospital for Children, Boston, MA, USA

Chapter 1

A History of Eosinophilic Esophagitis Chris A. Liacouras and Jonathan E. Markowitz

Keywords %OSINOPHILICESOPHAGITISs%SOPHAGEALEOSINIPHILIAs!LLERGICESOPHAGITIS

Introduction Eosinophilic esophagitis (EoE), an isolated esophageal eosinophilia associated with clinical symptoms, is a disease that has received a great deal of attention over the last 10–15 years. EoE, previously known as primary eosinophilic esophagitis, idiopathic eosinophilic esophagitis or allergic esophagitis, occurs in both children and adults. Prior to 1995, the literature contained only rare reports of individuals diagnosed with an isolated esophageal eosinophilia. However, since 1995, reports in the literature and information related to EoE have grown tremendously. This chapter focuses on the history of EoE, including initial reports of esophageal eosinophilia prior to 1995, the landmark article identifying EoE as a disorder in 1995, the growth of EoE in the literature since 1995, the development of the First International Gastrointestinal Eosinophilic Research Symposium (FIGERS) in 2006, and the creation of The International Gastrointestinal Eosinophilic Researchers (TIGERS).

C.A. Liacouras (*) Co-Director, Center for Pediatric Eosinophilic Disorders, The Children’s Hospital of Philadelphia, 34th and Civic Center Blvd, Philadelphia, PA 19104, USA Professor of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Pennsylvania School of Medicine, Philadelphia, PA, USA e-mail: [email protected] C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_1, © Springer Science+Business Media, LLC 2012

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History of Esophagitis Since 1970, the histologic hallmarks for reflux esophagitis have been basal zone hyperplasia, elongated papillae, and intraepithelial neutrophils [1–4]. Other nonspecific findings include dilated vascular channels in the lamina propria papillae and distended squamous or “balloon” cells. In 1982, Winter [5] reported the presence of intraepithelial eosinophils as an added criterion for the diagnosis of reflux esophagitis in children. In this study of 46 symptomatic pediatric patients and nine control subjects, the presence of esophageal eosinophils was correlated with 24-h pH probe monitoring, esophageal manometry, and other histologic features of gastroesophageal reflux, including papillary length and basal zone thickness. The presence of one of more intraepithelial eosinophils in the esophagus was established as a specific indicator of esophagitis. Abnormal esophageal acid clearance was correlated with other accepted morphologic features of esophageal injury. In addition, it was suggested that eosinophils were diagnostic of reflux esophagitis even if other accepted histologic abnormalities were absent. Although the majority of eosinophils were observed in the distal esophagus, the presence of more proximal eosinophils was associated with increasingly abnormal pH probe results. These findings were later confirmed in adults [6]. Over the years, apart from the diagnosis of reflux esophagitis, large numbers of esophageal eosinophils have been identified in children with eosinophilic gastroenteritis or allergic gastroenteritis [7], Crohn’s disease and, more recently, eosinophilic esophagitis.

History of Esophageal Eosinophilia During the last 25 years, several studies have identified patients with an isolated, severe eosinophilic esophagitis, which suggested an etiology other than acid reflux. In 1977 one of the first cases of esophageal eosinophilia was reported by Dobbins [8], involving a case of a 51-year-old male patient with asthma and allergies who developed dysphagia and substernal chest pain. Esophageal biopsies revealed a focal, marked eosinophilic infiltrate. Small bowel biopsies demonstrated villous flattening and an eosinophilia. The patient was diagnosed with eosinophilic gastroenteritis. In 1978, Landres [9] reported on the case of a patient with achalasia associated with esophageal eosinophilia who underwent esophageal myotomy that revealed eosinophilic infiltration of the muscular layer. In 1983, Matzinger [10] described an adolescent with dysphagia, food allergy, and a peripheral eosinophilia who underwent esophageal biopsy, which revealed eosinophilic infiltration of both the esophagus and stomach. In 1985, Lee [11] reported on a series of 11 patients with a severe esophageal eosinophilia, greater than 10 esophageal eosinophils per high power field (hpf), who presented with

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dysphagia, heartburn, vomiting, and esophageal strictures (3 of 11). However, reflux was not documented by 24-h pH probe. One patient was given steroids and clinically improved. Between 1978 and 1990, several reports were published linking radiographic abnormalities with esophageal eosinophilia [12–14]. Clinically, patients described in these reports presented with dysphagia, heartburn, chest pain, peripheral eosinophilia, regurgitation, and vomiting. In the majority of these patients, barium radiographic studies demonstrated an esophageal stricture. While most of these patients underwent repeated esophageal dilatation, one patient was given corticosteroids, upon which, both the clinical symptoms and the esophageal stricture resolved. In 1993, Attwood [15] reported one of the first studies comparing patients with isolated esophageal eosinophilia to patients with gastroesophageal reflux. He described 12 patients presenting with dysphagia who had more than 20 esophageal eosinophils/hpf (mean 56 eosinophils/hpf). All had visually normal esophageal mucosa and no esophageal anatomic abnormality – 11 had normal pH monitoring and seven had evidence of an allergic disorder. Only one patient had antral eosinophilia. This group was compared to another group, consisting of 90 patients with medically responsive gastroesophageal reflux (documented by an abnormal 24-h pH probe). Only 43 of these patients had esophageal eosinophils to a much lesser degree (mean 3.3 eosinophils/HPF). The author suggested that these patients represented a new clinicopathologic syndrome not previously described. Similarly, in 1995, Vitellas [16] reported on 13 male patients with idiopathic eosinophilic esophagitis and showed that the majority of these patients responded to corticosteroids. The patients’ clinical symptoms included dysphagia (12 of 13), allergic manifestations (10 of 13), peripheral eosinophilia (12 of 13) and proximal esophageal strictures (10 of 13). Vitellas suggests that the identification of these patients is important because treatment with corticosteroids is much more effective than esophageal dilatation. In 1993, Levine and Saul [17] suggested that idiopathic eosinophilic esophagitis should be considered in all patients with esophageal narrowing and a severe esophageal eosinophilia. These authors argued that the difference between the diagnosis of reflux esophagitis and idiopathic eosinophilic esophagitis depended upon the location of the eosinophilia, with the implication that, in idiopathic eosinophilic esophagitis, esophageal eosinophils were located predominantly in the proximal esophagus and that the distal esophagus was spared. In contrast, Ruchelli [18] demonstrated that a diagnosis of eosinophilic esophagitis should be considered based on the degree of esophageal eosinophilia regardless of location. Ruchelli identified 102 patients who had at least one intraepithelial esophageal eosinophil after undergoing endoscopic biopsy for symptoms of gastroesophageal reflux. Patients initially underwent upper endoscopy with distal esophageal biopsy and were subsequently treated with aggressive antireflux pharmacologic therapy. Ruchelli’s results indicated that the number of esophageal eosinophils/hpf predicted patient improvement (1.1 ± 0.3 eosinophils/hpf), relapse (6.4 ± 2.4) or reflux treatment failure (24.5 ± 6.1).

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Eosinophilic Gastroenteritis and Colitis The role of the eosinophil in eosinophilic gastritis is unclear, but its presence is the unifying factor in the diagnosis. Eosinophilic granules serve in the killing of parasites and act as inflammatory mediators and chemotactic agents [19]. Tissue damage may result from the interplay between immunoglobulins, complement, eosinophils, and other inflammatory cells. Antibody-antigen complexes may be responsible for the attraction of eosinophils into the tissue of the gastrointestinal tract in association with complement activation and deposition [20]. Mast cell-associated mediators have also been shown to affect eosinophils and may play a role in the mediation of disease in eosinophilic gastroenteritis (EG). Once present in the tissue, the eosinophil may possess the ability to modulate disease in positive or negative ways. The cell may serve to control the inflammatory cascade from mast cell degranulation. Enzymes present in eosinophil granules contain enzymes that counteract the damaging substances present in mast cells. However, eosinophil granules also contain vasoactive substances such as platelet-activating factor and leukotrienes, which may contribute to the inflammatory and clinical features of the disease [21]. The relationship between eosinophils and mast cells increases the confusion in categorizing EG. Mast cells typically are thought of in allergic disease, but IgE levels in EG are not consistently elevated. Almost 30 years ago, Moon and Kleinman classified EG into three categories: mucosal, muscular, and subserosal. Mucosal EG is the most common form and is signified by mucosal infiltration of eosinophils on biopsy or gastrointestinal edema on radiographic study [22]. Muscular EG is defined by eosinophilic infiltration of the muscular layer of the intestine and is associated with stenosis or obstruction of the gastrointestinal tract without ascites. Serosal EG is the least common form of EG and represents eosinophilic infiltration of the serosal layer associated with eosinophilic ascites. The diagnosis of EG is often missed. Biopsy results do not always coincide with the clinical picture, perhaps because of the patchy nature of the disease or the possibility of not identifying an eosinophilia with random intestinal biopsy. Mucosal EG has been reported to affect any portion of the gastrointestinal tract. In the majority of cases, the gastric antrum and small bowel are affected, resulting in nausea, vomiting, and epigastric pain. Patients with muscular EG present with symptoms of gastrointestinal obstruction or dysmotility. The muscular layer of the gastric antrum is most commonly affected and typically causes vomiting, abdominal pain, and delayed gastric emptying. Involvement of the small intestine and colon is less likely. Patients with serosal EG present with symptoms from ascites or intestinal perforation. Extraintestinal infiltration has also been described. In contrast to other forms of EG, eosinophilic colitis or proctitis commonly represents sensitivity to cow’s milk or soy protein, and symptoms abate with elimination of the offending antigen. Infants affected by this type of EG commonly lack systemic symptoms, leading to speculation that this disease may be a separate entity. In 1986, Goldman and Proujansky [7] reviewed 53 cases of allergic proctitis and gastroenteritis in children. Thirty-eight patients were identified as having symptoms and biopsy findings consistent with EG. Of the 38 patients with EG, all were found to have a mucosal eosinophilia of the gastric antrum. Seventy-nine percent also

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demonstrated a mucosal eosinophilia of the small intestine (duodenum), 60% had esophageal involvement, and in 52% eosinophilia was found in the gastric corpus. The majority of these patients had upper and lower gastrointestinal symptoms with multiple relapses, and many required corticosteroid therapy. In contrast, the remaining 15 patients were diagnosed with allergic proctitis. The majority of these children were aged less than 6 months and responded to dietary change without relapse. While the gastric antrum appears to be the most common location of disease, the patchy nature of the disease and the lack of full-thickness specimens on most endoscopic biopsies can lead to false negative biopsy results.

Eosinophilic Esophagitis In 1995, Kelly [23] reported on a group of children with esophageal eosinophilia who did not respond to antireflux therapy but instead improved on an amino-acid-based formula. This study involved ten patients with histologic esophagitis who were diagnosed with reflux esophagitis and who failed pharmacologic therapy. Six patients had a persistent esophageal eosinophilia despite undergoing a Nissen fundoplication. Only one patient had a 24-h pH probe performed, which showed no evidence of reflux. These patients were subsequently placed on a strict diet consisting of an amino-acidbased formula for a median of 17 weeks. Symptomatic improvement was seen with an average of 3 weeks after the introduction of the elemental diet (resolution in eight patients, improvement in two). In addition, all ten patients demonstrated a significant improvement in esophageal eosinophilia. Subsequently, all patients reverted to previous symptoms upon reintroduction of foods. While an exact etiology was not determined, Kelly suggests an immunologic basis, either a delayed hypersensitivity or a cell-mediated hypersensitivity response, as the cause for eosinophilic esophagitis. Liacouras confirmed the presence of EoE in 1998. He [24] identified 20 of 214 patients presenting with symptoms and histologic abnormalities suggestive of gastroesophageal reflux disease who remained symptomatic despite the use of H2-blockers, proton pump inhibitors, and prokinetic agents [25]. All of these patients had an isolated severe eosinophilic infiltration of the distal esophagus (mean of 34 ± 10 eosinophils/hpf) with normal antral/duodenal histology and minimal to no acid reflux by 24-h pH probe monitoring. Upon introduction of oral corticosteroids, 19 of 20 patients showed rapid improvement in clinical symptoms (average of 8 ± 3.5 days), and all 20 displayed histologic resolution of their esophageal eosinophilia within 1 month after being placed on corticosteroids. While corticosteroid therapy provides quick relief of symptoms and resolution of esophageal eosinophilia within 1 month, prolonged steroid therapy is not recommended. If symptoms recur soon after discontinuing steroid therapy (weeks to months), a strict elemental diet therapy should be instituted. However, if symptoms recur more than 1 year later, repeat short courses of corticosteroids are suggested. Shortly thereafter, several other treatment regimens have been reported. One case report in 1998 demonstrated rapid clinical improvement after treatment with topical corticosteroids [25]. Patients were instructed to use inhaled corticosteroids

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but to immediately swallow after inhalation in order to deliver the medication to the esophagus. Histologic improvement was not determined. The mast-cell-stabilizing agent cromolyn sodium has also been tried in children with EoE. In similar fashion to its use for children with EG, oral cromolyn has been given to patients with a severe esophageal eosinophilia in conjunction with other systemic signs and symptoms of allergic disease. However, no controlled reports have been performed, and efficacy for oral cromolyn in children with EoE has not been established. Surgical antireflux procedures were shown not to be effective in controlling patients with EoE. Liacouras [26] documented two cases of failed Nissen fundoplication in patients with symptoms suggestive of gastroesophageal reflux unresponsive to aggressive antireflux medication. In both cases, the symptoms and abnormal esophageal pathology remained after surgery. Physicians should not assume that chronic distal EoE results from acid reflux. In these cases, it is imperative that a 24-h pH probe be performed, and, if results are markedly abnormal, antireflux surgery might be considered. On the other hand, if the pH probe is normal or mildly abnormal, then the diagnosis of EoE is strongly suggested. Liacouras [24] demonstrated that the clinical and histologic features of eosinophilic esophagitis may evolve over years. Of 20 children with eosinophilic esophagitis, five patients did not show a severe esophageal eosinophilia on initial endoscopy. Each of these patients, however, demonstrated a severe esophageal eosinophilia on repeat endoscopy after failure of anti-reflux medication. In all of these patients, esophageal histology demonstrated more than 20 eosinophils/hpf. Initially, most of the clinical and basic research related to EoE was generated by pediatric gastroenterologists. The reason for this was likely based on the fact that pediatric gastroenterologists almost always performed mucosal biopsies regardless of the visual appearance of the gastrointestinal mucosa. Additionally, a number of children diagnosed with EoE often are fed a routine infant formula thereby allowing an easier transition to an amino-acid based formula. From 2000 to 2005, a number of pediatric gastroenterologists and allergists contributed important work to the understanding of EoE. Noel published information on the incidence of EoE [27], Rothenberg, Furuta, and Mishra contributed important information on pathophysiology [28–30], Putnam, Gupta, and Markowitz added information on the clinical manifestations [31–33] and Spergel and Aceves wrote articles on the allergic manifestations and treatment [34, 35]. Moreover, EoE became a major interest in adult patients. Straumann published the first notable work on the incidence, diagnosis and treatment of EoE [36]. In addition, Katzka reported on the clinical presentation, diagnosis, and treatment of EoE [37] while Hirano and Gonsalvas published information on dietary and medical therapy of EoE in adults [38, 39].

FIGERS In 2005, because of the significant increase in the number of articles related to EoE appearing in the literature and the enhanced interest among clinicians, a working group of pediatric and adult physicians spanning multiple specialties was created.

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The idea for this group was to develop cohesive guidelines in order to create a definition, diagnostic techniques, and therapies for individuals with EoE. The working group included pediatric and adult gastroenterologists, allergists, pathologists, and basic scientists. After a year of literature review, teleconferences and face-to-face meetings, the first international gastrointestinal eosinophilic research symposium (FIGERS) was held in October 2006 at the annual meeting held by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). During the meeting, more than 50 specialists were invited to participate in the development of EoE guidelines. In addition, over 300 NASPGHAN members also attended the conference as observers. During the discussion of EoE, the topics included definitions, pathophysiology, incidence, epidemiology, genetics, diagnosis, endoscopic techniques, histology, allergy evaluation, therapy and future research. This conference provided invaluable information and was the framework for the EoE Consensus statement published in Gastroenterology in 2007 [40].

TIGERS Following the FIGERS conference in 2007, physicians realized that a great deal of information was still unknown about many of the topics related to EoE. In addition, the literature on EoE was still rapidly growing. Thus, a subset of invited specialists formed a working group, The International Gastrointestinal Researchers (TIGERS), to not only respond to many of the unanswered questions left over from FIGERS but also to help develop future guidelines, research ideas and proposals related to EoE. Since that time, the members of TIGERS have increased worldwide knowledge of EoE in many ways. Their members created an EoE slide set used by more than 100 physicians to provide lectures and educations to clinicians all over the world. Moreover, they have helped to fund research grants to aid young scientists interested in advancing EoE knowledge, conducted research to help identify a possible genetic link in individuals with EoE, set up additional symposiums and meeting for several other international organizations, and helped to bring the study of EoE to the forefront among gastroenterologists, allergists, and pathologists worldwide.

Future EoE has become a major focus of interest among gastroenterologists, allergists, and pathologists over the last 15 years. Initially thought of as a rare disease limited to a few children receiving gastrostomy feedings in a specific locale, we now know that the occurrence of EoE is much more common than initially thought and is increasing in frequency worldwide. From only a few published articles a year in 1997, the literature on EoE has expanded to include more than 125 published peer-reviewed articles in 2009. The names of the authors and physicians listed in this chapter have not only contributed a great deal of knowledge to the understanding of EoE but also

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brought EoE to the forefront of National Medical Associations such as the AAAAI, the AGA, the ASGE, and the NASPGHAN. Because of the increasing interest in EoE, further research is required in this ever-increasing population of patients and the final chapter on the history of the disease has yet to be written.

References 1. Ismail-Beigi F, Horton PF, Pope CE. Histological consequences of gastroesophageal reflux in man. Gastroenterology. 1970;58:163–74. 2. Behar J, Sheahan DC. Histologic abnormalities in reflux esophagitis. Arch Pathol Lab Med. 1975;99:387–91. 3. Seefeld U, Krejs GJ, Siebenmann RE, et al. Esophageal histology in gastroesophageal reflux. Morphometric findings in suction biopsies. Dig Dis Sci. 1977;22:956–9. 4. Johnson LF, Demeester TR, Haggitt RC. Esophageal epithelial response to gastroesophageal reflux. A quantitative study. Dig Dis Sci. 1978;23:498–502. 5. Winter HS, Madara JL, Stafford RJ. Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology. 1982;83:818–23. 6. Brown LF, Goldman H, Antonioli DA. Intraepithelial eosiniophilis in endoscopic biopsies of adults with reflux esophagitis. Am J Surg Pathol. 1984;8:899–905. 7. Goldman H, Proujansky R. Allergic proctitis and gastroenteristis in children: clinical and mucosal biopsy features in 53 cases. Am J Surg Pathol. 1986;10:75–86. 8. Dobbins JW, Sheahan DG, Behar J. Eosinophilic gastroenteritis with esophageal involvement. Gastroenterology. 1977;72:1312–6. 9. Landres RT, Kuster GGR, Strum WB. Eosinophilic esophagitis in a patient with vigorous achalasia. Gastroenterology. 1978;74:1298–301. 10. Matzinger MA, Daneman A. Esophageal involvement in eosinophilic gastroenteritis. Pediatr Radiol. 1983;13:35–8. 11. Lee RG. Marked eosinophilia in esophageal mucosal biopsies. Am J Surg Pathol. 1985;9:475–9. 12. Teele RL, Katz AJ, Goldman H, Kettle RM. Radiographic features of eosinophilic gastroenteritis (allergic gastroenteropathy) of childhood. AJR Am J Roentgenol. 1979;132:575–80. 13. Picus D, Frank PH. Eosinophilic esophagitis. AJR Am J Roentgenol. 1981;136:1001–3. 14. Feczko PJ, Halpert RD, Zonca M. Radiologic abnormalities in eosinophilic esophagitis. Gastrointest Radiol. 1985;10:321–4. 15. Attwood SEA, Smyrk TC, Demeester TR, Jones JB. Esophageal eosinophilia with dysphagia: a district clinicopathologic syndrome. Dig Dis Sci. 1993;38:109–16. 16. Vitellas KM, Bennett WF, Bova JG, et al. Radiographic manifestations of eosinophilic gastroenteritis. Abdom Imaging. 1995;20:406–13. 17. Levine MS, Saul SH. Idophatic eosinophilic esophagitis: how common is it? Radiology. 1993;186:631–2. 18. Ruchelli E, Wenner W, Voytek T, et al. Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy. Pediatr Dev Pathol. 1999;2:15–8. 19. Wershill BK, Walker WA. The mucosal barrier, IgE-mediated gastrointestinal events, and eosinophilic gastroenteritis. Gastroenterol Clin North Am. 1990;21:387–402. 20. Cello JP. Eosinophilic gastroenteritis – a complex disease entity. Am J Med. 1979; 67:1097–104. 21. Sawaya SM, Misk RJ, Aftimos GP. Eosinophilic gastroenteritis: report of two cases and comment on the literature. Eur J Surg. 1992;158:439–41. 22. Moon A, Kleinman RE. Allergic gastroenteropathy in children. Ann Allergy Asthma Immunol. 1995;74:5–9.

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23. Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology. 1995;109:1503–12. 24. Liacouras CA, Wenner WJ, Brown K, Ruchelli E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr. 1998;26:380–5. 25. Faubion Jr WA, Perrault J, Bugart LF, et al. Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr. 1998;27:90–3. 26. Liacouras CA. Failed Nissen fundoplication in two patients who had persistent vomiting and eosinophilic esophagitis. J Pediatr Surg. 1997;32:1504–6. 27. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. 2004;51(9):940–1. 28. Rothenberg ME, Mishra A, Collins MH, Putnam PE. Pathogenesis and clinical features of eosinophilic esophagitis. J Allergy Clin Immunol. 2001;108(6):891–4. 29. Furuta GT. Clinicopathologic features of esophagitis in children. Gastrointest Endosc Clin N Am. 2001;11(4):683–715. 30. Mishra A, Hogan SP, Brandt EB, Rothenberg ME. IL-5 promotes eosinophil trafficking to the esophagus. J Immunol. 2002;168(5):2464–9. 31. Noel RJ, Putnam PE, Collins MH, Assa’ad AH, Guajardo JR, Jameson SC, et al. Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2004;2(7):568–75. 32. Lim JR, Gupta SK, Croffie JM, Pfefferkorn MD, Molleston JP, Corkins MR, et al. White specks in the esophageal mucosa: an endoscopic manifestation of non-reflux eosinophilic esophagitis in children. Gastrointest Endosc. 2004;59(7):835–8. 33. 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(4):777–82. 34. 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(2):363–8. 35. Aceves SS, Dohil R, Newbury RO, Bastian JF. Topical viscous budesonide suspension for treatment of eosinophilic esophagitis. J Allergy Clin Immunol. 2005;116(3):705–6. 36. Straumann A, Spichtin HP, Grize L, Bucher KA, Beglinger C. Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology. 2003;125(6):1660–9. 37. Katzka DA. Eosinophilic esophagitis. Curr Treat Options Gastroenterol. 2003;6(1):49–54. 38. Stevoff C, Rao S, Parsons W, Kahrilas PJ, Hirano I. EUS and histopathologic correlates in eosinophilic esophagitis. Gastrointest Endosc. 2001;54(3):373–7. 39. Gonsalves N, Policarpio-Nicolas M, Zhang Q, Rao MS, Hirano I. Histopathologic variability and endoscopic correlates in adults with eosinophilic esophagitis. Gastrointest Endosc. 2006;64(3):313–9. 40. Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342–63.

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Chapter 2

Epidemiology, Incidence, and Prevalence of EoE in Children Richard J. Noel

Keywords %OSINOPHILIC ESOPHAGITIS s 'ASTROESOPHAGEAL REmUX DISEASE s %PIDEMIOLOGYOF%O%s$EMOGRAPHICDESCRIPTORSOF%O%

Introduction Few pediatric diseases have produced similar volumes of clinical and basic research data in as short a time as eosinophilic esophagitis (EoE). Once believed to be a rare DISORDERTHATPOSSIBLYREPRESENTEDRECALCITRANTGASTROESOPHAGEALREmUXDISEASE %O% is now known to be a unique entity with a specific transcriptional signature, epidemiologic descriptors, histologic features, and treatments. This chapter delineates the epidemiology of pediatric EoE, including demographic descriptors and measures of frequency.

Esophageal Mucosal Eosinophilia in Pediatric Patients Unlike other segments of the gastrointestinal tract, the healthy esophageal epithelium has essentially no intraepithelial eosinophils. This finding has been documented by both cadaveric studies, and retrospective review of biopsies without pathologic diagnoses [1, 2]. When Winter et al. in 1982 described intraepithelial eosinophils on esophageal biopsies that correlated with abnormal pH probe studies, the esophageal mucosal eosinophil was identified as a marker for peptic esophagitis [3].

R.J. Noel (*) Division of Gastroenterology, Department of Pediatrics, Medical College of Wisconsin, 9000 W. Wisconsin Avenue, Milwaukee, WI 53226, USA e-mail: [email protected] C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_2, © Springer Science+Business Media, LLC 2012

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The concept that esophageal mucosal eosinophilia was not solely due to peptic DISEASEDEVELOPEDOVERTIME!PPROXIMATELYADECADEAFTER7INTERSOBSERVATIONS key studies by Attwood et al. [4] and Kelly et al. [5] suggested that high-grade esophageal mucosal eosinophilia may indicate a process distinct from peptic disEASEBECAUSETHEINmAMMATIONPERSISTEDDESPITETHERAPIESTHATMINIMIZEDESOPHAGEALACIDEXPOSURE2UCHELLIETALLATERNOTEDTHATTHEHIGHERDEGREEOFEOSINOPHILIA appeared to distinguish EoE from peptic disease [6]. This distinction was further supported by studies that documented EoE in patients with normal pH probe results [7]. Recent studies have noted a specific transcriptional signature [8] and unique histologic features [9= THAT DISTINGUISH %O% FROM OTHER ESOPHAGEAL INmAMMATORY processes. A systematic review of the literature in 2007 led to consensus recommendations that provided a definition for EoE according to histologic and clinical criteria, including a peak eosinophil density of 15 eosinophils per 400× microscopic field in the absence of evidence of peptic disease [10].

Epidemiologic Data in Pediatric EoE To date, two population-based studies on pediatric EoE have been published [11, 12]. Other retrospective series have provided demographic estimates from referral population from specific regions, including Western Australia and West Virginia [13, 14]. Additionally, large cohorts of referral patients are tracked at both the Cincinnati #HILDRENS(OSPITAL-EDICAL#ENTERAND#HILDRENS(OSPITALOF0HILADELPHIA;15, 16]. Other series have utilized survey results, from both patients and providers alike, to estimate demographic parameters of pediatric EoE [17, 18=$ATAWEREALSOEXTRAPOlated from case series whose intent was to describe a specific treatment or feature of EoE. Notably, regardless of the study type or geographic origin, demographic descriptors of the pediatric EoE population remain consistent across the literature, and support the case that EoE is a distinct diagnostic entity.

Geographic Distribution of EoE EoE affects children throughout the world. An internet-based patient survey tool provided data from 107 surveys that originated in multiple countries, including Canada, England, China, Israel, and the USA (32 states included) [17]. A survey of a national pathology database described 363 cases of EoE (42 pediatric) diagnosed in 26 of 34 states from which specimens were submitted [19]. A physician survey of EoE with 1,801 respondents noted cases in four regions of the USA (Northeast, Midwest, South, and West), with the highest prevalence rates in the Northeast [18]. EoE has also been reported in many European countries (Belgium, Denmark, France, Greece, Italy, the Netherlands, Spain, and Sweden), South and Central America !RGENTINA "RAZIL AND-EXICO *APAN .EW:EALAND AND!USTRALIA;10, 13, 20]. No cases of primary (allergic) EoE have been reported from the African continent.

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Age at Diagnosis The average age of diagnosis for pediatric EoE is between 6 and 10 years of age. 4HE TWO POPULATION BASED STUDIES PLACE THE AVERAGE AGE OF DIAGNOSIS AT APPROXImately 10 years of age [11, 12]. The larger Philadelphia referral cohort has a younger age of diagnosis, estimated at 6 years of age [16]. It is likely that many children with EoE have symptoms for years before the diagnosis is made. A retrospective series of 20 patients with EoE had a mean time between onset of symptoms and diagnosis of EoE of 4.5 ± 3.5 years (mean ± standard deviation) [21]. It is therefore clear that DATA REGARDING AGE OF DIAGNOSIS MAY NOT REmECT THE ACTUAL ONSET OF DISEASE Furthermore, it has been well established that children with EoE may not have SYMPTOMSTHATPARALLELTHEIRESOPHAGEALINmAMMATION;22], allowing for the occaSIONALUNEXPECTEDDIAGNOSISOF%O%MADEINANASYMPTOMATICPATIENT

Sex Distribution 7ITHOUTEXCEPTION LARGECASESERIESANDPOPULATION BASEDSTUDIESOF%O%DOCUMENT a large male predominance among their cohorts or study populations (Table 2.1). The two population-based studies of pediatric EoE describe male percentages of 71 and 65.2% [11, 12]. The large Philadelphia 14-year referral cohort is 75% male [16]. Multiple studies highlighting treatments or specific clinical features of EoE going back to 1997 also have a marked male predominance with percentages ranging from 70 to 92% [23–27]. Although a male predominance is consistent in pediatric EoE, its implications as to etiology, disease course, or outcome is unknown.

Presenting Symptoms Unlike the adult presentation of the disease where dysphagia and food impaction constitute the predominant presenting symptoms, the pediatric presentation of EoE varies dramatically across the pediatric age range (Table 2.2). Two studies, including a population-based study of Hamilton county (Cincinnati) [11] and a review of a large referral population (Philadelphia) [16] best highlight the evolution of symptoms across the pediatric age range. The youngest EoE patients present with feeding disorders characterized by feeding refusal and vomiting, sometimes associated with failure to gain weight. These youngest EoE patients may develop profound feeding aversion and require interdisciplinary care to guide feeding skill acquisition as the EoE is addressed medically [28]. Young children with feeding disorders may also be initially evaluated by otolaryngologists or speech and language pathologists who may not be aware of EoE [29]. In younger school-age children, the primary symptoms evolve to vomiting and abdominal pain. By adolescence, the disease mirrors that of adults with dysphagia and recurrent food impactions [30]. The fact that both

Table 2.1 Summary of publications with generalizable pediatric EoE epidemiologic data Guajardo et al. [17] Noel et al. [11] Cherian et al. [13] !SSAAD;4] Type Patient self-report Population-based Referral Referral survey population population Year 2002 2004 2006 2007 Cases 39 103 296 89 Mean age (years) 8 10.5 6.58 6.2 % Male 82 71 66.2 78.6 Gill et al. [14] Referral population 2007 44 9.0 63

Spergel et al. [16] Referral population 2008 620 6.2 75

2009 23 10 65.2

Prasad et al. [12] Population-based

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Table 2.2 Publications describing presenting symptoms of pediatric EoE according to fraction and population and/or patient age Guajardo et al. Noel et al. !SSAAD Gill et al. Spergel Prasad et al. [17] [11] [4] [14] [16] [12] Cases 39 103 89 44 620 23 Presenting % Median age Mean age % Median age % symptoms (%) (%) (%) Feeding NA 2 (13.6) 1 (3) NA 2.8 (19) NA disorder Vomiting 54 8.1 (26.2) 3.2 (59.5) 43 5.1 (25.4) 43.5 Abdominal 21 12 (26.2) 4.9 (24.7) 55 9 (14.1) 30.4 pain Dysphagia 36 13.4 (27.2) 4.3 (15.7) 9 11.1 (10) 60.9 Food 36 16.8 (6.8) 8.8 (6.7) NA 21.7 impaction Data are presented according to manner in which they are reported in the publication and include population percentage alone, median age and population percentage, or mean age and population percentage

Table 2.3 Publications describing racial breakdown of pediatric EoE populations !SSAAD;4] Spergel [16] Cases 89 620 Racial breakdown % White 94.4 90 % AA 4.5 4 % Asian NA 3

referral and population-based studies demonstrate similar progressions of symptoms over advancing age suggests that these features can be generalized to whole of pediatric EoE. Eventually, prospective cohort studies may be required to achieve a more precise understanding of how EoE symptoms evolve as children grow into adults.

Racial Distribution ,IMITEDDATAEXISTREGARDINGRACIALDISTRIBUTIONOF%O%4ABLE2.3). The issue has been best addressed by the large Philadelphia cohort and an 8-year retrospective study from Cincinnati [15, 16]. Both studies describe a large white predominance in the population (90–94.4%), with African-American and Asians representing only 4 and 3%, respectively. This distribution differs from that of asthma in North American populations, which occurs with greater frequency in African-Americans (15.8%) vs. whites (7.3%), Asians (6%), and Latinos (3.9%) [31]. Whether these DATATRULYREmECTACTUALRACIALDIFFERENCESIN%O%SUSCEPTIBILITYORUNDERREPORTINGOF minority EoE remains to be determined.

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Table 2.4 Publications describing prevalence of atopic disease in populations of children with EoE Guajardo Noel Gill Prasad et al. [17] et al. [11] !SSAAD;15] et al. [14] Spergel [16] et al. [12] Cases 39 103 89 44 620 23 64 57.4 NA 32 61 53.8 % Atopy, seasonal allergy, or rhinoconjunctivitis % Asthma 38 36.8 NA NA 50 63.6 % Eczema 26 NA NA NA 21 % Food allergic NA 46 75 NA NA 57.1

Association with Atopic Disease Compared with the general population, the frequency of atopic disease is much higher in patient populations with EoE (Table 2.4). While estimates vary, demographic studies of atopic diseases in children report a prevalence of 6% for asthma, 15% for allergic rhinitis, 10% for eczema, and 3% for food allergy [32–34]. In COMPARISON PREVALENCEOF%O%INPEDIATRICPOPULATIONSUNIFORMLYEXCEEDEDTHESE POPULATIONBASELINES4HE(AMILTON#OUNTY%O%POPULATIONEXCEEDEDPOPULATION prevalences by 6-, 3.8-, and 15-fold for asthma, rhinitis, and food allergy, respectively [11=4HEREFERRAL%O%POPULATIONFROM0HILADELPHIAEXCEEDEDPOPULATIONSTANDARDS by 8.3-, 4-, and 2-fold for asthma, rhinitis, and eczema, respectively [16]. While the EXACT MECHANISM FOR THE STRONG ASSOCIATION WITH ATOPIC DISEASE IS UNKNOWN IT IS LIKELYTHAT%O%ANDOTHERATOPICDISEASESSHARECOMMON4HINmAMMATORYMEDIAtors. Outside of animal models [35= NO DATA EXIST TO SUGGEST THE MECHANISM BY which asthma (or any other atopic process) promotes EoE in children.

Airborne Allergens and Seasonal Variation in EoE The promotion of EoE by a respiratory allergen was first demonstrated in a mouse model that developed EoE in response to intra-tracheal Aspergillus fumigatus sensiTIZATION THAT INVOLVED INTERLEUKIN  AND EOTAXIN ;36]. Subsequent animal data propose a further connection between the respiratory tract and esophagus by demonstrating that intra-tracheal interleukin-13 deposition can produce esophageal mucosal eosinophilia suggestive of EoE [35]. A human corollary to this concept was described in a case report from 2003 that described a 21-year-old female with no detectable dietary allergen sensitivities, but multiple environmental allergies, including trees, grasses, ragweed, Aspergillus, cat, dog, and dust mite. Over a course of 4 years, she underwent five diagnostic upper endoscopies and had significant esophageal mucosal eosinophilia only in May and September during specific pollen seasons. This case supported the notion that airborne allergens, like dietary allergens, can drive EoE in sensitized individuals

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WHO SWALLOW THE ALLERGENS OR CYTOKINES FROM THE NASO OROPHARYNX AND POSSIBLY directly activate the respiratory tract. Studies in atopic adults have also documented low-level esophageal mucosal eosinophilia during the pollen season that, alone, does not constitute EoE, but can contribute by raising the level of esophageal eosinophil recruitment [37]. The phenomenon of seasonal variation in levels of esophageal eosinophilia was described in a retrospective analysis of a referral population of 234 children with EoE [38]. In this study, the authors noted that during the winter months, they observed the lowest diagnostic frequency, as well as a trend toward lower severity of mucosal eosinophilia. Similarly in a population-based 30-year study of EoE patients in Olmstead County, MN [12], the highest frequency of diagnosis occurred in the summer/fall and the lowest in the winter months when the pollen counts were highest and lowest, respectively. Taken together, these data strongly support a contribution, if not the core cause for EoE, from airborne allergens. However, these data do cannot establish a causal mechanism for the role of airborne allergens in human EoE to a similar degree as that of amino acid-based formulas for dietary allergens [39]. These data suggest that EoE may point to a larger “allergy epidemic” and may not be a disease limited to the gastrointestinal tract. This topic is addressed in the consensus recommendations that patients with EoE receive comprehensive evaluation and management of atopic disease [10].

Frequency Metrics 4HREESTUDIESHAVEESTIMATEDTHEPEDIATRICDISEASEPREVALENCEATAPPROXIMATELY per 100,000 (Table 2.5) [11, 12, 18]. Compared with other well-established diseases in pediatric gastroenterology, EoE has a higher prevalence and is more likely to be ENCOUNTEREDINGENERALPRACTICE!TAREPORTEDYEARLYINCIDENCEOFAPPROXIMATELY per 100,000 pediatric population, EoE occurs more frequently than other entities such as biliary atresia [40=ANDINmAMMATORYBOWELDISEASE;41] that have an inciDENCEAPPROXIMATINGPER  The Hamilton County population-based study suggested a trend toward increasing annual incidence, from 9.09 per 100,000 in 2000, to 12.81 per 100,000 in 2003 with A PREVALENCE OF APPROXIMATELY  CASES PER   PEDIATRIC POPULATION ;11]. However, the trend for increasing incidence was not statistically significant. The data continue to be accrued in a prospective manner and will be reanalyzed in the

Table 2.5 Publications providing frequency estimates for pediatric EoE Cherian Gill Noel et al. [13] et al. [14] Book [18] et al. [11] Prevalence per 100,000 43 9 NA 52 Incidence per 100,000 12.8 NA 7.3 NA a $ATAINCLUDEBOTHPEDIATRICANDADULTSEX ANDAGE MATCHEDCASES

Prasad et al. [12]a 54 2.39

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future. The Olmstead County population-based study has noted increasing incidence FORAGEANDSEX MATCHEDCASESDESCRIBINGAPOPULATIONPREVALENCEOFCASESPER  MIXEDADULTANDPEDIATRICPOPULATION ;12]. Incidence has also increased FROMNEGLIGIBLEINnTOAPPROXIMATELYPER INn Despite these data, there may still be an element of recognition bias that contributes to a perception of increasing incidence. A systematic review of adult esophageal biopsy specimens between 1990 and 2005 found not significant increase in the frequency of biopsies with histologic features consistent with EoE and makes a case for increased recognition [42]. Conversely, a review of histologic specimens from children in Western Australia describes an 18-fold increase in prevalence over a similar time period, from 0.5 to 8.9 per 100,000 in 1995 and 2004, respectively [43]. In addition, the Philadelphia referral cohort data has shown a steady increase in EoE diagnosed in patients from Pennsylvania, New Jersey, and Delaware [16]. Ultimately, data from well-controlled, prospective, population samples will be required to answer this question in a definitive manner.

Environmental Theories for the Causation of EoE 7HILEPROGRESSHASBEENMADETOWARDEXPLAININGTHEMOLECULARANDIMMUNOLOGICAL basis of pediatric EoE [44= CHANGES IN GENE EXPRESSION PATTERN ALONE CANNOT EXPLAIN THE RAPID PACE AT WHICH %O% HAS BEEN ESTABLISHED AS A UNIQUE DISORDER Several theories implicate environmental forces as contributors to the disease onset in the pediatric population; these have been reviewed by Bonis [45]. It must be noted that these ideas, although intriguing conjectures, have not been directly tested regarding EoE.

EoE is Part of an Allergy Epidemic in the Context of the Hygiene Hypothesis Allergic disease (asthma, allergic rhinitis, atopic dermatitis) and autoimmune disease TYPE  DIABETES INmAMMATORY BOWEL DISEASE BOTH HAVE INCREASED IN PREVALENCE according to gradients of per capita gross national product and eradication of early life infectious disease [46]. The hygiene hypothesis suggests that as a population becomes wealthier, it becomes “cleaner” and previously common infectious diseases such as mumps, measles, hepatitis A, and tuberculosis are eradicated. As a consequence of improved hygiene, interaction between microbial proteins and Toll-like receptors does not occur, interfering with modulation of both Th1 and Th2 antigendriven pathways [47]. Additionally, some data suggest that eradication of Helicobacter pylori in a population is associated with development of atopic diseases [48]. Congruent with this model is the fact that the only eosinophilic esophagitis reported from the African continent is secondary to Gnathostoma spinigerum infection [49].

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Excesses or Deficiencies of Dietary Constituents Contribute to EoE Studies have identified altered dietary constituents as potential contributors to atopic DISEASE4HESEINCLUDEDECREASINGINTAKEOFANTIOXIDANTSINFRUITSANDVEGETABLES increasing intake of Z−6 polyunsaturated fatty acids, and decreasing intake of Z−3 polyunsaturated fatty acids as potential contributors to atopy in children [50]. Dietary increases in Z−6 fatty acids result in increased production of arachidonic acid and PGE2, promoting Th2 sensitization. Conversely, Z−3 fatty acids have INHIBITORY PROPERTIES ON CYCLOOXYGENASE RESULTING IN DECREASED PRODUCTION OF INmAMMATORY MEDIATORS $ECREASES IN THE ANTIOXIDANT DIETARY CONTENT HAVE ALSO BEENIMPLICATEDINTHEDEVELOPMENTOFATOPY/XIDANTSTRESSCANINDUCEPRODUCTION OFINmAMMATORYMEDIATORSTHATCANINDUCE4HCYTOKINEPRODUCTIONANDDECREASE Th2 cytokine activity.

Indiscriminate Use of Acid Suppressant Medication Contributes to EoE Acid digestion of dietary proteins interferes with binding of IgE and subsequent sensitization [51]. Theoretically, the use of proton pump inhibitors decreases the threshold for dietary protein sensitization and binding of IgE. Conversely, esophaGEAL MUCOSAL EOSINOPHILIA OCCURS AS A RESULT OF ACID REmUX DISEASE AND CAN BE reversed with acid-suppressant medications [52].

Disruption of the Esophageal Epithelial Barrier Contributes to EoE $ILATEDINTERCELLULARSPACESHAVEBEENIDENTIlEDINADULTSWITHNON EROSIVEREmUX DISEASE ALLOWINGTHEPOSSIBILITYTHATREmUX RELATEDINCREASEDINTERCELLULARPERMEABILITY MAY EXPOSE THE ESOPHAGEAL MUCOSA TO UNPROCESSED DIETARY ANTIGENS ;53]. Furthermore, microarray transcriptional studies from esophageal mucosal biopsies have identified overrepresented filaggrin loss-of-function mutations in a population of EoE patients when compared to healthy controls [54]. Filaggrins are components OFTHEGRANULARLAYEROFTHEEPIDERMISUNDEREXPRESSIONOFlLAGGRINSHASBEENASSOciated with eczema and ichthyosis vulgaris. Barrier disruption may also involve the skin and allow allergic sensitization prior to the induction of oral tolerance by introduction of proteins into the diet [55, 56].

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R.J. Noel

Constituents of Processed Food Contribute to EoE Successful treatment of EoE by amino acid-based diets and some elimination diets may be interpreted as reduction in intact dietary proteins that are recognized by IMMUNEEFFECTORS$IETARYTREATMENTMAYALSOBEINTERPRETEDASAREDUCTIONINEXPOsure to fertilizers, pesticides, antibiotics, and preservatives used in the food industry. A Dutch study reports a reduced risk in eczema in infants and toddlers who were fed diets that were 90% organic [57=&URTHERMORE IMAZAMOX RELATEDCOMPOUNDSHAVE fungicidal activity and may also function as haptens with immunogenic potential when bound to larger carrier molecules [58].

Conclusion EoE has been a dynamic disease in its short history. The fact that EoE is among the top entities listed in the differential diagnosis of adolescents with dysphagia or food impaction, or infants and toddlers with feeding disorder or vomiting with features BEYONDBENIGNINFANTILEREmUX SPEAKSVOLUMESFORTHEPEDIATRICIANSTHATHAVECONtributed to the knowledge pool since 1995. The demographic descriptors highlighted in this chapter suggest a profile for the typical patient with EoE. This patient may be a North American white male with vomiting or dysphagia, diagnosed between 6 and 10 years of age, with a personal and family history of atopic disease, including ASTHMA RHINITIS ANDFOODALLERGY7HILESUCHPATIENTSCLEARLYEXIST THEPROlLEONLY BRINGSTOGETHERPREVALENTFEATURESTHATARELIKELYTOEXISTALONGUNRELATEDAXES&UTURE research may eventually demonstrate underlying relationships between these currently disparate features. As research continues to add to the collective knowledge of pediatric EoE, our understanding of how EoE symptoms evolve in children, how specific patient factors determine long-term outcomes, and how the genetic complement of an individual and a specific population interacts with the environment to produce EoE.

References 1. Lowichik A, Weinberg AG. A quantitative evaluation of mucosal eosinophils in the pediatric gastrointestinal tract. Mod Pathol. 1996;9(2):110–4. 2. DeBrosse CW, Case JW, Putnam PE, Collins MH, Rothenberg ME. Quantity and distribution of eosinophils in the gastrointestinal tract of children. Pediatr Dev Pathol. 2006;9(3):210–8. 3. Winter HS, Madara JL, Stafford RJ, Grand RJ, Quinlan JE, Goldman H. Intraepithelial eosinoPHILSANEWDIAGNOSTICCRITERIONFORREmUXESOPHAGITIS'ASTROENTEROLOGY n 4. Attwood SE, Smyrk TC, Demeester TR, Jones JB. Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome. Dig Dis Sci. 1993;38(1):109–16. 5. Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson HA. Eosinophilic ESOPHAGITISATTRIBUTEDTOGASTROESOPHAGEALREmUXIMPROVEMENTWITHANAMINOACID BASEDFORmula. Gastroenterology. 1995;109(5):1503–12.

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6. Ruchelli E, Wenner W, Voytek T, Brown K, Liacouras C. Severity of esophageal eosinophilia PREDICTS RESPONSE TO CONVENTIONAL GASTROESOPHAGEAL REmUX THERAPY 0EDIATR $EV 0ATHOL 1999;2(1):15–8. 7. Steiner SJ, Gupta SK, Croffie JM, Fitzgerald JF. Correlation between number of eosinophils ANDREmUXINDEXONSAMEDAYESOPHAGEALBIOPSYANDHOURESOPHAGEALP(MONITORING!M J Gastroenterol. 2004;99(5):801–5.  "LANCHARD# 7ANG. 3TRINGER+& ETAL%OTAXIN ANDAUNIQUELYCONSERVEDGENE EXPRESSION profile in eosinophilic esophagitis. J Clin Invest. 2006;116(2):536–47. 9. Protheroe C, Woodruff SA, de Petris G, et al. A novel histologic scoring system to evaluate mucosal biopsies from patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2009;7(7):749–55,e711. 10. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342–63. 11. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. 2004;351(9): 940–1.  0RASAD '! !LEXANDER *! 3CHLECK #$ ET AL %PIDEMIOLOGY OF EOSINOPHILIC ESOPHAGITIS OVER three decades in Olmsted County, Minnesota. Clin Gastroenterol Hepatol. 2009;7(10):1055–61. 13. Cherian S, Smith NM, Forbes DA. Rapidly increasing prevalence of eosinophilic oesophagitis in Western Australia. Arch Dis Child. 2006;91(12):1000–4. 14. Gill R, Durst P, Rewalt M, Elitsur Y. Eosinophilic esophagitis disease in children from West Virginia: a review of the last decade (1995–2004). Am J Gastroenterol. 2007;102(10):2281–5. !SSAAD!( 0UTNAM0% #OLLINS-( ETAL0EDIATRICPATIENTSWITHEOSINOPHILICESOPHAGITIS an 8-year follow-up. J Allergy Clin Immunol. 2007;119(3):731–8. 16. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, et al. 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr. 2009;48(1):30–6. 17. Guajardo JR, Plotnick LM, Fende JM, Collins MH, Putnam PE, Rothenberg ME. Eosinophil-associated gastrointestinal disorders: a world-wide-web based registry. J Pediatr. 2002;141(4):576–81. 18. Book WM. Eosinophilic gastrointestinal disorders: disease prevalence in the United States. National Harbor, MD: NASPGHAN; 2009. 19. Kapel RC, Miller JK, Torres C, Aksoy S, Lash R, Katzka DA. Eosinophilic esophagitis: a prevalent disease in the United States that affects all age groups. Gastroenterology. 2008;134(5):1316–21. 20. Cury EK, Schraibman V, Faintuch S. Eosinophilic infiltration of the esophagus: gastroesophaGEALREmUXVERSUSEOSINOPHILICESOPHAGITISINCHILDRENnDISCUSSIONONDAILYPRACTICE*0EDIATR Surg. 2004;39(2):e4–7. 21. Noel RJ, Putnam PE, Collins MH, et al. Clinical and immunopathologic effects of swallowed mUTICASONEFOREOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOL n 22. Pentiuk S, Putnam PE, Collins MH, Rothenberg ME. Dissociation between symptoms and histological severity in pediatric eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2009;48(2):152–60. 23. Gupta SK, Fitzgerald JF, Chong SK, Croffie JM, Collins MH. Vertical lines in distal esophageal mucosa (VLEM): a true endoscopic manifestation of esophagitis in children? Gastrointest Endosc. 1997;45(6):485–9. 24. 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 Gastroenterol. 2000;95(6): 1422–30.  4EITELBAUM*% &OX6, 4WAROG&* ETAL%OSINOPHILICESOPHAGITISINCHILDRENIMMUNOPATHOLOGICALANALYSISANDRESPONSETOmUTICASONEPROPIONATE'ASTROENTEROLOGY n 26. 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(2):363–8. 27. Khan S, Orenstein SR, Di Lorenzo C, et al. Eosinophilic esophagitis: strictures, impactions, dysphagia. Dig Dis Sci. 2003;48(1):22–9.

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28. Pentiuk SP, Miller CK, Kaul A. Eosinophilic esophagitis in infants and toddlers. Dysphagia. 2007;22(1):44–8.  3MITH,0 #HEWAPROUG, 3PERGEL*- :UR+"/TOLARYNGOLOGISTSMAYNOTBEDOINGENOUGHTO diagnose pediatric eosinophilic esophagitis. Int J Pediatr Otorhinolaryngol. 2009;73(11):1554–7. 30. Focht DR, Kaul A. Food impaction and eosinophilic esophagitis. J Pediatr. 2005;147(4):540. 3IMON0! :ENG: 7OLD#- (ADDOCK7 &IELDING*%0REVALENCEOFCHILDHOODASTHMAAND associated morbidity in Los Angeles County: impacts of race/ethnicity and income. J Asthma. 2003;40(5):535–43. *OHNSON## /WNBY$2 :ORATTI%- !LFORD3( 7ILLIAMS,+ *OSEPH#,%NVIRONMENTAL epidemiology of pediatric asthma and allergy. Epidemiol Rev. 2002;24(2):154–75.  &ENNESSY - #OUPLAND 3 0OPAY * .AYSMITH + 4HE EPIDEMIOLOGY AND EXPERIENCE OF ATOPIC eczema during childhood: a discussion paper on the implications of current knowledge for health care, public health policy and research. J Epidemiol Community Health. 2000;54(8):581–9. 34. Sampson HA. Update on food allergy. J Allergy Clin Immunol. 2004;113(5):805–19,quiz 820. 35. Mishra A, Rothenberg ME. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, EOTAXIN  AND34!4 DEPENDENTMECHANISM'ASTROENTEROLOGY n 36. Mishra A, Hogan SP, Brandt EB, Rothenberg ME. An etiological role for aeroallergens and EOSINOPHILSINEXPERIMENTALESOPHAGITIS*#LIN)NVEST n /NBASI+ 3IN!: $OGANAVSARGIL" /NDER'& "OR3 3EBIK&%OSINOPHILINlLTRATIONOFTHE OESOPHAGEAL MUCOSA IN PATIENTS WITH POLLEN ALLERGY DURING THE SEASON #LIN %XP !LLERGY 2005;35(11):1423–31. 38. Wang FY, Gupta SK, Fitzgerald JF. Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children? J Clin Gastroenterol. 2007;41(5):451–3. 39. 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(4):777–82. 40. Yoon PW, Bresee JS, Olney RS, James LM, Khoury MJ. Epidemiology of biliary atresia: a population-based study. Pediatrics. 1997;99(3):376–82. 41. Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of CHILDRENWITHNEWLYDIAGNOSEDINmAMMATORYBOWELDISEASEIN7ISCONSINASTATEWIDEPOPULAtion-based study. J Pediatr. 2003;143(4):525–31. 42. Vanderheyden AD, Petras RE, DeYoung BR, Mitros FA. Emerging eosinophilic (allergic) esophagitis: increased incidence or increased recognition? Arch Pathol Lab Med. 2007;131(5): 777–9. 43. Potter JW, Saeian K, Staff D, et al. Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features. Gastrointest Endosc. 2004;59(3):355–61. 44. Rothenberg ME. Biology and treatment of eosinophilic esophagitis. Gastroenterology. 2009;137(4):1238–49. 45. Bonis PA. Putting the puzzle together: epidemiological and clinical clues in the etiology of eosinophilic esophagitis. Immunol Allergy Clin North Am. 2009;29(1):41–52,viii. 46. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002;347(12):911–20. 47. Vercelli D. Mechanisms of the hygiene hypothesis–molecular and otherwise. Curr Opin Immunol. 2006;18(6):733–7. 48. Blaser MJ, Chen Y, Reibman J. Does Helicobacter pylori protect against asthma and allergy? Gut. 2008;57(5):561–7. 49. Muller-Stover I, Richter J, Haussinger D. Infection with Gnathostoma spinigerum as a cause of eosinophilic oesophagitis. Dtsch Med Wochenschr. 2004;129(38):1973–5. $EVEREUX' 3EATON!$IETASARISKFACTORFORATOPYANDASTHMA*!LLERGY#LIN)MMUNOL 2005;115(6):1109–17,quiz 1118. 51. Untersmayr E, Jensen-Jarolim E. The role of protein digestibility and antacids on food allergy outcomes. J Allergy Clin Immunol. 2008;121(6):1301–8,quiz 1309–1310.

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.GO 0 &URUTA '4 !NTONIOLI $! &OX 6, %OSINOPHILS IN THE ESOPHAGUSnPEPTIC OR ALLERGIC eosinophilic esophagitis? Case series of three patients with esophageal eosinophilia. Am J Gastroenterol. 2006;101(7):1666–70. 53. Orlando LA, Orlando RC. Dilated intercellular spaces as a marker of GERD. Curr Gastroenterol Rep. 2009;11(3):190–4. 54. Blanchard C, Stucke EM, Burwinkel K, et al. Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. J Immunol. 2010;184(7):4033–41. 55. Lack G. The concept of oral tolerance induction to foods. Nestle Nutr Workshop Ser Pediatr Program. 2007;59:63–8,discussion 68–72. 56. Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol. 2008;121(6):1331–6. 57. Kummeling I, Thijs C, Huber M, et al. Consumption of organic foods and risk of atopic disease during the first 2 years of life in the Netherlands. Br J Nutr. 2008;99(3):598–605. 58. Gunther S, Hempel D, Dunkel M, Rother K, Preissner R. SuperHapten: a comprehensive database for small immunogenic compounds. Nucleic Acids Res. 2007;35(Database issue):D906–10.

sdfsdf

Chapter 3

Epidemiology of Eosinophilic Esophagitis in Adults Petr Hruz and Alex Straumann

Keywords %OSINOPHILIC ESOPHAGITIS s %SOPHAGEAL EOSINOPHILIA s %PIDEMIOLOGY s"IOPSYs0ATHOLOGYs%NDOSCOPY

Introduction %PIDEMIOLOGYISDERIVEDFROMTHE'REEKTERMS epiAMONGdemosPEOPLEAND logosSTUDY)TISTHEDOCTRINEOFFACTORSAFFECTINGTHEHEALTHANDTHEILLNESSOFPOPULATIONS ANDSERVESASTHEFOUNDATIONANDLOGICOFANYINTERVENTIONSMADEINPUBLIC HEALTHASWELLASINCLINICALPRACTICE%PIDEMIOLOGYRELIESONANUMBEROFSCIENTIlC DISCIPLINES SUCHASMEDICINE BIOLOGY GEOGRAPHY ANDSOCIALSCIENCE 4HE RELEVANCE OF ANY GIVEN DISEASE IS PRIMARILY DETERMINED BY THE FOLLOWING THREEFACTORS ITSepidemiological cornerstones, in particular, its incidence and PREVALENCEAMONGACERTAINPOPULATION)NCIDENCEISDElNEDASTHENUMBEROFNEW CASESOFTHETARGETDISEASEINTHEPOPULATIONATRISKWITHINASPECIlEDTIMEPERIOD 0REVALENCEISTHETOTALNUMBEROFCASESWITHTHETARGETDISORDERINTHEPOPULATIONAT RISKATASPECIlCTIMEPOINT )TSnatural history, which is, per definitionem, the lNALOUTCOMEWITHOUTANYINTERVENTION ASWELLASITSCOURSEASARESULTOFTHERAPEUTICMANIPULATIONAND WHETHERAGIVENDISEASEHASANexemplary pathogenesis WHOSE UNDERSTANDING IMPROVES THE GENERAL KNOWLEDGE OF BASIC PHYSIOLOGIC AND PATHOPHYSIOLOGICMECHANISMS

!3TRAUMANN*) $EPARTMENTOF'ASTROENTEROLOGY 5NIVERSITY(OSPITAL"ASEL Basel, Switzerland 3WISS%O%2ESEARCH'ROUP 2OEMERSTRASSE 4600 Olten, Switzerland E MAILALEXSTRAUMANN HINCH C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_3, © Springer Science+Business Media, LLC 2012

25

26

0(RUZAND!3TRAUMANN

%PIDEMIOLOGYISTHEREFOREONEOFTHELEADINGFACTORSDETERMININGTHECLINICALAND SOCIO ECONOMICRELEVANCEOFANYDISEASEANDTHUS THEKNOWLEDGEOFTHEEPIDEMIOLOGICPARAMETERSOFADISEASEISCRUCIALFORIDENTIFYINGRISKFACTORSASWELLASPATHOGENETICMECHANISMS FORPLANNINGPREVENTIVEMEASURESANDFORDETERMININGOPTIMAL TREATMENTAPPROACHES %OSINOPHILICESOPHAGITIS%O% ISCLINICO PATHOLOGICALLYCHARACTERIZEDBYESOPHAGEAL SYMPTOMS IN COMBINATION WITH A DENSE ESOPHAGEAL EOSINOPHILIA BOTH OF WHICHARE INTHISDISEASE REFRACTORYTOPROTONPUMPINHIBITORS;1=)TISIMPORTANTTO BEARTHISDElNITIONINMINDWHENPERFORMINGEPIDEMIOLOGICALSTUDIESORWHENANALYZINGTHELITERATURE4ODATE ONLYLIMITEDPOPULATION BASEDEPIDEMIOLOGICINFORMATIONON%O%ISAVAILABLE4HISISBECAUSEMOSTOFTHESTUDIESPUBLISHEDHAVEBEEN BASEDONRETROSPECTIVEANALYSESOFPATHOLOGYREPORTSWITHRE EXAMINATIONSOFBIOPSY SPECIMENS ORONRETROSPECTIVEANALYSESOFENDOSCOPYREPORTS(OWEVER ITISOBVIOUS THATONLYDATAFROMGEOGRAPHICALLYCONlNEDREGIONSSUBJECTEDTOLONGITUDINALANALYSIS PROVIDETHEBASISFROMWHICHSUBSTANTIVEANDVALIDEPIDEMIOLOGICSTATEMENTSCAN BEMADE

Epidemiological Facts Prevalence of Esophageal Eosinophilia )NTHEPERIPHERALBLOODOFHEALTHYINDIVIDUALS EOSINOPHILSAREFOUNDINCONCENTRATIONSOFUPTOCELLSPERMM3 and, under physiological conditions, are additionALLYFOUNDINTHEMUCOSAOFALLAREASOFTHEDIGESTIVETRACT except the esophagus ;2, 3=4HEPRESENCEOFEOSINOPHILSINTHEESOPHAGUSISTHEREFORECOMMONLYASSOCIATED WITH DISEASE .OTABLY ESOPHAGEAL EOSINOPHILIA IS NOT EXCLUSIVELY LIMITED TO %O%)NPARTICULAR EOSINOPHILICINlLTRATIONOFTHEDISTALPARTOFTHEESOPHAGUSHAS BEEN REPORTED IN PATIENTS HAVING GASTROESOPHAGEAL REmUX DISEASE '%2$  %SOPHAGEALEOSINOPHILIATHEREFOREREQUIRESAPROCESSOFDIFFERENTIALDIAGNOSISAND CANNOT APRIORI BEEQUATEDWITHEOSINOPHILICESOPHAGITIS;4]. )N BYTAKINGENDOSCOPICBIOPSIESOFTHEDISTALESOPHAGUSFROMAMONGA RANDOM REPRESENTATIVESAMPLEn  OFTHEADULT3WEDISHPOPULATIONMEAN AGEYEARS MEN 2ONKAINENETALDETERMINEDTHEPREVALENCEOFESOPHAGEAL EOSINOPHILSINTHEGENERALPOPULATION;5=%OSINOPHILICINlLTRATIONOFTHEESOPHAGEALEPITHELIUMWASARBITRARILYCLASSIlEDAShLOWGRADEvWITHnEOSINOPHILS(0& HIGH POWER lELD hPOSSIBLE %O%v WITH n EOSINOPHILS(0& hPROBABLE %O%v with 15 to dEOSINOPHILS(0& ANDhDElNITE%O%vWHENtEOSINOPHILS(0& WERE FOUND 4HE PREVALENCE OF ANY EOSINOPHILS IN THE MOST DISTAL PARTS OF THE ESOPHAGUSWASFOUNDTOBEINTHEGENERALPOPULATION PREDOMINANTLYAMONG MEN WITHOFTHESESUBJECTSREPORTINGREmUXSYMPTOMS4HISSUGGESTS THATTHEPRESENCEOFESOPHAGEALEOSINOPHILSMAYBEMORECOMMONINTHEGENERAL POPULATION THAN EXPECTED BUT MAY ALSO BE OF AMBIGUOUS CLINICAL SIGNIlCANCE

 %PIDEMIOLOGYOF%OSINOPHILIC%SOPHAGITISIN!DULTS

27

ESPECIALLYASTHEREARENODATAABOUTTHEPREVALENCEOFEOSINOPHILSINTHEMID AND PROXIMALPORTIONSOFTHEESOPHAGUSh$ElNITE%O%vWASFOUNDINFOURCASES OFTHEGENERALPOPULATION WHERETHREESUBJECTSREPORTEDTROUBLESOMEREmUXSYMPTOMS BUTENDOSCOPICALLY NOSIGNSOFEROSIVEESOPHAGITISWERENOTED4ABLE3.1). /NLYONESUBJECTWITHhDElNITE%O%vPRESENTEDWITHASTHMAANDDYSPHAGIA WHICH WOULDSUGGESTTHATTHISPATIENTWASSUFFERINGFROMCLINICO PATHOLOGICALLYDElNED %O%h0ROBABLE%O%vWASPRESENTINANDhPOSSIBLE%O%vINSUBJECTS)NTHE GROUPOFhPROBABLE%O%v THREESUBJECTSHADREmUXSYMPTOMSANDTWOHADSIGNSOF EROSIVEESOPHAGITIS ANDINTHEhPOSSIBLE%O%vGROUP HADREmUXSYMPTOMSAND  ENDOSCOPICALLY VISIBLE EROSIVE ESOPHAGITIS RESPECTIVELY /N EVALUATION OF THE TWOBIOPSYSITESTAKENATCMABOVE ANDAT THEZ LINE THEPRESENCEOFEOSINOPHILSWASPOSITIVELYASSOCIATEDWITHEROSIVEESOPHAGITIS HIATUSHERNIA NARROWING OFTHEESOPHAGEALLUMENANDESOPHAGEALULCER THEREBYSUGGESTINGTHATTHEPRESENCEOFESOPHAGEALEOSINOPHILS ESPECIALLYINTHEDISTALESOPHAGEALPORTIONS MAY BEAMANIFESTATIONOFREmUXDISEASE

Incidence and Prevalence of Eosinophilic Esophagitis !S%O%HASBEENREPORTEDONALLCONTINENTSEXCEPTFOR!FRICA THERESEEMSTOBEA BROAD DISTRIBUTION OF THE DISEASE WORLDWIDE 3EVERAL STUDIES HAVE ADDRESSED THE INCREASINGINCIDENCEANDPREVALENCEOF%O%INTHEADULTPOPULATIONDURINGTHELAST DECADES4HREEOFTHESESTUDIESTHATEVALUATEDGEOGRAPHICALLYCONlNEDREGIONSWILL BEDISCUSSEDHERE;6n8]. Data from Australia: “Townsville County” indicator area. 4OWNSVILLE LOCATEDIN 1UEENSLAND !USTRALIA ISAGEOGRAPHICALLYISOLATEDCOMMUNITYOF PEOPLE WITHACENTRALIZEDGASTROENTEROLOGYSERVICE;6=)NARETROSPECTIVEANDOBSERVATIONAL STUDY ADULTRESIDENTSWEREDIAGNOSEDWITH%O%AFTERREVIEWOFPHYSICIANRECORDS COMPUTERIZEDENDOSCOPIC ANDHOSPITALRECORDS5PTO3EPTEMBER ATOTALOF PATIENTSHADBEENDIAGNOSEDWITH%O%4HEREWERENOPATIENTSDIAGNOSEDWITH%O% BETWEEN  AND   PATIENTS BETWEEN  AND  AND  PATIENTS BETWEEN*ANUARYAND3EPTEMBERTHISINDICATESANINCREASINGINCIDENCE OF%O%INTHISGEOGRAPHICALLYCONlNEDREGIONIN!USTRALIA!TTHEENDOF THE PREVALENCEOF%O%WASPATIENTSPER INHABITANTS4ABLE3.1). Data from Europe, Switzerland: “Olten County” indicator area. The Olten County INDICATORAREAISSITUATEDINTHENORTHWESTERNPARTOF3WITZERLAND ANINDUSTRIALIZED %UROPEANCOUNTRY;8=3OME INHABITANTSLIVEINTHISGEOGRAPHICALLYCIRCUMSCRIBEDAREATHATISSURROUNDEDBYASTATEBORDERFORTHEPASTYEARS MOSTOFTHE INDIVIDUALCOMMUNITIESHAVEBEENURBANINCHARACTER4WOBOARD CERTIlEDGASTROENTEROLOGISTSWORKINGINCLOSELYCONNECTEDREFERRALPRACTICESIN/LTEN#ITYARERESPONSIBLE FOR THE GASTROINTESTINAL ') CARE OF THIS AREA "OTH GASTROENTEROLOGISTS WORK EXCLUSIVELYANDCONSISTENTLYWITHONESINGLEPATHOLOGYCENTER/FNOTE THEREGIONHAS

n

2ETROSPECTIVE COHORT

Australia

53!

#ROESEETAL;6]

0RASADETAL;13]

n

nONGOING

0ROSPECTIVE LONGITUDINALCOHORT

Switzerland

2ETROSPECTIVE COHORT

2006

0ROSPECTIVE RANDOMCOHORT

Sweden

2ONKAINENETAL;5] Eosinophilic esophagitis 3TRAUMANNETAL;8]

t%OS(0&ENDOSCOPIC SIGNSSYMPTOMS t%OS(0&ENDOSCOPIC signs t%OS(0&SYMPTOMS

t%OS(0&

Table 3.1 0REVALENCEOFESOPHAGEALEOSINOPHILIAANDOFEOSINOPHILICESOPHAGITISPOPULATION BASEDSTUDIES Origin Study design Study period Inclusion criteria Esophageal eosinophilia

0.054

0.0156

0.013

0.4

0REVALENCE

28 0(RUZAND!3TRAUMANN

 %PIDEMIOLOGYOF%OSINOPHILIC%SOPHAGITISIN!DULTS

29

EXPERIENCEDNORELEVANTDEMOGRAPHICCHANGESANDNOSTRUCTURALCHANGESTOTHEMEDICAL SYSTEMWITHINTHEPASTDECADES3INCE %O%PATIENTSWITH00) REFRACTORYESOPHAGEALSYMPTOMS %O% CONSISTENTENDOSCOPICABNORMALITIES ANDAPEAKINlLTRATIONOF THEESOPHAGEALEPITHELIUMWITHtEOSINOPHILS(0&AREPROSPECTIVELYENROLLEDINTO ACONTINUINGCOMMUNITY BASEDDATABASE4HEDIAGNOSTICANDENROLMENTPROCEDURES HAVEREMAINEDALMOSTUNCHANGEDDURINGTHEPASTYEARS !RECENTANALYSISOFTHISDATABASESUGGESTSTHATTHEINCIDENCEANDPREVALENCEOF %O%HASBEENSUBSTANTIALLYONTHERISEDURINGTHELASTYEARS"ETWEENAND  THEANNUALINCIDENCERATEWASBETWEENANDPATIENTSPER INHABitants. Between 2004 and 2006, this rate increased to 2.7 and, during the last 3 years, ONAVERAGE HASREACHEDEIGHTNEWLYDIAGNOSEDPATIENTSPER INHABITANTSPER YEAR!SIMILARINCREASEHASBEENOBSERVEDFORTHEPREVALENCERATE WHICHRANGED BETWEENANDINTHEYEARSn4ABLE3.1 4HEREAFTER THEPREVALENCE INCREASED FROM  IN  AND WAS UP TO  PER   INHABITANTS IN  .OTABLY THETOTALNUMBEROFESOPHAGEALGASTRO DUODENOSCOPIES%'$ PERFORMED INTHEREGIONREMAINEDALMOSTSTABLEDURINGTHISPERIOD ANDTHEDIAGNOSTICDELAY TIMEBETWEENONSETOFSYMPTOMSANDDIAGNOSISOF%O% DIDNOTDECREASESUBSTANTIALLYDURINGRECENTYEARS4HISISSUGGESTIVETHATTHEINCREASEININCIDENCEANDPREVALENCEOF%O%ISDUETONEITHERANINCREASEDAWARENESSOFTHEDISEASEBYTHETREATING PHYSICIANSNORTOMOREUPPERGASTROINTESTINALTRACTENDOSCOPIESBEINGPERFORMED Data from the USA: “Olmsted County” indicator area. 3IMILARRESULTSAREREPORTED FROM/LMSTED#OUNTY AGEOGRAPHICALLYCONlNEDREGIONIN-INNESOTA53! WHICH COMPRISESABOUT PEOPLE;7=3OCIODEMOGRAPHICALLY THECOMMUNITYMIRRORS THATOFTHE53WHITEPOPULATION#OUNTYRESIDENTSRECEIVETHEIRMEDICALCAREALMOST EXCLUSIVELYFROMTWOGROUPPRACTICES#ASESWEREIDENTIlEDBYANELECTRONICSEARCH USINGTHETERMSESOPHAGITISANDFOODBOLUSIMPACTIONINTHE2OCHESTER%PIDEMIOLOGY 0ROJECTDATABASE THEMEDICALRECORDSSTORAGESYSTEMFORTHISREGION0ATIENTSHAVING tEOSINOPHILS(0&ONENDOSCOPYWITHESOPHAGEALBIOPSIESWEREINCLUDEDINTHE ANALYSIS4HECUMULATIVEAGE ANDGENDER ADJUSTEDINCIDENCERATEBETWEENAND WASn PER INHABITANTS4HEPREVALENCEOF%O%INTHIS TIMESPANWASPER INHABITANTS4ABLE3.1). Analysis clearly indicated THATTHEINCIDENCEOF%O%INCREASEDOVERTIME WITHAPRONOUNCEDINCREASEINTHELAST REPORTED YEARPERIODn 4HEDIFFERENCESINTHEINCIDENCEANDPREVALENCE RATESBETWEEN/LMSTEDAND/LTENCOUNTIESMAYBEEXPLAINEDBYTHEDIFFERENTTHRESHOLD VALUESUSEDFORTHEHISTOLOGICDIAGNOSTICCRITERIONINTHETWOSTUDIEStVSt24 EOSINOPHILS(0& RESPECTIVELY  /FNOTE THEPREVALENCEOF%O%ATTHEENDOFWASAPPROXIMATELYPATIENTSPER  INHABITANTSIN4OWNSVILLE#OUNTY !USTRALIAIN/LTEN#OUNTY 3WITZERLAND ANDIN/LMSTED#OUNTY 53! RESPECTIVELY AND CONSIDERINGTHEMETHODOLOGICAL DIFFERENCESBETWEENTHETHREESTUDIES ROUGHLYWITHINTHESAMERANGE Prevalence of EoE on upper endoscopy and/or esophageal biopsy specimens. Other ADDITIONALINFORMATIONCONCERNINGTHEPREVALENCEOF%O%ISAVAILABLEFROMSTUDIESBASED ONANALYSESOFPATHOLOGICALORENDOSCOPICDATABASESINNON GEOGRAPHICALLYDElNED regions.

30

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"ETWEEN  AND  ONE ANALYSIS FROM A 53 PROVIDER #ARIS $IAGNOSTICS )RVING 48 OFGASTROINTESTINALPATHOLOGYSERVICESFORPHYSICIANSFROMCOMMUNITY BASED INDEPENDENTENDOSCOPYCENTERSIDENTIlEDCASESOF%O%INMORETHAN  UPPERENDOSCOPIES THEREBYACHIEVINGAPREVALENCERATEOFAPPROXIMATELYPER ENDOSCOPY PERFORMED ;9= ! REEXAMINATION OF ESOPHAGEAL BIOPSY SPECIMENS FROM TOPATHOLOGYDATABASEATTHE5NIVERSITYOF0ENNSYLVANIA SHOWEDACUMULATIVE PREVALENCE OF  TEN CASES PER  REVIEWED ESOPHAGEAL BIOPSIES BUT CLEARLYMORECASESWEREIDENTIlEDINTHEYEARSn;10], again indicating an INCREASING PREVALENCE OF %O% ! PROSPECTIVE STUDY PERFORMED BETWEEN -ARCH AND 3EPTEMBERATATERTIARY53MILITARYCAREHOSPITALENROLLEDCONSECUTIVEADULT PATIENTSWHOUNDERWENTAROUTINEUPPERENDOSCOPY0ATIENTSHAD%O%IFt20 eosinoPHILS(0&WEREPRESENTINBIOPSYSPECIMENS!HIGH%O%PREVALENCERATEOFWAS REPORTED;11=/THERSTUDIESSHOWTHATPATIENTSAREDIAGNOSEDWITH%O%INnOF THECASESWHENPATIENTSAREREFERREDFORANUPPERENDOSCOPYDUETODYSPHAGIA;12, 13], AND  OF PATIENTS WITH FOOD IMPACTIONS ARE REPORTED TO HAVE %O% ;14].Younger PATIENTSYEARS WITHDYSPHAGIAAREMORELIKELYTOHAVE%O%;12, 13]. "ASEDONTHESESTUDIES WECANCONCLUDETHATTHEPREVALENCEOFADULT%O%HAS CLEARLYBEENINCREASINGINTHELASTYEARS(OWEVER STILLTOBEDETERMINEDISWHETHER THISINCREASEISBASEDONANACCUMULATIONOF%O%CASESASTHEMORTALITYFROM%O%IS LOW ORWHETHERITISBASEDONANINCREASINGINCIDENCE ASSUGGESTEDBYRECENTSTUDIES INGEOGRAPHICALLYSTABLEAREAS

Demographic Profile of EoE Patients Gender !LL CLINICAL EPIDEMIOLOGICAL ENDOSCOPIC AND PATHOLOGICAL %O% STUDIES CONCORDANTLYDEMONSTRATETHATMALESAREMUCHMORECOMMONLYAFFECTEDWITH%O%THAN FEMALES)NMOSTSTUDIES BETWEENANDOFALLCASESDIAGNOSEDAREINMALES !NALYSISOFSTUDIESWITHDETAILEDDEMOGRAPHICINFORMATIONOFADULTPATIENTSSHOWED THAT ONAVERAGE OFTHOSEAFFECTEDWEREMALES THEREBYSUGGESTINGAMALE TO FEMALERISKRATIOOF;1=)NTERESTINGLY STUDIESFOCUSINGONTHELEADING%O%SYMPTOMSOFDYSPHAGIAANDFOODIMPACTIONREPORTTHISSTRIKINGMALEPREDOMINANCEAS WELL;12, 14n16].

Age Distribution, Age at Diagnosis, Age at Onset, Diagnostic Delay %O%CANBEFOUNDINALLAGEGROUPS;9=-OSTSTUDIESINVESTIGATINGADULT%O%FOUNDAN AVERAGEAGEFORSUBJECTSWITH%O%BETWEENANDYEARS WHICHSUGGESTSTHAT%O% ISADISEASEOFMIDDLE AGEDADULTS;6n9, 11, 12=)NDEED INANATIONAL53DATABASE MOST%O%CASESIDENTIlEDWEREINPATIENTSBETWEENANDYEARSOFAGE;9].

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)NTERESTINGLY AGE AT DIAGNOSIS DOES NOT AT ALL CORRELATE WITH ONSET OF %O% ATTRIBUTEDSYMPTOMS WHICHCANBECONSIDEREDASONSETOFDISEASE3EVERALSTUDIES REPORTASUBSTANTIALTIMELAGBETWEENONSETOFSYMPTOMSANDDIAGNOSISDIAGNOSTIC DELAY WHICH INSOMECASES CANBEATTRIBUTEDTOUNAWARENESSOFSENTINELFEATURESAT ENDOSCOPY ;6= #ROESE ET AL DESCRIBE AN AVERAGE DIAGNOSTIC DELAY OF  MONTHS RANGEn 3IMILARDATAAREREPORTEDFROMTHE%UROPEANCOUNTRIESOF'ERMANY AND3WITZERLAND)N'ERMANY THEAVERAGEDURATIONBETWEENONSETOFSYMPTOMSAND lNALDIAGNOSISOF%O%WASYEARSRANGEnYEARS ;16] while in Switzerland, FORPATIENTSWITHTHEMAINSYMPTOMOFDYSPHAGIA YEARSRANGEnYEARS WAS REQUIRED ;8= /F NOTE AN UPDATED ANALYSIS FROM THE /LTEN #OUNTY 3WITZERLAND DATABASE SHOWS THAT THE AVERAGE DIAGNOSTIC DELAY IN THE YEARS  TO  WAS 4.3 years (n RANGE n AND FROM  TO   YEARS n RANGE n ANDDIDTHEREFORENOTCHANGESIGNIlCANTLY5NDERTHEASSUMPTIONOFINCREASED AWARENESSBYPHYSICIANSFORTHEDISEASEINTHELASTYEARS THISSUGGESTSTHATASUBSTANTIALPROPORTIONOFTHEDIAGNOSTICDELAYCANBEATTRIBUTEDTOTHEPATIENTSTHEMSELVESPOSTPONINGMEDICALCONSULTATION

Social Status and Education #ASESOF%O%PATIENTSHAVEBEENREPORTEDWORLDWIDEANDIDENTIlEDINAVARIETYOF ETHNIC BACKGROUNDS INCLUDING #AUCASIAN !FRICAN !MERICAN (ISPANICS AND !SIANS (OWEVER THERE ARE NO CONTROLLED DATA ABOUT GEOGRAPHIC VARIATIONS OF PREVALENCEANDITREMAINSUNCLEARWHETHER%O%ISASSOCIATEDWITHANYPARTICULAR ETHNICORRACIALPREDILECTION ESPECIALLYASMOSTOFTHEREPORTEDSTUDIESANALYZED DATAPRIMARILYFROM#AUCASIANPATIENTS)NTERESTINGLY ASTUDYINTHE53!PROSPECTIVELY ANALYZED  PATIENTS AT A TERTIARY CARE MILITARY HOSPITAL WHO UNDERWENT ROUTINE UPPER ENDOSCOPY AND DEMONSTRATED THAT THERE WAS NO SIGNIFICANT RACE DIFFERENCE BETWEEN %O% POSITIVE AND %O% NEGATIVE PATIENTS #AUCASIAN %O% VS %O%– ;11= )N THIS STUDY !FRICAN !MERICANS  WERE SLIGHTLYMOREFREQUENTLYDIAGNOSEDWITH%O%THANWERE#AUCASIANS 4HERE WERENOCASESOF%O%DIAGNOSEDAMONG(ISPANICSOR!SIANS(OWEVER BECAUSEOF THISSTUDYSHIGHOVERALL%O%PREVALENCERATEOFONROUTINEUPPERENDOSCOPY THESEDATASHOULDBEINTERPRETEDWITHCAUTION ESPECIALLYWHENCOMPAREDTOTHE GENERAL POPULATION /THER STUDIES HAVE NOT REPORTED SUCH HIGH %O% PREVALENCE rates on routine endoscopy. /NECASE CONTROLSTUDYFROMA')ANDALLERGYCOHORTANALYZINGTHESOCIODEMOGRAPHICANDGEOGRAPHICCHARACTERISTICSOFCHILDRENWITH%O%INTHE0HILADELPHIAAREA 0ENNSYLVANIA 53! DEMONSTRATEDASIGNIlCANTDIFFERENCEBETWEEN%O%PATIENTS ANDCONTROLSINTERMSOFPREDOMINANCEOF#AUCASIANRACEANDOFMALEGENDER;17]. /THER NOTABLE FACTORS IDENTIlED WERE THAT %O% PATIENTS TENDED TO LIVE IN AFmUENT ENVIRONMENTS BE BETTER EDUCATED AND RESIDE MORE OFTEN IN SUBURBAN AREAS WHEN COMPAREDTOTHECONTROLGROUPSNEVERTHELESS AFTERADJUSTMENTFORRACEANDGENDER THESEDIFFERENCESCOULDNOLONGERBECONlRMED4HESERESULTSNOTWITHSTANDING DATA

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FROM SOCIOECONOMIC DISTRIBUTION ARE SPARSE AND MORE SYSTEMATIC EVALUATIONS ARE NEEDED TO ADDRESS THE IMPORTANT QUESTIONS OF THE CONTRIBUTION OF ENVIRONMENTAL INmUENCESFORTHEDEVELOPMENTOF%O%

Atopic Disease %O% IS CHARACTERIZED AS A CHRONIC 4 HELPER  TYPE INmAMMATORY DISORDER OF THE ESOPHAGUS;18=4HEACCUMULATIONOFEOSINOPHILSINTHEESOPHAGEALWALLOF%O% PATIENTS WITH SPECIlC PATTERNS OF CYTOKINE EXPRESSION RESEMBLE THE lNDINGS IN OTHERALLERGICDISEASES;19, 20= ANDITHASBEENPROPOSEDTHATEOSINOPHILSMIGRATE TOTHEESOPHAGUSINRESPONSETOVARIOUSINGESTEDANDORINHALEDALLERGENS)NDEED PATIENTSWITH%O%AREREPORTEDTOHAVEAHISTORYOFSEASONALALLERGIESINn ASTHMAINnANDFOODALLERGIESINn;6n8, 11, 12=)NAPROSPECTIVE EVALUATION 6EERAPPANETALREPORTEDTHATTHEPREVALENCEOFASTHMAWASSIGNIlCANTLY HIGHER IN THE %O% POSITIVE GROUP THAN IN THE %O% NEGATIVE GROUP ;11]. 3IMILARLY THOUGHNOTSIGNIlCANTLYDIFFERENT SEASONALALLERGIESANDFOODALLERGIES HADAHIGHERPREVALENCEAMONGTHE%O% POSITIVEGROUP!HIGHDEGREEOFATOPY WASDESCRIBEDINACASESERIESOFADULT%O%PATIENTS;21]. Atopic diathesis was FOUNDINOFTHEPATIENTS WITHALLERGICRHINITISBEINGTHEMOSTCOMMON AND  OF THE  WERE POLYSENSITIZED TO SEVERAL ENVIRONMENTAL ALLERGENS 4HE SAME STUDYIDENTIlEDWHEAT TOMATO CARROT ANDONIONASTHEMOSTCOMMONLYOBSERVED FOODALLERGENSINADULT%O%PATIENTS(OWEVER DESPITETHEFACTTHAT INCHILDREN FOODALLERGENSHAVEBEENIDENTIlEDASPATHOGENICFACTORSOF%O%ANDELEMENTAL ANDELIMINATIONDIETOFTENRESULTSINANIMPROVEMENTOREVENRESOLUTIONOFSYMPTOMS;22= THISISSTILLCONTROVERSIALINADULTS)NASMALLSTUDYOFSIXADULT%O% PATIENTS KNOWNSENSITIZATIONTOWHEATANDRYEDIDNOTAPPEARTOBECAUSATIVEASAN ELIMINATIONDIETDIDNOTIMPROVESYMPTOMSORENDOSCOPIClNDINGS;22]. Though OUTSIDETHESCOPEOFTHISCHAPTER THESECITEDSTUDIESSUGGESTTHAT%O%INCHILDREN DIFFERSINSOMEFEATURESFROM%O%INADULTS

Positive Family History 3TUDIESFROM!USTRALIAAND3WITZERLANDREPORTAPOSITIVEFAMILYHISTORYFORASTHMA INANDOF%O%PATIENTS RESPECTIVELY ANDTHATINn OTHERFAMILYMEMBERSAREALSOAFFECTEDBY%O%;7, 8=#OLLINSETALAT#INCINNATI#HILDRENS(OSPITAL -EDICAL#ENTER/HIO 53! IDENTIlEDFAMILIESWITHMORETHANONEPERSONDIAGNOSEDWITH%O%PATIENTSINTOTAL ;23=4HEDEMOGRAPHICCHARACTERISTICSSHOW THATTHEPATIENTSMEANAGEWASYEARSRANGEnYEARS ANDWERE MALES #ASES WERE ONLY FOUND AMONG #AUCASIANS !FFECTED FAMILY MEMBERS INCLUDEDSIBLINGSIN ANDCHILDRENANDTHEIRPARENTSIN4HEMOSTCOMMON COMPLAINT AT DIAGNOSIS WAS DYSPHAGIA REPORTED BY  OF PATIENTS 4HERE WERE

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CONSIDERABLEATOPICFEATURESREPORTEDINCASESOFFAMILIAL%%REPORTEDASTHMA ANDHADALLERGICRHINITIS-ORETHANOFPATIENTSHADSKINPRICKTESTSTHAT WEREREACTIVEEITHERTOFOOD ORAEROALLERGENS ORBOTH 4HESAME STUDYALSOFOCUSEDONTHECLINICAL PATHOLOGIC ANDMOLECULARCHARACTERIZATIONGENE EXPRESSIONUSINGGENOME WIDEMICROARRAY OFFAMILIALVERSUSSPORADIC%O%CASES AND SHOWED THAT CLINICAL MANIFESTATIONS ENDOSCOPIC lNDINGS AND HISTOLOGICAL ABNORMALITIESDIDNOTDIFFERBETWEENFAMILIALANDSPORADICCASES THEREBYSUGGESTING ACOMMONUNDERLYINGPATHOPHYSIOLOGICMECHANISM;24].

Symptoms 4HEMOSTCOMMONPRESENTINGSYMPTOMOFADULT%O%ISDYSPHAGIAFORSOLIDS OFTEN LEADING TO LONG LASTING FOOD IMPACTION WITH THE NECESSITY OF ENDOSCOPIC BOLUS REMOVAL2ETROSPECTIVEANALYSISOFINDICATIONSFORUPPERENDOSCOPYIN%O%PATIENTS SHOWSTHATTHERATEOFDYSPHAGIADIFFERSSUBSTANTIALLYAMONGSTUDIES4HEREASONSFOR THISARE lRST THERETROSPECTIVENATUREOFDATAACQUISITIONINMOSTSTUDIES ANDSECOND REPORTINGOFONLYTHEPRIMARYSYMPTOMVSREPORTINGOFMULTIPLESYMPTOMS)N MOST STUDIES DYSPHAGIA IS PRESENT IN n OF PATIENTS WITH %O% ;7n9, 16]. 3IMILARLY ALARGEVARIATIONCANBEOBSERVEDFORFOODIMPACTIONANDORTHENECESSITY OFBOLUSREMOVAL WHICHRANGESBETWEENANDINMOSTSTUDIES;6n8, 11, 24]. !SACONSEQUENCEOF%O%SMALEPREDILECTION ITISNOTSURPRISINGTHATFOODIMPACTION OCCURS MORE FREQUENTLY IN MEN ;15, 24]. Interestingly, patients undergoing UPPER ENDOSCOPY FOR THE DIAGNOSTIC WORK UP OF DYSPHAGIA OR FOOD IMPACTION ARE REPORTEDHAVING%O%WITHAPREVALENCEOFn ANDANEVENHIGHERRISKIFTHE AGEYEARS;12, 13=+APELETALDESCRIBEANINCREASINGPREVALENCEOF%O%IN PATIENTS HAVING DYSPHAGIA WHICH ROSE FROM  IN  TO  IN  ;9]. &INALLY PATIENTSPRESENTINGWITHDYSPHAGIAHAVEBEENOBSERVEDTOHAVEASIGNIlCANTLYHIGHERPEAKEOSINOPHILCOUNTONBIOPSYSPECIMENS;9=)NSUMMARY %O%IS LIKELYALEADINGCAUSEOFDYSPHAGIAANDFOODIMPACTION 3YMPTOMSRESEMBLING'%2$AREREPORTEDINDIFFERENTSTUDIESRANGINGFROM TOFOR%O%PATIENTS;6n9, 16=!LSO SYMPTOMSOFCHESTPAINANDABDOMINAL PAINAREREPORTEDINTHELITERATURE%VALUATIONOFTHESESYMPTOMSISCURRENTLYLIMITED BYALACKOFSTANDARDSYMPTOMDElNITION WHICHISAGAINMAINLYDUETOTHERETROSPECTIVENATUREOFDATAACQUISITIONINMOSTOFTHESTUDIES

Relevant Questions and Outlook $ESPITETHEFACTTHATTHEDATAPRESENTEDABOVEARESCARCEANDFURTHEREPIDEMIOLOGIC INVESTIGATIONISNEEDED THEYRAISESEVERALINTERESTINGQUESTIONSANDPRESENTOPPORTUNITIESFORSPECULATION4HEFOLLOWINGSECTIONADDRESSESSOMEOFTHESEASPECTS

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Eosinophilic Esophagitis: A Truly New or Only Newly Recognized Disease? 4OANSWERTHISQUESTION THEHISTORYOF%O%SRECOGNITIONlRSTHASTOBEELUCIDATED 4HREE CONDITIONS HAD TO BE PRESENT BEFORE A DIAGNOSIS OF %O% WAS POSSIBLE  ASSESSMENTOF%O% CONSISTENTSYMPTOMS UPPERENDOSCOPYAND HISTOLOGIC EXAMINATIONOFTHEESOPHAGEALTISSUE 4HE lRST IMPORTANT CONDITION INCLUDES RECOGNITION OF SYMPTOMS INDICATING ESOPHAGEAL DYSFUNCTION !DULT PATIENTS WITH %O% REPORT A TYPICAL history OF DYSPHAGIA;1, 25n27=ANDINCHILDRENSUFFERINGFROM%O% SWALLOWINGDISTURBANCESARE ALSOPRESENTAMONGTHELEADINGSYMPTOMS;1, 25, 28=(OWEVER ITISRARETOlND PATIENTSREPORTING%O% CONSISTENTSWALLOWINGDISTURBANCESBEFORETHES EVEN INLARGER%O%COHORTS4HISOBSERVATIONISSUGGESTIVETHATTHEONSETOF%O%WASA RARITYBEFORE Endoscopy ASTHESECONDCONDITIONNECESSARYFORDIAGNOSING%O% CURRENTLY REPRESENTSTHEMOSTIMPORTANTDIAGNOSTICTOOLFORPATIENTSWITHSYMPTOMSOFTHE UPPER')TRACT ANDISUSUALLYTHElRSTSTEPINTHEDIAGNOSTICWORK UPOFPATIENTS WITHDYSPHAGIA;29=5PPERENDOSCOPYWASWIDELYINTRODUCEDDURINGTHES )NTERESTINGLY ALMOST  YEARS PASSED BEFORE THE INITIAL COMPREHENSIVE SERIES OF ADULT%O%PATIENTSWEREPUBLISHED THEREBYLEADINGTOTHERECOGNITIONOF%O%ASA DISTINCTENTITY;25n27= %O% WAS THEREFORE NOT DETECTED BY ENDOSCOPISTS DURING THElRSTTWODECADESOFGASTROINTESTINALENDOSCOPY)NDEED ITISWELLKNOWNTHAT %O%DETECTIONBYENDOSCOPYISOFTENDIFlCULT;25, 30=.EVERTHELESS INASUBSTANTIAL FRACTION OF PATIENTS %O% EVOKES SPECTACULAR ABNORMALITIES ;6, 30] that lead PROMPTLYTOBIOPSYSAMPLING EVENWHENTHEDISEASEISUNKNOWN)TISTHEREFORE LIKELY THAT GASTROENTEROLOGISTS PERFORMING ENDOSCOPIES AT THE BEGINNING OF THE ENDOSCOPY ERA WOULD HAVE RECOGNIZED n AND WOULD HAVE TAKEN BIOPSIES n IN AT LEASTACERTAINFRACTIONOF%O%PATIENTS EVENDESPITETHELOWERQUALITYOFTHElRST generation endoscopes. The third condition, histological examinationUSINGHEMATOXYLINnEOSIN(% STAINING ASTANDARDMETHODFORDECADES ISNEEDEDTODETECTEOSINOPHILSINTHE TISSUE 0ATHOLOGISTS WOULD HAVE EASILY RECOGNIZED THE UNCOMMON lNDING OF A dense tissue eosinophilia in the esophagus. In the literature, this spectacular ABNORMALITY WAS lRST REPORTED IN  AS A CASE REPORT AND MISINTERPRETED AS VIGOROUSACHALASIA;31]. "ASEDONTHESECONSIDERATIONS ONECANCONCLUDETHATALLCONDITIONSNECESSARYFOR DIAGNOSING%O%WEREAVAILABLESINCETHEEARLYS BUTNEVERTHELESS %O%WASNOT OBSERVEDBEFORE 4OSUMUP THEREISTHUSAGAPOFMORETHANYEARSWHEN%O%WASNOTRECOGNIZED)NADDITION THEREISSTRONGEVIDENCETHAT%O% CONSISTENTSYMPTOMSDIDNOT OCCURBEFORETHES2EGARDINGTHESETIMELINES ITISTEMPTINGTOSPECULATETHAT %O%STARTEDDURINGTHELASTTWODECADESOFTHELASTCENTURY ANDTHUSPROVIDESSTRONG EVIDENCETHAT%O%ISTRULYANEWDISEASE

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Eosinophilic Esophagitis: A More-Prevalent or a More-Recognized Disease? )TISSTILLDEBATEDWHETHERTHEOCCURRENCEOFADULT%O%ISTRULYINCREASINGANDTHE DISEASEAFFECTSEVERMOREINDIVIDUALS ORWHETHERTHEDIAGNOSISISESTABLISHEDMORE FREQUENTLYASACONSEQUENCEOFTHEINCREASEDAWARENESSBYHEALTHCAREPROVIDERS !NSWERINGTHISQUESTIONREQUIRESPOPULATION BASEDLONG TERMANALYSIS 5NFORTUNATELY THEVASTMAJORITYOFSTUDIESADDRESSINGTHISQUESTIONRELYONRETROSPECTIVEANALYSESOFPATHOLOGYORENDOSCOPYDATABASES;9, 11, 32]. Data resulting FROMTHESEAPPROACHESTHEREFOREREPRESENT%O%CASESPERESOPHAGEALBIOPSYORPER UPPERENDOSCOPY BUTNOT%O%CASESPERSOMANYINHABITANTS2ONKAINENETALUSED APOPULATION BASED ENDOSCOPICAPPROACHTOACHIEVEROBUSTEPIDEMIOLOGICDATAIN THE3WEDISHPOPULATION;5=(OWEVER THEINTERPRETATIONOFTHISSTUDYISHAMPERED BYTWOFACTS&IRST THEYPERFORMEDANANALYSISBASEDMAINLYONHISTOLOGYREVEALING DATAABOUTTHEPREVALENCEOFESOPHAGEALEOSINOPHILIA WHICHCOULDBEDIFFERENTFROM THEPREVALENCEOF%O% ANDSECOND THISCROSS SECTIONALANALYSISWASPERFORMEDATA GIVENTIMEPOINTANDTHEREFOREPROVIDESNOINFORMATIONREGARDINGCHANGESINPREVALENCEOVERTIME4HEBESTEVIDENCEFORATRUEESCALATIONCOMESFROM!USTRALIA;6] AND3WITZERLAND;8=!SCITEDABOVE RETROSPECTIVEANALYSISBY#ROESEETALSHOWSA INCIDENCEOF%O%IN4OWNSVILLE#OUNTY !USTRALIABEFORE WHICHINCREASEDTO ANANNUALINCIDENCERATEWITHCASESBETWEENANDCASES  POPULATION YEARS  AND AGAIN INCREASED TO  NEW CASES PER YEAR  YEARS BY3EPTEMBER)N INVESTIGATORSIN3WITZERLAND CREATEDAPOPULATION BASEDDATABASEANDPROSPECTIVELYCAPTUREDALLADOLESCENTAND ADULT%O%PATIENTSLIVINGINTHECLEARLYDElNEDAREAOF/LTEN#OUNTY4HEINCIDENCE RATESRANGEDBETWEENANDCASESPERYEARPER INHABITANTS ANDSHOWEDAN INCREASINGTREND WHEREASTHECUMULATIVEPREVALENCEINCREASEDCONSTANTLYFROMTO CASESPER INHABITANTS&URTHERMORE THEDIAGNOSTICDELAYWASAPPROXIMATELY n YEARS AND REMAINED STABLE THROUGHOUT THE ENTIRE PERIOD INDICATING THAT THE DETECTIONOF%O%DIDNOTIMPROVEDURINGTHESETWODECADES )NSUMMARY THEREISSTRONGEVIDENCETHATTHEREISATRUEANDCONSTANTINCREASEIN THEPREVALENCEOF%O%)NCONTRAST WHETHERTHISINCREASEDPREVALENCEISDUETOAN INCREASE IN INCIDENCE OR ONLY DUE TO THE NON FATAL CHARACTER OF %O% ADDING EVER MORECASESTOTHEPATIENTPOOL ISSTILLCONTROVERSIALANDFURTHERPOPULATION BASED LONGITUDINALSTUDIESAREREQUIREDTOCONlRMTHISASSUMPTION

Eosinophilic Esophagitis: A Seasonal or a Perennial Disease? 4HISQUESTIONSEEKSTOENHANCETHESTILL LIMITEDUNDERSTANDINGOF%O%SPATHOGENESIS &OODALLERGENSASWELLASAEROALLERGENSHAVEBEENIMPLICATEDASCONTRIBUTINGFACTORS ININDUCINGANDMAINTAININGTHEEOSINOPHILICINmAMMATION;1, 33, 34]. Data supporting

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THERELATIONSHIPTOFOODALLERGIESCOMESPREDOMINANTLYFROMTHEPEDIATRICLITERATURE ;35=ANDINDEED SEVERALTYPESOFDIETSELIMINATINGPOTENTIALALLERGENSHAVEPROVEN EFlCACIOUSINTHETREATMENTOFCHILDRENWITH%O%;36n38]. In contrast, adults with %O%AREOFTENSENSITIZEDTOAEROALLERGENS;1, 22=&URTHEREVIDENCETHATAEROALLERGENSMIGHTPLAYACRUCIALROLEINTHEPATHOGENESISOF%O%WASPROVIDEDBYACASE REPORT DEMONSTRATING A SEASONAL VARIATION OF %O%S ACTIVITY IN PARALLEL TO POLLEN EXPOSURE;39=!CONlRMATIONOFASEASONALDEPENDENCYOF%O%WOULDBEANINDICATOR THATEXTERNALSEASONALFACTORS INPARTICULAR POLLEN COULDPLAYASUBSTANTIALROLEIN THEPATHOGENESISOFTHIS4H TYPEINmAMMATION 4ODATE TWOINVESTIGATORSHAVESEARCHEDFORASEASONALVARIATIONOF%O%SOCCURRENCE;40, 41=5NFORTUNATELY BOTHSTUDIESUSEDTHETIMEPOINTOFDIAGNOSTICENDOSCOPYINTHEANNUALCYCLEASTHEMARKEROFDISEASEONSET(OWEVER ITISKNOWNTHAT THEREISASUBSTANTIALGAPBETWEENONSETOFSYMPTOMSLIKELYONSETOFDISEASE AND DIAGNOSIS&ORINSTANCE INTHE3WISSCOHORT INCLUDINGMORETHANADOLESCENT AND ADULT %O% PATIENTS THERE IS A DIAGNOSTIC DELAY OF APPROXIMATELY n YEARS 4HEREFORE INMOSTPATIENTS THEDATEOFENDOSCOPYCANDElNITELYNOTBELINKEDTOTHE DATEOFONSETOFDISEASE#ONCLUSIONSREGARDINGTHEINmUENCEOFPOLLENINTHEPATHOGENESISOF%O%THATAREDRAWNFROMENDOSCOPICRATESARETHUSLIKELYTOBEHIGHLY SPECULATIVEANDMOSTPROBABLYMISLEADING 4AKENTOGETHER WITHTHEEXCEPTIONOFONESINGLECASEREPORT;39], there is no solid PROOFTHATEITHERTHElRSTONSETOF%O%ORTHECOURSEOFITSINmAMMATIONSHOWASEASONAL VARIATION OR THAT POLLEN EXPOSURE COULD PLAY A PATHOGENIC ROLE 0ROSPECTIVE STUDIES USINGEITHERASYSTEMATICASSESSMENTOFTHESYMPTOMCOURSEOROF%O%SINmAMMATORY ACTIVITYINCORRELATIONTOTHEPOLLENEXPOSUREARENEEDEDTOANSWERTHISQUESTION

Eosinophilic Esophagitis: An Industrialized or a Westernized Disease? 4HEVASTMAJORITYOF%O%CASESANDCOHORTSAREREPORTEDFROMINDUSTRIALIZEDCOUNTRIES SUCHASTHE53! %UROPE AND!USTRALIA WHEREASALMOSTNOREPORTSCOMEFROMTROPICAL AREASANDORDEVELOPINGCOUNTRIES;1]. This pattern is not surprising and corresponds WELL WITH THE PATTERN OF CLASSICAL ALLERGIC DISORDERS )T MIGHT BE EXPLAINED BY THE HYGIENETHEORYWHICHPOSTULATESTHATINDIVIDUALSWHOARENOTEXPOSEDTOINFECTIONS DURINGEARLYCHILDHOODAREPRONETODEVELOPALLERGIESASADOLESCENTSORADULTS;42]. (OWEVER REGARDINGTHEWORLDWIDEDISTRIBUTIONOF%O% ONEEXCEPTIONISSURPRISING *APANISNOTYETINFESTEDWITH%O%PERSONALCOMMUNICATION 4HISFACTCANNEITHERBE EXPLAINEDBYLACKOFEDUCATIONOF*APANESEGASTROENTEROLOGISTSNORBYINAPPROPRIATE diagnostic tools. Japanese gastroenterologists and pathologists are highly educated ANDBESTEQUIPPEDWITHHIGH TECHINSTRUMENTS%O%MUSTTHEREFOREBECONSIDEREDA WESTERNIZED BUTNOTANINDUSTRIALIZED DISEASE 4WOAPPARENTDIFFERENCESEXISTBETWEEN*APANANDTHEREMAININGINDUSTRIALIZED COUNTRIESNUTRITIONALHABITSANDGENETICS7HILEINWESTERNKITCHENmAVORS DAIRY PRODUCTS POTATOESANDBEEFAREFAMILIAR THE*APANESEKITCHENISDOMINATEDBYlSH ANDRICE ANDINADDITION OFTENINANUNCOOKEDFORM

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Conclusion 4HISOBVIOUSDIFFERENCEINNUTRITIONALHABITSTOGETHERWITHTHEFACTTHAT INSOMECASES %O%CANBETREATEDBYELIMINATIONOFDISTINCTFOODSRAISESTHEQUESTIONOFWHETHERONE OFTHEWESTERNFOODSCOULDBEATRIGGERFOR%O% ORINCONTRAST ONE*APANESEFOOD COULDEXERTAPROTECTIVEEFFECT(OWEVER THISSPECULATIONNEEDSFURTHERINVESTIGATION ANDGENETICFACTORSMUSTALSOBECONSIDERED)NELUCIDATINGTHEDENOUEMENTOFTHIS RELATIVELY NEW DISEASE IT IS IMPORTANT TO REALIZE THAT THOUGH NUMEROUS QUESTIONS REMAIN MUCHPROGRESSHASBEENMADE ANDEACHNEWSTUDYFURTHERSOURUNDERSTANDINGANDMOVESUSCLOSERTOALLEVIATINGTHEPATHOSOFAFFECTEDPATIENTS

References  &URUTA'4 ,IACOURAS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGYn  +ATO - +EPHART '- 4ALLEY .* ET AL %OSINOPHIL INlLTRATION AND DEGRANULATION IN NORMAL HUMANTISSUE!NAT2ECn  ,OWICHIK! 7EINBERG!'!QUANTITATIVEEVALUATIONOFMUCOSALEOSINOPHILSINTHEPEDIATRIC GASTROINTESTINALTRACT-OD0ATHOLn  !HMAD- 3OETIKNO2- !HMED!4HEDIFFERENTIALDIAGNOSISOFEOSINOPHILICESOPHAGITIS *#LIN'ASTROENTEROLn  2ONKAINEN* 4ALLEY.* !RO0 ETAL0REVALENCEOFOESOPHAGEALEOSINOPHILSANDEOSINOPHILIC OESOPHAGITISINADULTSTHEPOPULATION BASED+ALIXANDASTUDY'UTn  #ROESE * &AIRLEY 3+ -ASSON *7 ET AL #LINICAL AND ENDOSCOPIC FEATURES OF EOSINOPHILIC ESOPHAGITISINADULTS'ASTROINTEST%NDOSCn  0RASAD'! !LEXANDER*! 3CHLECK#$ ETAL%PIDEMIOLOGYOFEOSINOPHILICESOPHAGITISOVER THREEDECADESIN/LMSTED#OUNTY -INNESOTA#LIN'ASTROENTEROL(EPATOLn  3TRAUMANN! 3IMON(5%OSINOPHILICESOPHAGITISESCALATINGEPIDEMIOLOGY*!LLERGY#LIN )MMUNOLn  +APEL 2# -ILLER *+ 4ORRES # ET AL %OSINOPHILIC ESOPHAGITIS A PREVALENT DISEASE IN THE 5NITED3TATESTHATAFFECTSALLAGEGROUPS'ASTROENTEROLOGYn 7HITNEY -ILLER#, +ATZKA$ &URTH%%%OSINOPHILICESOPHAGITISARETROSPECTIVEREVIEWOF ESOPHAGEAL BIOPSY SPECIMENS FROM  TO  AT AN ADULT ACADEMIC MEDICAL CENTER !M *#LIN0ATHOLn 6EERAPPAN'2 0ERRY*, $UNCAN4* ETAL0REVALENCEOFEOSINOPHILICESOPHAGITISINANADULT POPULATION UNDERGOING UPPER ENDOSCOPY A PROSPECTIVE STUDY #LIN 'ASTROENTEROL (EPATOL n En -ACKENZIE 3( 'O - #HADWICK " ET AL %OSINOPHILIC OESOPHAGITIS IN PATIENTS PRESENTING WITHDYSPHAGIAnAPROSPECTIVEANALYSIS!LIMENT0HARMACOL4HERn 0RASAD '! 4ALLEY .* 2OMERO 9 ET AL 0REVALENCE AND PREDICTIVE FACTORS OF EOSINOPHILIC ESOPHAGITISINPATIENTSPRESENTINGWITHDYSPHAGIAAPROSPECTIVESTUDY!M*'ASTROENTEROL n "YRNE+2 0ANAGIOTAKIS0( (ILDEN+ ETAL2ETROSPECTIVEANALYSISOFESOPHAGEALFOODIMPACTIONDIFFERENCESINETIOLOGYBYAGEANDGENDER$IG$IS3CIn $ESAI4+ 3TECEVIC6 #HANG#( ETAL!SSOCIATIONOFEOSINOPHILICINmAMMATIONWITHESOPHAGEALFOODIMPACTIONINADULTS'ASTROINTEST%NDOSCn -ULLER3 0UHL3 6IETH- ETAL!NALYSISOFSYMPTOMSANDENDOSCOPIClNDINGSINPATIENTS WITHHISTOLOGICALDIAGNOSESOFEOSINOPHILICESOPHAGITIS%NDOSCOPYn

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0(RUZAND!3TRAUMANN

 &RANCIOSI*0 4AM6 ,IACOURAS#! ETAL!CASE CONTROLSTUDYOFSOCIODEMOGRAPHICANDGEOGRAPHIC CHARACTERISTICS OF  CHILDREN WITH EOSINOPHILIC ESOPHAGITIS #LIN 'ASTROENTEROL (EPATOL n 3TRAUMANN! "AUER- &ISCHER" ETAL)DIOPATHICEOSINOPHILICESOPHAGITISISASSOCIATEDWITH A4(  TYPEALLERGICINmAMMATORYRESPONSE*!LLERGY#LIN)MMUNOLn !KDIS#! !KDIS- 3IMON$ ETAL4CELLSAND4CELL DERIVEDCYTOKINESASPATHOGENICFACTORS INTHENONALLERGICFORMOFATOPICDERMATITIS*)NVEST$ERMATOLn  "OUSQUET* 6IGNOLA!- $EMOLY0,INKSBETWEENRHINITISANDASTHMA!LLERGYn 2OY 'HANTA3 ,AROSA$& +ATZKA$!!TOPICCHARACTERISTICSOFADULTPATIENTSWITHEOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOLn 3IMON$ 3TRAUMANN! 7ENK! ETAL%OSINOPHILICESOPHAGITISINADULTSnNOCLINICALRELEVANCEOFWHEATANDRYESENSITIZATIONS!LLERGYn #OLLINS-( "LANCHARD# !BONIA*0 ETAL#LINICAL PATHOLOGIC ANDMOLECULARCHARACTERIZATION OF FAMILIAL EOSINOPHILIC ESOPHAGITIS COMPARED WITH SPORADIC CASES #LIN 'ASTROENTEROL (EPATOLn +ERLIN0 *ONES$ 2EMEDIOS- ETAL0REVALENCEOFEOSINOPHILICESOPHAGITISINADULTSWITH FOODBOLUSOBSTRUCTIONOFTHEESOPHAGUS*#LIN'ASTROENTEROLn  !TTWOOD3% 3MYRK4# $EMEESTER42 ETAL%SOPHAGEALEOSINOPHILIAWITHDYSPHAGIA !DISTINCTCLINICOPATHOLOGICSYNDROME$IG$IS3CIn 3TRAUMANN! 3PICHTIN(0 "ERNOULLI2 ETAL)DIOPATHICEOSINOPHILICESOPHAGITISAFREQUENTLY OVERLOOKED DISEASE WITH TYPICAL CLINICAL ASPECTS AND DISCRETE ENDOSCOPIC lNDINGS 3CHWEIZ -ED7OCHENSCHRn 6ITELLAS +- "ENNETT 7& "OVA *' ET AL )DIOPATHIC EOSINOPHILIC ESOPHAGITIS 2ADIOLOGY n ,IACOURAS#! 3PERGEL*- 2UCHELLI% ETAL%OSINOPHILICESOPHAGITISA YEAREXPERIENCEIN CHILDREN#LIN'ASTROENTEROL(EPATOLn 6ARADARAJULU 3 %LOUBEIDI -! 0ATEL 23 ET AL 4HE YIELD AND THE PREDICTORS OF ESOPHAGEAL PATHOLOGYWHENUPPERENDOSCOPYISUSEDFORTHEINITIALEVALUATIONOFDYSPHAGIA'ASTROINTEST %NDOSCn 3TRAUMANN! 3PICHTIN(0 "UCHER+! ETAL%OSINOPHILICESOPHAGITISREDONMICROSCOPY WHITEONENDOSCOPY$IGESTIONn ,ANDRES24 +USTER'' 3TRUM7"%OSINOPHILICESOPHAGITISINAPATIENTWITHVIGOROUSACHALASIA'ASTROENTEROLOGYn  6ANDERHEYDEN!$ 0ETRAS2% $E9OUNG"2 ETAL%MERGINGEOSINOPHILICALLERGIC ESOPHAGITIS INCREASEDINCIDENCEORINCREASEDRECOGNITION!RCH0ATHOL,AB-EDn !RORA!3 9AMAZAKI+%OSINOPHILICESOPHAGITISASTHMAOFTHEESOPHAGUS#LIN'ASTROENTEROL (EPATOLn 2OTHENBERG-% -ISHRA! #OLLINS-( ETAL0ATHOGENESISANDCLINICALFEATURESOFEOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOLn  3PERGEL*- "EAUSOLEIL*, -ASCARENHAS- ETAL4HEUSEOFSKINPRICKTESTSANDPATCHTESTSTO IDENTIFYCAUSATIVEFOODSINEOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOLn  +AGALWALLA!& 3ENTONGO4! 2ITZ3 ETAL%FFECTOFSIX FOODELIMINATIONDIETONCLINICALAND HISTOLOGICOUTCOMESINEOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOLn  +ELLY+* ,AZENBY!* 2OWE0# ETAL%OSINOPHILICESOPHAGITISATTRIBUTEDTOGASTROESOPHAGEAL REmUXIMPROVEMENTWITHANAMINOACID BASEDFORMULA'ASTROENTEROLOGYn  /RENSTEIN32 3HALABY4- $I,ORENZO# ETAL4HESPECTRUMOFPEDIATRICEOSINOPHILICESOPHAGITISBEYONDINFANCYACLINICALSERIESOFCHILDREN!M*'ASTROENTEROLn &OGG-) 2UCHELLI% 3PERGEL*-0OLLENANDEOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOL n !LMANSA# +RISHNA- "UCHNER!- ETAL3EASONALDISTRIBUTIONINNEWLYDIAGNOSEDCASESOF EOSINOPHILICESOPHAGITISINADULTS!M*'ASTROENTEROLn  7ANG&9 'UPTA3+ &ITZGERALD*&)STHEREASEASONALVARIATIONINTHEINCIDENCEORINTENSITYOFALLERGIC EOSINOPHILICESOPHAGITISINNEWLYDIAGNOSEDCHILDREN*#LIN'ASTROENTEROLn "RAUN &AHRLANDER# 2IEDLER* (ERZ5 ETAL%NVIRONMENTAL EXPOSURE TO ENDOTOXIN AND ITS RELATIONTOASTHMAINSCHOOL AGECHILDREN.%NGL*-EDn

Chapter 4

Eosinophil Biology in the Pathogenesis of Eosinophilic Disorders Steven J. Ackerman

Keywords %OSINOPHIL s "IOLOGY s $IFFERENTIATION s -IGRATION s 2ECRUITMENT s!CTIVATIONs3ECRETION

Introduction )NTHEYEARSFOLLOWINGTHEIDENTIlCATIONOFTHEEOSINOPHILICLEUKOCYTEBY0AUL %HRLICHIN ASIGNIlCANTNUMBEROFDISEASESANDSYNDROMESCHARACTERIZEDBY BLOODORTISSUEEOSINOPHILIAWEREIDENTIlED(OWEVER SPECIlCFUNCTIONALROLESFOR THEEOSINOPHILINHOSTDEFENSEANDINNATEIMMUNITY ALLERGICANDRELATEDINmAMMATORYRESPONSES TISSUEINJURY REPAIR REMODELING ANDlBROSISHAVEONLYBEENDELINeated in the past ~30 years [1–3=4HESESTUDIESSERVEDTOCHARACTERIZEMANYOFTHE UNIQUEBIOLOGICCHARACTERISTICSOFBLOODANDACTIVATEDTISSUEEOSINOPHILS THEIRPREFORMED GRANULE PROTEINS AND INDUCIBLE LIPID OXIDATIVE AND CYTOKINE PRODUCTS FOCUSINGINITIALLYONTHEEOSINOPHILSPRO INmAMMATORYANDCYTOTOXICPOTENTIALIN THEPATHOGENESISOFALLERGIC PARASITIC ANDAVARIETYOFIDIOPATHICEOSINOPHIL ASSOCIATED SYNDROMES;4=2ECOGNITIONOFTHEEOSINOPHILASANEFFECTORCELLINASTHMAPATHOGENESISFUELEDTHEINITIALSURGEININTERESTINTHISGRANULOCYTE;5= ANDTHEhEPIDEMICSvOF EOSINOPHILMYALGIASYNDROMERELATEDTOINGESTIONOFTAINTEDl-tryptophan [6], and MORE RECENT IDENTIlCATION AND INCREASING PREVALENCE OF EOSINOPHILIC ESOPHAGITIS %O% HAVE MARKEDLY INCREASED CLINICAL AND PUBLIC AWARENESS AND INTEREST IN THE eosinophil [7].

3*!CKERMAN*) $EPARTMENTOF"IOCHEMISTRYAND-OLECULAR'ENETICS-# AND3ECTIONS OF(EMATOLOGY /NCOLOGYAND0ULMONARY #RITICAL#ARE 3LEEPAND!LLERGY 4HE5NIVERSITYOF)LLINOISAT#HICAGO#OLLEGEOF-EDICINE -OLECULAR"IOLOGY2ESEARCH "UILDING 2M 3!SHLAND!VENUE #HICAGO ), 53! E MAILSACKERMA UICEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_4, © Springer Science+Business Media, LLC 2012

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Fig. 4.1 2OLEOFTHEEOSINOPHILINTHEPATHOGENESISOF%O%RELATIONSHIPSTOCLINICAL ENDOSCOPICAND HISTOLOGICPATHOLOGIES%OSINOPHILACTIVATIONDURINGRECRUITMENTTOTHEESOPHAGUSOCCURSINRESPONSE TOEOTAXIN  PERIOSTIN ), ANDINTERACTIONSWITHVASCULARENDOTHELIUM EPITHELIUM ANDlBROBLASTS LEADINGTOTHEIREXPRESSIONOFlBROGENICFACTORSSUCHAS4'& E%OSINOPHIL EXPRESSED4'& E and GRANULEPROTEINS-"0 %08 INDUCEEPITHELIALBASALZONEHYPERPLASIA CONTRIBUTINGTOESOPHAGEAL THICKENING AND LUMINAL NARROWING %OSINOPHIL DERIVED 4'& E INDUCES lBROBLAST ACTIVATION WITH TRANSDIFFERENTIATIONTOMYOlBROBLASTSANDCONSEQUENTOVER PRODUCTIONOF%#-LEADINGTOSUBEPITHELIAL lBROSIS lXED NARROWINGSRINGS STRICTURES AND FOOD IMPACTIONS !LTERNATIVELY 4'& E EXPRESSEDBYEOSINOPHILSOR-"0%08DAMAGEDEPITHELIUMITSELFMAYINDUCEEPITHELIALTOMESENCHYMAL MYOlBROBLAST TRANSITION %-4 CONTRIBUTING TO SUBEPITHELIAL lBROSIS ;85]. EosinophilEXPRESSED4'& EMAYINDUCESMOOTHMUSCLECELLHYPERTROPHYHYPERPLASIALEADINGTOTHICKENINGOF THEESOPHAGEALMUSCULARISPROPRIA CONTRIBUTINGTODYSMOTILITY DYSPHAGIA TRANSIENTRINGS ANDNON STRICTURE FOOD IMPACTIONS %OSINOPHIL EXPRESSION OF 6%'& LIKELY SUPPORTS INCREASED ANGIOGENIC RESPONSESOFVASCULARENDOTHELIUMWITH6#!- ACTIVATIONBY), AND4.& D CONTRIBUTINGTO INCREASED EOSINOPHIL TRAFlCKING DILATED INTERCELLULAR SPACES ESOPHAGEAL THICKENING FURROWING LUMINALNARROWING ANDNON STRICTUREFOODIMPACTIONS5PDATEDANDREPRODUCEDINCOLORWITHPERMISSIONFROM;80=!CEVES33 !CKERMAN3*)MMUNOL!LLERGY#LIN.!Mn

4HE CURRENT PARADIGM THAT EOSINOPHILS SUBSERVE PRO INmAMMATORY AND TISSUE DAMAGINGROLESINTHEPATHOGENESISOFEOSINOPHIL ASSOCIATEDDISEASESANDHYPEREOSINOPHILICSYNDROMESSUCHAS%O%&IG4.1 ISSUPPORTEDBYAGROWINGNUMBEROF DElNITIVEMOUSEMODELANDHUMANSTUDIES!PIVOTALROLEFORTHEEOSINOPHILINTHE DEVELOPMENTOFTISSUEREMODELINGANDlBROSIS INPARTTHROUGHTHEIRELABORATIONOF REMODELINGANDlBROGENICGROWTHFACTORS ISNOWWIDELYACCEPTED;8–10]. Studies USING), KNOCKOUTMICEANDTWOSTRAINSOFEOSINOPHIL DElCIENTMICESTRONGLYSUPPORTTHECONCEPTTHATEOSINOPHILSCONTRIBUTETOTHEPATHOLOGYOFAIRWAYREMODELING ANDSUBEPITHELIALlBROSISINASTHMA;11, 12=ANDAREREQUIREDFOR4CELLPOLARIZATION

 %OSINOPHIL"IOLOGYINTHE0ATHOGENESISOF%OSINOPHILIC$ISORDERS

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FOR 4H RESPONSES IN THE LUNG IN RESPONSE TO ALLERGEN CHALLENGE ;13], and recent CLINICALTRIALSUSINGANTI ), ANTIBODY-EPOLIZUMABÍ TOABLATEEOSINOPHILSINTHE BONEMARROW BLOODANDTISSUESOFPATIENTWITHhEOSINOPHILICv BUTNOTNEUTROPHILIC ASTHMA SHOWEDEFlCACYINREVERSINGASPECTSOFEOSINOPHIL MEDIATEDTISSUEDAMAGE REMODELINGANDlBROSISINALLERGICDISEASESSUCHASASTHMA;14, 15], eosinophilic esophagitis (EoE) [16= ANDTHEHYPEREOSINOPHILICSYNDROME(%3 ;17]. This chapter WILLREVIEWBASICASPECTSOFEOSINOPHILCELLULAR MOLECULAR ANDIMMUNOBIOLOGYTHAT ARE PERTINENT TO UNDERSTANDING THEIR INmAMMATORY AND PATHOLOGIC ACTIVITIES THE MECHANISMSTHATREGULATEEOSINOPHILDEVELOPMENTANDEOSINOPHILIAINTHEBONEMARROW BLOOD ANDTISSUES ANDTHEIRRELATIONSHIPSTOTHEPATHOGENESISOFEOSINOPHIL MEDIATED allergic disorders such as EoE.

Eosinophil Morphology and Mediators of Inflammation %OSINOPHILSCONTAINANUMBEROFDISTINCTMEMBRANE BOUNDGRANULESPRODUCEDDURING THEIRDIFFERENTIATIONFROM), 2EOSINOPHILPROGENITORS%O0 INTHEBONEMARROW 4HESE INCLUDE  UNIFORMLY ELECTRON DENSE PRIMARY GRANULES PRESENT MAINLY IN EOSINOPHILPROMYELOCYTES SECONDARYSPECIlC GRANULESCONTAININGTHEHALLMARK ELECTRONDENSECRYSTALLOIDCOREANDLESSDENSEGRANULEMATRIXOFGRANULESIN MATURE EOSINOPHILS  AND  SMALL GRANULES SITES OF HYDROLYTIC ENZYMES SUCH AS ACIDPHOSPHATASEANDARYLSULFATASE THATMAYBEFUNCTIONALLYANALOGOUSTOCELLULAR LYSOSOMES4HESECONDARYGRANULEISTHEMAJORSTORAGESITEFORTHEEOSINOPHILSCATIONICPROTEINS WHICHCONFERTHEEOSINOPHILSUNIQUEAFlNITYFORACIDICmUORONEDYES SUCHASEOSIN THEBASISFOR0AUL%HRLICHSDISCOVERY ANDNAMINGOFTHEEOSINOPHIL IN  !S WELL EOSINOPHILS CONTAIN NON MEMBRANE BOUND LIPID RICH ORGANELLES CALLED LIPID BODIES ;18= THE NUMBERS OF WHICH INCREASE IN ACTIVATED EOSINOPHILS BOTHINVITROANDATSITESOFTISSUEINmAMMATORYREACTIONS;19=,IPIDBODIESINCORPORATEFATTYACIDSSUCHASARACHIDONATEANDLIKELYSERVEASINTRACELLULARDEPOTSFOR THEIRSTORAGEANDMETABOLISM INCLUDINGTHEFORMATIONOFLEUKOTRIENES SINCETHEY CONTAIN ALL OF THE REQUIRED EICOSANOID FORMING ENZYMES  LIPOXYGENASE LEUKOTRIENE#SYNTHASE CYCLOOXYGENASE ;20=4HESEORGANELLES ALONGWITHVESICULOTUBULARhSOMBREROvSTRUCTURESANDSMALLVESICLESINVOLVEDINTRANSPORTANDSECRETION DURINGEOSINOPHILACTIVATION;21= REPRESENTTHEMAJORSTORAGESITESFORTHEEOSINOPHILSPREFORMEDCYTOTOXICANDINmAMMATORYPROTEINS

The Granule Cationic Proteins )NITIALSTUDIESOFTHEBIOCHEMISTRY BIOLOGICACTIVITIESANDTISSUELOCALIZATIONOFTHE CATIONICENZYMESANDNON ENZYMATICPROTEINSISOLATEDFROMTHEEOSINOPHILSECONDARY GRANULE PROVIDED THE lRST CLUES TO THIS GRANULOCYTES ROLE IN THE PATHOGENESIS OF INmAMMATION AND TISSUE DAMAGE IN EOSINOPHIL ASSOCIATED DISEASES ;4]. As well, IMMUNOHISTOCHEMICALDETECTIONOFEOSINOPHIL SPECIlCGRANULECONSTITUENTSINTISSUE

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BIOPSIESPROVIDEDEVIDENCEFORTHEPARTICIPATIONOFTHEEOSINOPHILINDISEASESNOT NORMALLY ASSOCIATED WITH BLOOD OR TISSUE EOSINOPHILIA EG CERTAIN SKIN DISEASES SUCHASATOPICDERMATITIS;22=4HESESTUDIESPROVIDEDCOMPELLINGEVIDENCESUPPORTING APATHOLOGICEFFECTORROLEFOREOSINOPHILSINTHEINDUCTIONOFTISSUEANDEND STAGE ORGAN DAMAGE ;23= 4HESE CATIONIC GRANULE PROTEINS INCLUDE THE TWO MAJOR BASIC PROTEINS-"0  -"0  EOSINOPHILPEROXIDASE%08 ANDTHEEOSINOPHILSRIBONUCLEASES EOSINOPHIL DERIVEDNEUROTOXIN%$. 2.ASE ANDEOSINOPHILCATIONIC PROTEIN%#0 2.ASE  3TUDIESOFTHEMECHANISMSBYWHICHTHEEOSINOPHILGRANULECATIONICPROTEINSARE SECRETEDORRELEASEDINTOTISSUESHAVESHOWNTHATTHEYCANBEINDEPENDENTLYSELECTIVELY SECRETED DEPENDING ON THE TYPE AND STRENGTH OF THE ACTIVATING STIMULUS THROUGHANUMBEROFDIFFERENTSECRETORYPATHWAYSRANGINGFROMCLASSICALGRANULE FUSIONANDEXOCYTOSISEG INTHEKILLINGPARASITICHELMINTHS PIECEMEALDEGRANULATIONAVESICULARTRANSPORTPROCESSFROMSECONDARYGRANULESINTHEABSENCEOFEXOCYTOSIS AND CYTOLYTIC DEGRANULATION THE RELEASE OF INTACT MEMBRANE BOUND AND SECRETORY COMPETENT SECONDARY GRANULES DIRECTLY INTO THE TISSUE UPON EOSINOPHIL apoptosis/cell death) [24, 25]. )NADDITIONTOSECRETIONOFTHEIRPREFORMEDGRANULECATIONICPROTEINS EOSINOPHILS HAVETHECAPACITYTOEXPRESSPOTENTTOXICREACTIVEOXYGENSPECIES2/3 ;26], eicoSANOIDS EG PROSTAGLANDINS LEUKOTRIENES LIPOXINS AND OTHER INmAMMATORY LIPID MEDIATORS;18=SEEBELOW ANDIMPORTANTLY ASIGNIlCANTNUMBEROFHEMATOPOIETIC AND INmAMMATORY CYTOKINES KEY TO THE NORMAL AND PATHOPHYSIOLOGIC ROLES OF THE eosinophil [27, 28].

Cytokines and Growth Factors )NADDITIONTOTHEIRGRANULEPROTEINS EOSINOPHILSAREALSOACONSIDERABLESOURCEOF BOTHPREFORMEDSTORED ANDNEWLYSYNTHESIZEDCYTOKINES CHEMOKINESANDGROWTH FACTORS INCLUDING4HAND4HTYPECYTOKINES THATCANPARTICIPATEINLINKINGINNATE ANDADAPTIVEIMMUNERESPONSES REGULATIONOF4HRESPONSES LEUKOCYTECHEMOTAXIS TISSUEREMODELINGANDlBROSIS ANDCELLGROWTHANDSURVIVAL INCLUDINGTHEEOSINOPHILS OWNSURVIVALTHROUGHEXPRESSIONOF'- #3&4ABLE4.1) [27, 29]. Although T cells ANDOTHERLYMPHOCYTESGENERALLYEXPRESSGREATERAMOUNTSOFTHESECYTOKINESATSITES OFALLERGICTISSUEINmAMMATORYRESPONSES THEABILITYOFTHEEOSINOPHILTOBOTHSYNTHESIZEANDSTORETHESECYTOKINESINTHEIRCYTOPLASMICGRANULES ANDTOSECRETETHEM FROMBOTHTHEINTACTCELLANDFROMCELL FREESECONDARYGRANULESINTHETISSUE;25], SUGGESTSEOSINOPHILSMAYPROVIDEBOTHAMORERAPIDANDHIGHLYFOCUSEDRELEASEOF THESEIMMUNEREGULATORSATSITESOFALLERGICINmAMMATION;27, 29]. %OSINOPHILS ARE CLASSICALLY ASSOCIATED WITH THE DEVELOPMENT OF 4H POLARIZED ALLERGIC AND ANTI PARASITE HOST IMMUNE RESPONSES AND ARE RECRUITED INTO IMMUNE ENVIRONMENTS RICH IN 4H CYTOKINES PARTICULARLY ),  ),  AND ),  ),  THE EOSINOPHILOPOIETIN REGULATES THE DEVELOPMENT OF BLOOD AND TISSUE EOSINOPHILIA THROUGH ITS MULTIPLE ACTIONS ON EOSINOPHIL PROGENITOR %O0 CELL EXPANSION AND

 %OSINOPHIL"IOLOGYINTHE0ATHOGENESISOF%OSINOPHILIC$ISORDERS

43

Table 4.1 %OSINOPHILS EXPRESS AND SECRETE MULTIPLE STORED AND NEWLY SYNTHESIZED INTERLEUKINS CHEMOKINES ANDGROWTHFACTORSUPONPRIMINGANDACTIVATION Interleukins IL-1 (D and E), IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-11, IL-12, IL-13, IL-16, IL-17 Chemokines %PITHELIALCELL DERIVEDNEUTROPHILACTIVATINGPEPTIDE#8#, EOTAXIN##, GROWTH RELATED ONCOGENE#8#, INTERLEUKINE #8#, )&. JINDUCIBLEPROTEIN#8#, )&. INDUCIBLE4 CELLALPHACHEMOATTRACTANT#8#, MACROPHAGEINmAMMATORYPROTEIN ALPHA-)0D MONOCYTECHEMOATTRACTANTPROTEIN##, MONOKINEINDUCEDBY)&. J #8#, -#0 ##, -#0 ##, 2!.4%3##, Growth factors (EPARIN BINDINGEPIDERMALGROWTHFACTOR LIKEBINDINGPROTEIN(" %'& ,"0 NERVEGROWTH FACTOR.'& PLATELET DERIVEDGROWTHFACTOR0$'& "" TRANSFORMINGGROWTHFACTOR ALPHA 4'& D TRANSFORMINGGROWTHFACTOR BETA4'& E) Autocrine survival factors 'RANULOCYTE MACROPHAGECOLONY STIMULATINGFACTOR'- #3& Other immune regulators )NTERFERON GAMMA)&. J TUMORNECROSISFACTORALPHA4.& D) -ODIlEDWITHPERMISSIONFROM&ILLON3 !CKERMAN3* &URUTA'4%OSINOPHILS)N#HARLES. 3ERHAN 0ETER 7ARD AND $EREK 'ILROY EDITORS &UNDAMENTALS OF )NmAMMATION #HAPTER  #AMBRIDGE#AMBRIDGE5NIVERSITY0RESSPPn

TERMINALDIFFERENTIATIONINTHEBONEMARROW EOSINOPHILRECRUITMENT PRIMING AND ACTIVATIONINTISSUEINmAMMATORYSITES ANDCANALSOPROLONGEOSINOPHILSURVIVALIN RESPONSETOALLERGICSTIMULI;30, 31=(OWEVER ACTIVATEDEOSINOPHILSEXPRESSTHEIR OWN'- #3& WHICHSIGNALSINANAUTOCRINEMANNERTOPREVENTAPOPTOSIS;32], thus SIGNIlCANTLYPROLONGINGTHEIRTISSUESURVIVAL EGINTHELUNGINASTHMA;32, 33], and LIKELY IN THE ') TRACT IN EOSINOPHIL ASSOCIATED ') DISEASES SUCH AS %O% .OTABLY TREATMENTOFASTHMA;34] or EoE [35=PATIENTSWITHANTI ), ANTIBODY-EPOLIZUMAB ONLYDEPLETES^OFLUNGORESOPHAGEALEOSINOPHILS LIKELYDUETOTHEIRAUTOCRINE '- #3& MEDIATEDLONG TERMSURVIVALINTHESETISSUES !LTHOUGH ),  IS THE ONLY LINEAGE SPECIlC EOSINOPHILOPOIETIN BASAL LEVELS OF EOSINOPHILDIFFERENTIATIONOCCURSINTHEBONEMARROWINTHEABSENCEOF),  IE IN),  AND), 2KNOCKOUTMICE BUTTHESEMICEDONOTDEVELOPBLOODORTISSUEEOSINOPHILIA INRESPONSETOALLERGICORPARASITICCHALLENGES4HISSUGGESTS), SPRIMARYROLEISTHE RAPIDEXPANSIONOFTHEEOSINOPHILLINEAGEFORTHEDEVELOPMENTOFBLOODANDTISSUE EOSINOPHILIA#ONSISTENTWITHTHISISTHElNDINGTHAT), UPREGULATESEOSINOPHILPROGENITORCELLEXPRESSIONOFTHETRANSMEMBRANEISOFORMOFITSRECEPTORSPECIlCALLYTHE ),  BINDING D CHAIN OF THE HETERODIMERIC ), 2 AND DOWNREGULATES THE SOLUBLE hDECOYv ISOFORM OF THE D-chain [36= .UMEROUS STUDIES OF ),  IN EXPERIMENTAL MOUSEASTHMAMODELSUSINGGAIN OF FUNCTIONTRANSGENICLUNG SPECIlCOVER EXPRESSION AND LOSS OF FUNCTION ),  KNOCKOUTS AND ANTI ),  NEUTRALIZING ANTIBODIES HAVE CONlRMEDITSROLEINALLERGICRESPONSES PARTICULARLYINAMPLIFYINGBLOODANDTISSUE EOSINOPHILIA&OREXAMPLE TRANSGENICOVER EXPRESSIONOF), EITHERSYSTEMICALLYOR INANORGAN SPECIlCMANNERINTHEMOUSEISSUFlCIENTTOINDUCEEOSINOPHILIA;37–40], WHILEANTIBODYNEUTRALIZATIONORGENEKNOCKOUTOF), BLOCKSMULTIPLEASPECTSOFTHE ASTHMATIC RESPONSE ;41, 42= INCLUDING SUPPRESSION OF PULMONARY EOSINOPHILIA IN

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RESPONSETOALLERGENSENSITIZATIONINHALATIONCHALLENGE AIRWAYSHYPERREACTIVITY;43], ANDAIRWAYSREMODELINGINTERMSOFGOBLETCELLMUCUSMETAPLASIA SUBEPITHELIALlBROSIS AND AIRWAY SMOOTH MUSCLE HYPERPLASIA ;44= ,IKEWISE EOSINOPHIL TRAFlCKING TO THE ALLERGEN SENSITIZED AND CHALLENGED LUNG IS SIGNIlCANTLY REDUCED IN ),  DElCIENT KNOCKOUT MICEANDTHOSETREATEDWITHANTI ), NEUTRALIZINGANTIBODIES;41, 42, 44]. )MPORTANTLY CLINICALSTUDIESSHOWTHATANTI ), ANTIBODY-EPOLIZUMAB INASTHMATICS FULLY DEPLETES THEIR BONE MARROW AND BLOOD EOSINOPHILS SIGNIlCANTLY REDUCES PULMONARYEOSINOPHILSBY;15, 34, 45= ANDSHOWSEFlCACYINREDUCINGSPUTUM EOSINOPHILS AND ASTHMA EXACERBATIONS ;46= AND IMPROVING AIRWAY FUNCTION AND reducing steroid use [47= BOTHINPATIENTSWITHCLEARLYDElNEDREFRACTORY STEROID DEPENDENTEOSINOPHILICASTHMA %OSINOPHILSCANEXPRESSANUMBEROFCYTOKINESNORMALLYASSOCIATEDWITH4H 4CELLSSUCHAS), AND),  WHICHCANACTIVATEHUMANVASCULARENDOTHELIALAND RESPIRATORYEPITHELIALCELLSTOPRODUCEEOSINOPHILCHEMOTACTICCYTOKINESCHEMOKines) [48= THUS AMPLIFYING EOSINOPHIL RECRUITMENT TO THE TISSUES "OTH ),  AND ),  PRODUCEDINGREATERQUANTITIESBY4H4CELLSTHANEOSINOPHILS ALSORECRUITS AND ACTIVATES )G% PRODUCING " LYMPHOCYTES AND ENHANCES )G% MEDIATED ALLERGIC responses [49=5NLIKE),  ), HASADISTINCTROLEINALLERGICINmAMMATION ACTINGASAPRIMARYREGULATOROFALLERGEN INDUCEDAIRWAYINmAMMATIONANDGOBLETCELL MUCUS METAPLASIA IN ASTHMA ;50= AND EOSINOPHILIC ESOPHAGEAL INmAMMATION AND REMODELINGIN%O%;51–54=!LTHOUGHBOTH), AND), INDUCETHEEXPRESSIONOF EOTAXINS BY EPITHELIAL CELLS IN A 34!4 DEPENDENT MANNER ;55], IL-13 alone EXPRESSEDBY4CELLSOREOSINOPHILSTHEMSELVESINASTHMA %O%ANDOTHEREOSINOPHIL ASSOCIATED INmAMMATORY DISEASES ;51, 56= MAY PARTICIPATE AS AN IMPORTANT EOSINOPHILCHEMOATTRACTANT;31]. /FINTEREST EOSINOPHILSALSOPRODUCEANUMBEROFCYTOKINESASSOCIATEDWITH4H IMMUNERESPONSESINCLUDING),  ),  ),  4.& DAND)&. J, suggesting they SHARESOMEFUNCTIONALACTIVITIESWITH4H4CELLS;57–59=/FNOTE 4HCELLSARE RECRUITEDBY#8#,AMONOKINEINDUCEDBY)&. J AND#8#,)&. J INDUCIBLE protein-10) [60=), HASBEENSHOWNTOINHIBIT4HANDINCREASE4HDIFFERENTIATION OFEOSINOPHILSTHROUGHINDUCTIONOFNAÉVE4CELL), PRODUCTION;61=)NSOME4H MODELS OF INmAMMATION EOSINOPHIL DERIVED )&. J is increased [29]. In addition, 4.& DISESSENTIALFOREOSINOPHIL DERIVED)&. J INDUCEDSECRETIONOF4HCHEMOKines [59]. %OSINOPHILS ALSO SECRETE A NUMBER THE MAJOR CHEMOATTRACTANTS CHEMOKINES INVOLVEDINTHEIROWNRECRUITMENTINTOTISSUESINCLUDINGTHEEOTAXINSAND2!.4%3 SUGGESTINGEOSINOPHILSMAYAMPLIFYORPERPETUATETHEIRRECRUITMENTTOSITESOFALLERGIC INmAMMATORY RESPONSES EVEN AFTER THE INITIATING STIMULUS IS NO LONGER PRESENT IE MASTCELLOREPITHELIALCELLACTIVATION4HEEOTAXINS AND INPARTICULAR PRINCIPALLYSECRETEDBYBOTHACTIVATEDEPITHELIALCELLSAND4CELLS ARETHEMOSTHIGHLY SELECTIVEOFTHECHEMOKINESINVOLVEDINEOSINOPHILTISSUERECRUITMENTIDENTIlEDTODATE %OSINOPHILSSELECTIVELYEXPRESS##2ONTHEIRPLASMAMEMBRANE THECOGNATERECEPTOR FORTHEEOTAXINS)NCONTRAST 2!.4%3ISLESSEOSINOPHIL SELECTIVEANDINDUCESBOTH EOSINOPHIL AND NEUTROPHIL GRANULOCYTE INmUX WHEREAS THE CHEMOKINE -)0 D, also EXPRESSEDBYEOSINOPHILS ISPRIMARILYINVOLVEDINTHETRAFlCKINGOFNEUTROPHILS;62].

 %OSINOPHIL"IOLOGYINTHE0ATHOGENESISOF%OSINOPHILIC$ISORDERS

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%OSINOPHILSALSOPARTICIPATEINOTHERBIOLOGICALPROCESSES NOTTHELEASTOFWHICHIS REGULATIONOFTHEIMMUNEMICROENVIRONMENTINTHELUNGANDOTHERTISSUES;3, 13, 63], INCLUDINGTHEIRRECENTLYIDENTIlEDREQUIREMENTFORTHEDEVELOPMENTOF4H MEDIATED ALLERGICRESPONSESANDRECRUITMENTOFEFFECTOR4CELLSINTOTHELUNGINEXPERIMENTAL ALLERGICASTHMAMODELS;13= INDICATINGANIMPORTANTROLEINBRIDGINGINNATEANDADAPTIVE IMMUNE RESPONSES IN ALLERGIC AIRWAY INmAMMATION ;2, 3= %OSINOPHIL DElCIENT NAMEDh0(),v MICEHAVESIGNIlCANTLYBLUNTED4HCYTOKINERESPONSESINTHEAIRWAYSANDFAILTORECRUIT4HEFFECTOR4CELLSINTOTHELUNGDURINGALLERGICINmAMMATION [11, 13= !S WELL ),  DElCIENT MICE HAVE REDUCED ALLOGRAFT TRANSPLANT ASSOCIATED EOSINOPHILIA AND IMPAIRED DEVELOPMENT OF 4H INmAMMATION AT SITES OF ALLOGRAFT TRANSPLANTS IN THESE MICE SUGGESTING EOSINOPHILS MAY REGULATE IMMUNE RESPONSES leading to transplant rejection [64=-OREOVER ), AND), ARESTRONGLYASSOCIATED WITHTUMORCELLDEATHINSEVERALTYPESOFCANCER;65= ANDTUMORCELLSENGINEEREDTO OVER EXPRESS ),  BUT NOT ),  INDUCE TUMORS THAT UNDERGO EOSINOPHIL MEDIATED REGRESSIONINAMURINECANCERMODEL;66–68=/FNOTE ), THERAPYOFCANCERPATIENTS INA0HASE)CLINICALTRIALWASSHOWNTOINDUCEMILDEOSINOPHILIA SYSTEMICANDTISSUE SKIN EOSINOPHILACTIVATIONANDDEGRANULATION INCREASEDLEVELSOF-"0BOTHSYSTEMICALLYANDEXTRACELLULARINTHESKIN ANDSIGNIlCANTLYENHANCEDEOSINOPHILSURVIVAL DUETO),  '- #3&AND),  SUGGESTINGANASSOCIATIONBETWEEN), ANDEOSINOPHIL INDUCED PATHOLOGIES IN CERTAIN HUMAN CANCERS AND ALLERGIC RESPONSES ;69= /F INTEREST ALMOST ALL HUMAN AND MURINE TUMORS BECOME INlLTRATED BY EOSINOPHILS AT SOMEPOINTINTHEIRGROWTH;3, 70= WITHTHEPRESENCEOFEOSINOPHILSBEINGEITHERA POSITIVEORNEGATIVEPROGNOSTICFACTOR DEPENDINGONTHETYPEOFCANCER;3, 70]. &INALLY EOSINOPHILSAREAVERYRICHSOURCEOF4'& E [71–76= COMPRISETHEMAJOR 4'& E EXPRESSING CELL POPULATION IN THE AIRWAYS IN HUMAN ASTHMA ;73, 77] and EXPERIMENTALMOUSEASTHMAMODELS;44], and in the esophagus in EoE [71, 78], and ARECLINICALLYANDEXPERIMENTALLYASSOCIATEDWITHMULTIPLEASPECTSOFTISSUEREMODELINGEGEPITHELIALCELLHYPERPLASIA SMOOTHMUSCLEHYPERPLASIA ANGIOGENESIS AND lBROSIS ;10, 79= lBROBLAST ACTIVATION TRANSDIFFERENTIATION INTO MYOlBROBLASTS AND INCREASEDDEPOSITIONOFEXTRACELLULARMATRIX INMANYEOSINOPHIL ASSOCIATEDALLERGIC DISEASES AND HYPEREOSINOPHILIC SYNDROMES INCLUDING ASTHMA ;8, 9, 78] and EoE [71, 80= REVIEWED IN GREATER DETAIL BELOW  2ECENT STUDIES HAVE IMPLICATED THE EOSINOPHILINTHEDEVELOPMENTOFSUBEPITHELIALlBROSISTHROUGHTHEINDUCTIONOFEPITHELIALMESENCHYMALTRANSITION%-4 INTHEAIRWAYEPITHELIALCELLSINASTHMA;81–84] and in the esophagus in EoE [85].

Lipid Mediators Expressed By Eosinophils %OSINOPHILSEXPRESSALLOFTHEREQUIREDLIPOXYGENASEANDCYCLOOXYGENASEENZYMES INVOLVED IN THE GENERATION OF A VARIETY OF POTENT LIPID MEDIATORS OF INmAMMATION DERIVED FROM ARACHIDONIC ACID AND WHEN APPROPRIATELY ACTIVATED THEY SYNTHESIZE ANDSECRETELIPIDMEDIATORSINCLUDINGCYSTEINYLLEUKOTRIENESMAINLY,4#4), prostaglanDINS MAINLY 0'%2 AND PLATELET ACTIVATING FACTOR 0!&  4HESE EOSINOPHIL DERIVED

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EICOSANOIDS CAN INCREASE LEUKOCYTE TRAFlCKING AND ADHESION TO ENDOTHELIAL CELLS INDUCEAIRWAYSMOOTHMUSCLECONTRACTION INCREASEVASCULARPERMEABILITYANDMUCUS SECRETION ANDARECONSIDEREDONEOFTHEPRO INmAMMATORYFUNCTIONSOFTHEEOSINOPHIL;1], PARTICULARLYINLATE PHASEALLERGICREACTIONS)NCONTRAST EOSINOPHIL DERIVEDARACHIDONATE DERIVEDLIPIDMEDIATORSAREALSOLIKELYTOPARTICIPATEINTHERESOLUTIONOFALLERGIC INmAMMATION&OREXAMPLE AIRWAYCHALLENGEWITHALLERGENINAMOUSEASTHMAMODEL HASRECENTLYBEENSHOWNTOINITIATEAIRWAYBIOSYNTHESISOFFUNCTIONALLYSIGNIlCANT AMOUNTSOFLIPOXIN!4ANDINCREASEITSRECEPTOREXPRESSION.OTABLY ASTABLEANALOG OF,IPOXIN!4HASBEENSHOWNTOBLOCKTHEDEVELOPMENTOFAIRWAYHYPERRESPONSIVENESS DIMINISHAIRWAYINmAMMATION ANDDECREASEOVERALLLEUKOCYTERECRUITMENTAND ITSCONSEQUENTEXPRESSIONOF4HCYTOKINES),  ),  EOTAXINS PROSTANOIDS AND cysteinyl leukotrienes (i.e. LTC4) in the airways [45=!SWELL LIPOXIN!4 analogues HAVEBEENFOUNDTOBLOCKTHEDEVELOPMENTOFALLERGICPLEURALEOSINOPHILEFFUSIONS AND INHIBIT THE EARLY EDEMA AND NEUTROPHIL RECRUITMENT SEEN IN ALLERGIC RESPONSES [86=4HESELIPOXIN!4MEDIATEDRESPONSESWEREFOUNDTOBEINDEPENDENTOFMASTCELL DEGRANULATIONANDINCLUDEDINHIBITIONOFTHEGENERATIONANDACTIVITIESOF),  EOTAXIN ANDPLATELETACTIVATINGFACTOR;86=&INALLY EOSINOPHILSTHEMSELVESEXPRESSRECEPTORS FORTHECYSTEINYLLEUKOTRIENES#YS,42AND#YS,42 PROSTAGLANDINS0'$TYPE RECEPTOR AND0!&;87–89= CONSISTENTWITHTHEINDUCTIONOFEOSINOPHILRECRUITMENTBY LEUKOTRIENES ,4" $ % 0!& AND  OXO     EICOSATETRAENOIC ACID SUGGESTINGAROLEFORTHESECHEMOATTRACTANTLIPIDSINTHETISSUERECRUITMENTOFEOSINOPHILSTOSITESOFALLERGICREACTIONS;86, 90, 91].

Monitoring of Eosinophil Activity in Disease )NCREASEDAPPRECIATIONOFTHEIMPORTANCEOFBOTHTHENUMBERSANDFUNCTIONALSTATUS OFTISSUEEOSINOPHILS ASWELLASIMPORTANTFUNCTIONALDIFFERENCESBETWEENCIRCULATINGBLOODEOSINOPHILSANDTHOSERECRUITEDINTOTISSUESANDEXPOSEDTOCYTOKINESAND OTHER FACTORS IN THE TISSUE MICROENVIRONMENT ;92= LED TO THE DEVELOPMENT AND INCREASINGLYMOREROUTINEUSEOFAPPROACHESTOMONITOREOSINOPHILACTIVATIONINSITU 4ISSUEBIOPSIESAREROUTINELYEMPLOYEDFORBOTHTHECLINICALDIAGNOSISANDEXPERIMENTALEVALUATIONOFEOSINOPHILACTIVITYINDISEASESINVOLVINGTHESKIN;22, 93, 94], lungs [95–97= LYMPHNODES;98], heart [99], and other tissues such as the esophagus in EoE [100= CONTRIBUTINGSIGNIlCANTLYTOCURRENTAPPRECIATIONOFTHEEOSINOPHILS ROLESINDISEASEPATHOGENESIS PARTICULARLYTISSUEREMODELINGANDlBROSIS;78, 80]. 4HEDIFlCULTIES TEDIOUSNESS ANDSAMPLINGERRORSINHERENTINACCURATELYQUANTIFYING THENUMBERSANDFUNCTIONALSTATUSOFEOSINOPHILSINTISSUEBIOPSIES EVENUSINGANTIBODIESTHATRECOGNIZEEOSINOPHIL SPECIlCCELLSURFACEACTIVATIONMARKERSORSECRETION OFTHEGRANULECATIONICPROTEINSWITHQUANTITATIVEMORPHOMETRICASSESSMENTS STILL MAKESROUTINECLINICOPATHOLOGICEVALUATIONOFTISSUEEOSINOPHILSBYTHESEMETHODS SOMEWHATIMPRACTICALCLINICALLY!LTERNATIVESSUCHASANALYSISOFEOSINOPHIL SPECIlC BIOMARKERSINTISSUESECRETIONSFROMAFFECTEDORGANS EG BRONCHOALVEOLARLAVAGEOR INDUCEDSPUTUM HAVEMETWITHSOMESUCCESSINTHECLINICALANDEXPERIMENTALEVALUATION

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OF EOSINOPHIL PARTICIPATION IN DISEASES SUCH AS ASTHMA ;101= AND MORE RECENTLY USINGBIOPSYTISSUESECTIONSIN%O%;100=)NADDITIONTOROUTINEHISTOCHEMICALENUMERATIONOFEOSINOPHILSBY(%STAINING ANDIMMUNOHISTOCHEMICALLOCALIZATION OFCELL ASSOCIATEDANDSECRETEDEOSINOPHILGRANULECATIONICPROTEINSSUCHASEOSINOPHILPEROXIDASE%08 ;100=ANDEOSINOPHIL DERIVEDNEUROTOXIN%$. ;102], two ADDITIONALMETHODSWEREPREVIOUSLYUSEDTOMONITOREOSINOPHILACTIVATION SECRETION ANDPARTICIPATIONINTHEPATHOGENESISOFALLERGICDISEASE4HESEINCLUDEDIDENTIlCATIONOFACTIVATEDEOSINOPHILSERRONEOUSLY BYSTAININGWITHAMONOCLONALANTI %#0 ANTIBODY%'THATRECOGNIZEDASECRETED DEGLYCOSYLATEDFORMOFTHEPROTEINNO LONGERAVAILABLE ;103–105= ANDMEASUREMENTOFTHEEOSINOPHILGRANULECATIONIC PROTEINBIOMARKERSINCLUDING-"0 %#0 AND%$.BYRADIOIMMUNOASSAY;106–108], ANDMORERECENTLYBYCOMMERCIALLYAVAILABLE%,)3!SFOR%$. %#0 INVARIOUS BODYmUIDSINCLUDINGSERUM PLASMA URINE SPUTUM NASALLAVAGE AND"!,mUID [109=5NDERWELL CONTROLLEDSAMPLINGCONDITIONS MEASUREMENTSOFTHESEEOSINOPHIL GRANULEBIOMARKERSISANEXCELLENTINDICATOROFEOSINOPHILSECRETORYACTIVITYINVIVO ANDEOSINOPHILINVOLVEMENTINAVARIETYOFALLERGIC PARASITIC INmAMMATORY ANDSKIN diseases [93= SOMENOTNORMALLYASSOCIATEDWITHBLOODORTISSUEEOSINOPHILIA;110]. 3UCHMEASUREMENTSLIKELYREmECTINVIVOSECRETIONINTISSUESORSECRETORYACTIVITYOF EOSINOPHILS IN THE mUID SAMPLED ;109= OR BOTH AND HAVE PROVIDED COMPELLING EVIDENCEFORRELATIONSHIPSBETWEENEOSINOPHILSECRETORYACTIVITY PATHOGENESIS AND DISEASESEVERITY;111–113].

Eosinophil Development and Trafficking Eosinophilopoiesis in the Bone Marrow %OSINOPHILS DEVELOP FROM A RECENTLY RE DElNED POPULATION OF LINEAGE COMMITTED STEMCELL DERIVED#$), 2DEOSINOPHILPROGENITORS%O0 INTHEBONEMARROW [114= PRINCIPALLY IN RESPONSE TO 4 CELL DERIVED CYTOKINES THAT INCLUDE EOSINOPHIL LINEAGE SPECIlC),  ASWELLAS), AND'- #3&4HESECYTOKINESREGULATEEOSINOPHIL DIFFERENTIATIONANDFUNCTIONATANUMBEROFLEVELSINCLUDING %O0PROLIFERATION ANDTERMINALDIFFERENTIATION  PRIMING ACTIVATIONANDORSURVIVALOFEOSINOPHILS IN BLOOD AND TISSUES AND  RECRUITMENT OF EOSINOPHILS INTO ALLERGIC REACTIONS !CTIVATED 4H POLARIZED 4 CELLS ARE A PRIMARY SOURCE FOR THESE EOSINOPHIL ACTIVE CYTOKINESINALLERGICANDPARASITICDISEASES ANDHYPEREOSINOPHILICSYNDROMES EG (%3 (OWEVER OTHER LEUKOCYTES INCLUDING MAST CELLS MACROPHAGES AND NATURAL KILLERCELLS ANDENDOTHELIALCELLSANDSTROMALCELLSSUCHASlBROBLASTSAREALSOPRODUCERSOFTHESEFACTORS4HUS ),  PRINCIPALLYFROMACTIVATED4H4CELLS;115] and MAST CELLS ;116, 117= REGULATES THE DEVELOPMENT OF BLOOD AND TISSUE EOSINOPHILIA INVIVO;118–120=7HILE), AND'- #3&AREMULTIPOTENTCYTOKINESWITHACTIVITIESONMANYOTHERBLOODCELLLINEAGES ), ISEOSINOPHIL SELECTIVEANDPLAYSACRUCIALROLEINDRIVINGCOMMITTED%O0CELLPROLIFERATION TERMINALDIFFERENTIATION AND POST MITOTICACTIVATIONINTHEDEVELOPMENTOFEOSINOPHILIA;121=), ISMAXIMALLY

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ACTIVE ON THE ), 2 %O0 POOL THAT IS INITIALLY EXPANDED BY ),  AND '- #3& [121=!LTHOUGH), ISNECESSARYANDSUFlCIENTFORTHEDEVELOPMENTOFEOSINOPHILIA [121, 122= EOSINOPHILDIFFERENTIATIONITSELF ATLEASTINTHEMOUSE DOESNOTREQUIRE IL-5 [123=),  MEDIATEDUPREGULATEDEXPRESSIONOFTHE), RECEPTOR), 2 ON THE%O0ISAPREREQUISITEFOR),  INDUCEDEOSINOPHILTERMINALDIFFERENTIATIONAND DEVELOPMENTOFEOSINOPHILIA AND), OVER EXPRESSIONUNDERLIESMANYEOSINOPHIL ASSOCIATED DISEASES AND HYPEREOSINOPHILIC SYNDROMES SUCH AS (%3 ;124–126]. ),  OVEREXPRESSINGTRANSGENICMICEDEVELOPPROFOUNDEOSINOPHILIAS;37, 127= FURTHER EVIDENCE THAT ),  IS KEY IN PROMOTING BOTH THE PRODUCTION AND ACTIVITIES OF EOSINOPHILS #ONVERSELY ),  DElCIENT GENE KNOCKOUT MICE ;123, 128] do not DEVELOP SIGNIlCANT BLOOD OR TISSUE EOSINOPHILIA AIRWAYS HYPERRESPONSIVENESS TO CHOLINERGICS ANDAIRWAYSREMODELINGINMURINEALLERGICASTHMAMODELS;128], nor DOTHEYDEVELOPBLOODORTISSUEEOSINOPHILIAINRESPONSETOINFECTIONWITHHELMinth parasites [123= 4HE lNDING THAT ),  DElCIENT MICE STILL GENERATE BASAL NUMBERSOFBONEMARROWEOSINOPHILSlTSTHECURRENTPARADIGMTHATBASALBLOOD CELL DEVELOPMENT  OCCURS INDEPENDENTLY OF THE LINEAGE SPECIlC CYTOKINES IE %0/ ' #3& - #3& AND ),  AND  IS REGULATED AT THE LEVEL OF GENE TRANSCRIPTION THROUGH COMBINATORIAL NETWORKS OF TRANSCRIPTION FACTORS ACTING TO RESOLVE LINEAGE PROMISCUOUS GENE EXPRESSION PATTERNS IN EARLY UNCOMMITTED HEMATOPOIETICPROGENITORS;129–131].

Transcriptional Regulation of Eosinophil Lineage Commitment and Differentiation !VIAN MOUSE ANDHUMANSTUDIESHAVESHOWNTHATONLYAHANDFULOFTRANSCRIPTION FACTORSANDTHEIRFUNCTIONALINTERACTIONSAREKEYTOSPECIFYINGEOSINOPHILLINEAGE COMMITMENT AND TERMINAL DIFFERENTIATION ;132= 4HE COMBINATORIAL ACTIVITIES OF '!4!  #%"0D AND 05 ARE REQUIRED WITH '!4!  THE PIVOTAL PLAYER THAT DETERMINES IF GRANULOCYTE MACROPHAGE PROGENITORS WILL DIFFERENTIATE TO THE EOSINOPHIL'!4! REQUIRED ORNEUTROPHILANDMACROPHAGELINEAGESABSENCEOF '!4!  !SWELL A'!4! CO ACTIVATORCALLED&/' FRIENDOF'!4!  THAT IS REQUIRED FOR ERYTHROID DIFFERENTIATION FUNCTIONS INSTEAD AS A CO REPRESSOR OF GATA-1 in the eosinophil lineage [133= ANDMUSTBEDOWNREGULATEDFOREOSINOPHIL DIFFERENTIATION;134=4HUS EOSINOPHILDEVELOPMENTISDElCIENTIN'!4! KNOCKOUT MICE ;135= AND TRANSGENIC DELETION OF A HIGH AFlNITY DOUBLE '!4! SITE IN THE MURINE '!4!  PROMOTER ITSELF BLOCKS EOSINOPHIL DEVELOPMENT ;136= .OTABLY SIMILARHIGH AFlNITYDOUBLE'!4!SITESAREPRESENTINTHEPROMOTERSOFANUMBER OFHALLMARKEOSINOPHIL SPECIlCGENESINCLUDING-"0 %08 #,#'AL  ), 2D [137= ANDTHEEOTAXINRECEPTOR ##2;138=4HECURRENTCONSENSUSFORTHECOMBINATORIALTRANSCRIPTIONFACTORhCODEvTHATSPECIlESTHEEOSINOPHILRELATIVETOTHEOTHER HEMATOPOIETICLINEAGESISOUTLINEDIN&IG4.22EGULATIONOFBOTHTHELEVELSAND TIMEOFEXPRESSIONOFTHESETRANSCRIPTIONFACTORSAREREQUIREDTOGENERATEEOSINOPHILS SUCHTHATCOMMITMENTANDTERMINALDIFFERENTIATIONOFEOSINOPHILSFROM%O0

 %OSINOPHIL"IOLOGYINTHE0ATHOGENESISOF%OSINOPHILIC$ISORDERS

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Fig. 4.2 #OMBINATORIALTRANSCRIPTIONFACTORhCODESvTHATSPECIFYEOSINOPHILLINEAGECOMMITMENT ANDTERMINALDIFFERENTIATION'!4! ISBOTHNECESSARYANDSUFlCIENTTODRIVEEOSINOPHILDEVELOPMENT AND#%"0HISREQUIREDFOREOSINOPHILTERMINALDIFFERENTIATION%OSINOPHILSHAVERECENTLY BEENSHOWNTODEVELOPFROMADISTINCT#$), 2DEOSINOPHILPROGENITOR%O0 DERIVEDFROM THECOMMONMYELOIDPROGENITOR#-0 POOLANDNOTFROMTHEGRANULOCYTE MACROPHAGEPROGENITOR '-0 ASPREVIOUSLYTHOUGHT;114=#%"0D ##!!4ENHANCER BINDINGPROTEINDEry erythroCYTE FOG-1 FRIEND OF '!4!  GMP GRANULOCYTE MACROPHAGE PROGENITORS HSC CD34+ HEMATOPOIETICSTEMCELLSMacMACROPHAGEMegMEGAKARYOCYTEMEPMEGAKARYOCYTEERYTHROID PROGENITORSPMNPOLYMORPHONUCLEARLEUKOCYTEPU.1ETSFACTORIDENTICALTO3PI ONCOGENE  -ODIlEDANDUPDATEDWITHPERMISSIONFROM-C.AGNY+ 'RAF4-AKINGEOSINOPHILSTHROUGH SUBTLESHIFTSINTRANSCRIPTIONFACTOREXPRESSION*%XP-ED &n

REQUIRESCOORDINATEDEXPRESSIONOF# %"0D 05 AMODERATELEVELOF'!4!  AND ABSENCE OF &/'  ;132= !S WELL #%"0H EXPRESSED MAINLY DURING THE PROMYELOCYTE TO MYELOCYTE TRANSITION IS REQUIRED FOR EOSINOPHIL DEVELOPMENT STUDIESOF#%"0HKNOCKOUTMICESHOWEDTHATEOSINOPHILANDNEUTROPHIL DIFFERENTIATION REQUIRES #%"0H SINCE THESE MICE LACK TERMINALLY DIFFERENTIATED AND FUNCTIONALLY MATURE EOSINOPHILS AND NEUTROPHILS ;139, 140= 3IMILARLY PATIENTS WITHSPECIlCGRANULEDElCIENCY3'$ HAVEAMUTATIONINTHEIR#%"0H gene that LEADS TO A FAILURE OF BOTH NEUTROPHIL AND EOSINOPHIL DIFFERENTIATION WITH FAILED EXPRESSION OF IMPORTANT SECONDARY GRANULE PROTEIN GENES IN BOTH GRANULOCYTES [141='REATERUNDERSTANDINGOFTHECOMPLEXCOMBINATORIALANDFUNCTIONALINTERACTIONSOFTRANSCRIPTIONFACTORSTHATREGULATEEOSINOPHILLINEAGECOMMITMENT DIFFERENTIATION AND GENE EXPRESSION MAY LEAD TO NOVEL TARGETS FOR ABLATING EOSINOPHIL DEVELOPMENTINGENERAL ORSELECTIVELYKNOCKINGDOWNEOSINOPHILEXPRESSIONOFKEY INmAMMATORY MEDIATORS EG THE GRANULE CATIONIC PROTEINS OR EOTAXIN RECEPTOR ##2 AS NOVEL THERAPEUTIC APPROACHES TO TREATING EOSINOPHIL MEDIATED ALLERGIC diseases such as EoE.

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Eosinophilopoiesis and Eosinophil Extravasation 3TUDIESWITHANTI ), ANTIBODYINBOTHMOUSEANDHUMANSUBJECTSSHOWCLEARLYTHAT ), ISCRUCIALFORTHEGENERATIONOFBOTHALLERGICANDIDIOPATHICEOSINOPHILIAS;142, 143= AKEYINITIATINGSTEPINVOLVING%O0SURFACEEXPRESSIONOFTHEHIGH AFlNITY),  receptor (CD125/CD131) [144=5PTOTHISPOINT EOSINOPHILSANDBASOPHILSSHAREA COMMONDIFFERENTIATIONPATHWAY THEREMNANTSOFWHICHPERSISTEVENINTHEMATURE CELLSBLOODEOSINOPHILSEXPRESSLOWLEVELSOFTHEDCHAINOFTHEHIGHAFlNITY)G% RECEPTOR &CH2) ;145, 146= WHILE BASOPHILS EXPRESS LOW LEVELS OF -"0 ;147], Charcot-Leyden crystal protein/Galectin-10 (CLC/Gal-10) [148= %$. %#0 AND %08;149="OTHCELLSINTHEPERIPHERALBLOODEXPRESSTHEEOTAXINRECEPTOR##2 [150= !NOTHER SHARED DIFFERENTIATION MARKER IS 3IGLEC  3IGLEC & IN THE MOUSE [151, 152= EXPRESSEDMOREHIGHLYONBLOODEOSINOPHILSTHANBONEMARROWEOSINOPHILS ANDATHIGHERLEVELSTHANBASOPHILS;153, 154]. ),  DElCIENTMICEHAVEVERYFEWBONEMARROW TISSUE ANDCIRCULATINGEOSINOphils [123= WHILETHEOPPOSITEISTRUEFOR),  OVEREXPRESSINGTRANSGENICMICE;37, 127=4HEPRECISESIGNALSTHATREGULATEEOSINOPHILEGRESSFROMTHEBONEMARROWARE INCOMPLETELYUNDERSTOODBESIDESAROLEFOR), ITSELF;155= EOTAXIN ##, ANDPERHAPSOTHER##2LIGANDSPARTICIPATEINTHISPROCESS;156=!SWELL BLOCKING ANTIBODIES TO E INTEGRINS HAVE BEEN SHOWN TO PREVENT ),  MEDIATED EOSINOPHIL RELEASEFROMTHEBONEMARROW WHEREASBLOCKINGD4 integrins enhances their release. 4HEMECHANISMFORTHISISSTILLUNCLEAR BUTBOTH), AND##2AGONISTSHAVEBEEN REPORTEDTOALTERINTEGRINFUNCTIONINAMANNERTHATAIDSCELLULARDETACHMENTFROM VARIOUS COUNTER LIGANDS ;157–159= !LLERGEN SENSITIZATION AND CHALLENGE MURINE ASTHMAMODELSALSOSUGGESTTHATTHEEXTRAVASATIONOFEOSINOPHILSFROMTHEBONEMARROW is partly T cell dependent [160].

Eosinophil Mobilization, Trafficking, Survival, and Death at Sites of Tissue Inflammation )NHEALTHYINDIVIDUALS FOLLOWINGBONEMARROWEXTRAVASATION EOSINOPHILSRESIDEFOR ONLYASHORTTIMEINTHEPERIPHERALCIRCULATIONBEFORETRANSITINTOEXTRAVASCULARSITES PREFERENTIALLY IN TISSUES AND ORGANS EXPOSED TO THE EXTERNAL ENVIRONMENT MAINLY SUBMUCOUSMEMBRANESANDLOOSECONNECTIVETISSUEOFTHESKIN GASTROINTESTINALAND genital tracts, and the lungs [161=)NEOSINOPHIL ASSOCIATEDDISEASES BOTHTHEACUTE ANDCHRONICRECRUITMENTOFEOSINOPHILSINTOTISSUEINmAMMATORYSITESOCCURSPRINCIPALLY IN RESPONSE TO COMPONENTS OF CLASSICAL )G% MEDIATED EARLY AND LATE PHASE IMMEDIATEHYPERSENSITIVITYREACTIONS BUTALSOINRESPONSETOANUMBEROFNON ALLERGIC IMMUNOLOGICALLYMEDIATEDINmAMMATORYREACTIONSANDINIDIOPATHICHYPEREOSINOPHILICSYNDROMESSEEBELOW !SWELL DIURNALVARIATIONSINBLOODEOSINOPHILLEVELS AREWELLDOCUMENTED WITHTHELOWESTNUMBEROFINTRAVASCULAREOSINOPHILSEARLY INTHEMORNINGANDHIGHESTNUMBERLATEATNIGHT MIRRORINGTHECIRCADIANRHYTHMSIN

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ADRENALCORTICOSTEROIDLEVELSINTHEBLOOD;162=,IKEWISE DIURNALVARIATIONSALSO OCCURINTHEMOBILIZATION RECRUITMENT ANDACTIVATIONOFEOSINOPHILSINTISSUESIN DISEASESSUCHASNOCTURNALASTHMA;97, 163]. 4HEMECHANISMSBYWHICHEOSINOPHILSARESELECTIVELYRECRUITEDINLARGENUMBERS RELATIVE TO OTHER LEUKOCYTES IN INmAMMATORY REACTIONS ARE FAIRLY WELL UNDERSTOOD [31=THEIRMOBILIZATIONFROMTHEVASCULATURE ASFOROTHERLEUKOCYTES INVOLVESROLLING ANDADHERENCETOVASCULARENDOTHELIUMVIAl SELECTIN FOLLOWEDBYINTERACTIONSWITH INTERCELLULAR ADHESION MOLECULE  )#!-  THROUGH #$#$A B DEPENDENT MECHANISMS AND MIGRATION IN RESPONSE TO EOSINOPHIL SPECIlC CHEMOATTRACTANTS PARTICULARLYTHEEOTAXINS!DHERENCEVIA#$ INDEPENDENTMECHANISMSINVOLVES BINDINGTOCYTOKINE ACTIVATEDENDOTHELIALCELLSVIAEITHER% SELECTINALSOKNOWNAS ENDOTHELIAL LEUKOCYTE ADHESION MOLECULE  %,!- OR VASCULAR CELL ADHESION MOLECULE 6#!- 3ELECTIVERECRUITMENTOFEOSINOPHILSALSOINVOLVESADHESION TO6#!-VIATHEEINTEGRINVERYLATEACTIVATIONANTIGEN 6,!  EXPRESSEDBY EOSINOPHILSBUTNOTNEUTROPHILS;164=4HESELECTIVERECRUITMENTOFEOSINOPHILSINTO TISSUEINmAMMATORYSITESLIKELYINVOLVESBOTHTHESECOMPLEXINTERACTIONSWITHTHE ADHESION PATHWAYS AND CHEMOTACTIC GRADIENTS OF EOTAXIN  ##, EOTAXIN  ##, OR EOTAXIN  ##, DEPENDING ON THE TISSUE EG EOTAXIN  IN THE ESOPHAGUSIN%O% 4HEEOTAXINS THEMOSTPOTENTANDEOSINOPHIL SELECTIVECHEMOKINESIDENTIlEDTODATE BIND ANDSIGNALTHROUGHTHE##2RECEPTOREXPRESSEDSELECTIVELY ON EOSINOPHILS ;165–167= /THER LESS POTENT EOSINOPHIL CHEMOATTRACTANTS INCLUDECOMPLEMENTFRAGMENT#A PLATELETACTIVATINGFACTOR0!& ANDTHEEOSINOPHIL ACTIVE CYTOKINES ),  ),  '- #3& THAT PRIME EOSINOPHILS FOR ENHANCED MIGRATORYRESPONSESTOTHESEAGENTS/THERMOREPOTENTEOSINOPHILCHEMOATTRACTANTS ACTIVEINTHE−12 to 10−11-RANGE ^  FOLDMOREACTIVETHAN0!&AND#A INCLUDE THE SULlDOPEPTIDE LEUKOTRIENES ;168= ),  THE #$ 4 CELL DERIVED LYMPHOCYTE CHEMOATTRACTANT FACTOR ,#& THAT USES #$ EXPRESSED BY ACTIVATED eosinophils as its receptor [169= ANDTHECHEMOKINE2!.4%3##, WHICHIS CHEMOTACTICFORCERTAIN4 CELLSUBSETSANDMONOCYTES BUTNOTFORNEUTROPHILS;170] ITSPRODUCTIONBY#$4 CELLSINCUTANEOUSANDPULMONARYALLERGEN INDUCEDLATE PHASEREACTIONSMAYCONTRIBUTETOTHEEOSINOPHILRECRUITMENTINTHESERESPONSES 4WO INTERRELATED MECHANISMS THAT REGULATE THE TISSUE ACCUMULATION OF EOSINOphils are linked to eosinophil-associated pathophysiology [171=&IRST ), PLAYSA CRITICALROLEINEXPANDINGANDTERMINALLYDIFFERENTIATINGTHE%O0POOLSINTHEBONE MARROWINRESPONSETOPERIPHERALALLERGICOROTHERTISSUEINmAMMATORYSTIMULI4H cytokines such as IL-4 and IL-13 operate within tissues to regulate eosinophil transMIGRATIONFROMTHEVASCULARBED APROCESSTHATEXCLUSIVELYPROMOTESTISSUEACCUMULATION OF EOSINOPHILS OVER OTHER LEUKOCYTES LIKELY BY ACTIVATING THE EOSINOPHIL SPECIlCENDOTHELIALADHESIONPATHWAYSNOTEDABOVE ANDBYREGULATING THEPRODUCTIONOF), ANDEOTAXINEXPRESSIONINTHETARGETTISSUE!SWELL ), AND ), ACTASPOTENTINDUCERSOFTHEEOTAXINS;171=4HUS ), ANDTHEEOTAXINSCOOPERATELOCALLYTOSELECTIVELYPROMOTEEOSINOPHILIA THEFORMERWORKINGBOTHSYSTEMICALLYANDWITHINTHETISSUESTOPROMOTETHELOCALCHEMOATTRACTANTSIGNALSPROVIDED BYTHELATTER4HEREGULATIONOF), ANDEOTAXINLEVELSWITHINTISSUESBYCYTOKINES THATINCLUDE), AND),  ALLOWS4HCELLSTOCOORDINATEBOTHTISSUEANDBLOOD

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Fig. 4.3 &ACTORSTHATMAYINmUENCEEOSINOPHILLIFEORDEATHDECISIONSATSITESOFTISSUEINmAMMATION 3TIMULI THAT ARE KNOWN TO PROMOTE EOSINOPHIL PRIMING AND SURVIVAL ARE INDICATED AND ARE CONTRASTEDWITHTHOSETHATFACILITATEEOSINOPHILAPOPTOSISPROGRAMMED CELL DEATH  !LSO SHOWN ARE SOMEOFTHEPHENOTYPICCHARACTERISTICSTHATACCOMPANYTHEPRIMEDSTATEOFTHEEOSINOPHILCOMpared to those seen in eosinophils undergoing apoptosis. GM-CSFGRANULOCYTE MACROPHAGECOLONY STIMULATING FACTOR IL INTERLEUKIN IFNg INTERFERON J TGFb TRANSFORMING GROWTH FACTOR E TNFaTUMORNECROSISFACTOR D2EPRODUCEDWITHPERMISSIONFROM!CKERMAN3* "OCHNER"3 -ECHANISMSOFEOSINOPHILIAINTHEPATHOGENESISOFHYPEREOSINOPHILICDISORDERS)MMUNOL!LLERGY #LIN.!Mn!RTBY*ACQUELINE3CHAFFER

EOSINOPHILIA 4HESE OBSERVATIONS HIGHLIGHT THE IMPORTANCE OF TARGETING BOTH ),  ANDTHEEOTAXIN##2SIGNALINGSYSTEMSTOEFFECTIVELYBLOCKEOSINOPHIL ASSOCIATED INmAMMATIONANDTISSUEPATHOLOGY;171–173]. $ISEASES ASSOCIATED WITH PERIPHERAL BLOOD EOSINOPHILIA EG THE HYPEREOSINOPHILICSYNDROME(%3 AREFREQUENTLYASSOCIATEDWITHELEVATEDSERUMLEVELSOF),  ANDOR '- #3& ;174–177= AND ADMINISTRATION OF ),  OR '- #3& IN HUMANS RESULTSINARAPIDANDSUSTAINEDPERIPHERALBLOODEOSINOPHILIA;178, 179]. Eosinophils NORMALLY PERSIST IN THE PERIPHERAL CIRCULATION FOR APPROXIMATELY n H BEFORE MIGRATINGINTOEXTRAVASCULARTISSUESITES BUTTHEIRTRANSITTIMEINTHECIRCULATIONMAY BEEXTENDEDUNDERCONDITIONSTHATINDUCEPERIPHERALBLOODEOSINOPHILIA!LTHOUGH THEBONEMARROWISTHELARGESTRESERVOIROFEOSINOPHILPROGENITORS%O0 ANDDIFFERENTIATINGCELLS THEIRPREDOMINANTDESTINATIONINTHEHEALTHYINDIVIDUALISTHEGASTROINTESTINALTRACTHOMINGTOTHE')TRACTOCCURSINRESPONSETOCONSTITUTIVEEXPRESSION OFEOTAXIN ##, BYGUTEPITHELIALCELLS;180=/NCEEOSINOPHILSMIGRATEINTO EXTRAVASCULAR TISSUE SITES THEY DO NOT APPEAR TO RE CIRCULATE THROUGH THE BLOOD ALTHOUGHANIMALMODELSTUDIESSUGGESTTHATEOSINOPHILSIMPLANTEDINTOTHELUNGSCAN TRAFlCTOREGIONALLYMPHNODESWHERETHEYMAYPARTICIPATEINANTIGENPRESENTATION [181=%OSINOPHILSURVIVALINTISSUESISDEPENDENTONAUTOCRINEORLOCALPRODUCTION OFANTI APOPTOTICCYTOKINESSUCHAS), AND'- #3&OTHERLOCALLYPRODUCEDSURVIVALFACTORSMAYINCLUDE),  4.& D )&. J, leptin [182= ENGAGEMENTOF#$ [183] and others [1=&IG4.3 )NTHERIGHTTISSUEMICROENVIRONMENT STUDIESINDICATE THATEOSINOPHILSANDTHEIRPRECURSORSMAYBECAPABLEOFSURVIVINGFORSEVERALDAYS [184–186=TOMONTHS EVENAFTERADMINISTRATIONOFANTI ), ANTIBODYTHATDEPLETES BOTHBONEMARROWANDPERIPHERALBLOODEOSINOPHILS;34, 35=/FINTEREST EOSINOPHILSOBTAINEDBY"!,OFASTHMATICSUBJECTSORAFTERLUNGSUBSEGMENTALBRONCHOPROVOCATIONWITHALLERGEN SHOWPROLONGEDSURVIVALEXVIVOFORnHINTHEABSENCE

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OFEXOGENOUSSURVIVALCYTOKINES WHEREASTHEIRPERIPHERALBLOODCOUNTERPARTSDONOT [187, 188= CONSISTENTWITHEITHERINVIVOEXPOSURETOTHESECYTOKINESINTHEINmAMED AIRWAYS ORINDUCTIONOFAUTOCRINEEXPRESSIONOF'- #3&BYTHEEOSINOPHIL;32]. %OSINOPHILINTERACTIONSWITHSPECIlCTISSUEMATRIXPROTEINS PARTICULARLYlBRONECTIN AND LAMININ MAY ALSO BE IMPORTANT IN INDUCING THEIR AUTOCRINE '- #3& DRIVEN PROLONGEDSURVIVALWITHINTISSUES;189, 190]. Eosinophils in the tissues that do not ENCOUNTER THE NECESSARY SURVIVAL FACTORS UNDERGO RAPID APOPTOSIS AND PHAGOCYTIC CLEARANCE!SWELL THEREAREPATHWAYSTHATSELECTIVELYINDUCEEOSINOPHILAPOPTOSIS &OREXAMPLE CORTICOSTEROIDSRAPIDLYDECREASETHENUMBERSOFBOTHCIRCULATINGAND TISSUEEOSINOPHILS ALTHOUGHTHEMECHANISMSRESPONSIBLEFORTHISARECOMPLEXAND POORLY UNDERSTOOD LIKELY INVOLVING A COMBINATION OF DECREASED RELEASE FROM THE BONE MARROW DECREASED CIRCULATION TIME REDISTRIBUTION TO OTHER ORGANS SUCH AS SPLEEN OR INHIBITED EXPRESSION OF SURVIVAL CYTOKINES AND CHEMOKINES ;191–195]. /THERPRO APOPTOTICSTIMULIFOREOSINOPHILSINCLUDELIDOCAINE;196= 4'& E [197], 3IGLEC 3IGLEC &;198, 199= &AS#$ ;200] and CD30 [201]. Other drugs used TOREDUCEEOSINOPHILNUMBERSINHYPEREOSINOPHILICSYNDROMESINCLUDEHYDROXYUREA WHICHCAUSESAGLOBALINHIBITIONOFHEMATOPOIESIS AND)&. DTHATREDUCESTHENUMBERS OF CIRCULATING EOSINOPHILS ;202= 4YROSINE KINASE INHIBITORS PARTICULARLY IMATINIB MESYLATE 'LEEVEC HAVE PROFOUND EFFECTS ON EOSINOPHIL NUMBERS IN A SUBSET OF INDIVIDUALSWITH(%3WHOHAVEACHROMOSOMEDELETIONMUTATIONTHATGENERATESA FUSIONBETWEENTHE&)0,AND0$'&2D genes, resulting in a chronic eosinophil LEUKEMIADUETOTHECONSTITUTIVELYACTIVETYROSINEKINASE;203].

Eosinophil Activation and Functions Activation of Eosinophil Secretion and Degranulation %OSINOPHILPARTICIPATIONINTHEPATHOGENESISOFTISSUEINmAMMATION DAMAGE REMODELINGANDlBROSISINALLERGICDISEASESSUCHAS%O%REQUIRESMORETHANTHEIRSELECTIVE RECRUITMENT IETOTHEESOPHAGUS4HEACTIVATIONSTATEOFTHERECRUITEDEOSINOPHIL ANDIMPORTANTLY ITSEXPOSURETOCOMPONENTSOFTHEINmAMMATORYTISSUEMICROENVIRONMENT IS EQUALLY IMPORTANT IN DETERMINING ITS VARIED CONTRIBUTIONS TO TISSUE PATHOLOGY&OREXAMPLE STRAINSOF), TRANSGENICMICETHATEXPRESS), SYSTEMICALLY TYPICALLY HAVE PROFOUND BLOOD ORGAN AND TISSUE EOSINOPHILIA BUT IN THE ABSENCEOFADDITIONALSECRETORYSIGNALS SHOWLITTLEIFANYEOSINOPHIL MEDIATEDTISSUE PATHOLOGYANDREMAINRELATIVELYHEALTHY;37, 126]. The required secondary signals INCLUDECROSS LINKINGOFSURFACEIMMUNOGLOBULINRECEPTORS PARTICULARLYFOR)G!AND TOALESSEREXTENTFOR)G';168= ASWELLASEXPOSURETOACTIVATINGRATHERTHANPRIMING LEVELSOFANUMBEROFCYTOKINES CHEMOKINES COMPLEMENTANDLIPIDMEDIATORSFOR WHICHTHEYEXPRESSRECEPTORSINCLUDING), ITSELF THEEOTAXINS ),  THECYSTEINYL LEUKOTRIENES COMPLEMENT FRAGMENTS #A #A NEUROPEPTIDES AND OTHERS [30, 204=.OTABLYMISSINGFROMTHISLISTIS)G% FORWHICHTHEREISNOWAMPLEEVIDENCE

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THATMOUSEEOSINOPHILSDONOTEXPRESSTHEHIGHAFFINITY)G%RECEPTOR&CH2) AND HUMANEOSINOPHILS WHICHEXPRESSVERYLOWIFANYFUNCTIONAL&CH2)ONTHEIR SURFACE LACK THE E CHAIN OF THE RECEPTOR MAKING DIRECT ACTIVATION OF EOSINOPHILS highly unlikely [205–207=%OSINOPHILACTIVATIONBYMANYOFTHEABOVE MENTIONED AGONISTSINDUCESEOSINOPHILPIECEMEALDEGRANULATIONWITHSELECTIVESECRETIONOFTHE GRANULECATIONICPROTEINS%#0 %$. %08AND-"0 DEPENDINGONTHESTIMULUS THEGENERATIONOFREACTIVEOXYGENSPECIESDIRECTEDEXTRACELLULARLY2/3 EGSUPEROXIDE ANDLIPIDMEDIATORSINCLUDINGCYSTEINYLLEUKOTRIENE,4#4AND0!&!CTIVATED EOSINOPHILS ALSO GENERATE AND SECRETE A WIDE RANGE OF CYTOKINES AND CHEMOKINES including IL-1E AND 4'& E TWO OF THE MAJOR MEDIATORS OF EOSINOPHIL INDUCED TISSUEREMODELINGANDlBROSISSEENINMANYEOSINOPHIL ASSOCIATEDDISEASES;10, 75, 208, 209]. 4HE QUANTITIES OF CYTOKINES AND CHEMOKINES RELEASED BY ACTIVATED EOSINOPHILS INVITROANDATSITESOFALLERGICTISSUEINmAMMATIONINVIVOCANVARYWIDELYCOMPAREDTOOTHERLEUKOCYTES;27, 30=OFTHESE '- #3&ISONEOFTHOSEPRODUCEDIN GREATESTAMOUNTS;168= ANDASDISCUSSEDPREVIOUSLY FUNCTIONSASANAUTOCRINEANTI APOPTOTICSIGNALTHATPROLONGSEOSINOPHILSURVIVALATSITESOFTISSUEINmAMMATION!S WELL EOSINOPHILEXPOSURETOLOWLEVELSOF), ANDTHEEOTAXINSPRIMESTHEMFOR INCREASEDSECRETORYANDOXIDATIVERESPONSESTOOTHERPHYSIOLOGICALLYRELEVANTSTIMULI INCLUDING ),  ITSELF S)G! )&. J AND OTHERS THAT INDUCE THE SECRETION OF THE GRANULE PROTEINS %#0 %$. %08 -"0 AND EOSINOPHIL ELABORATED CYTOKINES 2!.4%3 ),  VIATHEPROCESSOFPIECEMEALDEGRANULATION0-$ ;210, 211], AUNIQUEMECHANISMTHATALLOWSFORTHEIRSELECTIVEMOBILIZATIONTHROUGHVESICULAR TRANSPORTTOTHEPLASMAMEMBRANEINTOTHEEXTRACELLULARSPACE;212, 213]. In conTRAST GRANULEFUSIONANDCLASSICALEXOCYTOSISARERARELYOBSERVEDINEOSINOPHILSAT SITESOFTISSUEINmAMMATION;214= BUTAREFREQUENTLYSEENINEOSINOPHIL MEDIATED KILLINGOFLARVALHELMINTHPARASITESSUCHASSCHISTOSOMULAOFSchistosoma mansoni. /NCESECRETED THEEOSINOPHILSGRANULEPROTEINSHAVEVARIEDPRO INmAMMATORY ACTIVITIES THAT HAVE BEEN EXTENSIVELY DElNED IN BOTH IN VITRO AND IN VIVO STUDIES THESE INCLUDE PLASMA MEMBRANE CELL AND TISSUE DAMAGING CYTOTOXICITIES ;215, 216=4HEYCANALSOSELECTIVELYACTIVATEOTHERINmAMMATORYCELLSSUCHASBASOPHILS ANDMASTCELLSTORELEASEVASOACTIVEMEDIATORSSUCHASHISTAMINE;217], and induce AN OXIDATIVE BURST IN NEUTROPHILS ;218= /F NOTE -"0 IS A POTENT ANTAGONIST OF INHIBITORY-MUSCARINICRECEPTORSINVITROANDINTHEAIRWAYSIN'UINEAPIGALLERGIC ASTHMAMODELS;219= ANDITPOTENTLYENHANCESTHEABILITYOF4'& EPRIMEDlBROBLASTSTOEXPRESSANDSECRETEMEMBERSOFTHEPRO INmAMMATORYANDPRO lBROTIC),  FAMILYOFCYTOKINESINCLUDING), AND), ;220=4HUS EOSINOPHILSCOMEFULLY ARMEDWITHPRE FORMEDMEDIATORSOFINmAMMATION TISSUEDAMAGE REMODELING AND lBROGENESISTHATARESECRETEDATSITESOFEOSINOPHILICINmAMMATIONINEOSINOPHIL ASSOCIATEDALLERGICDISEASESSUCHASASTHMAANDHYPEREOSINOPHILICSYNDROMESSUCH AS%O% ANDHAVETHECAPACITYWHENAPPROPRIATELYPRIMEDANDACTIVATEDTOSYNTHESIZEANDSECRETECYTOKINES CHEMOKINES ANDLIPIDMEDIATORSOFINmAMMATIONINTHE PROCESSOFTHEIRRECRUITMENTFROMTHEBONEMARROWANDPERIPHERALCIRCULATIONINTO TISSUESINRESPONSETOALLERGICEGMASTCELL BASOPHIL ANDOTHERINmAMMATORYAND OR4H4 CELLSTIMULI

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Pathogenesis of Tissue and End Organ Damage in Eosinophilic Diseases "ASEDONCURRENTUNDERSTANDINGOFEOSINOPHILFUNCTIONSINHYPEREOSINOPHILICCONDITIONS SUSTAINEDEOSINOPHILIA REGARDLESSOFITSORIGINIE REACTIVE CLONAL ALLERGICORIDIOPATHIC HASTHECAPACITYTOLEADTOENDORGANDAMAGE4HEMULTIPLEMANIFESTATIONSOF EOSINOPHIL ASSOCIATEDENDORGANDAMAGEARECONSIDERABLE;221= BUTNOTALLCASESOF SUSTAINEDBLOODORTISSUEHYPEREOSINOPHILIALEADTOENDORGANDAMAGE&OREXAMPLE PATIENTSWITHHYPEREOSINOPHILICSYNDROMESSUCHASEOSINOPHILICPNEUMONIAANDEPISODICANGIOEDEMAWITHEOSINOPHILIA;222=CHARACTERISTICALLYFAILTODEVELOPTHECARDIACDAMAGEANDENDOMYOCARDIALlBROSISASSOCIATEDWITHUNTREATEDEOSINOPHILIAIN PATIENTS WITH THE (%3 !S NOTED ABOVE ),  TRANSGENIC MICE WHICH DEVELOP EXTREMELYHIGHNUMBERSOFPERIPHERALBLOODEOSINOPHILS DONOTDEVELOPSIGNIlCANT TISSUE OR END ORGAN DAMAGE INDICATING THAT OTHER FACTORS ARE REQUIRED FOR TISSUE SPECIlCEOSINOPHILRECRUITMENT ACTIVATION ANDDAMAGE;37, 126]. Likewise, other FACTORSMAYBENECESSARYTOINDUCEEOSINOPHILICENDORGANTISSUEDAMAGE SUCHAS SECRETION OF EOSINOPHIL ACTIVE INmAMMATORY OR HEMATOPOIETIC CYTOKINES EG '- #3& GENETICPREDISPOSITION CLONAL4 CELLDYSFUNCTION 4 CELLPOLARIZATIONTOA 4H RATHER THAN 4H PHENOTYPE OR IN SITU PRODUCTION OF CYTOKINES THAT ENHANCE EOSINOPHILLONG TERMTISSUESURVIVALANDACTIVATIONBYBLOCKINGEOSINOPHILAPOPTOSIS !NUMBEROFTHEEOSINOPHILGRANULECATIONICPROTEINSARECAPABLEOFINDUCINGTHROMBOTICEVENTS;223= ENDOTHELIALANDENDOCARDIALDAMAGE;99= ANDNEUROTOXICITYTHE RIBONUCLEASES%$.AND%#0 ;224, 225=-"0AND%#0AREPOTENTCELLULARTOXINS CAPABLEOFDAMAGINGNORMALHOSTCELLSANDTISSUESINAMANNERREMINISCENTOFEND ORGANTISSUEDAMAGEASSOCIATEDWITHCHRONICTISSUEEOSINOPHILIA;168]. As well, upon PRIMINGANDACTIVATION THEEOSINOPHILHASTHECAPACITYTOUNDERGOAPOTENTRESPIRATORY BURST GENERATING 2/3 THAT CAN DIRECTLY OR IN ASSOCIATION WITH THE ENZYMATIC ACTIVITIESOF%08 INDUCESIGNIlCANTOXIDANT MEDIATEDTISSUEDAMAGE;226–228].

Eosinophil Induction and Regulation of Tissue Remodeling and Fibrosis /NEOFTHEMOSTEXPERIMENTALLYANDCLINICALLYWELL DElNEDROLESOFTHEEOSINOPHIL ISASANINDUCEROFTISSUEREMODELINGANDlBROSIS FORWHICHTHEPARADIGMSDEVELOPEDFOROTHEREOSINOPHIL MEDIATEDDISEASESPROVIDEINSIGHTSINTOTHEPATHOGENESIS ANDCLINICALMANIFESTATIONSOF%O%&IG4.1 4ISSUEREMODELINGIN4H MEDIATED ANDOTHEREOSINOPHIL ASSOCIATEDDISEASESWASlRSTCHARACTERIZEDINTHEHYPEREOSINOPHILICSYNDROME(%3 ANDASTHMA;9, 11, 63, 99=IN(%3 EOSINOPHILRECRUITMENT ACTIVATION AND SECRETION DEGRANULATION IN THE HEART LEADS TO SIGNIlCANT PATIENT MORBIDITY AND MORTALITY DUE TO THE DEVELOPMENT OF ENDOMYOCARDIAL lBROSIS AND ASSOCIATED CARDIAC FAILURE ;99, 208= !STHMA ANOTHER 4HEOSINOPHIL ASSOCIATED DISEASE ISCHARACTERIZEDBYSIGNIlCANTAIRWAYREMODELINGCONSISTINGOFGOBLETCELL

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METAPLASIA WITH HYPERPRODUCTION OF MUCOUS SMOOTH MUSCLE HYPERPLASIA AND HYPERTROPHY SUBEPITHELIAL lBROSIS AND INCREASED ANGIOGENESIS ;9] these structural CHANGESCONTRIBUTETOTHECLINICALMANIFESTATIONSOFBRONCHIALHYPERREACTIVITY AIRWAY EDEMA MUCOUSPLUGGING ANDSUBSEQUENTNARROWINGOFTHEAIRWAYLUMEN)NASUBSET OFPATIENTS THISAIRWAYSOBSTRUCTIONBECOMESIRREVERSIBLE!LTHOUGHTHEPATHOGENIC ROLEOFTHEEOSINOPHILIN(%3ISRELATIVELYCLEAR ITSROLEINASTHMAISSTILLBEINGRESOLVED [13, 63=-OUSEMODELSOFASTHMASUPPORTASIGNIlCANTCONTRIBUTIONOFTHEEOSINOPHIL TOAIRWAYPATHOLOGYANDREMODELING/FNOTE DOUBLETRANSGENICMICEEXPRESSINGBOTH AIRWAY EOTAXIN  AND SYSTEMIC ),  HAVE SEVERE HUMAN ASTHMA LIKE PATHOLOGIES INCLUDINGSUBEPITHELIALCOLLAGENDEPOSITIONTHATISESSENTIALLYELIMINATEDIFTHEANIMALS ARE CROSSED TO EOSINOPHIL DElCIENT MICE ;11, 40= )N THIS REGARD THE BEST HUMAN hEXPERIMENTvFORTHEEFFECTSOFEOSINOPHILDElCIENCYISTREATMENTOFPATIENTSWITHTISSUEEOSINOPHILIAWITHNEUTRALIZINGANTI ), ANTIBODIESTOREMOVETHEPRINCIPALEOSINOPHILOPOIETIC STIMULUS &OR EXAMPLE ASTHMATIC PATIENTS TREATED WITH MONOCLONAL ANTI ),  ANTIBODY -EPOLIZUMABÍ SHOWED DECREASED AMOUNTS OF SUBEPITHELIAL EXTRACELLULARMATRIXPROTEINSINTHEAIRWAYSINCLUDINGTENASCIN PRO COLLAGEN))) AND LUMICAN;15=3IMILARSTUDIESTESTINGTHEEFlCACYOFANTI ), ANTIBODIESFORTREATMENT OFPEDIATRIC;16] and adult EoE [35=SHOULDPROVIDEFURTHERINSIGHTSINTOTHEROLESOF THEEOSINOPHILINTHEVARIOUSASPECTSOFTISSUEREMODELINGANDlBROSISTHATCONTRIBUTE TOTHEPATHOGENESISOF%O%;229, 230=&IG4.1) and other EGIDs.

Pathogenic Mechanisms of Eosinophil-Mediated Tissue Fibrosis %OSINOPHILSARECONSIDEREDAMAJORINDUCEROFTISSUEREMODELINGANDlBROSIS;209] IN A VARIETY OF EOSINOPHIL ASSOCIATED ALLERGIC DISEASES AND HYPEREOSINOPHILIC SYNDROMESINCLUDINGASTHMA;8, 73= EOSINOPHILMYALGIASYNDROME;231], eosinophilic ENDOMYOCARDIAL lBROSIS ;208= IDIOPATHIC PULMONARY lBROSIS ;232= SCLERODERMA [231= ANDMOSTRECENTLY%O%;229, 230=%OSINOPHILSAREIMPLICATEDINlBROGENESIS THROUGHTHESECLINICALDISEASEASSOCIATIONS THEIRELABORATIONOFlBROGENICGROWTH FACTORSSUCHAS4'& E [74, 233= 0$'& "";234], IL-1E [10=ANDTHEIRSECRETIONOF THEGRANULEPROTEINS-"0;220=AND%08;235=4HEASSOCIATIONOFDEGRANULATING EOSINOPHILSANDGRANULEPROTEINDEPOSITIONINTISSUESWITHPATHOLOGICALlBROSISISA RECURRENTlNDINGINABROADGROUPOFEOSINOPHILICDISEASESINCLUDING%O%;100, 102, 236= ANDEOSINOPHILSAREONEOFTHEMAJOR4'& E producing cells in the esophagus in pediatric EoE [71=ANDINTHELUNGSOFASTHMATICS;73]. "OTHHUMANANDANIMALMODELSTUDIESPROVIDECOMPELLINGEVIDENCEFOREOSINOPHILSASEFFECTORSOFTISSUEREMODELINGANDlBROSIS!SNOTEDABOVE REDUCTIONIN BRONCHIALEOSINOPHILSBYONLY^INASTHMATICSTREATEDWITHANTI ), ANTIBODY -EPOLIZUMABÍ WASSUFlCIENTTODECREASETHEEXPRESSIONOF%#-PROTEINSINTHE RETICULARBASEMENTMEMBRANE;15= ANDANTI ), SIMILARLYDECREASEDBOTHEOSINOPHILS ANDDEPOSITIONOF%#-PROTEINSINTHESKINOFATOPICSUBJECTSINALLERGEN INDUCED late-phase reactions [14=$IRECTEVIDENCEFOREOSINOPHILINDUCTIONOFREMODELINGAND lBROSISCOMESFROMSTUDIESINEOSINOPHIL DElCIENTMICE DEMONSTRATINGTHEIRESSENTIAL

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ROLEINTHEDEVELOPMENTOFAIRWAYREMODELING INCLUDINGMUCUSGOBLET CELLMETAPLASIA SMOOTHMUSCLECELLHYPERPLASIA ANDSUBEPITHELIALlBROSIS;11, 12, 44]. !NUMBEROFGROWTHFACTORSANDCYTOKINESEXPRESSEDBYTHEEOSINOPHIL;27] are IMPLICATEDINTISSUEREMODELINGANDlBROSIS 4'& EBEINGTHEMOSTPOTENTLYlBROGENICANDWELLSTUDIED4'& EREGULATESTHEEXPRESSIONOFTHEPRO lBROGENICCYTOKINE ),  THEMYOlBROBLASTMARKERD SMOOTHMUSCLEACTIND-SMA) and other ECM proTEINS SUCH AS THE COLLAGENS AND ITS EXPRESSION IS CORRELATED WITH BRONCHIAL AIRWAY lBROSISANDASTHMASEVERITY;237= ANDITSOVER EXPRESSIONINTHELUNGINRODENTANIMAL MODELS INDUCES PULMONARY lBROSIS ;233= %OSINOPHIL lBROBLAST INTERACTIONS HAVE BEEN IMPLICATED IN THE GENERATION OF SUBEPITHELIAL lBROSIS AND AIRWAY REMODELING CHARACTERISTIC OF HUMAN ASTHMA IN MURINE ALLERGIC ASTHMA MODELS ;238, 239= BUT MECHANISTICASSESSMENTSOFEOSINOPHIL lBROBLASTINTERACTIONSTHATINDUCETISSUElBROSIS ARESTILLRELATIVELYLIMITED%OSINOPHILGRANULE-"0SYNERGIZESWITH4'& E or IL-1E PRIMEDLUNGlBROBLASTSTOINDUCESIGNIlCANTINCREASESINGENETRANSCRIPTIONANDSECRETION OFTHE), FAMILYOFINmAMMATORYANDlBROGENICCYTOKINES INCLUDING), AND),  [220= AND4'& E INDUCEDlBROBLASTSECRETIONOF), ISIMPLICATEDINTHEOVERPRODUCTIONOFCOLLAGENS TISSUEINHIBITOROFMETALLOPROTEINASES4)-0S ANDGLYCOSAMINOGLYCANS IN lBROGENESIS ;240, 241= %OSINOPHIL LUNG lBROBLAST CO CULTURE IN THE PRESENCE OF ),  INDUCES lBROBLASTS TO TRANS DIFFERENTIATE INTO MYOlBROBLASTS WITH INCREASEDEXPRESSIONOFD-SMA and ECM proteins [79=3IMILARLY EOSINOPHILSMAY INDIRECTLY IMPACT lBROBLAST PHENOTYPE AND lBROGENESIS THROUGH ACTIVATION OF THE EPITHELIAL MESENCHYMALTROPHICUNIT;242= EG THROUGHSECRETIONOF-"0AND%08 &IG4.1) [235=!LTERNATIVELY EOSINOPHILSMAYINDUCElBROGENESISTHROUGH4'& E INDUCTIONOFTHEEPITHELIALTOMESENCHYMALTRANSITION%-4 ASRECENTLYSHOWNTO OCCURINTHELUNGINASTHMA;243=ANDMOSTRECENTLYBYTHEAUTHORSLABORATORYINTHE esophagus in EoE [85]. 3UBEPITHELIALlBROSIS ACOMPONENTOFAIRWAYREMODELINGINASTHMA ISINITIATED BYINSULTSTHATINCLUDE4H MEDIATEDALLERGICRESPONSESEOSINOPHILSRECRUITEDINTO THE AIRWAYS ARE THOUGHT TO DRIVE THE DIFFERENTIATION OF AIRWAY lBROBLASTS TO MYOlBROBLASTSASCHARACTERIZEDBYTHEEXPRESSIONOFMYOlBROBLAST SPECIlCMARKers such as D 3-! THEDEPOSITIONOF%#-PROTEINSSUCHASCOLLAGENS lBRONECTIN ANDOTHER%#-CONSTITUENTSSUCHASTENASCINANDLUMICAN;9, 15, 242]. Correlations BETWEEN PULMONARY EXPRESSION OF EOTAXIN  EXPRESSION OF EOTAXIN  RECEPTOR ##2 4'& E1 ANDPULMONARYlBROSISHAVEBEENREPORTEDINABLEOMYCINMOUSE MODEL FURTHER SUPPORTING THIS GENERAL MECHANISM ;244= )N CONTRAST STUDIES OF EOSINOPHIL MEDIATED TISSUE REMODELING AND lBROSIS IN %O% HAVE BEEN LIMITED TO DATE PRINCIPALLYDUETOTHEDIFlCULTIESINHERENTINOBTAININGBIOPSIESCONTAININGSUFlCIENTESOPHAGEALLAMINAPROPRIABELOWTHESTIFFENEDHYPERPLASTICEPITHELIUM&OR THISREASON EVIDENCEFORPROGRESSIVEREMODELINGANDlBROSISOFTHEESOPHAGUSHAS BEEN DERIVED PRINCIPALLY FROM ENDOSCOPIC AND RADIOLOGIC FEATURES OF THE DISEASE [245=(OWEVER SEVERALRECENTSTUDIESBY!CEVESANDCOLLEAGUESSHOWTHATESOPHAGEAL BIOPSIES FROM PEDIATRIC %O% PATIENTS HAVE INCREASED SUBEPITHELIAL lBROSIS EXPRESSION OF 4'& E1 BY EOSINOPHILS AND ACTIVATION OF 4'& E 3-!$ MEDIATED SIGNALINGPATHWAYSCOMPAREDWITH'%2$ANDNORMALSUBJECTS;71]. Beyond these REPORTS THEMECHANISMSREGULATINGESOPHAGEALREMODELINGANDlBROSISINCHRONIC

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%O%HAVENOTBEENSYSTEMATICALLYSTUDIEDTODElNETHECHANGESINEPITHELIALCELLAND lBROBLASTPHENOTYPE THEROLEOFEOSINOPHIL lBROBLASTINTERACTIONS ORTHECONTRIBUTIONS OF%-4TOTHISPROCESS'ENOME WIDEEXPRESSIONPROlLINGSTUDIESOF%O%ESOPHAGEAL BIOPSIES IDENTIlED EOTAXIN  AS THE PRINCIPAL MEDIATOR OF EOSINOPHIL RECRUITMENTTOTHEESOPAHGUS;246= BUTINTERESTINGLYDIDNOTIDENTIFYMANYGENESINVOLVED INTISSUEREMODELINGANDlBROSIS(OWEVER ONEOFTHESEGENES PERIOSTIN ISEXPRESSED PREDOMINANTLY IN COLLAGEN RICH lBROUS CONNECTIVE TISSUES SUBJECT TO MECHANICAL STRESSESANDINWOUNDHEALING ANDWASREPORTEDTOPARTICIPATEINTHESUBEPITHELIAL lBROSISINASTHMA DOWNSTREAMOFTHE), AND), SIGNALS;247=0RIMARYESOPHAGEALlBROBLASTSRELEASEPERIOSTINWHENCULTUREDWITH), AND4'& E [248], and THEPERIOSTINLOCALIZEDMAINLYINVASCULARPAPILLAEPROJECTIONSOFSUBEPITHELIALLAMINA PROPRIA INTO THE EPITHELIUM IN THE ESOPHAGUS MAY CONTRIBUTE TO EOSINOPHIL RECRUITMENT BY INCREASING THEIR ADHESION TO lBRONECTIN ;248]. Thus, eosinophilDERIVED 4'& E BY INDUCING lBROBLAST EXPRESSION OF PERIOSTIN COULD PROVIDE AN ESOPHAGEALEOSINOPHILINmAMMATIONAMPLIlCATIONLOOP ANDITSCONSEQUENTINDUCTIONOFTHEESOPHAGEALREMODELINGANDlBROSISSEENIN%O%

Summary 4HEEOSINOPHILISCLEARLYAMULTIFUNCTIONALGRANULOCYTETHATPARTICIPATESINBOTHTHE PATHOGENESISANDPATHOPHYSIOLOGYOFALLERGICDISEASESINTERMSOFBOTHTHEINITIATION ANDPROPAGATIONOFALLERGICANDRELATEDINmAMMATORYRESPONSES INCLUDINGROLESIN TISSUEDAMAGE REPAIRANDREMODELING(OWEVER THEREISSTILLMUCHTOBEDETERMINED INTERMSOFTHECELLBIOLOGY IMMUNOBIOLOGY ANDEFFECTORROLESOFTHEEOSINOPHILIN THESEPROCESSES PARTICULARLYTHEEOSINOPHILSNEWLYRECOGNIZEDROLEASAREGULATOROF TISSUE MICROENVIRONMENTS INTO WHICH IT IS RECRUITED WHETHER HOMEOSTATICALLY IN health or in disease pathogenesis [2, 3=7HILESOMEASPECTSOFEOSINOPHILBIOLOGY ANDFUNCTIONSREVIEWEDINTHISCHAPTERAREBYNOMEANSCERTAIN IE THEYAREBASED ON MURINE AND OTHER ANIMAL MODEL STUDIES THE EOSINOPHILS PRESENCE AT MUCOSAL SURFACESINTHEGASTROINTESTINALTRACTINHEALTHYINDIVIDUALSSUGGESTSASENTRYROLEIN HOSTINNATEIMMUNITY4HEIRABNORMALPRESENCEINLARGENUMBERSINTHEESOPHAGUS IN%O%SUPPORTSAROLEFORTHEEOSINOPHILINTHEPATHOGENESISOFTHEPROFOUNDESOPHAGEALTISSUEREMODELINGANDlBROSISCHARACTERISTICOFTHISDISEASE&IG4.1). Acknowledgment $R!CKERMANWASSUPPORTEDINPARTBY.)(GRANT2!) A4RANSLATIONAL 2ESEARCH!WARDFROMTHE!MERICAN'ASTROENTEROLOGY!SSOCIATION!'! THE#AMPAIGN5RGING 2ESEARCH ON %OSINOPHILIC $ISEASES #52%$ THE 4HRASHER 2ESEARCH &OUNDATION AND THE !MERICAN0ARTNERSHIPFOR%OSINOPHILIC$ISEASES!0&%$ 

References 2OTHENBERG-% (OGAN304HEEOSINOPHIL!NNU2EV)MMUNOLn ,EE** *ACOBSEN%! -C'ARRY-0 3CHLEIMER20 ,EE.!%OSINOPHILSINHEALTHANDDISEASE THE,)!2HYPOTHESIS#LIN%XP!LLERGY!PR n

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*ACOBSEN%! 4ARANOVA!' ,EE.! ,EE**%OSINOPHILSSINGULARLYDESTRUCTIVEEFFECTORCELLS ORPURVEYORSOFIMMUNOREGULATION*!LLERGY#LIN)MMUNOL*UN n 'LEICH'* !DOLPHSON#2 ,EIFERMAN+-4HEBIOLOGYOFTHEEOSINOPHILICLEUKOCYTE!NNU 2EV-EDn &RIGAS % 'LEICH '* 4HE EOSINOPHIL AND THE PATHOPHYSIOLOGY OF ASTHMA * !LLERGY #LIN )MMUNOL n "ELONGIA%! -AYENO!. /STERHOLM-44HEEOSINOPHILIA MYALGIASYNDROMEANDTRYPTOPHAN!NNU2EV.UTRn &URUTA'4 ,IACOURAS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGY/CT n +AY !" 4HE ROLE OF EOSINOPHILS IN THE PATHOGENESIS OF ASTHMA 4RENDS -OL -ED !PR  n +AY!" 0HIPPS3 2OBINSON$3!ROLEFOREOSINOPHILSINAIRWAYREMODELLINGINASTHMA 4RENDS)MMUNOL3EP n 'OMES) -ATHUR3+ %SPENSHADE"- -ORI9 6ARGA* !CKERMAN3*%OSINOPHIL lBROBLAST INTERACTIONSINDUCElBROBLAST), SECRETIONANDEXTRACELLULARMATRIXGENEEXPRESSIONIMPLICATIONSINlBROGENESIS*!LLERGY#LIN)MMUNOL/CT n ,EE** $IMINA$ -ACIAS-0 ETAL$ElNINGALINKWITHASTHMAINMICECONGENITALLYDElCIENTINEOSINOPHILS3CIENCE n (UMBLES!! ,LOYD#- -C-ILLAN3* ETAL!CRITICALROLEFOREOSINOPHILSINALLERGICAIRWAYS REMODELING3CIENCE n *ACOBSEN %! /CHKUR 3) 0ERO 23 ET AL !LLERGIC PULMONARY INmAMMATION IN MICE IS DEPENDENT ON EOSINOPHIL INDUCED RECRUITMENT OF EFFECTOR 4 CELLS * %XP -ED   n 0HIPPS3 &LOOD 0AGE0 -ENZIES 'OW! /NG9% +AY!")NTRAVENOUSANTI ), MONOCLONALANTIBODYREDUCESEOSINOPHILSANDTENASCINDEPOSITIONINALLERGEN CHALLENGEDHUMANATOPIC SKIN*)NVEST$ERMATOL*UN n &LOOD 0AGE0 -ENZIES 'OW! 0HIPPS3 ETAL!NTI ), TREATMENTREDUCESDEPOSITIONOF %#-PROTEINSINTHEBRONCHIALSUBEPITHELIALBASEMENTMEMBRANEOFMILDATOPICASTHMATICS *#LIN)NVEST/CT n 3TEIN-, #OLLINS-( 6ILLANUEVA*- ETAL!NTI ), MEPOLIZUMAB THERAPYFOREOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOL$EC n 2OTHENBERG-% +LION!$ 2OUFOSSE&% ETAL4REATMENTOFPATIENTSWITHTHEHYPEREOSINOPHILICSYNDROMEWITHMEPOLIZUMAB.%NGL*-ED n 7ELLER0&,IPID PEPTIDEANDCYTOKINEMEDIATORSELABORATEDBYEOSINOPHILS)N3MITH( #OOK 2- EDITORS)MMUNOPHARMACOLOGYOFEOSINOPHILS,ONDON!CADEMICPn 7ELLER0& -ONAHAN %ARLEY2! $VORAK(& $VORAK!-#YTOPLASMICLIPIDBODIESOFHUMAN EOSINOPHILS3UBCELLULARISOLATIONANDANALYSISOFARACHIDONATEINCORPORATION!M*0ATHOL  n "OZZA04 9U7 0ENROSE*& -ORGAN%3 $VORAK!- 7ELLER0&%OSINOPHILLIPIDBODIES SPECIlC INDUCIBLE INTRACELLULAR SITES FOR ENHANCED EICOSANOID FORMATION * %XP -ED  n -ELO 2# 3PENCER ,! 0EREZ 3! 'HIRAN ) $VORAK !- 7ELLER 0& (UMAN EOSINOPHILS SECRETE PREFORMED GRANULE STORED INTERLEUKIN  THROUGH DISTINCT VESICULAR COMPARTMENTS 4RAFlC.OV n ,EIFERMAN+-!CURRENTPERSPECTIVEONTHEROLEOFEOSINOPHILSINDERMATOLOGICDISEASES *!M!CAD$ERMATOL0T n !CKERMAN3*#HARACTERIZATIONANDFUNCTIONSOFEOSINOPHILGRANULEPROTEINS)N-AKINO3 &UKUDA4 EDITORS%OSINOPHILSBIOLOGICALANDCLINICALASPECTS"OCA2ATON#2#0RESS p. 33–74. -OQBEL 2 ,ACY 0 .EW CONCEPTS IN EFFECTOR FUNCTIONS OF EOSINOPHIL CYTOKINES #LIN %XP !LLERGY$EC n .EVES*3 0EREZ3! 3PENCER,! ETAL%OSINOPHILGRANULESFUNCTIONEXTRACELLULARLYASRECEPTOR MEDIATEDSECRETORYORGANELLES0ROC.ATL!CAD3CI53! n

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Chapter 5

Role of Lymphocytes and Mast Cells in Eosinophilic Esophagitis Mirna Chehade and Hugh A. Sampson

Keywords %OSINOPHILIC ESOPHAGITIS s %SOPHAGEAL MUCOSA s &OOD ANTIGENS s!EROALLERGENSs,YMPHOCYTESs-ASTCELLSs%OSINOPHILS

Introduction %OSINOPHILICESOPHAGITIS%O% ISACHRONICINmAMMATORYDISEASEOFTHEESOPHAGUS CHARACTERIZED BY SIGNIlCANT EOSINOPHILIC INlLTRATION OF THE ESOPHAGEAL MUCOSA !LTHOUGHTHEEXACTPATHOGENESISOF%O%REMAINSUNCLEAR ANIMMUNOLOGICALREACTION TOFOODSANDPOSSIBLYTOAEROALLERGENSHASBEENIMPLICATEDBASEDONSEVERALSHORT TERM CLINICAL TRIALS CONSISTING OF DIETARY ELIMINATIONS WITH RESULTANT DISEASE REMISSION [1–4=ANDOBSERVATIONSOFSEASONALVARIABILITYINDISEASESEVERITY;5, 6=4HEIMMUNOLOGICALREACTIONTODIETARYANDENVIRONMENTALANTIGENSISTHOUGHTTOCONSISTOFA MIXOF)G% MEDIATEDANDNON )G% MEDIATED IE CELL MEDIATED ALLERGICREACTIONS;1, 3]. (ISTOPATHOLOGICALLY SIMILARTOALLERGICDISEASESINOTHERORGANS VARIOUSINmAMMATORYCELLSAREFOUNDININCREASEDNUMBERSINTHEESOPHAGUS INCLUDINGLYMPHOCYTES MASTCELLS ANDEOSINOPHILS THELATTERSERVINGASTHEDIAGNOSTICHALLMARKFORTHEDISease [7= )N THIS CHAPTER WE SUMMARIZE DATA DEMONSTRATING INCREASED NUMBERS OF LYMPHOCYTESANDMASTCELLSINTHEESOPHAGUSOF%O%PATIENTS7EALSODISCUSSEVIDENCEFORTHEROLEOFLYMPHOCYTESIN%O% FOCUSINGONTHEALLERGICPHENOTYPEOFSOME OFTHESECELLS3INCETHEROLEOFMASTCELLSIN%O%HASNOTBEENWELLSTUDIED WESPECULATEONTHEPOTENTIALROLEOFTHESECELLSINTHEPATHOGENESISOF%O%

M. Chehade (*) Mount Sinai CENTERFOR%OSINOPHILIC$ISORDERS *AFFE&OOD!LLERGY)NSTITUTE -OUNT3INAI3CHOOLOF-EDICINE /NE'USTAVE,,EVY0LACE Box 1198, New York, NY 10029, USA E MAILMIRNACHEHADE MSSMEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_5, © Springer Science+Business Media, LLC 2012

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The Esophagus Is an Immunological Organ 5NTILRECENTLY MOSTSTUDIESOFTHEESOPHAGUSFOCUSEDONITSPHYSICALPROPERTIESASA CONDUITOFFOOD)TSROLEASANIMMUNOLOGICALORGANDIDNOTEMERGEUNTILDISEASES such as EoE were studied. 4HENORMALESOPHAGUSISAHIGHLYDISTENSIBLEMUSCULARTUBETHATEXTENDSFROM THEEPIGLOTTISINTHEPHARYNXATTHELEVELOFTHE#VERTEBRA TOTHEGASTROESOPHAGEAL JUNCTIONATTHELEVELOFTHE4OR4VERTEBRA;8=4HEWALLOFTHEESOPHAGUSCONSISTSOFAMUCOSA SUBMUCOSA MUSCULARISPROPRIA ANDADVENTITIA REmECTINGTHEGENERAL STRUCTURAL ORGANIZATION OF THE GASTROINTESTINAL TRACT EXCEPT FOR THE LACK OF A serosal coat [8]. 4HEESOPHAGEALMUCOSAISCOMPOSEDOFTHREEPARTSANON KERATINIZINGSTRATIlED SQUAMOUSEPITHELIALLAYER LAMINAPROPRIA ANDMUSCULARISMUCOSA4HEEPITHELIAL LAYERHASMATURESQUAMOUSCELLSOVERLYINGBASALCELLSTHATHAVEGREATPROLIFERATIVE POTENTIAL 4HE BASAL CELL ZONE OCCUPIES n OF THE EPITHELIAL LAYER THICKNESS 6ARIOUS IMMUNE CELLS INCLUDING DENDRITIC CELLS LYMPHOCYTES AND MAST CELLS ARE PRESENTINTHEDEEPERPORTIONOFTHEEPITHELIALLAYER;7, 9, 10]. Eosinophils are norMALLYABSENTINTHEESOPHAGEALEPITHELIUM;7, 11=4HELAMINAPROPRIAISSITUATED BETWEENTHEEPITHELIALLAYERANDTHEMUSCULARISMUCOSA ANDCONSISTSOFLOOSEAREOLAR CONNECTIVETISSUE VASCULARSTRUCTURES ANDLEUKOCYTES4HEMUSCULARISMUCOSACONSISTS OFLONGITUDINALLYORIENTEDSMOOTHMUSCLEBUNDLES $EEPTOTHEMUCOSAISTHESUBMUCOSA CONSISTINGOFLOOSECONNECTIVETISSUECONTAININGBLOODVESSELS ARICHNETWORKOFLYMPHATICS LEUKOCYTES OCCASIONALLYMPHOID FOLLICLES NERVElBERS ANDSUBMUCOSALGLANDSTHATSECRETEMUCIN CONTAININGmUIDTO LUBRICATETHEESOPHAGUS4HEMUSCULARISPROPRIACONSISTSOFANINNERCIRCULARCOATAND ANOUTERLONGITUDINALCOATOFSMOOTHMUSCLEWITHANINTERVENINGMYENTERICPLEXUS 4HECOMBINATIONOFESOPHAGEALPERISTALSIS PRESENCEOFALOWERESOPHAGOGASTRIC JUNCTION SPHINCTER SQUAMOUS EPITHELIAL BARRIER SALIVARY AND SUBMUCOSAL GLAND PRODUCTS AND IMMUNE CELLS IN THE ESOPHAGUS CONTRIBUTES TO ESOPHAGEAL DEFENSE against injury.

Lymphocytes and Mast Cells Are Present in the Normal Esophagus )NTHENORMALESOPHAGEALEPITHELIUMOFHEALTHYINDIVIDUALS RARELYMPHOCYTESARE present [7, 12, 13= HISTORICALLYREFERREDTOASSQUIGGLECELLSBYHISTOPATHOLOGISTS DUE TO THEIR IRREGULAR NUCLEAR CONTOURS AS THEY TIGHTLY INTERMINGLE WITH EPITHELIAL CELLS ASSEENBYMICROSCOPICEXAMINATIONOFHEMATOXYLINANDEOSIN STAINEDSECTIONS OF THE ESOPHAGEAL EPITHELIUM ;13]. These squiggle cells were shown to be 4LYMPHOCYTES;12, 13=)NTHEESOPHAGEALEPITHELIALLAYER #$POSITIVE4LYMPHOCYTESAREMOREPREDOMINANTTHAN#$POSITIVECELLS;7, 9=WHEREAS#$4LYMPHOCYTES ARETHEPREDOMINANTONESINTHENORMALESOPHAGEALLAMINAPROPRIA;9="LYMPHOCYTES

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ONTHEOTHERHAND WHILEABSENTINTHEESOPHAGEALEPITHELIUMOFHEALTHYINDIVIDUALS [7= AREPRESENTINTHESUBEPITHELIALLAMINAPROPRIAALONGWITHTHE#$POSITIVE T cells [9]. -ASTCELLSAREPRESENTINTHEMUCOSAANDSUBMUCOSAOFTHEESOPHAGUSOFHEALTHY INDIVIDUALS;10=3UBTYPINGOFMASTCELLS-#T or MCTC) in the esophagus has not been done. )N%O% STUDIESCHARACTERIZINGLYMPHOCYTESANDMASTCELLSINTHEESOPHAGUSOF PATIENTSWITHTHEDISEASEARELIMITEDBYTHEDEPTHOFENDOSCOPICALLYOBTAINEDBIOPSIES-OSTBIOPSIESARELIMITEDTOTHEEPITHELIALLAYEROFTHEMUCOSA ANDVERYFEWARE DEEPENOUGHTOINCLUDEAPORTIONOFTHESUBEPITHELIALLAMINAPROPRIA"OTHLYMPHOCYTESANDMASTCELLSWEREFOUNDTOBEINCREASEDINNUMBERINTHEESOPHAGEALEPITHELIUMOFPATIENTSWITH%O%;7, 10].

Lymphocytes Are Increased in Number in the EoE Esophagus 4LYMPHOCYTESWEREFOUNDTOBEINCREASEDINTHEESOPHAGEALEPITHELIUMOFPATIENTS WITH%O%COMPAREDTOTHATOFHEALTHYCONTROLS DEMONSTRATEDBYIMMUNOHISTOCHEMICAL STAININGOFESOPHAGEALBIOPSIESFORTHE4 LYMPHOCYTEMARKER#$;7, 14, 15]. 4CELLSTENDEDTOBEDISTRIBUTEDINTHEDEEPERLAYERSOFTHEEPITHELIUM BEINGDENSER CLOSERTOTHEREGENERATIVEEPITHELIALBASALCELLLAYER;7]. Both T cell subsets, CD4 AND#$CELLS AREPRESENT WITHAMAINTENANCEOF#$PREDOMINANCEOVER#$ cells [7, 14=3INCEALLHISTOPATHOLOGICALSTUDIESARELIMITEDTOTHEESOPHAGEALEPITHELIUM ITISNOTKNOWNWHETHERTHISPREDOMINANCEISALSOTRUEINTHEDEEPER SUBEPITHELIALLAYERSOFTHEESOPHAGUSIN%O%4HEOVERALLNUMBEROF4LYMPHOCYTESINTHE DEEPERLAYERSOFTHE%O%ESOPHAGUSISALSONOTKNOWN " LYMPHOCYTES WERE SHOWN TO INlLTRATE THE ESOPHAGEAL EPITHELIUM OF %O% PATIENTS ASDEMONSTRATEDBYIMMUNOHISTOCHEMICALSTAININGFORTHE" CELLMARKER #$ ALBEITINSMALLNUMBERS;7, 16=4HEIRNUMBERINTHEDEEPERESOPHAGEALLAYERS in EoE patients has not been studied.

Lymphocytes May Play a Role in the Induction of EoE !POSSIBLEROLEFORLYMPHOCYTESINTHEINDUCTIONOFDISEASEIN%O%ISAVAILABLEBASED ONSTUDIESOFAMURINEMODELOFALLERGEN INDUCEDESOPHAGEALEOSINOPHILIADEVELoped by Mishra et al. [17= THOUGHTHEEOSINOPHILIAINTHEMOUSEMODELISMOSTLY CONCENTRATED IN THE DEEPER ESOPHAGEAL LAYERS INCLUDING THE LAMINA PROPRIA RATHER THANTHEESOPHAGEALEPITHELIUMASSEENINPATIENTSWITH%O%)NTHEIRMOUSEMODEL INTRANASALINSTILLATIONOF!SPERGILLUSFUMIGATUSASANANTIGENRESULTEDINPULMONARY ANDESOPHAGEALEOSINOPHILIA,YMPHOCYTESWEREFOUNDTOBEINCREASEDINTHEESOPHAGUS OF !SPERGILLUS TREATED MICE COMPARED TO SALINE TREATED MICE ;18]. Both B and 4LYMPHOCYTESWEREDETECTEDINTHEMUCOSALANDSUBMUCOSALREGIONSOFTHEESOPHAGUS3PECIlCALLY ATWOFOLDINCREASEIN"CELLSANDAFOUR TOlVEFOLDINCREASEIN

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#$ AND #$ 4 CELLS WERE FOUND 7HEN MICE LACKING " AND 4 CELLS 2!'  GENE DElCIENT WEREINTRANASALLYCHALLENGEDWITH!SPERGILLUSANTIGENINTHESAME FASHION NOESOPHAGEALEOSINOPHILICINlLTRATIONWASFOUND INDICATINGANIMPORTANT ROLE FOR LYMPHOCYTES IN %O% INDUCTION 7HEN THE AUTHORS PERFORMED THE SAME EXPERIMENTSUSING" CELL DElCIENTMICE)G( AND4 CELL DElCIENTMICE&OXN THEYWEREABLETODEMONSTRATETHAT4CELLS RATHERTHAN"CELLS WEREIMPORTANTINTHE INDUCTIONOFESOPHAGEALEOSINOPHILIA7ITHIN4 CELLPOPULATIONS #$RATHERTHAN #$CELLSWERESHOWNTOBEIMPORTANT#$ DElCIENTMICEWEREMODERATELYPROTECTEDFROMTHEINDUCTIONOF%O% WHILE#$D DElCIENTMICEDEVELOPED%O%INTHE REGULARFASHION )NHUMANS THEROLEOF4LYMPHOCYTES ESPECIALLY#$CELLS INTHEINDUCTIONOF %O%ISLESSCLEAR"OTH#$AND#$SUBSETSOF4LYMPHOCYTESHAVEBEENFOUNDTO DECREASE IN NUMBER IN THE ESOPHAGEAL EPITHELIUM OF PATIENTS WITH %O% FOLLOWING SUCCESSFULTREATMENTWITHTOPICALCORTICOSTEROIDS;7, 14=6ARIOUSDESCRIPTIVESTUDIES POINTTOA4 HELPERTYPE4H ADAPTIVEIMMUNITYIN%O% DETAILEDLATERINTHIS CHAPTER 4HE ROLE OF 4H CYTOKINES IN THE INDUCTION OF %O% WAS DEMONSTRATED IN MICEBYINTRATRACHEALDELIVERYOFTHE4HCYTOKINE),  WHICHRESULTEDINDOSE DEPENDENTESOPHAGEALEOSINOPHILIAVIAAN), AND34!4 DEPENDENTMECHANISM [19=4HESERESULTSIMPLICATE4HCELLSASPLAYINGACRUCIALROLEIN%O%PATHOGENESIS INHUMANS " LYMPHOCYTEFUNCTIONINHUMAN%O%HASNOTBEENEXAMINED"LYMPHOCYTES ARE KNOWN TO BE CAPABLE OF HOLDING ANTIGENS ON THEIR SURFACE FOR RECOGNITION BY SPECIlC4LYMPHOCYTESALONGWITH-(#CLASS))MOLECULES;20=!POTENTIALROLEFOR "LYMPHOCYTESIN%O%WASRECENTLYHIGHLIGHTEDBY6ICARIOETAL;16], who estabLISHEDTHATTHEESOPHAGEALMUCOSAIN%O%WASASITEOFINITIATIONANDDEVELOPMENT OF HUMORAL RESPONSES AND LOCAL )G% PRODUCTION )NCREASED " LYMPHOCYTES AND EXPRESSIONOFMOLECULARIMMUNOGLOBULINMACHINERYINTHEESOPHAGUSOFCHILDREN WITH%O%WASFOUND REGARDLESSOFTHEPATIENTSATOPICSTATUS4HESERESULTSPOINTTO APOSSIBLELOCAL)G% MEDIATEDRESPONSETOFOODSANDCOULDPROVIDEAPOSSIBLEEXPLANATIONASTOTHECLINICALRESPONSETOFOODELIMINATIONSDESPITETHEABSENCEOFFOOD SENSITIZATIONSBYSKINTESTSINSOMEPATIENTSWITH%O%;21]. .OSTUDIESHAVEADDRESSEDTHEPRESENCEORTHEROLEOFREGULATORY4CELLSIN%O% IMPORTANTINORALTOLERANCETOFOODS ANDTHEIRSECRETEDCYTOKINESSUCHAS4'& E. #O EXISTENCEOF4HPREDOMINANTDISEASESSUCHASCELIACDISEASEANDTHE4HDISease EoE [22, 23=POINTSTOAPOSSIBLEGLOBALDISTURBANCEINREGULATORYCELLFUNCTION IN%O% ANDWARRANTSFURTHERINVESTIGATION

T Lymphocytes in Patients with EoE Carry an Allergic Phenotype 3HORT TERM CLINICAL TRIALS MOSTLY IN CHILDREN WITH %O% HAVE ESTABLISHED A LINK BETWEENCOMMONFOODALLERGENSANDTHEINDUCTIONOF%O% POINTINGTOWARDANALLERGIC 4HTYPEOFIMMUNERESPONSE;1, 3, 4=)NADDITION THECYTOKINEMILIEUOFTHE

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ESOPHAGUSANDPERIPHERALBLOODOFPATIENTSWITH%O%WASFOUNDTOBECONSISTENT with a Th2 phenotype. In the peripheral circulation, Bullock et al. [24=EXAMINEDCYTOKINEEXPRESSIONBY PERIPHERALBLOODMONONUCLEARCELLS0"-#S ANDFOUNDTHATCHILDRENWITHACTIVE %O%HADANINCREASEDPERCENTAGEOF#$CELLSEXPRESSINGTHE4HCYTOKINE),  COMPARED TO NON ATOPIC CONTROLS 4HIS PERCENTAGE WAS LOWER IN %O% PATIENTS IN REMISSION THAN IN PATIENTS WITH ACTIVE DISEASE 3TRAUMANN ET AL ;15= MEASURED CYTOKINESECRETIONBY0"-#SOF%O%PATIENTSINRESPONSETOINVITROSTIMULATION WITH PHYTOHEMAGGLUTININ A POLYCLONAL 4 CELL STIMULANT )NCREASED RELEASE OF THE 4HCYTOKINE), WASFOUNDINOFTHEPATIENTSSTUDIED9AMAZAKIETAL;25] FOUND SIMILAR RESULTS WITH SPECIlC ALLERGEN STIMULANTS 0"-#S FROM  ADULT PATIENTSWITH%O%WEREINCUBATEDINVITROWITHFOODALLERGENEXTRACTSANDAEROALLERGEN EXTRACTS &OOD EXTRACTS CONSISTED OF MILK EGG SOY WHEAT AND PEANUT #OMPARED TO HEALTHY CONTROLS 0"-#S FROM %O% PATIENTS SECRETED SIGNIlCANTLY MOREOFTHE4HCYTOKINES), ANDOR), INRESPONSETOVARIOUSALLERGENS EVEN INTHEABSENCEOFCLEAR CUTSENSITIZATIONTOTHEALLERGENSWHENSERUMLEVELSOFALLERGEN SPECIlC)G%WEREMEASURED2ESULTSFROMTHESESTUDIESARELIMITEDBYTHEFACTTHAT MANY%O%PATIENTSSTUDIEDHADCONCOMITANTALLERGICDISEASESTHATMAYHAVECONTRIBUTEDTOTHE4HRESPONSE!STUDYCOMPARING%O%PATIENTSTOALLERGICCONTROLSIS NEEDEDTOCONlRMTHESElNDINGS )NCREASEDLEVELSOFTHE4HCYTOKINES), AND), WEREFOUNDINTHEESOPHAGUS OF PATIENTS WITH %O% COMPARED TO THAT OF CONTROLS ;15, 26, 27]. IL-13 likely PLAYSANIMPORTANTROLEINTHEPATHOGENESISOF%O%7HENSTIMULATEDWITH),  INVITRO ESOPHAGEALEPITHELIALCELLSWERESHOWNTOPRODUCEHIGHLEVELSOFEOTAXIN  [27= AHIGHLYINDUCEDCHEMOKINEIN%O%SHOWNTOREGULATEEOSINOPHILRESPONSES INVITRO;28=ANDTOCORRELATEWITHTHESEVERITYOFESOPHAGEALEOSINOPHILIAINCHILDREN with EoE [29=/NEMAJORLIMITATIONINALLTHESEESOPHAGEALCYTOKINESTUDIESISTHE LACKOFIDENTIlCATIONOFTHESPECIlCINmAMMATORYCELLSPRODUCINGTHESE4HCYTOKINES4HEREFORE THECONTRIBUTIONOFLYMPHOCYTESTOTHEPRODUCTIONOF4HCYTOKINES ISNOTYETKNOWN ESPECIALLYGIVENTHATOTHERIMMUNECELLSARECAPABLEOFSECRETING THESE CYTOKINES &OR EXAMPLE ESOPHAGEAL INTRAEPITHELIAL EOSINOPHILS OF PATIENTS WITH%O%WEREFOUNDTOEXPRESS), AND), BYIMMUNOHISTOCHEMICALSTAINING OFESOPHAGEALBIOPSIES;30=3TUDIESADDRESSINGTHESPECIlCCONTRIBUTIONOFESOPHAGEALLYMPHOCYTESINTOTHEPRODUCTIONOF4HCYTOKINESINTHEESOPHAGUS ESPECIALLY INRESPONSETOSPECIlCDIETARYALLERGENS NEEDTOBEPERFORMED

Mast Cells Are Increased in Number in the EoE Esophagus 6ARIOUSSTUDIESHAVEDEMONSTRATEDANINCREASEINMASTCELLNUMBERINTHEESOPHAGEAL EPITHELIUM OF PATIENTS WITH %O% COMPARED TO THAT OF HEALTHY INDIVIDUALS THREE TO SEVENFOLDINCREASE ;10, 29=-ASTCELLSWEREMOSTLYLOCATEDINTHEDEEPERLAYERSOFTHE EPITHELIUM CLOSETOTHEBASALEPITHELIALREGENERATIVELAYERANDTOOTHERIMMUNECELLS SUCHASDENDRITICCELLSANDLYMPHOCYTES;31=4HENUMBEROFESOPHAGEALINTRAEPITHELIAL

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MASTCELLSWASFOUNDTOCORRELATEWITHTHATOFINTRAEPITHELIALEOSINOPHILS;10, 29], and WASFOUNDTODECREASESIGNIlCANTLYFOLLOWINGSUCCESSFUL%O%THERAPY;7].

Possible Mechanisms of Mast Cell Activation in EoE 3EVERALSTUDIESHAVEDEMONSTRATEDTHATMASTCELLSEXISTINANACTIVATEDSTATEINTHE ESOPHAGEALEPITHELIUMOFSOMEPATIENTSWITH%O% ASEVIDENCEDBYMASTCELLDEGRANULATIONANDRELEASEOFTRYPTASEINTOTHEESOPHAGEALMUCOSA SEENUPONIMMUNOHISTOCHEMICALSTAININGOFESOPHAGEALTISSUEFORTRYPTASE;31=/THEREVIDENCEOFMAST CELLACTIVATIONWASALSOPROVIDEDBYELECTRONMICROSCOPICEXAMINATIONOFESOPHAGEALMASTCELLSIN%O% DEMONSTRATINGFEATURESOFDEGRANULATION;32=5SINGMICROARRAY ANALYSIS OF ESOPHAGEAL TISSUE FROM %O% PATIENTS AND CONTROLS SEVERAL MAST CELL GENES WERE FOUND TO BE INDUCED IN %O% SIXFOLD INCREASE FOR TRYPTASE TWOFOLD INCREASEFORCHYMASE AND FOLDINCREASEFORCARBOXIPEPTIDASE! ;29]. 4HEMECHANISMOFACTIVATIONOFMASTCELLSIN%O%HASNOTBEENDETERMINED)N ALLERGICDISEASESSUCHAS%O% ONEWOULDEXPECTFOOD SPECIlC)G%CROSS LINKINGON THEMASTCELLSURFACEVIATHEHIGHAFlNITY)G%RECEPTOR&CH2) TOBETHEPREDOMINANT MECHANISM(OWEVER MANYPATIENTSWITH%O%DONOTDEMONSTRATEEVIDENCEOFCLEAR CUT FOOD SENSITIZATION AS MEASURED BY ELEVATED SERUM FOOD SPECIlC )G% LEVELS OR POSITIVE PRICK SKIN TESTS TO FOODS ;21= !LTHOUGH ABSENCE OF SYSTEMIC SENSITIZATION DOESNOTRULEOUTALOCALRESPONSERESTRICTEDTOESOPHAGEALTISSUE 6ICARIOETALFOUND ESOPHAGEALMASTCELLSTHATARENOTBEARING)G%ONTHEIRSURFACEINSOMECHILDRENWITH EoE [16=!HIGHERPERCENTAGEOFESOPHAGEALMASTCELLSBEARING)G%WASFOUNDIN CHILDRENWITH%O%WHOHAVECONCOMITANTATOPYASTHMA ALLERGICRHINITIS ORECZEMA THANINNON ATOPIC%O%CHILDREN4HEREFORE OTHERMECHANISMSFORMASTCELLACTIVATION BESIDESCROSS LINKINGOF)G%ONTHECELLSURFACEMAYEXISTIN%O% !LTERNATIVEPATHWAYSFORMASTCELLACTIVATIONTHATAREINDEPENDENTOF)G%INCLUDE STEMCELLFACTOR COMPLEMENTFRAGMENTS NEUROPEPTIDES ANDEOSINOPHIL DERIVEDPROTEINS NONEOFWHICHHAVEBEENINVESTIGATEDIN%O%;33–35=4HEEOSINOPHIL DERIVED GRANULARPROTEINS MAJORBASICPROTEIN ANDEOSINOPHILCATIONICPROTEIN AREOFPARTICULARINTERESTSINCETHEYHAVEBEENSHOWNTOBEINCREASEDINTHEESOPHAGEALEPITHELIUMOF%O%PATIENTSANDWEREFOUNDTOBEPARTICULARLYPREVALENTINTHEEXTRACELLULAR SPACE FOLLOWING EOSINOPHILIC DEGRANULATION ;10= ALLOWING POTENTIAL ACTIVATION OF MASTCELLS

Possible Role of Mast Cells in the Pathogenesis of EoE 4HEROLETHATMASTCELLSPLAYINTHEPATHOGENESISOF%O%HASNOTBEENSTUDIED7HEN ACTIVATED MASTCELLSAREKNOWNTORELEASEAVARIETYOFMEDIATORS EITHERSTOREDIN THEIRPREFORMEDGRANULES ORSYNTHESIZEDFOLLOWINGACTIVATION4ABLE5.1) [34]. As a RESULT MASTCELLSMAYHAVEANEFFECTONSEVERALIMMUNEANDNON IMMUNECELLSIN EoE, hence contributing to its pathogenesis.

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Table 5.1 -OLECULESRELEASEDBYMASTCELLSUPONACTIVATION;34] #LASSOFPRODUCT %XAMPLES "IOLOGICALEFFECTS %NZYME 4RYPTASE CHYMASE AND 2EMODELCONNECTIVETISSUEMATRIX carboxypeptidase 4OXICMEDIATOR

(ISTAMINEANDHEPARIN

)NCREASEVASCULARPERMEABILITY #AUSESMOOTHMUSCLECONTRACTION

Cytokine

IL-4 and IL-13 ),  ),  AND'- #3&

3TIMULATEANDAMPLIFY4HRESPONSE 0ROMOTEEOSINOPHILPRODUCTIONAND ACTIVATION 0ROMOTESINmAMMATIONANDSTIMULATES CYTOKINEPRODUCTIONBYMANYCELLTYPES

4.& D #HEMOKINE

-)0 D

!TTRACTSMONOCYTES MACROPHAGES AND neutrophils

,IPIDMEDIATOR

Leukotrienes C4, D4, and E4

#AUSESMOOTHMUSCLECONTRACTION )NCREASEVASCULARPERMEABILITY 3TIMULATEMUCUSSECRETION Attracts leukocytes !MPLIlESPRODUCTIONOFLIPIDMEDIATORS !CTIVATESNEUTROPHILS EOSINOPHILS AND platelets

0LATELET ACTIVATINGFACTOR

#ROSSTALKBETWEENMASTCELLSANDEOSINOPHILSMAYBEANIMPORTANTCONTRIBUTOR TOTHEPATHOGENESISOF%O%INHUMANS!CTIVATEDINTESTINALMASTCELLSWERESHOWNTO BEAPOTENTSOURCEOF), INPATIENTSWITHINTESTINALINmAMMATORYDISEASES;36], a CYTOKINEIMPORTANTINEOSINOPHILICRECRUITMENT4RYPTASEWASALSOSHOWNTOSTIMULATETHESELECTIVERELEASEOFINTERLEUKIN ;37], a cytokine that participates in eosinoPHILICMIGRATION;38=5SINGMASTCELL DEPLETEDMICE $ASETAL;39=ALSODEMONSTRATED AROLEFORMASTCELLSINEOTAXIN INDUCEDEOSINOPHILACCUMULATIONAFTERALLERGENSENSITIZATION4HEREFORE CROSSTALKBETWEENMASTCELLSANDEOSINOPHILSMAYBEATWO WAYPHENOMENON POSSIBLYCONTRIBUTINGTOTHEPATHOGENESISOF%O% 5PONACTIVATION MASTCELLSAREALSOCAPABLEOFRELEASING4HCYTOKINESSUCHAS IL-4, IL-5, and IL-13 [34= ANDTHEREFOREMAYBECONTRIBUTINGTOTHE4HPHENOTYPE present in EoE [15, 26, 27=&URTHERMORE THROUGHSECRETIONOFTHECYTOKINE4.& D, MASTCELLSARECAPABLEOFCOORDINATINGANDDRIVINGA4HIMMUNERESPONSETOANTIGENSTHROUGHMATURATIONAND4HSKEWINGOFDENDRITICCELLS;40]. Dendritic cells are FOUNDINTHEESOPHAGUSMOSTLYCONCENTRATEDINTHEDEEPERLAYERSOFTHEESOPHAGEAL EPITHELIUM CLOSETOOTHERIMMUNECELLSINCLUDINGMASTCELLS;9]. -ASTCELLSMAYALSOPARTICIPATEINTHEPATHOGENESISOF%O%THROUGHTHEIREFFECTON NON IMMUNE CELLS -AST CELL COMPONENTS SUCH AS HISTAMINE AND LEUKOTRIENES ARE KNOWN TO HAVE THE CAPACITY TO CAUSE SMOOTH MUSCLE CONTRACTION ;34= 4HEREFORE THEYMAYHYPOTHETICALLYPLAYANIMPORTANTROLEINMUSCULARDISTURBANCESFOUNDIN SOMEPATIENTSWITH%O%;41]. 3IMILAR TO EOSINOPHILS MAST CELLS ALSO ARE CAPABLE OF SECRETING 4'& E [33], a CYTOKINE IMPLICATED IN ESOPHAGEAL SUBEPITHELIAL lBROSIS IN %O% ;42= (OWEVER ESOPHAGEALlBROSISIN%O%WASFOUNDTOBEASSOCIATEDWITHACTIVATEDESOPHAGEAL EOSINOPHILS BUTNOTACTIVATEDESOPHAGEALMASTCELLSINAPEDIATRICSTUDY;10].

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$ESPITETHEPOTENTIALROLEFORMASTCELLSIN%O% THEUSEOFLEUKOTRIENERECEPTOR ANTAGONISTSINTHERAPYHASSHOWNLIMITEDRESPONSE7HENUSEDATHIGHDOSESINADULT PATIENTSWITH%O% THELEUKOTRIENERECEPTORANTAGONISTMONTELUKASTRESULTEDINCLINICAL RESPONSE IN SOME PATIENTS BUT NO HISTOLOGICAL REMISSION OF THE DISEASE ;43]. &URTHERMORE LEUKOTRIENELEVELSWERENOTFOUNDTOBEINCREASEDINTHEESOPHAGEAL MUCOSAOFCHILDRENWITH%O%;44=3TUDIESARENEEDEDTOELUCIDATETHEEXACTROLEOF MASTCELLSINTHEPATHOGENESISOF%O%ANDTHESTAGEATWHICHTHEYPLAYAROLEINTHE disease, so that therapeutic trials can be tailored accordingly.

Conclusion )NCONCLUSION SEVERALIMMUNECELLSORCHESTRATEDISEASEPATHOGENESISIN%O% AMONG WHICH LYMPHOCYTES AND MAST CELLS LIKELY PLAY AN IMPORTANT ROLE ,YMPHOCYTES ESPECIALLY4CELLS AREINCREASEDINTHE%O%ESOPHAGUS ANDTHEESOPHAGEALMILIEUIS COMPATIBLEWITHANALLERGIC4HPHENOTYPE(OWEVER THECONTRIBUTIONOFLYMPHOCYTESINTOTHIS4HMILIEUISSTILLUNCLEAR-ASTCELLSAREALSOINCREASEDINTHE%O% ESOPHAGUS BUTTHEIREXACTROLEINTHEDISEASEPATHOGENESISISSTILLUNCLEAR&IGURE5.1 SUMMARIZESTHEPROPOSEDROLETHATTHESECELLSMAYPLAYIN%O%&URTHERTRANSLATIONAL STUDIESARENEEDEDTOCLARIFYTHEROLEFORTHESETWOIMPORTANTIMMUNECELLS TOALLOW FUTURETAILOREDBIOLOGICALTHERAPIESFOR%O%

Fig. 5.1 0ROPOSEDROLEPOTENTIALLYPLAYEDBYLYMPHOCYTESANDMASTCELLSINEOSINOPHILICESOPHAGITIS

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Chapter 6

Esophageal Remodeling in Eosinophilic Esophagitis Louanne M. Tourangeau and Seema S. Aceves

Keywords 3QUAMOUS EPITHELIUM s %SOPHAGEAL EPITHELIUM s ,AMINA PROPRIA s-USCULARISMUCOSAs3UBMUCOSAs-USCULARISPROPRIAs%PITHELIALEOSINOPHILIA

Introduction The normal esophagus is composed of layers from the lumen to the adventitia. The NON KERATINIZEDSTRATIlEDSQUAMOUSEPITHELIUMABUTSTHELUMENWHILETHESUBEPITHELIALREGIONSCONTAINTHEUNDERLYINGLAMINAPROPRIA MUSCULARISMUCOSA SUBMUcosa, and muscularis propria [1]. The esophageal epithelium contains regenerative CELLSINTHEBASALZONE WHICHUSUALLYCOMPRISESOFTHETOTALEPITHELIALHEIGHT and projections of lamina propria, known as the vascular papillae, that extend to approximately one third of the thickness of the squamous epithelium [2]. In the NORMALESOPHAGUS THE,0COMPRISESNON lBROTIC RETICULARCOLLAGENlLAMENTSAND the epithelium is devoid of eosinophilic infiltration. Therefore, epithelial eosinophilia indicates a pathologic condition [3] (Fig. 6.1).

S.S. Aceves (*) Division of Allergy, Immunology, Departments of Pediatrics and Medicine, University of California, Rady’s Children’s Hospital, San Diego, CA, USA e-mail: [email protected]; [email protected] C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_6, © Springer Science+Business Media, LLC 2012

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Fig. 6.1 Esophageal pathology in eosinophilic esophagitis. A representative IMAGEOFABIOPSYFROMAN EoE patient demonstrates BASALZONEHYPERPLASIAAND epithelial eosinophil accumulation. The lamina propria demonstrates SIGNIlCANTlBROSISWITH increased collagen density

Esophageal Fibrosis and Remodeling in EoE Although Eosinophilic Esophagitis (EoE) is a clinicopathological diagnosis with typical endoscopic features such as esophageal pallor, linear furrowing, white plaques, and esophageal strictures as well as characteristic clinical symptoms such ASDYSPHAGIA ABDOMINALPAIN ANDPOORAPPETITE ULTIMATELY THEDIAGNOSISOF%O% relies on the histologic finding of q15 eosinophils per high power field despite acid BLOCKADE;4=)TSHOULDBEMENTIONEDTHATTHEREARESEVERALADDITIONALDISEASESTATES THAT CAN BE ACCOMPANIED BY ESOPHAGEAL EOSINOPHILIC INlLTRATION WHICH HAVE NOT BEEN SYSTEMATICALLY ASSESSED FOR ASSOCIATED lBROSIS 4HESE INCLUDE GASTROESOPHAgeal reflux disease, the hypereosinophilic syndrome, eosinophilic gastroenteritis, INmAMMATORY BOWEL DISEASE COLLAGEN VASCULAR DISEASES AND DRUG REACTIONS ;3] (Fig. 6.1). 3UBEPITHELIALlBROSISWASlRSTNOTEDTOBEAFEATUREOF%O%INADULTPATIENTS;11]. (ISTOLOGICALLY lBROSISCANBEDElNEDASANINCREASEINTHETOTALCOLLAGENDEPOSITION INTHESUBEPITHELIUM;5=ANDREmECTSANIMPORTANTCOMPONENTOFAMOREGLOBALPROCESS referred to as “tissue remodeling”. In essence, remodeling is a response of tissue regeneration and repair to injurious and inflammatory states. Tissue remodeling as

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Fig. 6.2 Eosinophil activation and remodeling in EoE: (a) Epithelial changes due to epithelial cells in the esophagus increasing eotaxin-3 transcription in a STAT6-dependent manner when stimulated with IL-13 resulting in BZH and intracellular edema. (b) Eosinophil expression of vascular endotheLIALGROWTHFACTOR6%'& WITHVASCULARCELLADHESIONMOLECULE ACTIVATION6#!-  BY),  and TNF-D (alpha) increased eosinophil trafficking leads to structural changes including non-stricture food impactions. (c) Eosinophil-derived TGF-EINDUCESMYOlBROBLASTSWHICHINCREASESTHE%# MATRIXLEADINGTOlBROSIS RINGS STRICTURES ANDFOODIMPACTIONS!DDITIONALFACTORSLIKELYCONTRIBUTING TO lBROSIS INCLUDE PERIOSTIN ),  E, MBP, EPO, IL-13, and IL-5. (d) Activated eosinophils express TGF-E which may induce smooth muscle hypertrophy and dysfunction leading to muscuLARISPROPRIATHICKENINGWHICHCANCONTRIBUTETOTHEDEVELOPMENTOFRINGS FOODIMPACTIONS DYSMOtility, and dysphagia. (Adapted from!CEVES33 !CKERMAN3!2ELATIONSHIPSBETWEENEOSINOPHILIC INmAMMATION TISSUEREMODELING ANDlBROSISINEOSINOPHILICESOPHAGITIS)MMUNOL!LLERGY#LIN. Am. 2009;29:199; Fox VL, et al. High resolution EUS in children with eosinophilic “allergic” ESOPHAGITIS'ASTRO%NDO !CEVES33 .EWBURY2/ $OHIL2 ETAL%SOPHAGEAL remodeling in pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2007;119:210; with permission.)

ARESULTOF4HANDEOSINOPHILICDISEASEWASINITIALLYDESCRIBEDINTHEHYPEREOSINOPHILIC syndrome and in asthma [6–9= !STHMATIC AIRWAY REMODELING HAS A NUMBER OF HISTOLOGICFEATURESANDHASBEENWELLCHARACTERIZEDTOINCLUDEEPITHELIALCELLMETAPLASIATOAMUCOUS PRODUCINGPHENOTYPE SUBEPITHELIALlBROSIS ANGIOGENESIS AND SMOOTHMUSCLEHYPERTROPHYANDHYPERPLASIA7HILEANIMALMODELSHAVEBEENPIVotal in understanding the mechanisms of asthmatic airway remodeling, the true clinical consequences and natural history of human airway remodeling remain enigmatic, especially in children, due to adequate surrogate asthma disease markers SUCH AS WHEEZE COUGH AND AIRWAY OBSTRUCTION ON PULMONARY FUNCTION TESTING

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4HESESURROGATEMARKERSOBVIATETHENEEDFORREPEATEDTISSUEPROCUREMENT!SSUCH THECORRELATIONSBETWEENAPATIENTSCLINICALSTATEANDHISHERTISSUESTATEAREDIFlCULT to determine. In contrast, EoE is currently a disease without an adequate serologic or surrogate marker of activity. As such, patients with EoE require repeated tissue BIOPSYINORDERTOFOLLOWTHEIRCLINICALCOURSE4HISLENDSINVESTIGATORSTHEOPPORTUnity to study eosinophil-associated tissue remodeling over time and in response to therapy. Importantly, it also will allow us to understand the presence and clinical effects of eosinophil-associated tissue remodeling in young children. In addition, the relevance of remodeling to severe EoE complications such as stricture formation CANBEEVALUATED)NDEED %O%STUDIESHAVEBEGUNTOPROVIDEANEWMODELFORUNDERstanding the mechanisms and clinical implications of tissue remodeling in children and adults. !LTHOUGHlRSTNOTEDINADULTPATIENTS ESOPHAGEALlBROSISALSOOCCURSINCHILDREN with EoE [10, 11=)N TWOPEDIATRICSTUDIESDOCUMENTEDLAMINAPROPRIAlBROsis in pediatric EoE patients. Aceves et al. demonstrated that pediatric patients with LONG STANDINGORSTRICTURE ASSOCIATED%O%HADSIGNIlCANTLYMORElBROSISTHANPEDIatric patients with a histologically normal esophagus or patients with reflux esophagitis [12=#HEHADEANDCOLLEAGUESRETROSPECTIVELYREVIEWEDBIOPSIESOF%O% PATIENTS AND FOUND THAT  HAD SUBEPITHELIAL lBROSIS ;13= .OTABLY OF lBROTIC PATIENTS  HAD DYSPHAGIA AND  HAD FOOD IMPACTIONS $YSPHAGIA WAS NOT PARTOFTHE%O%SYMPTOMCOMPLEXINTHEABSENCEOFlBROSISANDlBROSISAPPEARED TO PRECEDE THE DEVELOPMENT OF DYSPHAGIA !DDITIONALLY lBROSIS WAS NOT SIGNIlcantly linked to peripheral eosinophil counts, duration of symptoms, or the presence of food or environmental allergies. Endoscopically, all patients with concentric RINGSHADBOTHlBROSISANDDYSPHAGIA;13=(OWEVER FURTHERSTUDIESDONEBYOUR GROUPHAVEDEMONSTRATEDTHATlBROSISISNOTISOLATEDTOPATIENTSWITHDYSPHAGIA strictures, or concentric rings and can occur even in children as young as 24 months [14=!SSUCH lBROSISAPPEARSTOBEANINTEGRALPARTOF%O%PATHOGENESISTHATCAN BEGINEARLYINLIFE

Potential Mechanisms of Esophageal Fibrosis in EoE Pro-fibrotic Factors Transforming Growth Factor beta-1 (TGFb1) )NORDERTOASSESSPOTENTIALPRO lBROTICMOLECULESTHATCOULDCONTRIBUTETOESOPHAgeal remodeling in pediatric EoE, we analyzed the expression of transforming GROWTHFACTOR BETA 4'&E1) and its signaling molecule phosphorylated Smad2/3 (pSmad2/3). 7GFEBINDSTOITSRECEPTORCOMPLEX4'&E RI/RII, resulting in a signal transduction cascade that phosphorylates the Smad transcription factor comPLEX ALLOWING NUCLEAR TRANSLOCATION AND TRANSCRIPTIONAL ACTIVATION OF PRO lBROTIC

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TARGET GENES 0EDIATRIC %O% PATIENTS HAVE INCREASED NUMBERS OF 4'&E1-positive CELLS IN THE LAMINA PROPRIA COMPARED WITH SUBJECTS WITH GASTROESOPHAGEAL REmUX disease (GERD) or patients with a histologically normal esophagus [12]. Consistent with activation of the TGFE SIGNALING PATHWAY THERE ARE INCREASED NUMBERS OF nuclear pSmad2/3 positive cells in the lamina propria of EoE patients as compared with GERD or normal patients. Messenger RNA for TGFE1 is also increased in EoE patients as compared with controls [15]. In vitro studies have suggested the clinical consequences of elevated TGFEIN%O%5SING%O%lBROBLASTS "LANCHARD et al. demonstrated that TGFE1 can increase the production of the extracellular matrix protein, periostin [16]. Importantly, human esophageal eosinophils produce TGFE1, directly implicating the eosinophil in EoE remodeling.

Interleukin-5 ),  IS AN ESSENTIAL EOSINOPHILOPOETIC FACTOR THAT CAN BE SUFlCIENT FOR INCREASING eosinophil trafficking into the esophagus. IL-5 overexpression using a mini-osmotic pump or T cell transgene results in significant esophageal eosinophil accumulation. In addition, animal models of EoE have demonstrated that intranasal Aspergillus fumigatus induces EoE concurrent with pulmonary eosinophilia in Aspergillus challenged mice as compared with naïve mice. In this model system, Aspergillus causes significantly increased collagen accumulation in the lamina propria of allergenCHALLENGEDANIMALS)NADDITIONTOSUBEPITHELIALlBROSIS THETHICKENEDMUSCULARIS mucosa also demonstrates increased collagen deposition in the stromal papillae BETWEENTHESMOOTHMUSCLEBUNDLES!SSUCH THISANIMALMODELREmECTSMULTIPLE COMPONENTSOFBOTHESOPHAGEALANDAIRWAYREMODELINGINCLUDINGlBROSIS MUSCULAR HYPERTROPHY ANDBASALCELLPROLIFERATION;15]. )NADDITIONTOlBROSIS -ISHRAETALDEMONSTRATEDFURTHERFEATURESOFESOPHAGEAL remodeling in allergen-challenged mice. Specifically, transcript levels of TGFE1 and the mucin MUC5AC gene were increased in allergen-induced EoE as compared with control mice. Interestingly, MUC5AC mRNA levels were also significantly increased IN%O%HUMANSUBJECTSCOMPAREDWITHHEALTHYCONTROLS4HEROLEOF), ANDEOSINOPHILSSEEBELOW WASSHOWNTOBECRITICALINMURINE%O% ASSOCIATEDESOPHAGEALREMODeling. IL-5-deficient mice did not show a significant increase in collagen deposition in the lamina propria, stromal papillae, or muscularis mucosa following allergen stimulation. The lamina propria collagen thickness was 21.2 ± 2.2 Pm in the allergen-challenged wild type mouse versus 5.2 ± 1.0 Pm in the IL-5 gene-deficient mouse. Additionally, THE HISTOLOGIC lNDING OF BASAL ZONE HYPERPLASIA WAS SIGNIlCANTLY LOWER IN THE ),  knockout mice as compared with allergen-challenged wild type mice [15]. Demonstrating potential sufficiency of IL-5 to induce esophageal remodeling, CD2-IL-5 transgenic mice demonstrate worsened esophageal remodeling with a thickened epithelium, expansion of connective tissue, and collagen accumulation in the lamina propria and the stromal papillae than their wild type counterparts. )NTERPLAYOFEOSINOPHILCHEMOKINESWITH), WASSUGGESTEDBYTHEFACTTHATEOTAXIN  DElCIENT#$ ), DOUBLETRANSGENICMICEWERERELATIVELYPROTECTEDFROMESOPHAGEAL

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remodeling [15]. Interestingly, systemic over-expression of IL-5 did not induce esophageal remodeling, leading to the conclusion that the local effects of IL-5 are necessary to induce esophageal remodeling. It is interesting to note that IL-5 and eotaxins can synergize to activate eosinophils and, as such, the induction of eosinoPHILDEGRANULATIONMAYBEPIVOTALTOTHEREMODELINGPROCESS

Interleukin-13 Murine models have demonstrated that pulmonary expression of IL-13 is sufficient FORINDUCINGSIGNIlCANTAIRWAYlBROSIS3TUDIESHAVESHOWNTHAT), M2.!LEVELS ARE SIGNIlCANTLY HIGHER IN BIOPSY SPECIMENS FROM %O% PEDIATRIC PATIENTS WHEN compared with normal controls [17]. Additionally, cultured EoE epithelial cells increase eotaxin-3 transcription in a STAT6-dependent (signal transducer activation transcription-6) manner when stimulated with IL-13 [17, 18]. Interestingly, IL-13 also induces the expression of periostin, which causes increase in eosinophil adherENCETOTHEEXTRACELLULARMATRIXANDSUBSEQUENTEOSINOPHILACCUMULATIONINTARGET TISSUES POTENTIALLY PROVIDING A POSITIVE FEEDBACK LOOP FOR ESOPHAGEAL EOSINOPHIL trafficking. 2ECENTLY :UO AND COLLEAGUES UTILIZED MURINE MODELS TO ASSESS THE ABILITY OF increased airway IL-13 to induce EoE in the esophagus [19]. Transgenic (CC10iIL-13) mice, with IL-13 overexpression in the lung, demonstrated increased esophAGEAL),  ACCUMULATIONOFEOSINOPHILANDCOLLAGENWITHlBROSIS ANGIOGENESIS ANDINCREASEDOVERALLESOPHAGEALCIRCUMFERENCE4ISSUEREMODELINGAPPEAREDTOBE independent of eosinophils, and IL-13-induced esophageal eosinophilia appeared to BEDEPENDENTONEOTAXIN BUTNOTONEOTAXIN &URTHERMORE AN), 2D2 (alpha) DELETIONCAUSEDASIGNIlCANTINCREASEIN), INDUCEDlBROSIS4HESERESULTSSUGGEST THAT TISSUE REMODELING MAY BE LARGELY INDEPENDENT OF EOSINOPHILS AND THAT ), MAYBESUFlCIENTTOINDUCEESOPHAGEALlBROSISINVIVO!SSUCH THElBROTIC PROCESSMAYBEINHIBITEDBY), 2D2, which may function as a potential future therapeutic target.

Inflammatory Cells %OSINOPHILSHAVELONGBEENCONSIDEREDAKEYCELLULARCOMPONENTOFTISSUElBROSIS [20=ANDHAVEBEENIMPLICATEDINAVARIETYOFDISEASESASAMAJOREFFECTORCELLCAUSING lBROGENESISTHROUGHTHEIRPRODUCTIONOFANDINTERACTIONSWITHlBROGENICGROWTH factors, such as TGFE1 [21, 22], PDGF-BB [23], IL-1E [24] and through their granule products such as MBP [25] and eosinophil peroxidase [26]. Eosinophil DEGRANULATIONHASBEENIMPLICATEDINSEVERALDISEASESTATES INCLUDING%O%)NDEED eosinophil granules alone can respond to IL-5 and function as cell-independent organelles [27]. We initially demonstrated that human esophageal eosinophils in EoE could express TGFE1 [12]. Definitive proof of the importance of the eosinophil in EoEassociated tissue remodeling comes from Mishra and colleagues who demonstrated

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THATANIMALSLACKINGEOSINOPHILSDUETOTHEMUTATIONDELTADOUBLE'!4!AREPROTECTED FROM%O% ASSOCIATEDlBROSIS;15]. Recent data demonstrate that tryptase-positive mast cells in EoE also produce TGFE1 [29, 30]. Aceves et al. explored the role of mast cells in esophageal smooth muscle, the functional role of mast cell TGF-E1 expression in contractility of human esophageal smooth muscle cells in vitro, and the effect of topical steroid therapy on TRYPTASE POSITIVEMASTCELLSANDCHYMASE POSITIVEMASTCELLS%O%SUBJECTSHADSIGNIlCANTLYHIGHERNUMBERSOFTRYPTASE POSITIVEMASTCELLSMEDIANOFCELLSMM2 in EoE versus median of 85 cells/mm2 in controls; p = 0.002) and TGF-E1-positive cells in the smooth muscle as compared to normal controls (p = 0.005). Interestingly, the tryptase-positive mast cells expressed TGF-E1 which enhanced the contraction OFPRIMARYHUMANESOPHAGEALSMOOTHMUSCLECELLSINVITRO7HILETOPICALBUDESonide significantly decreased epithelial tryptase-positive mast cells, lamina propria tryptase- and chymase-positive mast cells remained a relatively static population AND DID NOT DIFFER BETWEEN %O% AND CONTROL SUBJECTS !DDITIONALLY THEY DEMONSTRATEDTHENOVELlNDINGTHATINPATIENTSWITH%O% THEABSOLUTENUMBEROFMASTCELLS INTHESMOOTHMUSCLEISSIGNIlCANTLYGREATERTHANTHENUMBEROFEOSINOPHILS!SA RESULT THEYPROPOSEAPOSSIBLELINKBETWEENTHEMASTCELLNUMBERSANDTHESMOOTH MUSCLECONTRACTILITYINPATIENTSWITH%O%SIMILARTOTHATSEENINASTHMATICSUBJECTS !SSUCH MASTCELLSMAYALSOPARTICIPATELARGELYINTHElBROTICPROCESSDURING%O% pathogenesis. Studies using mast cell-deficient mice in experimental EoE have not YETBEENREPORTED

Structural Cells of the Esophagus Epithelium During inflammation or injurious conditions of the esophagus such as acid reflux OR%O% THEESOPHAGEALLAYERSCANBEUNIFORMLYINVOLVEDINSTRUCTURALCHANGES&OR EXAMPLE INBOTHREmUXANDEOSINOPHILICESOPHAGITIS THEBASALZONECANBECOME HYPERPLASTIC)N%O% ANACTIVEPROLIFERATIONOFTHEBASALCELLSLEADSTOSIGNIlCANT BASAL ZONE HYPERPLASIA .OT UNCOMMONLY THE BASAL ZONE OCCUPIES  OF THE total epithelial height in EoE [11]. In addition, the lamina propria papillae elongate and intercellular edema occurs within the esophageal epithelium during EoE [2]. )NDEED BASALZONEHYPERPLASIACANBECONSIDEREDANEPITHELIALFEATUREOFESOPHAgeal tissue remodeling. Studies of esophageal tissue from EoE patients have shown increased epithelial expression of eotaxin-3 as the principal mediator of eosinophil recruitment [31].

Fibroblasts %SOPHAGEALlBROBLASTSHAVEBEENSHOWNTOPRODUCEPERIOSTINWHENCULTUREDWITH TGFEOR), BUT THEIRNUMBERS FUNCTION ANDPHENOTYPEASWELLASTHEIRROLEIN

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DISEASEPROGRESSIONTOlBROSISREQUIRESFURTHERSTUDY!RECENTABSTRACTDEMONSTRATED the potential for epithelial-mesenchymal transformation in EoE, the severity of which correlated with the degree of eosinophilia, TGFEEXPRESSION ANDlBROSIS;28]. One of the identified genes in genome-wide expression profiling studies of EoE ESOPHAGEALTISSUEWASPERIOSTIN3TUDIESHAVESHOWNTHATPRIMARYESOPHAGEALlBROBLASTSRELEASEPERIOSTINWHENSTIMULATEDWITH), AND4'&E [16]. As such, periostin expression in the vascular papillae and lamina propria could increase eosinophil TRAFlCKINGBYALLOWINGEOSINOPHILADHESIONTOlBRONECTIN;16].

Vascular Changes in Remodeling Esophageal remodeling, like airway remodeling, is associated with increased vascular DENSITY)N OURGROUPREPORTEDINCREASEDNUMBERSOFESOPHAGEALBLOODVESSELS USING THE ENDOTHELIAL MARKER VON7ILLEBRAND FACTOR IN %O% PATIENTS AS COMPARED with GERD and normal control patients [12]. Furthermore, EoE patients had INCREASED NUMBERS OF BLOOD VESSELS EXPRESSING THE ACTIVATION MOLECULE 6ASCULAR Cell Adhesion Molecule (VCAM)-1 as compared with GERD patients and normal controls [12]. It is interesting to postulate that Th2 cytokines such as IL-4 and IL-13 COULDINCREASEVASCULAREXPRESSIONOF6#!- IN%O% THEREBYALLOWINGEOSINOPHIL and inflammatory cell trafficking via the VCAM-1 ligand, Very Late Antigen (VLA)-4.

Clinical Implications of Esophageal Fibrosis and Response to Therapies Correlation of Remodeling with Symptoms and Endoscopy !RECENTLYPUBLISHEDPROSPECTIVESTUDYDEMONSTRATEDTHATFEATURESOFESOPHAGEAL remodeling correlated with typical symptoms and endoscopic features in pediatric EoE patients [32=3PECIlCALLY LAMINAPROPRIAlBROSISANDINmAMMATIONCORRELATES WITHDYSPHAGIAWHILEEPITHELIALINmAMMATION BASALZONEHYPERPLASIA ANDDILATED intracellular spaces correlate with dysphagia + anorexia/early satiety [32]. Endoscopic features also correlate with histological remodeling features. While epithelial CHANGESCORRELATEDWITHWHITEPLAQUESANDLICHENIlCATIONLINEARFURROWS SUBEPITHELIALlBROSISWASASSOCIATEDSPECIlCALLYWITHLICHENIlCATIONANDLINEARFURROWS Interestingly, in our cohort of patients, only the symptoms of dysphagia and ANOREXIAEARLY SATIETY WERE CAPABLE OF IDENTIFYING %O% PATIENTS FROM THOSE with reflux esophagitis and remodeling features correlated only with these EoE symptoms [32].

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Natural History The most significant complication of EoE is esophageal stricture formation and it ISLIKELYTHATlBROSISPLAYSANIMPORTANTROLEINTHEESOPHAGEALNARROWINGLEADING to strictures. We have reported that patients who are non-responders to therapy have PERSISTENT ESOPHAGEAL REMODELING SOMETIMES WITH PROGRESSION OF lBROSIS ;14]. (OWEVER THE PREDISPOSING FACTORS FOR A MORE lBROTIC %O% PHENOTYPE AND THE PREDICTORSFORPROGRESSIONTOSTRICTURESNEEDSTOBECLARIlED4HELONG TERMNATURAL HISTORY OF ESOPHAGEAL lBROSIS IN %O% PATIENTS HAS NOT BEEN FULLY ELUCIDATED BUT unlike other disease states where repeated tissue procurement is not required as a ROUTINEPARTOFCLINICALCARE %O%OFFERSANEWABILITYTOANSWERTHESEIMPORTANT questions.

Effects of Therapeutic Interventions on EoE Associated Esophageal Remodeling Corticosteroids The question of whether therapeutic interventions can reduce esophageal remodeling IS BEGINNING TO BE ELUCIDATED /UR GROUP RECENTLY DEMONSTRATED THAT ESOPHAGEAL REMODELINGIMPROVEDFOLLOWINGTOPICALCORTICOSTEROIDUSEINTHESUBSETOFPATIENTS who responded to therapy [14]. Patients were defined as “responders” (d7 epithelial EOSINOPHILSPERHPFFOLLOWINGBUDESONIDETHERAPY ANDhNON RESPONDERSvEPITHELIALEOSINOPHILSPERHPFFOLLOWINGBUDESONIDETHERAPY &OLLOWINGTHERAPYWITH ORALVISCOUSBUDESONIDEFORATLEASTMONTHS RESPONDERSHADASIGNIlCANTDECREASE INTHEDEGREEOFLAMINAPROPRIAlBROSISWHEREASTHENON RESPONDERSHADUNCHANGED lBROSISFOLLOWINGTREATMENTWITHBUDESONIDE )N ADDITION POTENTIAL MEDIATORS OF lBROSIS INCLUDING 4'&E1 and its signaling pathway transcription factor, pSmad2/3, were decreased in the lamina propria of RESPONDER PATIENTS BUT NOT IN NON RESPONDERS FOLLOWING BUDESONIDE THERAPY 4HE MEANNUMBEROF4'&E1 positive cells prior to therapy was not significantly different BETWEEN RESPONDERS MEAN 4'&E1 positive cells/hpf) and non-responders (mean = 109 TGFE1 positive cells/hpf ). After 3 months of therapy with swallowed BUDESONIDE THE RESPONDERS HAD SIGNIlCANT DECREASES IN THE NUMBERS OF 4'&E1 positive cells per high power field (hpf) as compared with the non-responders 3EE4ABLE6.1) [14]. To assess the effects of steroid therapy on the downstream pathway from TGFE1, P3MADPOSITIVECELLSWEREEXAMINEDBEFOREANDAFTERTHERAPY3IMILARNUMBERS OFP3MADPOSITIVECELLSWEREFOUNDBEFOREINITIATIONOFTHERAPY!FTERORALVISCOUSBUDESONIDEUSE THEMEANNUMBEROFP3MADPOSITIVECELLSINRESPONDERS decreased to 86; non-responders continued to have a mean of 119 pSmad2/3 positive cells per hpf. Similarly, responders demonstrated a decrease in VCAM-1 positive vessels

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Table 6.1 0ATIENTDATATABULATEDBEFOREANDAFTERTREATMENTWITHORALVISCOUSBUDESONIDE Responders Non-responders Epithelial score Before tx: 2.2 Before tx: 2.5 After tx: 0.2 After tx: 2.3 LP eosinophils per hpf Before tx: 12.5 Before tx: 13 After tx: 1.8 After tx: 32 ,0lBROSISSCORE Before tx: 1.6 Before tx: 2.3 After tx: 0.67 After tx: 2.9 TGFE1 positive cells per hpf Before tx: 84 Before tx: 109 After tx: 35 After tx: 97 pSmad2/3 positive cells Before tx: 152 Before tx: 156 After tx: 86 After tx: 119 VCAM-1 positive vessels per hpf Before tx: 19 Before tx: 21 After tx: 13 After tx: 20 Dilated Intercellular Spaces Before tx: 0.55 Before tx: 0.71 After tx: 0 After tx: 0.70 4HEEPITHELIALSCOREWASGENERATEDBYADDINGTHE":(SEVERITYSCOREGRADEDASTOWITH n n AND TOTHE%PITHELIAL$ESQUAMATIONSCOREGRADEDASABSENT   PRESENT  %PITHELIAL EDEMA WAS DETERMINED AS DILATED INTERCELLULAR SPACES AND BASED ON THE PRESENCEORABSENCEOFTHISlNDING4HE,0lBROSISSCOREWASASSESSEDUSINGAN(%STAIN ANDWASGRADEDFROMTOBASEDONTHETHICKNESSOFCOLLAGENBUNDLESANDTHENUMBEROFlBROBLASTS present [14]

and epithelial edema following therapy. The non-responders did not have a significant change. It is important to note that the responders and non-responders had similar SEVERITY PRIOR TO THERAPY IN ALL ASPECTS OF REMODELING INCLUDING lBROSIS 4'&E1, pSmad2/3, and VCAM-1. !SSUCH ITAPPEARSTHATTOPICALCORTICOSTEROIDSARECAPABLEOFINDUCINGREMISSION and/or improvements in esophageal remodeling in those patients who have decreased ESOPHAGEALEPITHELIALEOSINOPHILNUMBERSFOLLOWINGCORTICOSTEROIDTHERAPY(OWEVER the dynamic nature of these changes and the potential progression to strictures in NON RESPONDERPATIENTSREMAINSTOBEUNDERSTOOD

Anti-IL5 !HUMANIZEDMONOCLONALANTI ),ANTIBODYINITIALLYSHOWEDPROMISEASAPOTENTIAL TREATMENTOPTIONFOR%O%PATIENTS)NONESMALLOPEN LABELSTUDY ITWASDEMONSTRATEDTHATANTI ),MEPOLIZUMAB THERAPYWASASSOCIATEDWITHIMPROVEMENTIN %O% ASSOCIATED STRICTURES ESOPHAGEAL NARROWING BASAL ZONE HYPERPLASIA AND eosinophilic inflammation [33=)NCONTRAST APLACEBO CONTROLLEDADULT%O%STUDY SHOWEDTHATMEPOLIZUMABMONOTHERAPYREDUCEDTHEAVERAGENUMBERSOFEOSINOPHILSINTHEESOPHAGEALTISSUEOFPATIENTSWITHSEVERE%O%BYAPPROXIMATELY BUTDIDNOTEFFECTIVELYREDUCEPATIENTSCLINICALSYMPTOMSCORES;34]. In addition to decreases in esophageal eosinophils, Straumann and colleagues reported decreased expression of TGFE1 following anti-IL-5 as well as decreased expression of T ENASCIN # A BASEMENT MEMBRANE PROTEIN &URTHER STUDIES ARE NEEDED TO SEE IF

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A NTI ), REDUCESSUBEPITHELIALCHANGESOFlBROSISANDVASCULARITY4WORECENTLY completed pediatric trials of anti-IL-5 in EoE will help to determine the answers to these questions in children.

Esophageal Dilation A recent study Schoepfer et al. investigated the effectiveness, safety, and impact of esophageal dilation with or without additive anti-eosinophilic medication on underLYINGINmAMMATIONANDlBROSISIN%O%PATIENTS4HEYFOUNDTHATESOPHAGEALDILAtion was effective for dysphagia, with a median duration of symptom relief of 15 months with dilation alone and 17 months in the cohort with dilation plus antieosinophilic medication [35]. Of note, they did not find a difference in eosinophilic infiltration or total eosinophilic load following dilation. Furthermore, they did not IDENTIFYANYSIGNIlCANTDIFFERENCEINBASALCELLHYPERPLASIA SPONGIOSIS ORPAPILLARY elongation pre- versus post-dilation. Schoepfer and colleagues found an increase in SUBMUCOSAL lBROSIS WITH DISEASE DURATION ;35]. In summary, they concluded that DILATIONISEFFECTIVEATDECREASINGDYSPHAGIASYMPTOMSINTHESHORT TERMBUTDOES NOTHAVEANYEFFECTONTHEUNDERLYINGlBROTICCHANGESORONEOSINOPHILICINlLTRATION !DDITIONALLY ITISEFFECTIVEFORDEALINGWITHSTRICTURESBUTDOESNOTAFFECTTHEEVOLUTIONOFlBROSISOR%O%ITSELFANDTHUSDOESNOTOFFERASOLUTIONTOTHEUNDERLYING driving pathology of EoE.

Potential Future Targets to Decrease Esophageal Fibrosis in EoE !CEVESAND!CKERMANHAVESPECULATEDONDIFFERENTTHERAPIESBOTHINTHECONTEXTOF additive medications to IL-5 therapy or perhaps as lone therapy. These include BLOCKING EOSINOPHIL RECRUITMENT THROUGH POSSIBLE ANTAGONISM OF EOTAXIN  OR THE eotaxin-3 receptor, CCR3, on eosinophils [5]. As mentioned previously, recent evidence from murine models of EoE show that IL-4, IL-5, IL-13, and STAT-6 signalING ARE IMPORTANT IN THE DEVELOPMENT OF EXPERIMENTAL %O% AND THAT BLOCKADE OF THESEABROGATESESOPHAGEALEOSINOPHILIA;36]. As a result, these cytokines and their SIGNALINGPATHWAYSMAYBEQUERIEDASPOTENTIALTARGETSFORTHERAPY

IL-13 !SNOTEDABOVE ), HASBEENDESCRIBEDASANINCREASINGLYIMPORTANTCYTOKINEIN the underlying pathology of EoE and esophageal epithelial cells are known to express the IL-13 receptor [18,37]. Blanchard et al. recently reported dysregulation of the epidermal differentiation complex gene (EDC) expression in EoE. The authors

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examined the effects of IL-13 on EDC gene expression and the presence of gene VARIANTSINTHE%$#GENElLAGGRININHUMANSUBJECTSWITH%O%4HEYCONCLUDEDTHAT THEPRIMARYDEFECTINEPITHELIALRESPONSESINSUBJECTSWITH%O%ISNOTINTRINSICTOTHE EPITHELIUMBUTISMORELIKELYSECONDARYTOTHEEFFECTSOF),  ASAREGULATOROF EDC genes [38=4HEREFORE AGENTSTHATINTERFEREWITH), COULDPROVETOBEHIGHLY EFFECTIVEFORPATIENTSWITH%O%AND IF), ISCAPABLEOFRECAPITULATINGREMODELING %O%FEATURESASITDOESINASTHMA ITCOULDPOSSIBLYAIDINTHEPREVENTIONOFESOPHAGEALlBROSIS

Eotaxin-3 and CCR3 Blockade %OTAXIN HASBEENSHOWNTOBETHESINGLE MOSTDYSREGULATEDGENEINESOPHAGEALTISSUEINPATIENTSWITH%O%ANDANEOTAXIN GENE3.0HASBEENASSOCIATED WITHINCREASEDSUSCEPTIBILITYTO%O%;31]. This idea was supported through the use of a murine model where a genetic deletion in the eotaxin-3 receptor, CC chemokine receptor 3 (CCR3), protected mice from developing EoE [31]. Interestingly, IL-4 and IL-13 induce expression of eotaxins [17]. As a result, eotaxin-3 and its receptor CCR3 remain promising potential targets for future therapeutic options.

TGFb1 Elevated levels of TGFE HAVE BEEN DEMONSTRATED IN ADULT AND PEDIATRIC %O% Functional consequences of TGFE1 in EoE include increased expression of prolBROTIC AND PRO EOSINOPHIL GENES SUCH AS PERIOSTIN ;16]. We have demonstrated that a single nucleotide polymorphism in the TGFE1 gene is associated with therapeutic response in EoE patients [14]. As such, TGFE1 may serve as a therapeutic TARGET IN %O% ESPECIALLY IN PATIENTS WHO ARE PRONE TO A MORE lBROTIC DISEASE phenotype.

Summary /VERALL THELONG TERMEFFECTSOFSUBEPITHELIALESOPHAGEALlBROSISIN%O%HAVEYET TOBEFULLYUNDERSTOOD4HEREISAGREATDEALOFPROMISEINTERMSOFTHEEFFECTIVENESS OFTOPICALESOPHAGEALCORTICOSTEROIDTHERAPYINREVERSALOFlBROTICCHANGEINPATIENTS who respond to steroid therapy in terms of eosinophil decreases in the epithelium. (OWEVER TREATMENTOPTIONSFORTHESTEROID NON RESPONSIVEPATIENTSSTILLNEEDSTOBE studied and potential therapies identified. In addition, the genetic predisposition to AlBROTIC STRICTURE ASSOCIATEDVARIANTOF%O%REQUIRESFURTHERINVESTIGATION

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Acknowledgements 4HEAUTHORSTHANK$R2OBERT.EWBURYFOR%%IMAGE!UTHORSUPPORTFROM the Women in Allergy Junior Faculty Development Grant and NIH/NIAID R01AI092135 (SSA) and NIHT32 AI training grant to UCSD (LMT).(SSA) and NIH T32 Training grant (LT)

References 1. Odze RD. Pathology of eosinophilic esophagitis: what the clinician needs to know. Am J Gastroenterol. 2009;104(2):485–90. 2. DeNardi FG, Riddell RH. The normal esophagus. Am J Surg Pathol. 1991;15(3):296–309.  "HATTACHARYA " ET AL )NCREASED EXPRESSION OF EOTAXIN  DISTINGUISHES BETWEEN EOSINOPHILIC esophagitis and gastroesophageal reflux disease. Hum Pathol. 2007;38(12):1744–53. 4. Furuta GT, Straumann A. Review article: the pathogenesis and management of eosinophilic oesophagitis. Aliment Pharmacol Ther. 2006;24(2):173–82.  !CEVES33 !CKERMAN3*2ELATIONSHIPSBETWEENEOSINOPHILICINmAMMATION TISSUEREMODELING ANDlBROSISINEOSINOPHILICESOPHAGITIS)MMUNOL !LLERGY #LIN .ORTH !M   197–211. xiii-xiv.  *ACOBSEN%!ETAL%OSINOPHILSANDASTHMA#URR!LLERGY!STHMA2EP n  +AY !" 0HIPPS 3 2OBINSON $3 ! ROLE FOR EOSINOPHILS IN AIRWAY REMODELLING IN ASTHMA Trends Immunol. 2004;25(9):477–82. 8. Lee JJ et al. Defining a link with asthma in mice congenitally deficient in eosinophils. Science. 2004;305(5691):1773–6. 9. Tai PC et al. Deposits of eosinophil granule proteins in cardiac tissues of patients with eosinophilic endomyocardial disease. Lancet. 1987;1(8534):643–7. 10. Straumann A et al. Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology. 2003;125(6):1660–9. 11. Parfitt JR et al. Eosinophilic esophagitis in adults: distinguishing features from gastroesophageal reflux disease: a study of 41 patients. Mod Pathol. 2006;19(1):90–6. 12. Aceves SS et al. Esophageal remodeling in pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2007;119(1):206–12. #HEHADE-ETAL%SOPHAGEALSUBEPITHELIALlBROSISINCHILDRENWITHEOSINOPHILICESOPHAGITIS J Pediatr Gastroenterol Nutr. 2007;45(3):319–28. 14. Aceves SS et al. Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy. 2010;65(1):109–16. 15. Mishra A et al. Esophageal remodeling develops as a consequence of tissue specific IL-5induced eosinophilia. Gastroenterology. 2008;134(1):204–14. 16. Blanchard C et al. Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses. Mucosal Immunol. 2008;1(4):289–96. -ISHRA! 2OTHENBERG-%)NTRATRACHEAL), INDUCESEOSINOPHILICESOPHAGITISBYAN),  eotaxin-1, and STAT6-dependent mechanism. Gastroenterology. 2003;125(5):1419–27. 18. Blanchard C et al. IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and REVERSIBILITYWITHGLUCOCORTICOIDS*!LLERGY#LIN)MMUNOL n :UO , ET AL ),  INDUCES ESOPHAGEAL REMODELING AND GENE EXPRESSION BY AN EOSINOPHIL INDEPENDENT ), 2A INHIBITEDPATHWAY*)MMUNOL n 'HARAEE +ERMANI- 0HAN3(4HEROLEOFEOSINOPHILSINPULMONARYlBROSIS2EVIEW )NT J Mol Med. 1998;1(1):43–53. 'AULDIE*ETAL4RANSFORMINGGROWTHFACTOR BETAGENETRANSFERTOTHELUNGINDUCESMYOlBROBLASTPRESENCEANDPULMONARYlBROSIS#URR4OP0ATHOLn /HNO)ETAL4RANSFORMINGGROWTHFACTORBETA4'&BETA GENEEXPRESSIONBYEOSINOPHILS in asthmatic airway inflammation. Am J Respir Cell Mol Biol. 1996;15(3):404–9. 23. Ohno I et al. Eosinophils as a potential source of platelet-derived growth factor B-chain (PDGF-B) INNASALPOLYPOSISANDBRONCHIALASTHMA!M*2ESPIR#ELL-OL"IOL n

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'OMES ) ET AL %OSINOPHIL lBROBLAST INTERACTIONS INDUCE lBROBLAST ),  SECRETION AND EXTRACELLULARMATRIXGENEEXPRESSIONIMPLICATIONSINlBROGENESIS*!LLERGY#LIN)MMUNOL 2005;116(4):796–804. 2OCHESTER#,ETAL%OSINOPHIL lBROBLASTINTERACTIONS'RANULEMAJORBASICPROTEININTERACTS WITH), ANDTRANSFORMINGGROWTHFACTOR BETAINTHESTIMULATIONOFLUNGlBROBLAST),  TYPE cytokine production. J Immunol. 1996;156(11):4449–56. 26. Pegorier S et al. Eosinophil-derived cationic proteins activate the synthesis of remodeling facTORSBYAIRWAYEPITHELIALCELLS*)MMUNOL n .EVES*3 2ADKE!, 7ELLER0&#YSTEINYLLEUKOTRIENESACTINGVIAGRANULEMEMBRANE EXPRESSED receptors elicit secretion from within cell-free human eosinophil granules. J Allergy Clin Immunol. 2010;125(2):477–82. 28. Akhtar N et al. Epithelial mesenchymal transition in eosinophilic esophagitis: identification ANDCONTRIBUTIONSTOESOPHAGEALREMODELINGANDlBROSIS*!LLERGY#LIN)MMUNOL Suppl 1):161. 29. Aceves SS et al. Mast cells infiltrate the esophageal smooth muscle in patients with eosinoPHILIC ESOPHAGITIS EXPRESS 4'& B AND INCREASE ESOPHAGEAL SMOOTH MUSCLE CONTRACTION J Allergy Clin Immunol. 2010;126(6):1198–204. !BONIA*0 &RANCIOSI*0 2OTHENBERG-%4'& BMEDIATOROFAFEEDBACKLOOPINEOSINOPHILIC esophagitis – or should we really say mastocytic esophagitis? J Allergy Clin Immunol. 2010;126(6):1205–7. 31. Blanchard C et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J Clin Invest. 2006;116(2):536–47. !CEVES33 .EWBURY2 $OHIL-! "ASTIAN*& $OHIL2!SYMPTOMSCORINGTOOLFORIDENTIFYing pediatric patients with eosinophilic esophagitis and correlating symptoms with inflammation. Ann Allergy Asthma Immunol. 2009;103(5):401–6. 3TEIN-,ETAL!NTI ), MEPOLIZUMAB THERAPYFOREOSINOPHILICESOPHAGITIS*!LLERGY#LIN Immunol. 2006;118(6):1312–9. 3TRAUMANN ! ET AL !NTI INTERLEUKIN  ANTIBODY TREATMENT MEPOLIZUMAB IN ACTIVE EOSINOPHILICESOPHAGITISARANDOMISED PLACEBO CONTROLLED DOUBLE BLINDTRIAL'UTn 35. Schoepfer AM et al. Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation. Am J Gastroenterol. 2009;105(5):1062–70. 2OTHENBERG-% (OGAN304HEEOSINOPHIL!NNU2EV)MMUNOLn 37. Kagami S, Saeki H, Komine M. Interleukin-4 and interleukin-13 enhance CCL26 production in a human keratinocyte cell line, HaCaT cells. Clin Exp Immunol. 2005;141:459–66. "LANCHARD#ETAL#OORDINATEINTERACTIONBETWEEN), ANDEPITHELIALDIFFERENTIATIONCLUSTER genes in eosinophilic esophagitis. J Immunol. 2010;184(7):4033–41.

Chapter 7

The Genetic Basis of Eosinophilic Esophagitis* Joseph D. Sherrill and Marc E. Rothenberg

Keywords %OSINOPHILICESOPHAGITISs'ENETICINmUENCESs'ENEREGULATORYNETWORKS s0OLYGENICDISORDERs$.!

Introduction 4HEEPIDEMIOLOGYOFEOSINOPHILICESOPHAGITIS%O% ACHRONICINmAMMATORYCONDITION of the esophagus, indicates a worldwide increase in disease prevalence over the last 10 years with a disease bias among certain demographic populations [1, 2]. Retrospective studies have shown the prevalence of EoE is almost three times higher in males and is primarily restricted to Caucasians [3, 4]. The disease risk among siblings of EoE patients is estimated to be 40 times higher [5] than the risk of asthma, a more widely prevalent disease with a well-accepted genetic component. These factors suggest that EoE is a polygenic disorder with a heritable genetic basis. Snapshots of whole-genome expression patterns from patient-derived biopsies and GENOME WIDEPOLYMORPHISMMAPPINGOFPATIENT$.!HAVEPROVIDEDGREATINSIGHT ATTHEMOLECULARLEVELINTOTHEGENETICINmUENCESCONTRIBUTINGTO%O%)NTHISCHAPTER we will highlight seminal studies that have identified critical gene regulatory networks that are operational in EoE and discuss genetic polymorphisms associated with disease susceptibility.

4HISWORKWASSUPPORTEDINPARTBY.)(5!) .)(2$+ THE0(3'RANT0 $+ $EPARTMENTOF$EFENSE &OOD!LLERGY0ROJECT THE"UCKEYE&OUNDATION THE#AMPAIGN 5RGING 2ESEARCH FOR %OSINOPHILIC $ISORDERS #52%$ &OUNDATION AND THE $ANA &OUNDATION (UMAN)MMUNOLOGY#ONSORTIUM*$3WASSUPPORTEDBYA4.)(TRAININGGRANT(,  M.E. Rothenberg (*) Department of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, MLC 7028, 3333 Burnett Avenue, Cincinnati, OH 45229, USA e-mail: [email protected] C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_7, © Springer Science+Business Media, LLC 2012

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The EoE Transcriptome Gene expression profiling of diseased tissue describes in accurate detail the global changes in gene expression that may serve as key molecular markers in disease. Work by Blanchard, et al. used such an approach to analyze whole-genome expression patterns from patient esophageal biopsies and defined a characteristic gene signature that differentiates EoE from normal individuals [6]. The expression levels of 574 genes (230 downregulated and 344 upregulated transcripts) were significantly altered in EoE, representing approximately 1% of transcripts in the human genome. This molecular profile was independent of patient gender, age, and atopic history and correlated with esophageal eosinophil levels. There was also a high level of conservation among sporadic and familial EoE cases [7]. Moreover, there was a clear distinction in gene expression not only between EoE patients and normal controls but also between EoE and non-EoE chronic esophagitis patients [6], indicating the presence of a unique EoE “transcriptome”. Interestingly, the EoE transcriptome ISDYNAMICINNATUREASEVIDENCEDBYTHEREVERSIBILITYOFALARGEMAJORITYOFTHE dysregulated genes (98%) in patients responsive to swallowed glucocorticoid therapy, AMECHANISMTHATISMEDIATEDINPARTBY&+ BINDINGPROTEIN;8]. However, there exists a subset of dysregulated genes including cadherin-like 26, uroplakin 1B, periostin, and desmoglein 1 [9] that are resistant to glucocorticoids, suggesting alternative mechanisms of transcriptional regulation or potential disease-associated mutations affecting glucocorticoid-responsive elements. A prominent source for the gene transcriptional changes in EoE is the nonimmune cells of the esophagus, namely esophageal epithelial cells. Global expression analysis of cultured primary esophageal epithelial cells stimulated with IL-13 recapitulated the transcript profile observed in EoE patient biopsies to a high degree (Spearman p < 0.0001) [9]. As expected, many of the non-overlapping genes between THETWOMODELSYSTEMSWEREIMMUNECELL SPECIlC REmECTINGTHEPRESENCEOFTHESE cell types within the biopsy tissue itself. Taken together, these seminal studies suggest that a large number of gene networks, many of which are sensitive to IL-13, operate synergistically in a conserved and disease-specific manner to contribute to EoE pathogenesis. The most highly dysregulated gene in the esophagus of EoE patients is the eosinophil chemoattractant eotaxin-3 (CCL26), which was overexpressed 53-fold in EoE esophageal biopsies compared to normal esophageal biopsies. Eotaxin-3 belongs to the eotaxin family of CC chemokines (eotaxins 1–3) that stimulate eosinophil migration through binding to the G protein-coupled receptor CCR3 and activation of DOWNSTREAMSIGNALINGPATHWAYS.OTABLY EOTAXINSANDWERENOTDIFFERENTIALLY regulated at the transcript level, indicating a specific contribution of eotaxin-3 in the disease [6]. Moreover, the level of eotaxin-3 gene expression correlated with the number of infiltrating eosinophils and mast cells [6]. Eotaxin-3 was also the most highly upregulated gene in cultured esophageal epithelial cells, with IL-13 inducing 279-fold expression compared to untreated cells [9=)MMUNOmUORESCENCEANDINSITU hybridization studies on esophageal biopsies localized eotaxin-3 expression within

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esophageal epithelial cells [6]. In vivo models have further supported the essential role of eotaxin-3 in EoE; for example, CCR3-deficient mice are protected from esophageal eosinophilia following intranasal allergen challenge in a mouse model of experimental EoE [6]. In addition to enhanced expression of eosinophil-associated genes such as eoatxin-3, molecular markers of other key cell lineages involved in EoE have also been established. As previously noted, multiple immune cell types can be found WITHINTHEESOPHAGUSOF%O%PATIENTS&ORINSTANCE THEPRESENCEOFMASTCELLSWITHIN the lamina propria and epithelium of the esophagus in addition to eosinophils is a distinguishing feature of EoE that separates the disease from chronic esophagitis [10]. Within the EoE transcriptome, increases in expression levels of mast cellSPECIlCGENESINCLUDINGCARBOXYPEPTIDASE! HIGH AFlNITY)G%RECEPTOR&CE2) and mast cell tryptase-D (sigma) were also observed (13-, 4-, and 6-fold, respectively) [6]. Correlated with the increased esophageal mast cell numbers is an increase in resident B cell populations, particularly within the epithelium and vascular papillae; likewise, a similar increase was observed in B cell-specific transcripts involved in class switch recombination and IgE production [11]. The esophageal epithelium is at the forefront of EoE pathogenesis at both the tissue and molecular levels. Many of the pathological features of the esophagus that are associated with EoE indicate gross defects in cell adherence, cell proliferation, AND EXTRACELLULAR MATRIX DEPOSITION &URTHER HISTOLOGICAL ANALYSES OF %O% PATIENT esophageal biopsies have shown intercellular edema and acanthylosis [12], marked basal epithelial hyperplasia, and fibrotic lamina propria [13]. Meanwhile, the effect of IL-13 on esophageal epithelial cell gene expression, including the dramatic induction of eotaxin-3 expression, strikingly mimics the gene expression pattern observed in vivo. Thus, it is not surprising that a vast number of dysregulated genes in EoE regulate critical processes that control epithelial structure and promote tissue remodeling. Spanning a 1.6 Mbp interval on 1q21 is a cluster of genes that regulate terminal differentiation and formation of the cornified envelope of the epithelium termed the epidermal differentiation complex (EDC) [14]. Interestingly, the expression levels of many of the EDC genes including filaggrin and several small prolineRICHREPEAT3022 FAMILYMEMBERS# $ AND AREDOWNREGULATEDIN%O% ALSO implicating a role for the EDC in the diseased state of the esophageal epithelium [15]. The mechanism(s) of downregulation are partially dependent on IL-13, as IL-13 treatment directly dampens transcript levels of filaggrin, involucrin, and 3022GENESINVITRO;15]. Loss of filaggrin expression and subsequent defects in epidermal barrier function have been demonstrated in atopic dermatitis [16, 17], which frequently co-occurs with EoE. However, no significant difference in filaggrin expression was observed between atopic and non-atopic EoE patients [15], suggesting an alternative function for filaggrin in regulating the epithelial structure within the human esophagus. Thus far, the functions of EDC genes have been studied primarily in the context of the epidermis; as a result, little is known about how these genes contribute to the normal architecture of the esophageal epithelium. The epithelium of the human esophagus is comparatively simpler in terms of structure than the epidermis, being

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composed of stratified squamous epithelial cells and lacking a cornified layer. Despite these histological differences, one hypothesis is that the EDC genes preserve the integrity of the esophageal barrier in a similar fashion as the epidermis and that loss of this function through decreased EDC gene expression could underlie the esophageal tissue fragility that is associated with EoE [18]. Alternatively, esophageal barrier dysfunction could augment exposure to food antigens and contribute to the subsequent development of food allergies that is frequent in EoE patients [19, 20]. Increased expression of additional, non-EDC genes that govern tissue remodeling has also been identified in EoE. Studies of cardiac development and remodeling have described periostin as a cell adhesion molecule that regulates extracellular matrix deposition [21, 22]. Surprisingly, periostin is induced dramatically by 47-fold in the esophagus of EoE patients [6] with periostin protein localized in the lamina propria [23=4'& E, which has been shown to be expressed by eosinophils and mast cells in EoE patient biopsies [24, 25], induced a dramatic upregulation of periostin expression in primary esophageal fibroblasts, indicating a potential mechanism for the tissue fibrosis observed in EoE [23]. A functional role for periostin in EoE was evidenced both in vitro and in vivo as exogenous periostin was shown to directly enhance eosinophil adhesion, and periostin-null mice were protected from lung and esophageal eosinophilia following intranasal allergen challenge, respectively [23]. 0ERIOSTINHASALSOBEENSHOWNTOENHANCECROSS LINKINGOFCOLLAGENlBRILSBYUPREGulating the cleavage of mature, active lysyl oxidase [26]. Interestingly, a lysyl oxidase family member, lysyl oxidase-like 4 (LOXL4) is induced ninefold in IL-13-treated primary esophageal epithelial cells [9], suggesting a coordinate interaction between two highly upregulated genes (periostin and LOXL4) to synergistically promote esophageal tissue remodeling in EoE. In summary, the identification of an EoE transcriptome has yielded a global view of the unique changes in gene expression associated with the disease. It has become evident that there exist two broad classifications of dysregulated transcripts, one specific to the infiltrating immune cells within the esophageal biopsies and the other from the affected esophageal epithelium. However, these genes do not act individually to promote disease, but rather act in concert with one another as demonstrated BY THE EFFECTS OF ),  AND 4'& E (beta) on eotaxin-3 and periostin expression, respectively. Thus, while a number of critical genes involved in the development and pathogenesis of EoE have been identified, much work remains in defining the interactions between larger gene networks that can cooperatively affect disease severity.

Genetic Risk Variants in EE The high rate of EoE within families indicates that genetic heritability plays a predisposing role in disease susceptibility. Approaches commonly employed to idenTIFYSINGLENUCLEOTIDEPOLYMORPHISMS3.0 SLINKEDWITHDISEASERISKTYPICALLYFALL INTOTWOCATEGORIESTHECANDIDATEGENEAPPROACH WHICHFOCUSESON3.0SINGENES

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known to be potentially involved in a particular disease (based on pathophysiology), ANDTHEGENOME WIDEAPPROACH WHICHSCREENSINANUNBIASEDMANNERFORALL3.0S across the genome that associate with disease. The availability of the EoE transcriptome paved the way for the identification of the first EoE risk variant in the eotaxin-3 gene [6=4HEEOTAXIN 3.0RSRESIDESINTHEc untranslated region of the gene with the minor G allele having a frequency of approximately 22% in the Caucasian population. However, the G allele was significantly overrepresented in EE patients (32% compared to 22% in controls) with an associated p = 0.007 and odds ratio = 1.63 [6]. The association was further confirmed in a separate familybased model of disease risk allele transmission in which the minor G allele was transmitted more frequently than the T allele (p = 0.005, odds ratio = 2.13) from heterozygous parents to an affected offspring [6]. Mutations in a second EoE candidate gene, filaggrin, were screened for by restriction fragment length polymorphism mapping in 329 EoE patients and 157 normal controls [15]. Multiple studies have shown variants of filaggrin are associated with increased susceptibility to atopic dermatitis [27]. One rare filaggrin polymorphism in particular, 2282del4 (rs61816761), results in a null frameshift mutation and was not only identified as a risk variant for atopic dermatitis [28] but also occurred in 3% (20 out of 329) of EoE patients. This association was significant (p = 0.018) when compared to 157 normal controls (minor allele frequency = 0.6%) with an odds ratio = 4.89. The combined frequency of 2282del4 ANDANOTHERlLAGGRIN3.0 28 WHICHENCODESANONSENSEMUTATION WASALSO significantly associated with EoE (p = 0.036, odds ratio = 2.38) compared to normal controls. The results from these candidate gene approaches collectively demonstrate that polymorphisms in two EoE signature genes, eotaxin-3 and filaggrin, confer disease susceptibility. Moreover, the fact that both eotaxin-3 and filaggrin are derived from the esophageal epithelium further underscores the significance of this tissue in disease pathogenesis. With the progress toward completing the human haplotype map [29] and the ADVENTOF3.0GENOTYPINGCHIPSCAPABLEOFGENOTYPINGGREATERTHAN63.0SACROSS the human genome, many common variants have been identified as risk variants for multiple heritable human diseases. This genome-wide association approach was USEDTOIDENTIFY%O%RISKVARIANTSBYINTERROGATING 3.0SINTWOINDEPENdent EoE patient populations (ntotal = 351) and two independent control populations (ntotal = 3,104) [30]. Surprisingly, in both case-control cohorts a single EoE susceptiBILITYLOCUSONQWASUNCOVERED&IG7.1 INWHICH3.0SRESIDEDWITHINA SINGLE HAPLOTYPE BLOCK SPANNING THE THYMIC STROMAL LYMPHOPOIETIN 43,0 AND 7$ REPEAT DOMAIN  7$2 GENES 43,0 IS AN EPITHELIAL DERIVED ),  LIKE cytokine shown to act on multiple immune cell types to regulate mucosal immune responses [31], whereas WDR36 is co-regulated with IL-2 expression in activated T cells [32] and is a susceptibility gene for primary open-angle glaucoma [33]. Interestingly, this same chromosome locus was linked with peripheral blood eosinophilia [34= SUGGESTINGAROLEFOREITHER43,0OR7$2INPROMOTINGEOSINOPHILIA 4HE STRONGEST ASSOCIATED %O% RISK VARIANT FROM THE Q BLOCK WAS THE 3.0 RSLOCATEDINTHEUPSTREAMREGIONOF43,0 REACHINGGENOME WIDESIGNIlCANCE

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Fig. 7.1 An EoE susceptibility locus on 5q22. A Manhattan plot of the meta-analysis from the two case-control cohorts genotyped in the EoE genome-wide association study is shown. Represented by dotsARETHEINDIVIDUAL3.0SPLOTTEDBYCHROMOSOMALBASEPAIRLOCATIONANDTHEIRASSOCIATED −log10 p values. HighlightedARETHESIGNIlCANTLYASSOCIATED3.0SINTHEQLOCUSCOVERINGTHE GENESENCODING43,0AND7$2&IGUREADAPTEDFROM2OTHENBERG ETAL.AT'ENETICS 42:289–91. Used with permission

with a combined p = 3.19 × 10−9 across the two case-control cohorts and an odds ratio of ~0.6 [30=%XPRESSIONANALYSISFROMESOPHAGEALBIOPSIESSHOWEDTHAT43,0 BUTNOT 7$2 M2.!LEVELSWEREININCREASEDIN%O%.OTABLY AGENOTYPEEFFECTON43,0 expression was observed where EoE patients homozygous for the protective G allele for rs3806932 had significantly lower levels of expression compared to the other genOTYPES4HEDRAMATICEFFECTSOF43,0ONDENDRITICCELLS;35], B and T lymphocytes, mast cells [36, 37], and eosinophils [38] toward a Th2 phenotype have implicated 43,0ASAKEYINITIATOROFALLERGICDISEASES!ROLEFOR43,0INASTHMAHASALSOBEEN DEMONSTRATED BY INCREASED 43,0 EXPRESSION IN HUMAN ASTHMATIC LUNG LAVAGE mUID [39= ASTHMA LIKE PHENOTYPES IN LUNG SPECIlC 43,0 TRANSGENIC MICE ;40], and the ASSOCIATIONOF43,0WITHASTHMASUSCEPTIBILITY;41, 42]. However, inclusion of patient ASTHMASTATUSHADNOEFFECTONTHEASSOCIATIONBETWEEN43,0VARIANTSAND%O% WHICH is particularly remarkable given the high prevalence of asthma in the two EoE patient populations (20–40%) [30=&URTHERPHENOTYPICANALYSISUSINGALLERGICANDNON ALLERGIC CONTROLCOHORTSDEMONSTRATEDTHATTHESTRENGTHOFTHE43,03.0ASSOCIATIONWITH%O% was independent of allergic status [43]. In this study, an additional association between %O% AND A CODING 3.0 RS !LA TO 6AL IN THE 43,0 RECEPTOR WHICH IS encoded in a pseudoautosomal region on the X and Y chromosomes, was identified within male EoE patients, suggesting a potential mechanism for the increased male predilection of EoE [43]. The association of polymorphisms in eotaxin-3 and filaggrin and the identification of 5q22 as a susceptibility locus for EE have begun to uncover the role of genetic variation in EoE (Table 7.1). However, much work remains to determine the TRUECAUSALVARIANTSANDTHEIREFFECTSONGENEEXPRESSION M2.!STABILITY ANDPROTEINTRANSLATION)NPARTICULAR THECOMMONFREQUENCYOF3.0SINTHEQHAPLOTYPE BLOCKWITHINTHEGENERALPOPULATIONSUGGESTSTHATTHE%O% ASSOCIATED3.0SARENOT

Candidate gene (170 cases, 466 controls) (199 male cases, 78 male controls)

43,0Q 43,0RECEPTOR (Xp22;Yp11)

Sherrill et al. [43]

rs10062929 rs36133495

b

3.16 × 10−6b 0.039

0.018

0.36–0.45c 2.05

4.89

0.54–0.73c

3.19 × 10−9b

rs3806932

rs61816761

Odds ratio 1.63a

Associated p 0.007a

3.0 rs2302009

p value and odds ratio reported for case-control analysis &ISHERSCOMBINEDp value from meta-analysis of all study case-control cohorts c Odds ratio range from all study case-control analyses

a

Candidate gene (329 cases, 157 controls)

&ILAGGRINQ

Blanchard et al. [15]

Table 7.1 Genetic studies identifying EoE risk variants Gene Reference (chromosome) Study design Blanchard Eotaxin-3 (7q11) Candidate gene et al. [15] (117 cases, 225 controls) (67 trios) 43,07$2 Genome-wide Rothenberg (5q22) association et al. [30] (351 cases, 3,104 controls)

Significance Identifies the first EoE risk variant in the most highly induced EoE transcriptome gene Links EoE to genetic susceptibility locus for blood eosinophilia and gene region of Th2 regulating cytokine 43,0lNDINGREPLICATEDINAN independent case-control cohort Associates a rare null mutation in an EDC gene with EoE; mutation previously linked to enhanced atopic dermatitis susceptibility $ETERMINESTHE43,0ASSOCIATIONIS independent of allergic status and VALIDATES43,0ASAN%O%SUSCEPTIBILITYGENE!SSOCIATESACODING3.0IN THE43,0RECEPTORWITHMALE%O% patients

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causal, but most likely co-segregate with one or more causal variant(s). Moreover, the fact that the identified polymorphisms are present only in a percentage of EoE patients indicates that additional EoE risk variants exist.

Conclusion Our current understanding of the genetic basis of EoE is that a complex set of ESOPHAGEAL EPITHELIAL AND IMMUNE CELL DERIVED GENES INVOLVING EOTAXIN  43,0 and filaggrin, impacted by variation at the single nucleotide level, synergize to creATEAPRIMEDINmAMMATORYENVIRONMENTWITHINTHEESOPHAGUSTHATISMANIFESTEDIN %O%&IG7.2).

Fig. 7.2 Genetic regulation of the esophageal environment in EoE. The EoE transcriptome, an integrated network of esophageal epithelial- and immune cell-derived gene products that is regulated by IL-13 and/or impacted by genetic polymorphisms, mediates the pathophysiological changes of the esophagus in EoE

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References 1. Rothenberg ME. Biology and treatment of eosinophilic esophagitis. Gastroenterology. Oct 2009;137(4):1238–49.  &RANCIOSI*0 4AM6 ,IACOURAS#! 3PERGEL*-!CASE CONTROLSTUDYOFSOCIODEMOGRAPHIC and geographic characteristics of 335 children with eosinophilic esophagitis. Clin Gastroenterol Hepatol. Apr 2009;7(4):415–9.  3PERGEL*- "ROWN 7HITEHORN4& "EAUSOLEIL*, ETALYEARSOFEOSINOPHILICESOPHAGITIS CLINICALFEATURESANDPROGNOSIS*0EDIATR'ASTROENTEROL.UTR*AN n  .OEL 2* 0UTNAM 0% 2OTHENBERG -% %OSINOPHILIC ESOPHAGITIS . %NGL * -ED !UG 2004;351(9):940–1.  "LANCHARD# 7ANG. 2OTHENBERG-%%OSINOPHILICESOPHAGITISPATHOGENESIS GENETICS AND THERAPY*!LLERGY#LIN)MMUNOL.OV n  "LANCHARD# 7ANG. 3TRINGER+& ETAL%OTAXIN ANDAUNIQUELYCONSERVEDGENE EXPRESSION PROlLEINEOSINOPHILICESOPHAGITIS*#LIN)NVEST&EB n  #OLLINS-( "LANCHARD# !BONIA*0 ETAL#LINICAL PATHOLOGIC ANDMOLECULARCHARACTERIZAtion of familial eosinophilic esophagitis compared with sporadic cases. Clin Gastroenterol Hepatol. Jun 2008;6(6):621–9. 8. Caldwell JM, Blanchard C, Collins MH, et al. Glucocorticoid-regulated genes in eosinophilic ESOPHAGITISAROLEFOR&+"0*!LLERGY#LIN)MMUNOL!PR nE  "LANCHARD# -INGLER-+ 6ICARIO- ETAL), INVOLVEMENTINEOSINOPHILICESOPHAGITIS transcriptome analysis and reversibility with glucocorticoids. J Allergy Clin Immunol. Dec 2007;120(6):1292–300. !BONIA *0 "LANCHARD # "UCKMEIER "" ET AL )NVOLVEMENT OF MAST CELLS IN EOSINOPHILIC esophagitis. J Allergy Clin Immunol. Jul 2010;126(1):140–9. 6ICARIO- "LANCHARD# 3TRINGER+& ETAL,OCAL"CELLSAND)G%PRODUCTIONINTHEESOPHAGEAL mucosa in eosinophilic esophagitis. Gut. Jan 2010;59(1):12–20. 0ARlTT*2 'REGOR*# 3USKIN.' *AWA(! $RIMAN$+%OSINOPHILICESOPHAGITISINADULTS DISTINGUISHING FEATURES FROM GASTROESOPHAGEAL REmUX DISEASE A STUDY OF  PATIENTS -OD 0ATHOL*AN n &URUTA'4 ,IACOURAS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. Oct 2007;133(4):1342–63. 3OUTH!0 #ABRAL! )VES*( ETAL(UMANEPIDERMALDIFFERENTIATIONCOMPLEXINASINGLE -BPLONGCONTINUUMOFOVERLAPPING$.!CLONEDINBACTERIAINTEGRATINGPHYSICALANDTRANscript maps. J Invest Dermatol. Jun 1999;112(6):910–8.  "LANCHARD# 3TUCKE%- "URWINKEL+ ETAL#OORDINATEINTERACTIONBETWEEN), ANDEPITHELIAL differentiation cluster genes in eosinophilic esophagitis. J Immunol. Apr 2010;184(7):4033–41. &ALLON0' 3ASAKI4 3ANDILANDS! ETAL!HOMOZYGOUSFRAMESHIFTMUTATIONINTHEMOUSE&LG GENEFACILITATESENHANCEDPERCUTANEOUSALLERGENPRIMING.AT'ENET-AY n /2EGAN'- 3ANDILANDS! -C,EAN7( )RVINE!$&ILAGGRININATOPICDERMATITIS*!LLERGY Clin Immunol. Sep 2009;124(3 Suppl 2):R2–6. 18. Jacobs Jr JW, Spechler SJ. A systematic review of the risk of perforation during esophageal dilation for patients with eosinophilic esophagitis. Dig Dis Sci. Jun 2010;55(6):1512–5. !SSAAD!( 0UTNAM0% #OLLINS-( ETAL0EDIATRICPATIENTSWITHEOSINOPHILICESOPHAGITIS an 8-year follow-up. J Allergy Clin Immunol. Mar 2007;119(3):731–8. 20. Spergel JM. Eosinophilic esophagitis in adults and children: evidence for a food allergy component in many patients. Curr Opin Allergy Clin Immunol. Jun 2007;7(3):274–8. #ONWAY3* -OLKENTIN*$0ERIOSTINASAHETEROFUNCTIONALREGULATOROFCARDIACDEVELOPMENT and disease. Curr Genomics. Dec 2008;9(8):548–55. 3NIDER0 (INTON2" -ORENO 2ODRIGUEZ2! ETAL0ERIOSTINISREQUIREDFORMATURATIONAND extracellular matrix stabilization of noncardiomyocyte lineages of the heart. Circ Res. Apr 2008;102(7):752–60.

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"LANCHARD# -INGLER-+ -C"RIDE- ETAL0ERIOSTINFACILITATESEOSINOPHILTISSUEINlLTRATION in allergic lung and esophageal responses. Mucosal Immunol. Jul 2008;1(4):289–96. !CEVES33 .EWBURY2/ $OHIL2 "ASTIAN*& "ROIDE$(%SOPHAGEALREMODELINGINPEDIATRIC eosinophilic esophagitis. J Allergy Clin Immunol. Jan 2007;119(1):206–12. 25. Aceves SS, et al. JACI. Dec 2010;126(6):1198–204. -ARUHASHI 4 +II ) 3AITO - +UDO ! )NTERACTION BETWEEN PERIOSTIN AND "-0  PROMOTES proteolytic activation of lysyl oxidase. J Biol Chem. Apr 2010;285(17):13294–303. "ARNES+#!NUPDATEONTHEGENETICSOFATOPICDERMATITISSCRATCHINGTHESURFACEIN J Allergy Clin Immunol. Jan 2010;125(1):16–29. e1–11; quiz 30–11. 0ALMER#. )RVINE!$ 4ERRON +WIATKOWSKI! ETAL#OMMONLOSS OF FUNCTIONVARIANTSOFTHE EPIDERMALBARRIERPROTEINlLAGGRINAREAMAJORPREDISPOSINGFACTORFORATOPICDERMATITIS.AT Genet. Apr 2006;38(4):441–6. )NTERNATIONAL (AP-AP #ONSORTIUM 4HE )NTERNATIONAL (AP-AP 0ROJECT .ATURE $EC 2003;426(6968):789–96. 30. Rothenberg ME, Spergel JM, Sherrill JD, et al. Common variants at 5q22 associate with pediATRICEOSINOPHILICESOPHAGITIS.AT'ENET!PR n :IEGLER3& !RTIS$3ENSINGTHEOUTSIDEWORLD43,0REGULATESBARRIERIMMUNITY.AT)MMUNOL Apr 2010;11(4):289–93. -AO- "IERY-# +OBAYASHI36 ETAL4LYMPHOCYTEACTIVATIONGENEIDENTIlCATIONBYCOREGULATEDEXPRESSIONON$.!MICROARRAYS'ENOMICS*UN n 33. Monemi S, Spaeth G, DaSilva A, et al. Identification of a novel adult-onset primary open-angle GLAUCOMA0/!' GENEONQ(UM-OL'ENET-AR n  'UDBJARTSSON$& "JORNSDOTTIR53 (ALAPI% ETAL3EQUENCEVARIANTSAFFECTINGEOSINOPHILNUMBERSASSOCIATEWITHASTHMAANDMYOCARDIALINFARCTION.AT'ENET-AR n 3OUMELIS6 2ECHE0! +ANZLER( ETAL(UMANEPITHELIALCELLSTRIGGERDENDRITICCELLMEDIATED ALLERGICINmAMMATIONBYPRODUCING43,0.AT)MMUNOL*UL n !LLAKHVERDI: #OMEAU-2 *ESSUP(+ ETAL4HYMICSTROMALLYMPHOPOIETINISRELEASEDBY HUMANEPITHELIALCELLSINRESPONSETOMICROBES TRAUMA ORINmAMMATIONANDPOTENTLYACTIVATES MASTCELLS*%XP-ED&EB n /KAYAMA9 /KUMURA3 3AGARA( ETAL&CEPSILON2) MEDIATEDTHYMICSTROMALLYMPHOPOIETIN production by interleukin-4-primed human mast cells. Eur Respir J. Aug 2009;34(2):425–35. 7ONG#+ (U3 #HEUNG0& ,AM#743,0INDUCESCHEMOTACTICANDPRO SURVIVALEFFECTSIN EOSINOPHILS IMPLICATIONS IN ALLERGIC INmAMMATION !M * 2ESPIR #ELL -OL "IOL 3EP 2010;43(3):305–15. 39. Ying S, O’Connor B, Ratoff J, et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. Aug 2008;181(4):2790–8. 40. Zhou B, Comeau MR, De Smedt T, et al. Thymic stromal lymphopoietin as a key initiator of ALLERGICAIRWAYINmAMMATIONINMICE.AT)MMUNOL/CT n (E*1 (ALLSTRAND43 +NIGHT$ ETAL!THYMICSTROMALLYMPHOPOIETINGENEVARIANTISASSOCIated with asthma and airway hyperresponsiveness. J Allergy Clin Immunol. Aug 2009;124(2):222–9. (ARADA- (IROTA4 *ODO!) ETAL&UNCTIONALANALYSISOFTHETHYMICSTROMALLYMPHOPOIETIN variants in human bronchial epithelial cells. Am J Respir Cell Mol Biol. Mar 2009;40(3):368–74.  3HERRILL*$ 'AO03 3TUCKE%- ETAL6ARIANTSOFTHYMICSTROMALLYMPHOPOIETINANDITSRECEPTOR associate with eosinophilic esophagitis. J Allergy Clin Immunol. Jul 2010;126(1):160–5.

Chapter 8

Relationships Between Eosinophilic Esophagitis and Eosinophilic Gastroenteritis Dan Atkins and Glenn T. Furuta

Keywords %OSINOPHILIC ESOPHAGITIS s %OSINOPHILIC GASTROENTERITIS s -UCOSAL EOSINOPHILIAs%OSINOPHILICGASTROINTESTINALDISEASES

Introduction Over the last two decades, an increased recognition of gastrointestinal mucosal eosinophilia has heightened awareness and stimulated discussion regarding a number of often confusing but clinically relevant questions. What constitutes pathological mucosal eosinophilia? What are pathophysiolgical mechanisms leading to this response? What diseases are characterized by mucosal eosinophilia? What treatments resolve mucosal eosinophilia and its associated symptoms? This chapter will focus on describing the differences between and similarities shared by a narrow group of diseases referred to as eosinophilic gastrointestinal diseases or EGIDs. EGIDs are a group of gastrointestinal diseases characterized by a wide range of abdominal symptoms that occur in association with intestinal eosinophilia, when other causes of eosinophilia have been ruled out [1, 2]. Traditional descriptions of these diseases categorized them by histological groupings (mucosal, muscular, serosal) whereas more recent classifications have subdivided EGIDs by the primary organ affected [eosinophilic esophagitis, eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE) and eosinophilic colitis (EC)] [2, 3].

G.T. Furuta (*) National Jewish Health, University of Colorado Denver School of Medicine, The Children’s Hospital Denver, Denver, CO, USA Gastrointestinal Eosinophilic Diseases Program, Children’s Hospital Colorado, National Jewish Health, University of Colorado Denver School of Medicine, 13123 East 16th Ave. B290, Aurora, CO 80016, USA e-mail: [email protected] C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_8, © Springer Science+Business Media, LLC 2012

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Historical Perspective Kaijser first described eosinophilic gastroenteritis in 1937 in the German surgical literature as a heterogeneous group of diseases characterized by abdominal symptoms and intestinal eosinophilia [4]. In 1970, Klein published a case series of seven patients with eosinophilic gastroenteritis and divided them into different subtypes according to where the eosinophilia was predominant, i.e., mucosal, muscular and serosal disease [3]. This categorization provides a useful clinical paradigm that correlates with disease presentation: i.e. mucosal disease presents with diarrhea or bleeding, muscular involvement often manifests with symptoms of obstruction and serosal disease with ascites. The publication of two studies that spanned 57 years and included 99 patients provided the greatest insights into the clinical features and natural history of eosinophilic gastroenteritis [5, 6]. In 1990, Tally et al. published their experiences with 40 adults with eosinophilic gastroenteritis who were seen from 1950 to 1987 [5]. According to the Klein criteria, patients were categorized into mucosal disease (23), muscular disease (12) and subserosal disease (5) phenotypes. In 2010, the same group published their experience with 59 patients seen from 1987 to 2007 with an observed shift to predominantly mucosal disease (52) compared to muscular disease (3) and subserosal disease (4) [6]. While the clinical experience documents that EG is a rare disease with only three patients per year seen in a large tertiary care center (out of four million patients total), these studies document a rise from approximately one patient per year from 1950 to 1987 to three patients per year from 1897 to 2007. No complications were identified in these patients although the long-term follow-up period was short. Thus, over the past 7 decades, a diverse set of patients has been described with idiopathic gastrointestinal eosinophilia and a variety of distinct and perhaps changing phenotypes. Concurrent with these reports, findings in another group of patients were leading to the definition of another disorder involving mucosal eosinophilia in another part of the GI tract. The first report surfaced in 1978, when an adult patient with achalasia and esophageal eosinophilia was described [7]. Over the course of the next 15 years a series of case reports described esophageal rings and strictures as the radiological hallmarks of eosinophilic esophagitis or EoE [8, 9]. In 1993 and 1994, two articles described 22 adults with isolated esophageal eosinophilia and dysphagia [10, 11]. These early reports provided clear clinical descriptions of adults with dysphagia accompanied by endoscopic findings of esophageal rings, furrows and exudates were accompanied by esophageal eosinophilia. In 1995, ten children were described with symptoms of GERD recalcitrant to medical and, in some cases surgical management, with esophageal eosinophilia, who responded to an elemental formula [12]. Together, these reports set the stage for the coming decades during which the clinicopathological features of a new esophageal inflammatory disease, EoE, would be recognized and refined. The acronym of EoE will be used in this chapter because the original acronym of EE is often confused with erosive esophagitis by gastroenterologists.

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In summary, EGIDs have become increasingly recognized as a group of diseases that present with a variety of abdominal complaints that share a unifying histological feature, intestinal eosinophilia. Though linked by the presence of an eosinophilic infiltrate, EoE, EG, EGE and EC, also share distinct clinical phenotypes that are important to recognize.

Gastrointestinal Mucosal Eosinophils Enumeration of Eosinophils While the normal presence of eosinophils in the mucosae of the stomach, intestine and colon is well recognized, the exact numbers that distinguish physiological from pathological eosinophilic infiltration is uncertain. Two studies, one from Dallas, Texas and another from Cincinnati, Ohio, have addressed this in small numbers of children [13, 14]. These studies compared the numbers of eosinophils along the entire length of the gastrointestinal tract yielding two strikingly similar findings. First, eosinophils increase in numbers within the mucosae along the length of the gastrointestinal tract. Second, the greatest numbers of eosinophils are present in the distal small bowel and cecum. The reasons for this pattern of eosinophil distribution are unclear but speculations include various environmental factors (dietary patterns and climate), host factors (age, gender) and/or the specific microenvironmental conditions of each intestinal organ that may be dictated by exposure to various food particles, enzymes and/or microbiota. Metrics used to distinguish “physiological” from “pathological” numbers of eosinophils in routine practice and research studies are quite varied and include: eosinophil number (presence of one/both nuclear lobes in conjunction with eosinstained granules), degranulation, size of a high power field (HPF), number of HPFs counted, mucosal location of the eosinophils (epithelia, lamina propria etc.) and number of biopsies examined [15–19]. Other associated morphological features such as presence of other inflammatory cells that might aid in defining chronicity of the inflammation may also be helpful. In a busy clinical practice, routine scrutiny, this level of detail may not be possible, but it is often critical in isolated cases in which eosinophils predominate. For example, “reactive eosinophilia” may actually represent a normal host response rather than a pathological finding. As the clinical need increases and research progresses, these features and others will need to be examined in greater detail and, in some circumstances, validated. Other studies to document mucosal inflammation such as contrast radiography, capsule visualization, CAT and MRI scans, push enteroscopy and others await further definition and validation. Interpretations of histological patterns is of paramount importance only when taking into consideration the clinical context in which they were obtained.

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Esophageal Eosinophilia In comparison to other areas of the GI tract, the histological interpretation of esophageal eosinophilia is reasonably straightforward. Since eosinophils are not found in the healthy esophagus, the presence of eosinophils usually indicates a pathological process. The predominant causes of esophageal eosinophilia are gastroesophageal reflux disease and eosinophilic esophagitis. Symptomatic individuals with >15 eosinophils/HPF in whom other etiologies have been excluded and who respond to anti-allergic treatments including dietary exclusions and steroids, have eosinophilic esophagitis [20]. The diagnostic decision point of 15 eos/HPF was agreed upon after vigorous debate among a group of pediatric and adult gastroenterologists, pathologists and allergists during the First International Gastrointestinal Eosinophil Research Symposium in 2006 [21]. The basis for this choice was founded on clinical experiences of those involved as well as the current published literature. This threshold was intentionally set on the low end with the proviso that all other causes of esophageal eosinophilia had been excluded. Continuing scrutiny will likely lead to a revision of this criterion as more data emerges and clinical experience increases.

Eosinophilia of the Stomach, Small Intestine and Colon In contrast, interpretation of mucosal eosinophilia in GI organs distal to the esophagus is complex requiring astute judgement and careful consideration of whether the finding is related to a pathological process or represents an appropriate response to an exogenous insult. Because of the current lack of clarity in diagnostic criteria for these EGIDs, the finding of mucosal eosinophilia has sometimes led to the over diagnosis of EGIDs in patients who may in fact have functional abdominal pain or inflammatory bowel diseases.

Pathophysiological Mechanisms Associated with Mucosal Eosinophilia When considering the mechanisms that result in eosinophil migration to the intestinal mucosa, it is critical to consider the regulation of this process in at least four separate locations [22]. The bone marrow is the site of differentiation, maturation and proliferation of progenitor cells into eosinophils. The vascular endothelium regulates the selective transport of eosinophils to mucosal sites. When stimulated, a variety of cells in the intestinal mucosae release chemotactic factors, forming gradients that beckon eosinophils to their terminal locations. Finally, resident and recruited cells in the mucosae stimulate newly arrived eosinophils in a regulated fashion to synthesize and release biologically active

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products including granule proteins, cytokines, arachidonic acid mediators and reactive oxygen species. To date, the extent of the consequences of these eosinophil products in the gastrointestinal tract are unknown, but correlations with findings in other organs can be speculated. For instance, studies of the murine lung associate the presence of activated eosinophils with increased smooth muscle contraction, diminished epithelial permeability, goblet cell hyperplasia and tissue remodelling.

Esophageal Eosinophilia Murine models of esophageal eosinophilia have been developed that, similar to the human condition, rely on chronic exposure of the esophageal mucosa to an exogenous immunogen [23–26]. Murine systems utilized the ubiquitous aeroallergen, Aspergillus fumigates and more recently extracts from, cockroach/dust mites to stimulate esophageal eosinophilia. To determine which eosinophil-associated chemokines control this response, experiments were performed using IL-5 and eotaxin-1 null mice. In contrast to the robust esophageal eosinophilia observed in wild type mice, IL-5 null mice were significantly protected from eosinophilia [24]. Additional studies showed that eotaxin-1 was sufficient, but not necessary for esophageal eosinophilia. Translational studies support a role for IL-5 in this response. Mucosal biopsies from adults with EoE have provided immunohistochemical evidence of increased IL-5 [27]. On the basis of these findings, several therapeutic trials have been performed using IL-5 as a therapeutic target. In the first two case series, a dramatic reduction in eosinophilia, symptomatology, mucosal eosinophilia and in once case, resolution of esophageal stenosis was reported [28, 29]. Since then a blinded study of 11 adults showed that intravenous anti-IL5 infusions lead to a significant decrease in esophageal eosinophils and remodelling mediators and a slight, but not significant, reduction in dysphagia [30]. This lack of symptom reduction is likely due to redundant pathways promoting eosinophilia and the lack of scoring systems that adequately measure symptoms. In fact, basic and translational studies support roles for a number of other mediators including IL-13, eotaxin-3 and thymic stromal lymphopoeitin in the pathogenesis of EoE [31–33]. Although eosinophils remain the hallmark of EoE, their exact functional role in this disorder remains uncertain. Functional studies have shown that EoE patients exhibit increased sensitivity to intraluminal noxious stimuli and have altered motility with increased isolated contractions but do not demonstrate increased acid or nonacid reflux [34–37]. Murine research and translational studies in humans support a role for eosinophils in esophageal remodelling and fibrosis [38–42]. Studies remain technologically encumbered by the fact that tissue sampling is limited to the superficial mucosa and that esophageal functional assessments are invasive, uncomfortable, time-consuming and expensive. Overcoming these hurdles will allow further understanding of eosinophil functions in esophagitis.

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Eosinophilia of the Stomach, Small Intestine and Colon In contrast to the above studies, less is known about the pathogenesis of eosinophilia in gastrointestinal organs beyond the esophagus. Most studies have focused on the clinical and histological descriptions of EG, EGE and EC, but several basic studies have shed light on mechanisms of eosinophil participation in GI inflammation. Using murine models, eotaxin-1 has been shown to be the key mediator for eosinophil accumulation in the gastric mucosa [43–45]. Following sensitization and challenge to ovalbumin, wild type mice developed eosinophilic gastritis and gastric dysmotility. When the same protocol was administered to eotaxin-1 deficient mice, eosinophilia was diminished to the level observed in unchallenged control mice. Translational studies have shown that the immune milieu of the mucosa affected by eosinophilia is skewed towards a Th2 phenotype [46]. Several studies have identified a key role for eosinophils in colitis. Following induction of chemically induced colitis with dextran sodium sulfate (DSS), the colonic mucosae of mice develop increased mucosal eosinophilia [47–49]. When DSS is administered to mice deficient in eosinophils, colitis is diminished as evidenced by disease activity indices and histological parameters. In vitro studies determined that eosinophils can participate in loss of epithelial barrier function and induction of proinflammatory cytokine release from mast cells [50–53]. Whether these studies are truly reflective of the pathophysiology of EGIDs remains to be determined. Goals of future studies will be to account for the genetic predisposition toward a Th2/eosinophilic response, altered development of oral tolerance, mechanisms governing an altered epithelial barrier predisposing to sensitization upon exposure, impact of microbial populations/microbial sensing in different GI mucosal microenvironments on the development of eosinophilic inflammation and the role of exogenous/swallowed food, chemicals and medications on the epithelia and mucosa.

Clinical Implications of Mucosal Eosinophilia Whereas the previous section identified different potential pathophysiological mechanisms for mucosal eosinophilia, it is important to consider the clinical ramifications of this finding in different parts of the GI tract and their potential impact on therapeutic interventions.

Differences Between EoE and Other EGIDs Clinical presentations. EoE occurs with an estimated prevalence of 1–4 in 10,000, has a male predominance and typically presents with GERD-like symptoms in the young and food impaction/dysphagia in adolescents and adults [20]. The esophagus

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affected by EoE typically appears abnormal as manifested by edema and exudates in children and evidence of remodelling in adults. Bleeding is rare and the mucosa often feels “rubbery” during procurement of mucosal biopsies [54]. In contrast, limited data suggest that other EGIDs occur much less frequently than EoE, do not show gender predilection, and present with bleeding, diarrhea, or abdominal pain [1]. Epithelial exudates as seen on endoscopy in patients with EoE is rare. The typical endoscopic findings in EGIDs include mucosal friability, ulceration and polyp formation with some mucosal surfaces appearing normal. Complications. Some patients with EoE develop strictures that are localized or occasionally involve long segments of the esophagus. In addition, the esophageal mucosa can become “fragile” and disrupt longitudinally, sometimes merely in response to passage of the endoscope [55]. Ulceration is rarely seen in children with EoE. In contrast, strictures or narrowings are not commonly reported in other EGIDs. Symptoms of partial obstruction are typically related to muscular involvement but fibrosis is not a typical finding. It is difficult to know whether this problem is fully recognized in other EGIDs because of the limitations of endoscopic analysis; push enteroscopy and capsule endoscopy may allow for better characterization of EGIDs in the future.

Similarities Between EoE and EGID Mucosal eosinophilia does not typically “spread”. To date, clinical experiences suggest that esophageal eosinophilia usually remains stable over time and does not spread proximally towards the mouth or distally to the stomach, small intestine or colon. Nonetheless, EGIDs can be patchy diseases that can be missed by random mucosal biopsies. It is important to remember that typical mucosal pinch biopsies, obtained at the time of an endoscopy, are limited to sampling 3 mm of the mucosal surface. In the esophagus, this size biopsy represents 0.01% of the total esophageal surface area and much less in the rest of the GI tract. If a patient with EoE begins developing lower intestinal symptoms such as diarrhea or blood in the stool, studies to identify the etiologic causes should be obtained. Depending on symptom severity, this may be limited to simple stool studies or lactose breath tests, or, alternatively, require colonoscopy and capsule endoscopy to determine if other causes exist. In contrast, if dysphagia develops in someone with eosinophilic colitis, EoE may be present and a barium esophagram and upper endoscopy may be necessary. No obvious trend toward malignancy. Malignant potential does not appear to be increased in any EGID. Case reports describe adults with Barrets esophagus, myofibroblastic esophageal malignancy and leiomyomatosis in association with esophageal eosinophilia [56–58]. Whether these represent chance occurrences or true relationships with EoE is not yet certain [59]. EGIDs themselves have not been associated with other gastrointestinal or extraintestinal malignancies but mucosal eosinophilia in itself has been associated with malignancies or their associated

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treatments. Prior to assigning a diagnosis of EGIDs, malignancy or a drug effect should be considered and/or ruled out in the appropriate clinical setting. Feeding/eating dysfunction. An emerging body of literature implicates EGIDs in the development of feeding dysfunction in children [60–65]. Whether this represents a non-specific occurrence that occurs with any gastrointestinal inflammatory disease or is unique to EGIDs remains to be determined. Nonetheless, when children exhibit significant evidence of feeding dysfunction, especially if they have atopic diseases, EGIDs, as well as other GI diseases such as gastroesophageal reflux disease (GERD) or food allergy, should be considered as a potential underlying cause. In adults, eating problems may manifest themselves as coping behaviors. A patient may deny problems with swallowing or eating, but, in fact, may have developed strategies that permit the ingestion of foods that allow for the avoidance of symptoms. For instance, chewing food for long periods, swallowing food with a glass of water or cutting foods into small pieces may have developed over time.

Therapeutic Implications of Mucosal Eosinophilia The majority of patients with EGIDs, regardless of the type, respond to treatment with corticosteroids. However, the vehicle used to administer the corticosteroid may vary. Systemic administration of corticosteroids provides therapeutic benefit in most patients with EGIDs. Alternatively, topical steroids have successfully reduced clinicopathological features of EoE, despite the fact that the exact distribution and pharmacokinetics remain unknown. Some patients do not respond to steroid preparations for a number of reasons including a lack of corticosteroid receptors, non-adherence, inadequate delivery to the target mucosa site or improper administration technique and inadequate dosing. A large body of data underscores the clinical impact of dietary exclusions in the treatment of EoE and some EGIDs. Clinical experiences suggest that the more proximal the eosinophilia in the gastrointestinal tract, the more likely that a nutritional approach involving dietary elimination will be effective.

Summary Eosinophilic gastrointestinal diseases (eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis and eosinophilic colitis) represent a broad category of diseases with different clinicopathological features and likely different pathogenetic mechanisms. EoE appears to be increasing in incidence while other EGIDs remain rare. Though both are characterized by increased eosinophils in the gastrointestinal tissues and associated with allergic diseases, increasing evidence suggests that there may be different mechanisms responsible for this histological finding depending on

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the organ involved. Over the course of the next decades, phenotypic patterns of EGIDs will continue to be identified by observant health care providers. Identifying the specific mechanisms governing these phenotypes will reveal a number of novel molecular pathways. Identification of these pathways and their associated biomarkers, will allow for targeted treatments, monitoring protocols and prevention strategies.

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61. Duca AP, Dantas RO, Rodrigues AA, Sawamura R. Evaluation of swallowing in children with vomiting after feeding. Dysphagia. 2008;23:177–82. 62. Haas AM, Maune NC. Clinical presentation of feeding dysfunction in children with eosinophilic gastrointestinal disease. Immunol Allergy Clin North Am. 2009;29:65–75. ix. 63. Mukkada VA, Haas A, Maune NC, Capocelli KE, Henry M, Gilman N, et al. Feeding dysfunction in children with eosinophilic gastrointestinal diseases. Pediatrics. 2010;126(3):e672–7. 64. Pentiuk SP, Miller CK, Kaul A. Eosinophilic esophagitis in infants and toddlers. Dysphagia. 2007;22:44–8. 65. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, et al. 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr. 2009;48:30–6.

Chapter 9

Clinical Manifestations of Eosinophilic Esophagitis in Children Philip E. Putnam

Keywords %OSINOPHILICESOPHAGITISs$IETARYANTIGENSs$YSPHAGIAs%OSINOPHIL INmAMMATIONs%SOPHAGEALDILATIONs,AMINAPROPRIAlBROSIS

Introduction Eosinophilic esophagitis (EoE) is a condition that affects nearly all ages. The HISTOLOGICAL FEATURES ARE UNMISTAKABLE BUT THE CLINICAL FEATURES ARE NONSPECIlC and vary among individuals as well as across age ranges. The clinical manifestations are explored and placed into context for the evaluating physician. %O%ISACHRONICDISEASEWITHRARESPONTANEOUSREMISSION BUTITISMANAGEABLE SUCHTHATSYMPTOMSANDINmAMMATIONCANBEKEPTATBAYWITHCONSISTENT EFFECTIVE therapy for most individuals. Patients and their physicians need to understand that THEPROCESSOFESTABLISHINGTHEDIAGNOSISANDMAINTAININGCONTROLOVERTHEINmAMmation are intertwined and require attention over many years. EoE typically develops as a manifestation of adverse reaction to food antigens, ALTHOUGHTHEREISACLEARSUBSETOFPATIENTSWHOSEESOPHAGITISDOESNOTRESPONDTO any degree of dietary elimination, up to and including an elemental diet with an AMINO ACID BASED FORMULA &OR REASONS THAT HAVE NOT BEEN FULLY ELUCIDATED %O% occurs mainly in males, many of whom have other manifestations of atopy, such as chronic rhinitis, eczema, asthma, or food allergies.

P.E. Putnam (*) Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, ML 2010, Cincinnati, OH 45229, USA Cincinnati Center for Eosinophilic Disorders, 3333 Burnet Ave, ML 2010, Cincinnati, OH 45229, USA e-mail: [email protected] C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_9, © Springer Science+Business Media, LLC 2012

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3OMEOFTHEOVERTMANIFESTATIONSOFTHEESOPHAGITISMAYBEDIFlCULTTOSEPARATE from those of the atopy (e.g., sore throat). To further complicate the evaluation of children who have EoE as a manifestation of food allergy, it is common for a child or caregiver to alter the diet or environment in response to consistent or perceived EXPOSURE RELATEDSYMPTOMS&OREXAMPLE VOMITINGGENERATEDCONSISTENTLYBYEXPOSURETOAPARTICULARFOODOFTENRESULTSINELIMINATIONOFTHATANTIGENBEFOREANYEVALUATIONHASBEENUNDERTAKEN)FTHEDIAGNOSISIS%O% ONGOINGSYMPTOMSDESPITETHE withdrawal of that antigen will drive additional investigation, and the existing eosinoPHILICINmAMMATIONWILLMOSTLIKELYBEARESPONSETOATLEASTONEOTHERDIETARYANTIGENTOWHICHTHEREISINSUFlCIENTIMMEDIATERESPONSETORECOGNIZETHEASSOCIATION The challenge for the evaluating physician is to understand that symptoms may HAVEBEENAFFECTEDBYDIRECTOREMPIRICTHERAPEUTICMANEUVERS4OCOMPLICATETHE EVALUATION SYMPTOMSVARYBYAGE ANDTHEAGEATONSETOFSYMPTOMSANDTHEAGEAT PRESENTATIONCANBEQUITEDISPARATE4HEREFORE THEPHYSICIANMUSTBECOGNIZANTOF the stage in the condition that the evaluation is taking place. Some symptoms may HAVECOMEANDGONE OTHERSMAYHAVEPROGRESSED ANDSOMEMAYHAVEBEENMANAGEDBYPRIORATTEMPTSATTHERAPY 4HEPHYSICIANSROLEISMADEMOREDIFlCULTBYTHEINFORMATIONFROMRECENTSTUDIESTHATHAVEDETERMINEDTHATTHEREISLITTLEPREDICTABLECORRELATIONBETWEENSYMPtoms and the degree of histologic esophagitis [1]. One cannot assume that the ABSENCE OF SYMPTOMS IS A REmECTION OF THE ABSENCE OF INmAMMATION AND SOME symptoms may persist despite the resolution of histologic esophagitis. The goal of therapy for EoE is control over symptoms and resolution of esophagitis [2= 4HE DISPARITY BETWEEN SYMPTOMS AND THE DEGREE OF ESOPHAGITIS CREATES A DILEMMA FOR THE TREATING PHYSICIAN )F SIGNIlCANT INJURY TO THE ESOPHAGEAL WALL occurs as a consequence of chronic inflammation, and if the inflammation is present WITHOUT SYMPTOMS THE INmAMMATION MUST BE CONTROLLED EVEN IN THE ABSENCE OF SYMPTOMS,AMINAPROPRIAlBROSIS SEENINCHILDRENANDADULTSWHOHAVE%O% HAS BEENSEENTOIMPROVEWITHTHERAPY SUCHTHATPREVENTIONOFPERMANENTINJURYSHOULD BEPOSSIBLEWITHWELL MAINTAINEDTREATMENT;3=0ROGRESSIVElBROSISCONSEQUENTTO inadequate control over the inflammation responds, if temporarily, to esophageal DILATATION BUTDILATATIONSHOULDNOTBENECESSARYWITHEFFECTIVETREATMENT;4, 5]. To SUMMARIZE ASSESSMENTOFBOTHSYMPTOMSANDHISTOLOGYISREQUIREDTODIRECTTREATment and assure consistent control over the inflammatory process.

Symptoms Esophageal inflammation of any sort has the potential to cause chest pain, odynophagia, or dysphagia. Associated symptoms, such as nausea, vomiting, effortless regurgitaTION EARLYSATIETY POORLYLOCALIZEDABDOMINALPAIN ANDANOREXIA ARELESSSPECIlC REmECTIONSOFESOPHAGEALPATHOLOGYTHATHAVEBEENREPORTEDBYCHILDRENWHOHAVE %O%)NDIVIDUALSWHOHAVE%O%CANPRESENTWITHANYCOMBINATIONOFTHESE;6–10].

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#ASESERIESHAVEREPORTEDTHATSYMPTOMSFROM%O%VARYBYAGEINAFASHIONTHAT ISNOTUNIVERSAL BUTCOMMONENOUGHTOWARRANTCOMMENT;11]. Age may also interFERESYMPTOMREPORTING4HEEVALUATIONOFYOUNGCHILDRENISNECESSARILYAFFECTEDBY INTERPRETATIONANDREPORTINGBYANOBSERVERTHEPARENTORCAREGIVER RATHERTHANTHE patient, so there is always some element of uncertainty as to the sophistication and precision of the report, particularly when the outward manifestation of esophagitis ISNONSPECIlCEG POORFEEDING  )NFANTSANDTODDLERSAREMORELIKELYTOPRESENTWITHDIFlCULTYFEEDING MANIFEST as gagging, choking, food refusal, and perhaps vomiting. Early school age children TENDTOPRESENTWITHVOMITINGORABDOMINALPAIN WHEREASOVERTDYSPHAGIAISMOST common in adolescents and adults. These generalizations have held up quite well ACROSSSEVERALCASESERIES BUTTHEREAREINDIVIDUALSWHOSESYMPTOMSAREDIFFERENT FROMTHOSEMORECOMMONLYREPORTEDBYTHEIRAGECOHORT

Dysphagia 4HE TERM hDYSPHAGIAv HAS BEEN DILUTED SOMEWHAT IN PEDIATRIC PRACTICE IN RECENT YEARS BEINGUSEDMOREBROADLYTOINDICATEFEEDINGPROBLEMSRATHERTHANBEINGSTRICTLY APPLIEDTODISORDEREDSWALLOWING4HETERMDOESNOTDISTINGUISHWELLBETWEENDISORDERSOFOROPHARYNGEALSWALLOWINGANDPUREESOPHAGEALPROBLEMS&EEDINGDISORDERS MAYWELLINCLUDEOVERTDYSPHAGIA BUTINFANTSORTODDLERSWHOAREDEVELOPMENTALLY UNABLETODESCRIBEACCURATELYTHOSEABNORMALSENSATIONSANDPERCEPTIONSTHATINTERFEREWITHTHEIRABILITYTOFEEDSUCCESSFULLYMAYBELABELEDASHAVINGDYSPHAGIADESPITE THEABSENCEOFOVERTESOPHAGEALPATHOLOGY0HYSICALANDPSYCHOLOGICALINTERFERENCE with feeding develop as a consequence of a multitude of disorders in children, including EoE [12=&EEDINGDISORDERSAREONEOFTHEMORECOMMONPRESENTATIONSINTODDLERS WHO HAVE %O% BUT THE LACK OF HISTORY FROM THE AFFECTED CHILD PRECLUDES AN understanding of exactly why. Extrapolating from the descriptions from older children, one may speculate that toddlers have pain, nausea, or the perception of food going down slowly that result in symptoms, such as food refusal or aversion, gagging or retching. Intermittent or persistent dysphagia, which is the most common symptom from EoE in adults, tends to appear in late childhood or early adolescence. Although posSIBLE AT YOUNGER AGES IT IS OFTEN THE PRIMARY COMPLAINT IN ADOLESCENTS )T IS NOT unusual for an adolescent to present with a food impaction that requires urgent ADMISSIONFORENDOSCOPICREMOVALOFTHEBOLUS;13]. Those individuals, who have COMPLETEESOPHAGEALOBSTRUCTIONCOMPLAINOFSOMETHINGBEINGSTUCKUSUALLYMEAT AREUNABLETOSWALLOWTHEIRSALIVAANDHAVENOOVERTRESPIRATORYCOMPROMISE4HEY are easily recognized in the Emergency Department – carrying a vessel of some sort containing their clear saliva, which they must expectorate instead of swallow. The ESOPHAGEALLUMENISFULLOFLIQUIDABOVETHEIMPACTION SUCHTHATANYFURTHERATTEMPT TO SWALLOW WOULD BE UNSUCCESSFUL AND LEAD TO SPILLAGE INTO THE AIRWAY CAUSING

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COUGHINGANDCHOKING4HOSEWITHNEARCOMPLETEOBSTRUCTIONAREABLETOSUCCESSFULLY SWALLOW ENOUGH SALIVA SUCH THAT THEY DO NOT NEED THE CONTAINER BUT THEY ARE NEVERTHELESSUNABLETOSWALLOWABOLUSOFANYTHINGELSEANDAREACUTELYAWAREOF SOMETHINGBEINGSTUCK %NDOSCOPYWITHBIOPSIESATTHETIMEOFFOODBOLUSRETRIEVALISBOTHIMMEDIATELY THERAPEUTICANDDIAGNOSTIC WITHBIOPSIESSETTINGINTOMOTIONTHEPROCESSOFEXPLAINing the dysphagia and treating the underlying disorder to prevent future impactions. )TISGOODPRACTICETOBIOPSYTHEESOPHAGUSREMOTEFROMTHEPOSITIONOFTHEBOLUS IN any child or adult with a food impaction [14=%VENANONFOODFOREIGNBODY SUCHAS a coin, may fail to pass through an inflamed esophagus, so an exam of the esophagus APARTFROMTHEFOREIGNBODYISIMPORTANTTOMAKETHEDIAGNOSISWHENTHEOPPORTUnity presents itself. &OODBOLUSIMPACTIONSINTHOSEWHOHAVE%O%GENERALLYOCCURINTHEABSENCEOF OVERTLUMINALNARROWINGBYEITHERSTRICTUREORSMALLCALIBERESOPHAGUS-ANOMETRIC ABNORMALITIESARENONSPECIlC BUTTHEEFlCIENCYOFPERISTALSISMUSTBESUFlCIENTLY DIMINISHEDTOPRECLUDENORMALFOODBOLUSTRANSIT;15]. !SASYMPTOM DYSPHAGIAFROM%O%MAYBEOFANYDEGREE ANDITMAYBEINTERmittent, persistent, or progressive. Older individuals with chronic dysphagia tend to DOAREMARKABLEJOBOFADAPTINGTOTHELIMITATIONINSWALLOWINGBYEATINGSLOWLY DRINKINGEXTRAmUIDSTOENCOURAGEPASSAGETHROUGHTHEESOPHAGUS ANDBYAVOIDING THEFOODTEXTURESANDCONSISTENCIESTHATAREMOSTPROBLEMATICFORTHEMEG MEAT ANDTHICKBREADS -ANYCHILDRENDENYORUNDERREPORTTHEIRDYSPHAGIA HAVINGGAINED SUFlCIENT COMPENSATORY SKILL TO AVOID THE SYMPTOM WITHOUT RECOGNIZING EXACTLY why they eat the way they do. 0AINISNOTASIGNIlCANTFEATUREOFADYSPHAGIA BUTWHENPRESENTSHOULDSUGGEST a diagnosis other than EoE, even if the patient also has the perception of impaired esophageal transit. Pill-induced esophagitis and viral esophagitis (usually herpetic) MAYPRODUCEREMARKABLEULCERATIONOFTHEESOPHAGEALMUCOSATHATISVERYPAINFUL )TCREATESTHEPERCEPTIONOFALTEREDPASSAGEOFTHEFOODBOLUS CREATINGDYSPHAGIA along with odynophagia. However, when compared to primary dysphagia, the indiVIDUALWHOHASPILL INDUCEDESOPHAGITISISMORELIKELYTOBEBOTHEREDBYODYNOPHAGIA ANDRELUCTANTTOATTEMPTTOEATBECAUSEOFTHEPAIN4HEHISTORYISUSUALLYVERYSUGgestive of pill-induced esophagitis, as the patient reports taking medications, such AS TETRACYCLINE OR ORAL CONTRACEPTIVES WITHOUT SUFlCIENT mUID AND MAY RECALL THE dose that seemed not to proceed normally down the esophagus. Dysphagia is not unique to EoE. Progressive dysphagia for solids and liquids associated with regurgitating undigested food, night cough, weight loss and/or RECURRENT PNEUMONIA ARE FEATURES OF ACHALASIA !CHALASIA SHOULD BE APPARENT ON BARIUMESOPHAGOGRAPHYANDCONlRMEDBYMANOMETRICSTUDYOFTHEESOPHAGUS4HE dysphagia of achalasia is qualitatively different from that of EoE and develops INSIDIOUSLY"ECAUSETHEESOPHAGUSBECOMESPROGRESSIVELYDILATEDDUETOTHEDISTAL FUNCTIONAL OBSTRUCTION IN WELL DEVELOPED ACHALASIA IT FUNCTIONS LIKE A RESERVOIR RETAININGFOODANDLIQUIDTHATARETHENAVAILABLETOBEREGURGITATEDANDPOTENTIALLY ASPIRATED#OMMONCOMORBIDITIESOF%O% INCLUDINGFOODALLERGY ASTHMA ECZEMA and chronic rhinitis are not expected in achalasia.

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In addition to achalasia, the differential diagnosis of dysphagia in a child is R ELATIVELYLIMITED ANDINCLUDESFOREIGNBODYINTHEESOPHAGUS ESOPHAGITISORPEPTIC strictures due to poorly controlled gastroesophageal reflux disease (GERD), Schtazki RING ANDEXTRINSICVASCULARCOMPRESSIONOFTHEESOPHAGUSIE BYANABERRANTSUBCLAVIANARTERY #ONGENITALESOPHAGEALSTRICTURESDOOCCUR BUTARERARE!NASTOMOTIC STRICTURES AFTER TRACHEOESOPHAGEAL lSTULA 4%& REPAIR ARE NOT UNUSUAL #HILDREN WHOHAVEHADA4%&REPAIREDOFTENHAVEDYSPHAGIADUETOTHEINTRINSICDYSMOTILITY OFTHECONGENITALLYABNORMALESOPHAGUS EVENINTHEABSENCEOFOVERTLUMINALNARrowing at the anastomotic site. Importantly, we and others have diagnosed EoE in CHILDRENWHOHAVE6!4%2SYNDROMEOROTHERCONDITIONINWHICHA4%&WASTHE PRIMARYANATOMICABNORMALITY;16].

Evaluation of Dysphagia &ORTHEPHYSICIAN DYSPHAGIAREQUIRESCONSIDERABLETHOUGHTANDAGGRESSIVEDIAGNOSTIC evaluation. The history is crucial to gain an understanding of severity and chronicity. The causes of dysphagia for liquids are different from the causes of dysphagia for solids, so the evaluation is necessarily different depending on the consistency that is mishandled. EoE should only cause dysphagia for solids; therefore, if dysphagia for liquids is the presenting concern, an alternative diagnostic strategy is employed. Warning signs, such as weight loss due to inadequate intake, demand urgent evaluaTIONANDEFFECTIVETREATMENT)TMAYBEDIFlCULTTOEXTRACTTHEENTIREPICTUREFROMAN ADOLESCENTWHOISRELUCTANTTOADMITTOHAVINGAPROBLEMBUTTHEFAMILYWILLBEWELL ACQUAINTEDWITHTHEMEALTIMEDISRUPTIONGENERATEDBYTHEDYSPHAGIA There are no set rules for the evaluation of dysphagia for solids. Videofluoroscopic EVALUATIONOFSWALLOWINGASSESSESBOLUSHANDLINGFROMLIPSTOUPPERESOPHAGUS BUT MAYNOTINCLUDEATHOROUGHINVESTIGATIONOFTHELENGTHOFTHEESOPHAGUS-ODIlED BARIUM ESOPHAGOGRAM CAN ASSESS THE BOLUS PASSAGE OF DIFFERENT CONSISTENCIES through the esophagus, and is a good method for detecting stenotic areas that impede SOLIDFOODBOLUSPASSAGE)TMAYSUGGESTDYSMOTILITYIFTHEBOLUSDOESNOTPROGRESS NORMALLYTOTHESTOMACHDESPITENORMALCALIBER Contrast radiography to document the anatomy and gross function of the esophaGUSISOFTENPERFORMEDlRSTTOGENERATEAhROADMAPvOFTHEESOPHAGUS4HEPRESENCE LOCATION AND CALIBER OF A STRICTURE SHOULD BE EVIDENT ON ESOPHAGOGRAM AS should achalasia. !DDITIONALTESTSAVAILABLETOEVALUATETHEESOPHAGUSINCLUDEESOPHAGEALMANOMETRYANDENDOSCOPY!TISSUEDIAGNOSISOBTAINEDATENDOSCOPYISESSENTIALWHENAN INmAMMATORY DISORDER IS RESPONSIBLE FOR DYSPHAGIA &OR MILD INTERMITTENT DYSPHAGIATHATLACKSTHECLINICALFEATURESOFASTRICTURE ENDOSCOPYALONEMAYBESUFlCIENTTOESTABLISHADIAGNOSIS AVOIDINGTHERADIATIONEXPOSUREOFTHECONTRASTSTUDIES -ANOMETRIC EVALUATION MAY BE REQUIRED TO CONlRM THE DIAGNOSIS OF ACHALASIA OR OTHERCONDITIONTHATAFFECTSESOPHAGEALPERISTALSISINTHEABSENCEOFINmAMMATION BUTISNOTINDICATEDINTHEROUTINEEVALUATIONOF%O%

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)SOLATEDDYSPHAGIAFORLIQUIDSISRARELY IFEVER AFEATUREOF%O% BUTWHENPRESENT in a child who has EoE should promote an aggressive search for other pathology, SUCHASALARYNGEALCLEFTOR#HIARIMALFORMATIONOROTHERPOSTERIORFOSSAORBRAINSTEMLESION 4HOSECONDITIONSHAVEBEENDISCOVEREDINCHILDRENWHOALSOHAVE%O% They impact the pharyngeal phase of swallowing and cause choking on liquids. The MOSTDIRECTMEANSFORDETECTIONOFTHESEANOMALIESINCLUDEBRAIN-2)WITHATTENTION to the posterior fossa, and direct laryngoscopy for the cleft.

Pain Although EoE can create rather striking inflammation endoscopically and histologiCALLY ODYNOPHAGIAISNOTCHARACTERISTICOFIT#OMPLAINTSOFEPIGASTRICORPERIUMBILICALABDOMINALPAINMAYSEEMILLOGICALASAMANIFESTATIONOFESOPHAGITIS BUTTHESE COMPLAINTSARECOMMONINCHILDREN IFVAGUEANDNONSPECIlC (EARTBURNANDCHESTPAINSOMETIMESSUBSTERNALANDSEVERE AREASSOCIATEDWITH %O% BUTSELDOMARESOLEPRESENTINGCONCERNS)NTERMITTENTORCHRONICSORETHROAT with the child clearly indicating a pharyngeal rather then intrathoracic source of discomfort is more common in the author’s experience. 0AINASSOCIATEDWITH%O%CORRELATESPOORLYWITHTHENUMBEROFEOSINOPHILSHPF ONBIOPSY DOESNOTNECESSARILYIMPROVEWITHTREATMENTONTHEONEHANDANDMAYBE COMPLETELYABSENTDESPITERATHERREMARKABLEINmAMMATIONONTHEOTHER;1]. 3CHOOLAGEDCHILDRENMAYPRESENTWITHABDOMINALPAINASTHEMOSTBOTHERSOME manifestation of EoE, and sometimes have symptoms, such as dysphagia, that PROVIDEACLINICALCLUETHATESOPHAGEALPATHOLOGYMAYBEATFAULT/NESHOULDBE PARTICULARLYCONCERNEDFORTHEPOSSIBILITYOF%O%INAMALEWHOHASABDOMINALPAIN associated with asthma, eczema, or food allergies.

Vomiting 6OMITINGISAVERYDISTRESSINGSYMPTOMTOCHILDRENANDTHEIRFAMILIES ANDARGUABLY GETSATTENTIONEARLIERTHANLESSTROUBLESOMECONCERNS!LTHOUGHTHEEFFORTLESSREGURgitation of reflux in infancy is common and inconsequential most of the time, overt retching and vomiting is seldom normal. Delayed evaluation and diagnosis remains ADOGGEDCOMPLAINTFROMFAMILIESOFBABIESWHOVOMITBUTAREBRUSHEDOFFBYMEDICALPROVIDERSIFWEIGHTGAINISADEQUATE4HEIMPLICATIONTHATVOMITINGISACCEPTABLE ASLONGASWEIGHTGAINCONTINUESISABSURD .ONBILIOUS NONBLOODYEMESISHASAVERYLONGDIFFERENTIALDIAGNOSISTHATINCLUDES EoE. GI physicians typically depend on the history, pattern, and associated symptoms in making an initial assessment as to the etiology of vomiting. Warning signs, SUCHASWEIGHTLOSS HEMATEMESIS ORBILIOUSEMESISWARRANTAGGRESSIVEEVALUATION

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)NITIALSTUDYBYUPPER')SERIESISUSEFULTOBROADLYEVALUATEFORSERIOUSCONDITIONS that need urgent attention (e.g., pyloric stenosis or malrotation). When anatomic CONCERNSHAVEBEENALLAYED FURTHEREVALUATIONFORINFECTIOUS INmAMMATORY TOXIC METABOLIC ANDNONGASTROINTESTINALCAUSESFORVOMITINGISUNDERTAKEN WITHTHEHIStory and physical directing the order and priority of testing. Perhaps the most common features of the vomiting associated with EoE is the DEVELOPMENTOFTHESYMPTOMINTHESECONDHALFOFTHElRSTYEAROFLIFEWHENSOLID FOODSAREINTRODUCEDTOTHEDIET/FTENERRONEOUSLYATTRIBUTEDTOREmUX THISVOMITING is true vomiting, not the effortless regurgitation that characterizes GERD, which USUALLYHASALREADYPEAKEDBYMONTHSOFAGE;17=/NRAREOCCASIONS ITMAYBE CONSISTENTLYANDOBVIOUSLYATTRIBUTABLETOTHEINGESTIONOFAPARTICULARFOODANTIGEN IN WHICHCASEFOODHASBEENTAKENFROMTHEDIETBEFOREPRESENTATIONTOTHEGASTROENTERologist or allergist. Chronic, intermittent vomiting not associated with a particular antigen is more often the complaint.

Other Symptoms Some children are found to have eosinophilic esophageal inflammation during evaluation for symptoms that are clearly not of esophageal origin, such as diarrhea. $IARRHEACANBEAMANIFESTATIONOFEOSINOPHILICINmAMMATIONINTHESMALLINTESTINE or colon, and individuals with eosinophilic gastroenteritis may well have esophageal INVOLVEMENT #HILDREN WHO HAVE OTHER INmAMMATORY BOWEL DISORDERS INCLUDING gluten-sensitive enteropathy (celiac disease) or Crohn’s disease can have eosinophil-predominant esophageal inflammation that meets the criteria for EoE histologically [18]. However, it is not appropriate to make a clinical diagnosis of EoE when there is a clear diagnosis of another condition such as Crohn’s that could account for the histologic changes. Similarly, the presence of systemic symptoms, such as fever or weight loss, should promote evaluation for a disease process other than EoE. #HILDRENHAVEBEENDIAGNOSEDWITH%O%AFTERPRESENTINGWITHAIRWAYCOMPLAINTS !GOODEXAMPLEISRECURRENTCROUP WITHNOSYMPTOMSBETWEENEPISODESOFCROUP )TISDIFlCULTTOCONCEIVEOFAPATHOGENETICMECHANISMTHATMIGHTUNDERLIETHEDEVELOPMENTOFEPISODICAIRWAYSYMPTOMSFROMESOPHAGEALPATHOLOGYINTHEABSENCEOF CLINICALLYSIGNIlCANT'%2$ BUTSUCHINDIVIDUALSHAVEBEENIDENTIlED,ONGITUDINAL studies to determine the impact of treatment for the EoE on the frequency or severITYOFTHECROUPHAVENOTBEENREPORTED Other respiratory symptoms are common in children with EoE. Chronic rhinitis and reactive airways are the predominant complaints. Presentation to the otorhinolaryngologist with a complaint of hoarseness or adenotonsillar hypertrophy is also POSSIBLE;18, 19=)TISCONCEIVABLETHATTHESEASSOCIATEDCONDITIONSARENOTPRIMARY MANIFESTATIONS OF THE ESOPHAGEAL INmAMMATION BUT RATHER CONCURRENT MANIFESTAtions of immune dysregulation or atopy. Irrespective of the mechanism, symptoms, or mode of presentation, active management of the esophagitis is important.

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Associated Conditions %O%DOESOCCURINCHILDRENWHOHAVEOTHERMEDICALCONDITIONS)THASBEENDIAGNOSED in children who have Down syndrome, Pfeiffer syndrome, VATER syndrome, [synDROMEINCLUDINGVERTEBRALDEFECTS6 ANALATRESIA! 4%&WITHESOPHAGEALATRESIA (TE), and radial or renal dysplasia (R)], and CHARGE syndrome (association of COLOBOMA OF THE EYE HEART ANOMALY ATRESIA CHOANAL RETARDATION OF MENTAL AND SOMATIC DEVELOPMENT MICROPHALLUS EAR ABNORMALITIES ANDOR DEAFNESSCOLOBOMAS heart defect, renal anomaly). There is no evidence to date to suggest or support any SORTOFCOMMONPATHOGENETICMECHANISM4HEAUTHORHASOBSERVED%O%INCHILDREN WHOHAVEOTHERNEUROLOGICALANDNEURODEVELOPMENTALCONDITIONS INCLUDINGCEREBRAL PALSY SEIZURES AUTISMSPECTRUM ATTENTIONDElCITDISORDER ASWELLASSTRUCTURALBRAIN conditions, such as Chiari malformation. Once again, the association is loose without SUGGESTIONOFANYCAUSE EFFECTRELATIONSHIP BUTTHELOOSEASSOCIATIONSTILLDEMANDSTHAT %O%BEINCLUDEDINTHEDIFFERENTIALOFGASTROINTESTINALSYMPTOMSINTHESECHILDREN

The Impact of Chronic Disease !SNOTEDABOVE EVALUATIONOFTHECHILDWITH%O%MIGHTBEINITIATEDATONEOFMANY points in the course of the illness. Some children who have EoE have had a protracted or more severe course prior to evaluation and may have signs of poorly conTROLLEDDISEASE SUCHASINADEQUATEWEIGHTGAIN NUTRITIONALDElCIENCIES POORFEEDING SKILLS ORPOORBEHAVIOR ANDLIMITEDSOCIALSKILLSSURROUNDINGMEALSANDFEEDING)T IS ARGUABLE THAT SOME OF THESE SYMPTOMS ARE PRIMARY MANIFESTATIONS OF DISEASE WHEREASOTHERSDEVELOPASACONSEQUENCECHRONICILLNESS DIFlCULTTHERAPY ORLIMITED exposure to expected feeding opportunity at critical times during development. One of the duties of the examining physician is to understand the impact of the CONDITIONONTHEFAMILYANDTHECHILD&AMILIESSTRUGGLEWITHMULTIPLEISSUES SOME OFWHICHARETHEFRUSTRATIONSOFTRYINGTOMAINTAINDIFlCULTDIETARYRESTRICTIONS THE lNANCIALIMPACTOFMEDICALCARE ANDTHECOSTOFSPECIALFORMULAS4HEIMPACTOFTHE WORKPERFORMEDBYTHEPARENTSANDTHESTRESSITENGENDERS TOMAINTAINARESTRICTED DIETCANNOTBEUNDERESTIMATED$IETARYRESTRICTIONSAFFECTALLASPECTSOFABUSYLIFESTYLE&AMILYMEALTIMEISDISRUPTED ANDEATINGINANYOTHERVENUE SUCHASARESTAUrant at school, or at a friend’s or relative’s home is a challenge. It is somewhat easier to control the diet and environment for preschool children at home on a restricted DIETTHANFOROLDERCHILDRENWHOARENOTCONSISTENTLYUNDERTHEOBSERVATIONOFRESPONSIBLEADULTS4HEFURTHERLOSSOFCONTROLOVERADOLESCENTS THEIRDIET ANDTHEIRMEDICATIONISVERYCOMMONINCLINICALPRACTICE ANDSHOULDBEANTICIPATED Because EoE is a chronic condition, it is important to assure that patients and THEIRFAMILIESUNDERSTANDTHENEEDFORBOTHIMMEDIATEANDSUSTAINEDTHERAPY ANDTHE POTENTIALIMPACTONQUALITYOFLIFEOFVARIOUSTREATMENTS&AMILIESNEEDTOBEEDUcated as to the effort that is required to maintain any therapeutic regimen.

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Conclusion: A Multidisciplinary Approach EoE can impact children and their families at many levels – at once physically, SOCIALLY EMOTIONALLY DEVELOPMENTALLY lNANCIALLY(AVINGATEAMAPPROACHTOSUPPORT THE NEEDS OF PATIENTS AND THEIR FAMILIES IS PARTICULARLY VALUABLE IN PROVIDING comprehensive care. Core services from gastroenterology, allergy/immunology, and PATHOLOGY ARE ESSENTIAL )N ADDITION SUBSTANTIAL SUPPORT FROM A DIETICIAN SOCIAL WORKER ANDSPEECHANDLANGUAGEPATHOLOGISTFACILITATESGLOBALEVALUATIONANDTREATMENT2EADYACCESSTOOTHERSUBSPECIALISTSWHOHAVEEXPERIENCEANDEXPERTISEIN %O%ANDITSCOMORBIDITIESIE OTORHINOLARYNGOLOGIST PSYCHOLOGISTORDEVELOPMENtal specialist, pulmonologist, and surgeon), assures consistent evaluation and cliniCALCAREOFASSOCIATEDPROBLEMS

References  0ENTIUK 3 0UTNAM 0% #OLLINS -( 2OTHENBERG -% $ISSOCIATION BETWEEN SYMPTOMS AND histological severity in pediatric eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2009;48(2):152–60.  &URUTA '4 ,IACOURAS #! #OLLINS -( 'UPTA 3+ *USTINICH # 0UTNAM 0% ET AL &IRST )NTERNATIONAL 'ASTROINTESTINAL %OSINOPHIL 2ESEARCH 3YMPOSIUM &)'%23 3UBCOMMITTEES Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342–63.  !CEVES 33 .EWBURY 2/ #HEN $ -UELLER * $OHIL 2 (OFFMAN ( ET AL 2ESOLUTION OF remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy. 2010;65(1):109–16.  3TRAUMANN! 3PICHTIN(0 'RIZE, "UCHER+! "EGLINGER# 3IMON(5.ATURALHISTORYOF primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology. 2003;125(6):1660–9.  3CHOEPFER!- 'SCHOSSMANN* 3CHEURER5 3EIBOLD& 3TRAUMANN!%SOPHAGEALSTRICTURESIN adult eosinophilic esophagitis: dilation is an effective and safe alternative after failure of topical corticosteroids. Endoscopy. 2008;40(2):161–4.  3PERGEL*- "ROWN 7HITEHORN4& "EAUSOLEIL*, &RANCIOSI* 3HUKER- 6ERMA2 ETAL years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr. 2009;48(1):30–6.  /RENSTEIN32 3HALABY4- $I,ORENZO# 0UTNAM0% 3IGURDSSON, -OUSA( ETAL4HE SPECTRUMOFPEDIATRICEOSINOPHILICESOPHAGITISBEYONDINFANCYACLINICALSERIESOFCHILDREN Am J Gastroenterol. 2000;95(6):1422–30. Erratum in: Am J Gastroenterol. 2001;96(7):2290.  !SSAAD !( 0UTNAM 0% #OLLINS -( !KERS 2- *AMESON 3# +IRBY #, ET AL 0EDIATRIC patients with eosinophilic esophagitis: an 8-year follow-up. J Allergy Clin Immunol. 2007;119(3):731–8.  &RANCIOSI*0 4AM6 ,IACOURAS#! 3PERGEL*-!CASE CONTROLSTUDYOFSOCIODEMOGRAPHIC and geographic characteristics of 335 children with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2009;7(4):415–9. 10. Velázquez V, Camacho C, Mercado-Quiñones AE, Irizarry-Padilla J. Eosinophilic esophagitis and allergies in the pediatric population of Puerto Rico. Bol Asoc Med P R. 2009; 101(2):21–2. .OEL 2* 0UTNAM 0% 2OTHENBERG -% %OSINOPHILIC ESOPHAGITIS . %NGL * -ED  351(9):940–1.

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0ENTIUK30 -ILLER#+ +AUL!%OSINOPHILICESOPHAGITISININFANTSANDTODDLERS$YSPHAGIA 2007;22(1):44–8. 2OBLES -EDRANDA# 6ILLARD& LE'ALL# ,UKASHOK( 2IVET# "OUVIER2 ETAL3EVEREDYSphagia in children with eosinophilic esophagitis and esophageal stricture: an indication for BALLOONDILATION*0EDIATR'ASTROENTEROL.UTR n 2AJAGOPALAN* 4RIADAlLOPOULOS'2INGS RELATEDESOPHAGEALMEATBOLUSIMPACTIONBIOPSY lRST DILATELATER$IS%SOPHAGUS %n .URKO3 2OSEN2 &URUTA'4%SOPHAGEALDYSMOTILITYINCHILDRENWITHEOSINOPHILICESOPHAGItis: a study using prolonged esophageal manometry. Am J Gastroenterol. 2009;104 (12):3050–7. /LIVEIRA# :AMAKHSHARY- -ARCON0 +IM0#%OSINOPHILICESOPHAGITISANDINTERMEDIATE ESOPHAGITIS AFTER TRACHEOESOPHAGEAL lSTULA REPAIR A CASE SERIES * 0EDIATR 3URG  43(5):810–4. .ELSON30 #HEN%( 3YNIAR'- #HRISTOFFEL++0REVALENCEOFSYMPTOMSOFGASTROESOPHAGEAL REmUX DURING INFANCY ! PEDIATRIC PRACTICE BASED SURVEY 0EDIATRIC 0RACTICE 2ESEARCH Group. Arch Pediatr Adolesc Med. 1997;151(6):569–72. 18. Leslie C, Mews C, Charles A, Ravikumara M. Celiac disease and eosinophilic esophagitis: a true association. J Pediatr Gastroenterol Nutr. 2010;50(4):397–9. 19. Dauer EH, Ponikau JU, Smyrk TC, Murray JA, Thompson DM. Airway manifestations of pediatric eosinophilic esophagitis: a clinical and histopathologic report of an emerging association. Ann Otol Rhinol Laryngol. 2006;115(7):507–17.

Chapter 10

Clinical Presentation of Eosinophilic Esophagitis in Adults Nirmala Gonsalves

Keywords %OSINOPHILICESOPHAGITISs$YSPHAGIAs&OODIMPACTIONs%NVIRONMENTAL allergens

Introduction /VER THE PAST DECADE EOSINOPHILIC ESOPHAGITIS %O% HAS EMERGED AS ONE OF THE MOST COMMON CAUSES OF DYSPHAGIA AND FOOD IMPACTION IN ADULTS 4HIS CHRONIC CONDITION IS CHARACTERIZED BY INCREASED ESOPHAGEAL EOSINOPHILS IN THE SETTING OF ESOPHAGEAL SYMPTOMS 7HILE %O% MAY OCCUR IN CONJUNCTION WITH EOSINOPHILIC gastroenteritis, the rising field is related to the subset with isolated esophageal eosinophilia [1=$EVELOPMENTOF%O%INADULTSISLIKELYDUETOAMULTITUDEOFFACTORS INCLUDINGESOPHAGEALACIDEXPOSURE FOODANDENVIRONMENTALALLERGENS ANDGENETIC PREDISPOSITION7HILEINVESTIGATIONINTOEACHOFTHESEAREASISACTIVELYBEINGSTUDIED ANDDISCUSSEDINFURTHERDETAILELSEWHEREINTHISBOOK THISCHAPTERWILLHIGHLIGHTTHE CLINICALPRESENTATIONOF%O%INADULTS

Epidemiology /VERTHEPASTYEARS %O%HASBECOMEAGLOBALEPIDEMICINBOTHADULTSANDCHILDREN 4HEESTIMATEDINCIDENCEOFTHISDISEASEINADULTSISCASESPER ANDAPREVALENCEOFPER BASEDONDATAFROMA3WISSCOHORT;2=4HISTRENDHASALSOBEEN SEENINADULTSINTHE53WITHINCIDENCEOFADULTCASESIN/LMSTEDCOUNTYRISINGFROM .'ONSALVES*) $EPARTMENTOF-EDICINE $IVISIONOF'ASTROENTEROLOGY .ORTHWESTERN5NIVERSITY &EINBERG3CHOOLOF-EDICINE .3T#LAIR3T 3UITE #HICAGO ),  53! E MAILN GONSALVES NORTHWESTERNEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_10, © Springer Science+Business Media, LLC 2012

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 PERSON YEARSINTO PERSON YEARSIN;]. Looking ATANADULTPATIENTPOPULATIONPRESENTINGWITHDYSPHAGIA INCIDENCEOF%O%HASBEEN FOUNDTOBEASHIGHAS;=4HESENUMBERSSUGGESTTHATTHEINCIDENCEANDPREVALENCEOF%O%ISAPPROXIMATINGTHATOFOTHERMORECOMMONIMMUNOLOGICDISORDERS SUCHASINmAMMATORYBOWELDISEASE;5=&URTHERMORE THESEESTIMATESLIKELYUNDERESTIMATETHETRUEINCIDENCEANDPREVALENCEOF%O% SINCETHESEDATAAREBASEDONSYMPTOMATICPATIENTSPRESENTINGFORENDOSCOPY

Clinical Features 4HEMOSTCOMMONINITIALPRESENTATIONOFADULTSWITH%O%ISSOLIDFOODDYSPHAGIA )N MANY ADULTS SYMPTOMS HAVE PRECEDED THEIR DIAGNOSIS BY n YEARS ;6= 4HIS DELAYOFDIAGNOSISWASATTRIBUTEDPREVIOUSLYTOTHELACKOFRECOGNITIONOFTHISDISEASE BYTHEMEDICALCOMMUNITY4HANKFULLY OVERTHEPASTYEARS INCREASEDAWARENESS ABOUTTHISCONDITIONINGASTROENTEROLOGISTS ALLERGISTS ANDPATHOLOGISTHAVELEADTO MORE TIMELY DIAGNOSIS AND TREATMENT !S A RESULT OF THIS DELAY HOWEVER MANY PATIENTSHAVEBECOMEADEPTATACCOMMODATINGFORTHEIRESOPHAGEALDYSFUNCTIONBY CHEWINGWELL EATINGVERYSLOWLY DRINKINGEXCESSIVELIQUIDSDURINGMEALS ORAVOIDING THEIR TRIGGER FOODS 4HESE PATIENTS MAY ACTUALLY DENY DYSPHAGIA SYMPTOMS UPON INITIALQUESTIONING THEREFOREACAREFULHISTORYINCLUDINGTHESEACCOMMODATIONSKILLS ISESSENTIALINELICITINGTHISINFORMATION /THER FEATURES SUCH AS FOOD IMPACTION HEARTBURN AND CHEST PAIN MAY ALSO BE seen [7=)NONESERIES ASMANYASOFADULTFOODIMPACTIONCASESENCOUNTERED INANEMERGENCYDEPARTMENTSETTINGWEREATTRIBUTABLETO%O%ANDTHEREFOREESOPHAGEAL BIOPSIES PERFORMED AT THE TIME OF A FOOD IMPACTION IS ADVOCATED TO MAKE A TIMELYDIAGNOSIS;8=#AUTIONMUSTALSOBETAKENATTHETIMEOFFOODIMPACTIONAS THEREHAVEBEENCASESOFENDOSCOPICPERFORATIONDURINGTHESEINSTANCES;9]. Patients MUSTALSOBECOUNSELEDONSEEKINGMEDICALATTENTIONQUICKLYINTHISSETTINGBECAUSE THEREHAVEBEENCASESOFSPONTANEOUSESOPHAGEALPERFORATIONINPATIENTSTRYINGTO DISLODGETHEFOODBOLUSBYRETCHING 4HEPATIENTPOPULATIONIN%O%TENDSTOBEMALEPREDOMINANTINBOTHTHEADULTAND PEDIATRICPOPULATION!MONGADULTPATIENTSINREPORTS WEREMALESWITH AMEANAGEOFYEARSRANGEn ;7]. Although reports also suggest a Caucasian PREDILECTION %O%HASBEENDESCRIBEDMORERECENTLYIN!FRICAN!MERICANS ,ATIN !MERICANS AND!SIANS;, 10=4HEREHASBEENNOGEOGRAPHICTRENDFORTHEPRESENTATIONOF%O%INADULTSINTHE53ASCASESHAVEBEENREPORTEDACROSSTHECOUNTRYBOTH in rural and urban settings [11]. (ISTORICALLY THIS DIAGNOSIS WAS OFTEN OVERLOOKED IN ADULTS WITH MANY PATIENTS UNDERGOINGREPEATEDENDOSCOPIESANDDILATIONSWITHALTERNATEDIAGNOSESOF3CHATZKI ring or gastroesophageal reflux disease (GERD) [6=!NOTHERREASONFORTHEDELAYIN DIAGNOSISOF%O%ISTHATEOSINOPHILICINVOLVEMENTOFTHEESOPHAGEALMUCOSAPREVIOUSLYIMPLICATED'%2$3OMESUGGESTEDTHATQUANTITATIVETHRESHOLDSOFEOSINOPHILIC INlLTRATIONMADETHEDISTINCTIONLOWERCOUNTSWEREPRESUMABLYRELATEDTO'%2$

 #LINICAL0RESENTATIONOF%OSINOPHILIC%SOPHAGITISIN!DULTS



WHILEHIGHERCOUNTSBEINGDIAGNOSTICOF%O%;12=3UCHACUT OFFVALUEHASPROVEN PROBLEMATIC HOWEVER DUETOTHEHIGHPREVALENCEOF'%2$INADULTSANDPOTENTIAL OVERLAPBETWEEN'%2$AND%O% $UE TO THIS DILEMMA RECENT CONSENSUS GUIDELINES HAVE ADVOCATED THAT '%2$ SHOULDBEADEQUATELYTREATEDWITHACIDSUPPRESSIONORRULEDOUTWITHAP( MONITORING STUDYINTHEDIAGNOSTICWORKUPFOR%O%;7=4HISISESPECIALLYIMPORTANTBECAUSE THEREAREINCREASINGNUMBEROFADULTSMANIFESTINGWITHBOTH'%2$AND%O%ANDTHE interplay between these two entities is unknown. EoE should be considered the leading diagnosis in adults presenting with dysPHAGIAANDAHISTORYOFATOPICCONDITIONSSUCHASASTHMA ALLERGICRHINITIS ECZEMA ORATOPICDERMATITIS)NTWOADULTSERIES ALLERGYTESTINGWASUSEDTODEMONSTRATETHE PRESENCEOFATOPYINADULTS;1 1=)NANOTHERADULTSERIES SEASONVARIATIONINTHE PRESENTATIONOF%O%INADULTSWASNOTEDSUGGESTINGTHEASSOCIATIONOFAEROALLERGENS and EoE [15=7HILEEMPIRICELIMINATIONDIETSHAVEBEENSHOWNTOBETHERAPEUTICIN ADULTSWITH%O% ALLERGYTESTINGWASNOTPREDICTIVEINTHESEPATIENTS;16=5NTILMORE INFORMATIONISGATHEREDONTHEPREDICTIVEVALUEOFALLERGYTESTINGINADULTSWITH%O% IT IS REASONABLE TO HAVE PATIENTS UNDERGO AN ALLERGIC EVALUATION TO HELP IDENTIFY potential triggers. &AMILIALCLUSTERINGHASBEENRECOGNIZEDINADULTSANDCHILDRENWITH%O% SUGgesting a genetic predisposition [17n19= )N A CASE SERIES OF  PEDIATRIC %O% PATIENTS HADSIBLINGSWITH%O%ANDHADAPARENTWITHEITHERANESOPHAGEAL stricture or known EoE [20=4HEREFORE ANIMPORTANTCOMPONENTTOINCLUDEINHISTORYTAKINGINADULTSWITH%O%ISATHOROUGHFAMILYHISTORYASADDITIONALCASESMAY be identified. 4HE BASIS FOR THIS GENETIC PREDISPOSITION TO %O% CONTINUES TO BE INVESTIGATED %OTAXIN  AGENEENCODINGANEOSINOPHIL SPECIlCCHEMOATTRACTANT HASRECENTLYBEEN IDENTIlEDASTHEMOSTHIGHLYINDUCEDGENEINPEDIATRIC%O%PATIENTS;21=4REATMENT WITHTOPICALCORTICOSTEROIDSDOWNREGULATEDESOPHAGEALEOTAXIN LEVELSSUGGESTING THECHANGETOBEREVERSIBLE;22=7HILEFORMALGENEANALYSISHASNOTYETBEENEXTENSIVELYSTUDIEDINADULTS IMMUNOHISTOCHEMICALSTAININGFOREOTAXIN INESOPHAGEAL TISSUEOFADULT%O%PATIENTSWASSIGNIlCANTLYINCREASEDCOMPAREDTOPATIENTSWITH REmUXSUGGESTINGASIMILARTRENDTOTHEPEDIATRICDATA;2=!NOTHERADULTSTUDYFURTHER SUPPORTINGAROLEOFEOTAXIN DEMONSTRATEDINCREASEDLEVELSOFEOTAXIN INESOPHAGEALTISSUEOF%O%ADULTSCOMPAREDTOCONTROLSANDFOUNDTHATTHISGENEEXPRESSION DECREASEDINRESPONSETOTREATMENTWITHDIETARYELIMINATION;2].

Natural History 7HILEDElNINGTHENATURALHISTORYANDPROGRESSIONOF%O%ISCRITICALINDEVELOPING GOALSOFTREATMENTANDMANAGEMENTOFTHISILLNESS LIMITEDNATURALHISTORYDATAEXIST TOHELPGUIDECURRENTRECOMMENDATIONS'IVENTHEINCREASEDMORBIDITYTHATCAN BEASSOCIATEDWITHCOMPLICATIONSOF%O%SUCHASFOODIMPACTIONS AKEYGOALOF MANAGEMENT IS TO PREVENT DISEASE RECURRENCE AND COMPLICATIONS )N THE LONGEST



.'ONSALVES

AVAILABLENATURALHISTORYSTUDY 3TRAUMANNETALFOLLOWEDMEDICALLYUNTREATED ADULTSPATIENTSFORANAVERAGEOFYEARS;25=$URINGTHISTIME EXPERIENCED CONTINUED DYSPHAGIA AND ONE THIRD HAD UNDERGONE ESOPHAGEAL DILATION 7HILE ESOPHAGEALEOSINOPHILIAPERSISTED LEVELSINTERESTINGLYDECLINEDINMOSTPATIENTSDURING THE FOLLOW UP PERIOD "ARRETTS METAPLASIA HAS BEEN REPORTED IN PATIENTS WITH EoE but it is unclear as to whether or not this is a causal relationship [26]. Esophageal MALIGNANCYRELATEDTO%O%HASNOTBEENREPORTED BUT AGAIN THEREISLIMITEDLONG TERMDATAAVAILABLE)NTHEAUTHORSEXPERIENCEWITHASERIESOFADULTPATIENTS WITH%O% PATIENTSTENDEDTOHAVESYMPTOMPROGRESSIONANDINCREASEDFREQUENCYOF FOODIMPACTIONASTHEYEARSOFDYSPHAGIAPROGRESSED;27].

Conclusion %OSINOPHILICESOPHAGITISREMAINSANEMERGINGCLINICALENTITYWITHINCREASINGINCIDENCEINADULTS!LTHOUGHFOODANDAEROALLERGENSHAVEBEENIMPLICATEDINTHEDISEASE THENATURALHISTORYOFTHEDISORDERISUNKNOWN3EVERECOMPLICATIONSINCLUDING lBROSIS NARROWCALIBERESOPHAGUS ANDSTRICTUREAREWELLKNOWNBUTPREDICTORSFOR WHICHPATIENTSWILLDEVELOPTHESECOMPLICATIONSAREUNKNOWN#OMMONSYMPTOMS INADULTSTHATIMPLICATE%O%AREDYSPHAGIA FOODIMPACTIONS HEARTBURN ANDATYPICAL CHESTPAIN)TISIMPORTANTTOASKPATIENTSABOUTTHEIRALLERGICHISTORYINCLUDINGDIETARY ALLERGIES DIETARYINTOLERANCE ASTHMA ORSEASONALALLERGYINADDITIONTOANYFAMILY HISTORY OF THESE DISORDERS OR DYSPHAGIA $URING ENDOSCOPY FOR SUSPECTED %O% IN ADULTS MULTIPLE BIOPSIES SHOULD BE OBTAINED AT MULTIPLE LEVELS IN THE ESOPHAGUS REGARDLESSOFENDOSCOPICFEATURESDUETOTHEPATCHYNATUREOFTHEDISEASE;6]. It is ALSOHELPFULTOALERTTHEPATHOLOGISTOFYOURSUSPICIONANDREQUESTEOSINOPHILCOUNTS ON ESOPHAGEAL BIOPSIES 4HANKFULLY WITH INCREASED AWARENESS BY GASTROENTEROLOGISTS ALLERGISTSANDPATHOLOGISTSOVERTHEPASTSEVERALYEARS %O%ISBEINGRECOGNIZED EARLIERINADULTSLEADINGTOMOREEFFECTIVETREATMENTSANDHOPEFULLYBETTEROUTCOMES FORPATIENTS

References  2OTHENBERG-%0ATHOGENESISANDCLINICALFEATURESOFEOSINOPHILICESOPHAGITIS*!LLERGY#LIN )MMUNOL n  3TRAUMANN! 3IMON(5%OSINOPHILICESOPHAGITISESCALATINGEPIDEMIOLOGY*!LLERGY#LIN )MMUNOL n  0RASAD '! !LEXANDER *! 3CHLECK #$ ET AL %PIDEMIOLOGY OF EOSINOPHILIC ESOPHAGITIS OVER THREEDECADESIN/LMSTED#OUNTY -INNESOTA#LIN'ASTROENTEROL(EPATOL n  6EERAPPAN'2 0ERRY*, $UNCAN4* ETAL0REVALENCEOFEOSINOPHILICESOPHAGITISINANADULT POPULATION UNDERGOING UPPER ENDOSCOPY A PROSPECTIVE STUDY #LIN 'ASTROENTEROL (EPATOL  nE 

 #LINICAL0RESENTATIONOF%OSINOPHILIC%SOPHAGITISIN!DULTS



 +UGATHASAN3 *UDD2( (OFFMANN2' ETAL%PIDEMIOLOGICANDCLINICALCHARACTERISTICSOF CHILDRENWITHNEWLYDIAGNOSEDINmAMMATORYBOWELDISEASEIN7ISCONSINASTATEWIDEPOPULATION BASEDSTUDY*0EDIATR n  'ONSALVES. 0OLICARPIO .ICOLAS- :HANG1 ETAL(ISTOPATHOLOGICVARIABILITYANDENDOSCOPIC CORRELATESINADULTSWITHEOSINOPHILICESOPHAGITIS'ASTROINTEST%NDOSC n  &URUTA'4 ,IACOURAS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGY n  $ESAI4+ 3TECEVIC6 #HANG#( ETAL!SSOCIATIONOFEOSINOPHILICINmAMMATIONWITHESOPHAGEALFOODIMPACTIONINADULTS'ASTROINTEST%NDOSC n  3HIM,3 'REHAN-/ESOPHAGEALPERFORATIONDURINGENDOSCOPYFORFOODIMPACTIONINPATIENTS WITHEOSINOPHILICOESOPHAGITIS*'ASTROENTEROL(EPATOL  !SSAAD! 0UTNAM0% #OLLINS-( ETAL%OSINOPHILICESOPHAGITISASSOCIATIONWITHALLERGIC DISORDERS'ASTROINTEST%NDOSC#LIN.!M n +APEL2# -ILLER*+ 4ORRES# ETAL%OSINOPHILICESOPHAGITISINTHE53APREVALENTDISEASE THATAFFECTSALLAGEGROUPS'ASTROENTEROLOGY n -ORROW *" 6ARGO ** 'OLDBLUM *2 ET AL 4HE RINGED ESOPHAGUS HISTOLOGICAL FEATURES OF '%2$!M*'ASTROENTEROL n 2OY 'HANTA 3 ,AROSA $& +ATZKA $! !TOPIC CHARACTERISTICS OF ADULTS WITH EOSINOPHILIC ESOPHAGITIS#LIN'ASTROENTEROL(EPATOL n 0ENlELD *$ ,ANG $- 'OLDBLUM *2 ET AL 4HE ROLE OF ALLERGY EVALUATION IN ADULTS WITH EOSINOPHILICESOPHAGITIS*#LIN'ASTROENTEROL n !LMANSA# +RISHNA- "UCHNER!- ETAL3EASONALDISTRIBUTIONINNEWLYDIAGNOSEDCASESOF EOSINOPHILICESOPHAGITISINADULTS!M*'ASTROENTEROL n 'ONSALVES. 9ANG' $OERmER" ETAL!PROSPECTIVECLINICALTRIALOFSIXFOODELIMINATIONDIET ANDREINTRODUCTIONOFCAUSATIVEAGENTSINADULTSWITHEOSINOPHILICESOPHAGITIS'ASTROENTEROLOGY  ! 0ATEL 3- &ALCHUK +2 4HREE BROTHERS WITH DYSPHAGIA CAUSED BY EOSINOPHILIC ESOPHAGITIS 'ASTROINTEST%NDOSC n -EYER '7 %OSINOPHILIC ESOPHAGITIS IN A FATHER AND A DAUGHTER 'ASTROINTEST %NDOSC   :INK$! !MIN- 'EBARA3 ETAL&AMILIALDYSPHAGIAANDEOSINOPHILIA'ASTROINTEST%NDOSC  n ,IACOURAS#! 3PERGEL*- 2UCHELLI% ETAL%OSINOPHILICESOPHAGITISA YEAREXPERIENCEIN CHILDREN#LIN'ASTROENTEROL(EPATOL n "LANCHARD# 7ANG. 3TRINGER+& ETAL%OTAXIN ANDAUNIQUELYCONSERVEDGENE EXPRESSION PROlLEINEOSINOPHILICESOPHAGITIS*#LIN)NVEST n ,UCENDO!* .AVARRO- #OMAS# ETAL4REATMENTWITHTOPICALSTEROIDSDOWNREGULATES),  EOTAXIN ##, AND EOTAXIN ##, GENE EXPRESSION IN EOSINOPHILIC ESOPHAGITIS !M * 'ASTROENTEROL n  "HATTACHARYA " #ARLSTEN * 3ABO % ET AL )NCREASED EXPRESSION OF EOTAXIN  DISTINGUISHES BETWEENEOSINOPHILICESOPHAGITISANDGASTROESOPHAGEALREmUXDISEASE(UM0ATHOL  n 'ONSALVES . (SU "LATMAN + (IRANO ) ET AL 4HE ROLE OF PERMEABILITY INmAMMATION AND PROLIFERATIONGENESINADULTSWITHEOSINOPHILICESOPHAGITISANDTHEIRALTERATIONINRESPONSETO DIETARYTHERAPY'ASTROENTEROLOGY3 3TRAUMANN! 3PICHTIN(0 'RIZE, ETAL.ATURALHISTORYOFPRIMARYEOSINOPHILICESOPHAGITIS AFOLLOW UPOFADULTPATIENTSFORUPTOYEARS'ASTROENTEROLOGY n 7OLFSEN(# (EMMINGER,, !CHEM32%OSINOPHILICESOPHAGITISAND"ARRETTSESOPHAGUS WITHDYSPLASIA#LIN'ASTROENTEROL(EPATOL ! 4OTO% +ERN% -OY.ETAL$URATIONOFDYSPHAGIAISASSOCIATEDWITHINCREASEDFREQUENCYOF DYSPHAGIA AND FOOD IMPACTION IN ADULTS WITH EOSINOPHILIC ESOPHAGITIS 'ASTROENTEROLOGY 3

sdfsdf

Chapter 11

Relationship of Eosinophilic Esophagitis to Gastroesophageal Reflux* Edaire Cheng, Harland S. Winter, and Stuart Spechler

Keywords %OSINOPHILIC ESOPHAGITIS s 'ASTROESOPHAGEAL REmUX DISEASE s 0ROTON PUMPINHIBITORMEDICATIONs%SOPHAGEALP(MONITORINGs!CIDREmUX

Introduction In a recent consensus report sponsored by the American Gastroenterological !SSOCIATION)NSTITUTEANDTHE.ORTH!MERICAN3OCIETYOF0EDIATRIC'ASTROENTEROLOGY (EPATOLOGY AND.UTRITION EOSINOPHILICESOPHAGITIS%O% ISDElNEDAShAPRIMARY clinicopathologic disorder of the esophagus, characterized by esophageal and/or upper gastrointestinal tract symptoms in association with esophageal mucosal biopsy specimens containing tINTRAEPITHELIALEOSINOPHILS(0&ANDthe absence of pathologic gastroesophageal reflux disease (GERD) as evidenced by a normal pH monitoring study of the distal esophagus or lack of response to high-dose proton pump inhibitor (PPI) medication [1=4HISDElNITIONIMPLIESTHAT'%2$AND%O% AREMUTUALLYEXCLUSIVEDISORDERS ANDTHAT'%2$CANBEDElNEDBYANABNORMALP( MONITORINGRESULTORALACKOFRESPONSETO00)THERAPY%SOPHAGEALP(MONITORING HASSUBSTANTIALLIMITATIONSASATESTFOR'%2$ ANDSOMEPATIENTSWHOHAVEVERIlED REmUXESOPHAGITISCANHAVENORMALESOPHAGEALP(MONITORINGRESULTS;2]. Lack of RESPONSETO00)THERAPYIS ATBEST ASUBJECTIVEINDEXFOR'%2$ ANDEVENAPOSITIVE

4HISWORKWASSUPPORTEDBYTHE/FlCEOF-EDICAL2ESEARCH $EPARTMENTOF6ETERANS!FFAIRSAND THE.ATIONAL)NSTITUTESOF(EALTH2 #!

*

S. Spechler (*) $EPARTMENTOF-EDICINE 6!.ORTH4EXAS(EALTHCARE3YSTEMANDTHE5NIVERSITYOF4EXAS 3OUTHWESTERN-EDICAL#ENTER $ALLAS 48 53! e-mail: [email protected] C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_11, © Springer Science+Business Media, LLC 2012

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RESPONSETO00)THERAPYMAYNOTBEDUETOTHECONTROLOFACIDREmUXSEEBELOW  4HEREISMUCHEVIDENCETOSUGGESTTHATTHEINTERACTIONBETWEEN'%2$AND%O%CAN BECOMPLEX ANDTHATTHENOTIONOFESTABLISHINGACLEARDISTINCTIONBETWEENTHETWO disorders is too simplistic [3=)NDEED MANYINVESTIGATORSHAVECHOSENTOINCLUDE SUBJECTSWITHABNORMALACIDREmUXDOCUMENTEDBYP(MONITORINGINTHEIRSERIESOF patients with EoE [–6]. )N 7INTERETALWERETHElRSTTOREPORTTHATTHElNDINGOFEOSINOPHILSINTHE ESOPHAGEALEPITHELIUMCOULDBEUSEDASADIAGNOSTICCRITERIONFORREmUXESOPHAGITIS in children [7=)NTHATSTUDY THEPRESENCEOFEVENAFEWINTRAEPITHELIALEOSINOPHILS in the esophagus was found to correlate with abnormal acid clearance determined BYOVERNIGHTESOPHAGEALP(PROBEMONITORING)NTRAEPITHELIALEOSINOPHILSCOULDBE FOUNDINALLLEVELSOFTHEESOPHAGUS ANDINVOLVEMENTOFTHEPROXIMALESOPHAGUS WASASSOCIATEDWITHGREATERABNORMALITIESINTHEP(PROBESTUDY4HESEOBSERVATIONS SUGGEST THAT FOR SOME PATIENTS WITH '%2$ THE IMMUNE RESPONSE MANIFESTED BY INTRAEPITHELIALEOSINOPHILSMAYEXTENDINTOTHEUPPERESOPHAGUSINAPATTERNSIMILAR to that reported for patients with EoE.

Proposed Mechanisms Underlying an Association Between Gastroesophageal Reflux and Esophageal Eosinophils &OUR MAJOR MECHANISMS HAVE BEEN PROPOSED TO EXPLAIN THE ASSOCIATION BETWEEN '%2$ANDESOPHAGEALEOSINOPHILS;3= '%2$ THROUGHEPITHELIALINJURYORSTIMulation, causes the production of cytokines and other molecules that attract small NUMBERSOFEOSINOPHILSTOTHEESOPHAGUS  '%2$AND%O%COEXISTBUTAREUNRELATED  %O%CONTRIBUTESTOORCAUSES'%2$ OR '%2$CONTRIBUTESTOORCAUSES %O%4HESEMECHANISMSARECONSIDEREDINDIVIDUALLYBELOW

GERD, Through Epithelial Injury or Stimulation, Causes the Production of Cytokines and Other Molecules that Attract Small Numbers of Eosinophils to the Esophagus 2EPORTSHAVEDESCRIBEDANUMBEROFPOTENTIALMECHANISMSWHEREBY'%2$MIGHT cause the esophageal epithelium to produce molecules that recruit eosinophils. In CULTURES OF HUMAN ESOPHAGEAL MICROVASCULAR ENDOTHELIAL CELLS FOR EXAMPLE ACID EXPOSUREINDUCESTHEEXPRESSIONOFVASCULARCELLADHESIONMOLECULE 6#!-  an adhesion molecules recognized by ligands on the eosinophil cell surface [8, 9]. In a preparation of human esophageal mucosa, acid causes the release of platelet ACTIVATINGFACTOR0!& APHOSPHOLIPIDTHATATTRACTSANDACTIVATESEOSINOPHILS;10]. 4HEESOPHAGEALMUCOSAOFPATIENTSWITHREmUXESOPHAGITISEXHIBITSELEVATEDLEVELSOF

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CHEMOKINESTHATMIGHTATTRACTEOSINOPHILS SUCHAS),  -#0  AND2!.4%3;11], and Souza has shown that esophageal squamous epithelial cells in culture secrete ), WHENTHEYAREEXPOSEDTOACIDIlEDBILESALTS;12]. It is not clear which, if any, OFTHESEMOLECULESCONTRIBUTESTOTHEMILDEOSINOPHILICINlLTRATIONOFTHEESOPHAGEAL SQUAMOUSEPITHELIUMTHATCANBEFOUNDINPATIENTSWITH'%2$

GERD and EoE Coexist but Are Unrelated 3URVEYSSUGGESTTHATAPPROXIMATELYOFADULTSIN7ESTERNCOUNTRIESHAVE'%2$ [13, 1=4HEREFORE IF'%2$DOESNOTPROTECTAGAINST%O%ORVICEVERSA THENONE WOULDEXPECTTHATAPPROXIMATELYOFADULTPATIENTSWITH%O%WOULDHAVE'%2$ by chance alone. It seems unlikely that either of these disorders protects against the other. )NCHILDRENWITH%O% REPORTSDESCRIBINGTHERESULTSOFESOPHAGEALP(MONITORING SUGGESTTHATABNORMALACIDREmUXISUNCOMMON;15–17=(OWEVER THEVALIDITYOF THESEREPORTSISQUESTIONABLEBECAUSE INCHILDREN THESENSITIVITYANDSPECIlCITYOF ESOPHAGEALP(MONITORINGASATESTFOR'%2$ARENOTWELLESTABLISHED;18=&ACTORS THATCONFOUNDTHEINTERPRETATIONOFESOPHAGEALP(MONITORINGSTUDIESINCHILDREN include differences in the methodology of probe placement among different medical CENTERS VARIABILITYINTHEUSEANDTIMINGOFGENERALANESTHESIABEFOREPROBEPLACEMENT AND DISRUPTION OF THE CHILDS NORMAL ACTIVITIES DUE TO THE DISCOMFORT AND PHYSICALRESTRICTIONSIMPOSEDBYTHETRANSNASALP(CATHETER;19–21]. )N ADULTS WITH %O% THE FREQUENCY OF PATHOLOGICAL ACID REmUX APPEARS TO BE inordinately high [6, 22= &OR EXAMPLE  H ESOPHAGEAL P( MONITORING REVEALED ABNORMALACIDREmUXIN OFADULTSWITH%O%INONESTUDY;22= ANDIN  OFINANOTHER;6=4HEPRECISEFREQUENCYOF'%2$INPATIENTSWITH%O% REMAINSUNCLEAR ANDCONTROVERSYREGARDINGTHEDElNITIONOF%O%CONFOUNDSESTIMATESOFTHATFREQUENCY4HECONSENSUSDElNITIONOF%O%MENTIONEDABOVEEXCLUDES PATIENTSWITH'%2$AND THEREFORE STRICTADHERENCETOTHATDElNITIONWOULDRESULT INAFREQUENCYOF'%2$INPATIENTSWITH%O%

EoE Contributes to or Causes GERD #ONCEIVABLY EOSINOPHIL SECRETORY PRODUCTS COULD CAUSE '%2$ BY INCREASING GASTROESOPHAGEAL REmUX AND BY IMPAIRING THE ABILITY OF THE ESOPHAGUS TO CLEAR ITSELFOFREmUXEDMATERIAL&OREXAMPLE EOSINOPHILSPRODUCEVASOACTIVEINTESTINAL PEPTIDEAND0!& AGENTSTHATCANRELAXTHELOWERESOPHAGEALSPHINCTERANDTHEREBY PREDISPOSETOREmUX;23, 2]. Eosinophils also secrete interleukin (IL)-6, which can weaken esophageal muscle contractions, an effect that might impair esophageal

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peristalsis and acid clearance [25, 26]. In addition, some eosinophil secretory PRODUCTSHAVECYTOTOXICEFFECTSTHATMIGHTRENDERTHEESOPHAGEALEPITHELIUMMORE SUSCEPTIBLETOINJURYBYREmUXEDGASTRICMATERIAL;27–29=&OREXAMPLE EOSINOPHILS PRODUCEMAJORBASICPROTEIN WHICHHASBEENSHOWNTOIMPAIRBARRIERFUNCTIONIN monolayers of human colonic carcinoma cells [30]. In the bronchial mucosa of PATIENTSWITHASTHMA EOSINOPHILICINlLTRATIONISASSOCIATEDWITHDAMAGETOCELLULAR TIGHT JUNCTIONS AND DILATION OF THE INTERCELLULAR SPACES ;31= &INALLY EOSINOPHILS INDUCE THE MUCOSAL REMODELING WITH lBROSIS CHARACTERISTIC OF %O% AND SUCH lBROSISALSOMIGHTAFFECT,%3FUNCTIONANDPERISTALSISASITDOESINPATIENTSWITH scleroderma [32].

GERD Contributes to or Causes EoE -ECHANISMSWHEREBY'%2$MIGHTCAUSELOW GRADEINlLTRATIONOFTHEESOPHAGUS BY EOSINOPHILS ARE DISCUSSED ABOVE )N ADDITION '%2$ CAN CAUSE EPITHELIAL DAMAGE THAT CONCEIVABLY MIGHT PREDISPOSE TO THE DEVELOPMENT OF ALLERGIC ESOPHAGITIS4YPICALFOODALLERGENSHAVEAMOLECULARWEIGHTBETWEENANDK$ [33] and, normally, the esophageal epithelium is highly impermeable to such large molecules [3=&OREXAMPLE 4OBEYFOUNDTHATTHENORMALRABBITESOPHAGUSWAS VIRTUALLY IMPERMEABLE TO EPIDERMAL GROWTH FACTOR A PEPTIDE WITH A MOLECULAR WEIGHTOFK$ ANDTODEXTRANSWITHAMOLECULARWEIGHTOFK$;3]. When that ESOPHAGEALEPITHELIUMWASEXPOSEDTOACIDANDPEPSIN HOWEVER ITBECAMEPERMEABLETOEPIDERMALGROWTHFACTORANDTODEXTRANSASLARGEASK$"YINCREASING ESOPHAGEALPERMEABILITY THEREFORE '%2$COULDRENDERTHESQUAMOUSEPITHELIUM PERMEABLETOALLERGENS)TISALSOCONCEIVABLETHAT'%2$ INDUCEDRECRUITMENTOF IMMUNECELLSTOTHEESOPHAGEALEPITHELIUMMIGHTCONTRIBUTETOTHELOCALDEVELOPment of allergies.

Anti-inflammatory Effects of PPIs 4HE00)S WHICHBLOCKGASTRICACIDSECRETIONBYINHIBITINGTHEPROTONPUMPOFTHE gastric parietal cell, are widely regarded as the agents of choice for treating acidPEPTICDISORDERS SUCHAS'%2$&ORPATIENTSWHOHAVEGASTROINTESTINALSYMPTOMS OFUNCERTAINETIOLOGY IMPROVEMENTWITH00)THERAPYTRADITIONALLYHASBEENCONSIDERED PRIMA FACIE EVIDENCE OF AN ACID PEPTIC DISEASE (OWEVER IT HAS NOT BEEN WIDELYAPPRECIATEDTHAT00)S INADDITIONTOTHEIRANTISECRETORYEFFECTS HAVEANTIOXIDANTPROPERTIESANDDIRECTEFFECTSONNEUTROPHILS MONOCYTES ENDOTHELIALCELLS AND EPITHELIAL CELLS THAT MIGHT PREVENT INmAMMATION ;35]. The mechanisms proPOSED TO UNDERLIE THE ANTI INmAMMATORY EFFECTS OF THE 00)S ARE SUMMARIZED IN Table 11.1.

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Table 11.1 0ROPOSEDMECHANISMSUNDERLYINGANTI INmAMMATORYEFFECTSOFPROTONPUMPINHIBITORS !NTIOXIDANTEFFECTS $IRECTSCAVENGINGOFREACTIVEOXYGENSPECIES 2EPLENISHMENTOFPROTECTIVESULFHYDRYLMOLECULESINTHEGASTRICMUCOSA )NDUCTIONOFHEMEOXYGENASE  %FFECTSONINmAMMATORYCELLS )NHIBITIONOFOXIDATIVEBURSTINNEUTROPHILS Impaired phagocytosis of microorganisms by neutrophils $ECREASEDEXPRESSIONOFADHESIONMOLECULESBYNEUTROPHILSANDMONOCYTES Impaired neutrophil migration Effects on endothelial cells $ECREASEDEXPRESSIONOFADHESIONMOLECULES $ECREASEDPRODUCTIONOFPRO INmAMMATORYCYTOKINES Effects on epithelial cells $ECREASEDPRODUCTIONOFPRO INmAMMATORYCYTOKINES %FFECTSONGUTMICROmORA Growth inhibitory and killing effects on a number of bacteria and fungi !DAPTEDFROM+EDIKA 22;35=5SEDWITHPERMISSION

Antioxidant Effects )NmAMMATIONCAUSESTISSUEDAMAGETHROUGHOXIDATIVEINJURIESMEDIATEDBYAGENTS LIKEHYPOCHLOROUSACID ANOXIDANTPRODUCEDBYPHAGOCYTES ANDBYTRANSITIONMETALS like iron and copper [36, 37=/MEPRAZOLEHASBEENSHOWNTOPREVENTTHEOXIDATION of E CAROTENEBYHYPOCHLOROUSACID ANDTOINHIBITTHEOXIDATIONOFDEOXYRIBOSESUGAR mediated by iron and copper [37, 38]. Similarly, lansoprazole inhibits the copperINDUCEDOXIDATIONOFLOW DENSITYLIPOPROTEINS,$,S ;39], and both pantoprazole AND LANSOPRAZOLE CAN SCAVENGE HYDROXYL RADICALS GENERATED DURING CHEMICAL REACTIONSINVOLVINGTRANSITIONMETALS;38, 0=)NRATSSUBJECTEDTORESTRAINTANDCOLDSTRESS WHICHSTIMULATESTHEGASTRICMUCOSATOPRODUCEHYDROXYLRADICALSTHATCAUSEULCERATION OMEPRAZOLEPREVENTSGASTRICULCERSEVENWHENITISGIVENINDOSESTOOLOWTO inhibit gastric acid secretion [0=%SOMEPRAZOLEHASBEENSHOWNTOPREVENTGASTRIC glutathione depletion in rats treated with indomethacin [1=00)SALSOMIGHTPROTECT AGAINSTOXIDATIVEDAMAGEINTHEGASTROINTESTINALTRACTBYINDUCINGTHEENZYMEHEME OXYGENASE  IN ENDOTHELIAL AND EPITHELIAL CELLS ;2= (EME OXYGENASE  CATALYZES HEMEDEGRADATION THEREBYGENERATINGBILIRUBIN WHICHHASANTIOXIDANTEFFECTS AND CARBONMONOXIDE WHICHHASCYTOPROTECTIVEPROPERTIES

Effects on Inflammatory Cells )NTHESTOMACH 00)SBLOCKTHEP TYPE(+, K+!40ASEOFPARIETALCELLSTHATSECRETES ACIDINTOTHEGASTRICLUMEN3OMENONGASTRICCELLS LIKENEUTROPHILS HAVEVACUOLAR



E. Cheng et al.

V TYPE (+!40ASESTHATPUMPACIDINTOTHEEXTRACELLULARSPACEANDINTOINTRACELLULAR organelles like lysosomes [3, =4HESEV TYPE(+!40ASESAPPEARTOBESUSCEPTIBLE TOINHIBITIONBY00)S;5=AND THEREFORE ITISCONCEIVABLETHAT00)SMIGHTINTERFERE WITHCERTAINNEUTROPHILFUNCTIONS)NDEED 00)SHAVEBEENSHOWNTOINHIBITNEUTROPHIL CHEMOTAXISANDTOINTERFEREWITHTHEGENERATIONOFREACTIVEOXYGENSPECIES2/3 BY neutrophils [6–9=)NNEUTROPHILSANDENDOTHELIALCELLS WHICHALSOHAVEV TYPE PROTONPUMPS 00)SHAVEBEENFOUNDTOINHIBITTHEEXPRESSIONOFADHESIONMOLECULES THAT ENABLE NEUTROPHILS TO HOME INTO DISEASED TISSUES )N HUMAN UMBILICAL VEIN ENDOTHELIALCELLSSTIMULATEDWITHINTERLEUKIN  FOREXAMPLE 00)SINHIBITTHEEXPRESsion of intercellular adhesion molecule-1 (ICAM-1) and VCAM-1, and decrease endothelial-dependent neutrophil adhesion [50=!LTHOUGHTHESEDATASHOWTHAT00)S CANINTERFEREWITHNEUTROPHILICINmAMMATION ITISNOTCLEARTHATTHISINTERFERENCEIS EFFECTEDBYTHEINHIBITIONOFTHEV TYPE(+!40ASESOFNEUTROPHILSANDENDOTHELIAL cells [51].

Effect on the Production of Pro-inflammatory Cytokines by Epithelial and Endothelial Cells 00)SHAVEBEENSHOWNTOINHIBITTHEPRODUCTIONOFCERTAINPRO INmAMMATORYCYTOKines by epithelial and endothelial cells. Gastric mucosal production of IL-8, a potent neutrophil chemoattractant, appears to play an important role in mediating gastric INmAMMATIONMEDIATEDBYINFECTIONWITHHelicobacter pylori [52]. In a human gasTRICCANCERCELLLINEANDINHUMANUMBILICALVEINENDOTHELIALCELLSSTIMULATEDWITHH. pyloriEXTRACT FOREXAMPLE OMEPRAZOLEANDLANSOPRAZOLEBLOCKTHEPRODUCTIONOF IL-8 [53].

Clinical Implications of Anti-inflammatory Effects of PPI’s for Esophageal Eosinophilia 00)SCLEARLYAREEFFECTIVEFORTHETREATMENTOF'%2$ ANDTHEREAREDATATOSUGGEST THAT00)SALSOHAVEAPRIMARYROLEINTHETREATMENTOFESOPHAGEALEOSINOPHILIA;6]. In BOTHDISORDERS ITISNOTCLEARWHETHERTHEBENElCIALEFFECTSOFTHESEAGENTSAREDUE SOLELYTOGASTRICACIDINHIBITION ORWHETHERTHEANTI INmAMMATORYEFFECTSOFTHE00)S CONTRIBUTEASWELL.EVERTHELESS THEDATADISCUSSEDABOVERAISEASERIOUSCHALLENGE TOTHECOMMONCLINICALPRACTICEOFASSUMINGTHATASYMPTOMATICRESPONSETO00) TREATMENTISPROOFOFANUNDERLYINGACID PEPTICDISORDER)TISCONCEIVABLETHATTHE 00)SCOULDHAVEBENElCIALEFFECTSINANYNUMBEROFINmAMMATORYDISEASES INCLUDINGESOPHAGEALEOSINOPHILIA INWHICHACIDANDPEPSINMAYORMAYNOTHAVEAROLE !NINmUENTIALREPORTPUBLISHEDINDESCRIBEDTHREEPEDIATRICPATIENTSWHOHAD PROFOUNDESOPHAGEALEOSINOPHILIAANDSYMPTOMS ALLOFWHICHRESOLVEDCOMPLETELY WITH00)TREATMENT;5=!LTHOUGHNONEOFTHETHREEHADAHISTORYTYPICALOF'%2$

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THE AUTHORS CONCLUDED THAT THE RESPONSE TO 00) THERAPY WAS PROOF FOR UNDERLYING REmUXDISEASE ANDTHATTHEPROFOUNDESOPHAGEALEOSINOPHILIAWASAMANIFESTATIONOF PEPTICESOPHAGITIS(OWEVER APOSITIVERESPONSETO00)THERAPYDOESNOTNECESSARILY DISTINGUISH'%2$

Potential Role for PPIs in the Pathogenesis of EoE 00)SARECONSIDEREDAlRST LINETHERAPYFORPATIENTSSUSPECTEDOFHAVINGESOPHAGEAL eosinophilia [55=)RONICALLY HOWEVER RECENTSTUDIESALSOHAVESUGGESTEDAPLAUSIBLE HYPOTHESISWHEREBY00)S BYINTERFERINGWITHTHEPEPTICDIGESTIONOFDIETARYPROTEINS AND BY INCREASING GASTRIC MUCOSAL PERMEABILITY MIGHT CONTRIBUTE TO THE DEVELOPment of EoE [56–58]. -OSTRECOGNIZEDFOODALLERGENSAREGLYCOPROTEINCOMPONENTSTHATHAVEAMOLECULAR weight between 3 and 90 kD [33, 59=0EPTIDESSMALLERTHANK$MAYNOTBECAPABLE of inducing an immunological response [60=4HECLASS)MAJORHISTOCOMPATIBILITY COMPLEX-(#CLASS) OFANTIGEN PRESENTINGCELLSTYPICALLYPRESENTSPEPTIDESCOMPRISINGnAMINOACIDRESIDUESTOCYTOTOXIC4LYMPHOCYTES ANDSMALLERPEPTIDE fragments may be ignored by the immune system [61, 62=4HESEOBSERVATIONSSUGGESTTHATFOODPROTEINSTHATARERAPIDLYDIGESTEDINTOINDIVIDUALAMINOACIDS DIPEPtides, and tripeptides would be unlikely to induce an immunological response. The digestion of food proteins normally begins in the stomach through the action OFPEPSINPROTEINASESINTHEGASTRICJUICE4HEOPTIMALP(FORTHEENZYMATICACTIVITY OFTHEPEPSINSISBETWEENAND ANDMOSTOFTHEIRPROTEINASEACTIVITYCEASESAT P( LEVELS ABOVE  ;63, 6= !CID SUPPRESSIVE MEDICATIONS LIKE 00)S FREQUENTLY RAISE THE GASTRIC P( ABOVE LEVELS WHERE PEPSIN IS NOT ACTIVE ;6= 5NDER THOSE circumstances, dietary proteins that normally would be partially digested in the STOMACHCANREACHTHEDUODENUMLARGELYINTACT#ONCEIVABLY THATMIGHTEXPOSETHE SMALLINTESTINETOFOODALLERGENSTHATORDINARILYWOULDHAVEBEENDESTROYEDBYPEPTIC DIGESTIONAND THEREBY PREDISPOSETOTHEDEVELOPMENTOFFOODALLERGY)NPATIENTS WITH'%2$ FURTHERMORE THESEUNDIGESTEDALLERGENSCOULDBEREmUXEDBACKINTOTHE esophagus where they might initiate an immune response that contributes to the DEVELOPMENTOF%O% !SECONDMECHANISMWHEREBY00)SMIGHTCONTRIBUTETOTHEPATHOGENESISOF%O% INVOLVESTHEIREFFECTSONMUCOSALPERMEABILITY/NEGROUPOFINVESTIGATORSRECENTLY FOUNDTHATTHEIRPATIENTSWITHREmUXESOPHAGITISAND"ARRETTSESOPHAGUS MANYOF WHOMWEREON00)S HADABNORMALSUCROSEPERMEABILITYTESTS;65]. In a subsequent STUDY THOSEINVESTIGATORSPERFORMEDSUCROSEPERMEABILITYTESTSIN'%2$PATIENTS before and after 8 weeks of treatment with esomeprazole [58]. Although the RESEARCHERSORIGINALLYTHOUGHTTHAT00)TREATMENTSHOULDIMPROVEMUCOSALBARRIER FUNCTION THEY WERE SURPRISED TO lND THAT MOST PATIENTS EXHIBITED A SUBSTANTIAL INCREASEINMUCOSALPERMEABILITYTOSUCROSEAFTER00)TREATMENT4HISUNANTICIPATED EFFECT WAS CONlRMED IN A GROUP OF HEALTHY CONTROL SUBJECTS WHO ALSO DEVELOPED ABNORMALSUCROSEPERMEABILITYTESTSDURINGDAYSOF00)TREATMENT)NPATIENTSTAKING



E. Cheng et al.

00)S THEREFORE LARGEANDPOTENTIALLYALLERGENICPEPTIDESTHATESCAPEPEPTICDIGESTION BECAUSEOFACIDINHIBITIONMIGHTBETAKENUPTHROUGHTHE00) INDUCEDMUCOSALLEAK to elicit an immunological response. 5NTERSMAYRANDHERCOLLEAGUESIN6IENNAHAVESHOWNTHATTHEPEPTICDIGESTIONOF CERTAIN FOOD ALLERGENS IS EXQUISITELY SENSITIVE TO SMALL VARIATIONS IN P( ;66, 67]. 4HEY ALSO HAVE FOUND THAT MICE TREATED WITH 00)S DEVELOP ALLERGEN SPECIlC )G% ANTIBODIESWHENTHEYAREFEDCERTAINlSHANDNUTPREPARATIONS;68, 69]. In a clinical STUDY 5NTERSMAYRASSAYEDSERUM)G%LEVELSINADULTOUTPATIENTSWHOHADNO HISTORYOFALLERGYANDWHOWERETREATEDWITHAHISTAMINE( RECEPTORANTAGONISTOR A00)FORMONTHS;70=4ENPERCENTOFTHESEPATIENTSEXHIBITEDARISEIN)G%ANTIBODYLEVELS ANDNEW FOOD SPECIlC)G%ANTIBODIESDEVELOPEDIN)NASIMILAR STUDYOFOUTPATIENTSTAKINGANTISECRETORYMEDICATIONSFORMONTHS OF PATIENTSDEVELOPEDHAZELNUT SPECIlC)G%ANTIBODIESOFTHOSEDEVELOPEDSPECIlC SKINREACTIVITYANDMANIFESTEDCLINICALFOODALLERGYTOHAZELNUTS;69]. 4HE00)OMEPRAZOLEWASRELEASEDFORCLINICALUSEINTHELATESAND TODAY 00)SAREAMONGTHEMOSTCOMMONLYUSEDMEDICATIONSINTHEWORLD;71, 72=00)S AREUSEDREGULARLY NOTONLYINADULTS BUTOFTENINYOUNGCHILDRENWITH'%2$WHO might take these medications for years [73, 7=!FTERDAYSOFCONVENTIONAL DOSE 00)THERAPY GASTRICP(RISESTOLEVELSFORAPPROXIMATELYOFTHEDAY;75]. 7ITHHIGHERDOSES ASAREPRESCRIBEDOFTENINCLINICALPRACTICE GASTRICP(LEVELSCAN REMAINFORMORETHANOFTHEDAY;76=!TTHESEP(LEVELS THERECANBE little peptic digestion of a number of potential food allergens that normally would BEPARTIALLYDEGRADEDINTHESTOMACH4HERAPIDEMERGENCEOF%O%APPROXIMATELY ONEDECADEAFTER00)USAGEBECAMEWIDESPREADWOULDlTWELLWITHA00) ASSOCIATED food allergic disorder. 00)SHAVEBEENAMAINSTAYOFTHERAPYFORPATIENTSWITH'%2$FORMORETHANTWO DECADES ANDTHEYHAVEESTABLISHEDANEXCELLENTTRACKRECORDFORSAFETY$ESPITETHE PLAUSIBLEMECHANISMSDISCUSSEDABOVE BYNOMEANSISITCLEARTHAT00)SHAVECONTRIBUTED TO THE RISING FREQUENCY OF %O% .EVERTHELESS THIS INTERESTING HYPOTHESIS clearly warrants further study.

References  &URUTA '4 ,IACOURAS #! #OLLINS -( 'UPTA 3+ *USTINICH # 0UTNAM 0% ET AL &IRST )NTERNATIONAL 'ASTROINTESTINAL %OSINOPHIL 2ESEARCH 3YMPOSIUM &)'%23 3UBCOMMITTEES %OSINOPHILICESOPHAGITISINCHILDRENANDADULTSASYSTEMATICREVIEWANDCONSENSUSRECOMMENDATIONSFORDIAGNOSISANDTREATMENT'ASTROENTEROLOGYn  -ATTIOLI 3 0ILOTTI 6 3PANGARO - 'RIGIONI 7& :ANNOLI 2 &ELICE 6 ET AL 2ELIABILITY OF  HOURHOMEESOPHAGEALP(MONITORINGINDIAGNOSISOFGASTROESOPHAGEALREmUX$IG$IS3CI n  3PECHLER3* 'ENTA2- 3OUZA2&4HOUGHTSONTHECOMPLEXRELATIONSHIPBETWEENGASTROESOPHAGEALREmUXDISEASEANDEOSINOPHILICESOPHAGITIS!M*'ASTROENTEROLn  2ODRIGO3 !BBOUD' /H$ $E-EESTER32 (AGEN* ,IPHAM* ETAL(IGHINTRAEPITHELIAL EOSINOPHIL COUNTS IN ESOPHAGEAL SQUAMOUS EPITHELIUM ARE NOT SPECIlC FOR EOSINOPHILIC ESOPHAGITISINADULTS!M*'ASTROENTEROLn

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Chapter 12

Radiographic Diagnosis of Eosinophilic Esophagitis Marc S. Levine and David A. Katzka

Keywords %OSINOPHILIC ESOPHAGITIS s "ARIUM ESOPHAGOGRAPHY s %SOPHAGEAL MUCOSAs"IOPSYs%NDOSCOPY

Introduction The diagnosis of eosinophilic esophagitis (EoE) continues to evolve as we gain a better understanding of this fascinating disease. EoE initially was diagnosed pathoLOGICALLYBYAHIGHNUMBEROFINTRAEPITHELIALEOSINOPHILSINTHEESOPHAGUS BUTTHE DIAGNOSISISNOWBASEDONSEVERALHISTOLOGICPARAMETERSINCOMBINATIONWITHKEY DEMOGRAPHIC CLINICAL ANDENDOSCOPICFEATURES$ESPITENUMEROUSENDOSCOPICSTUDIES ON%O% THEROLEOFBARIUMESOPHAGOGRAPHYINDIAGNOSINGTHISDISEASEHASRECEIVED little attention in the gastroenterology literature. Lack of interest in esophagography is related to recognized advantages of endoscopy for directly visualizing the esophAGEALMUCOSAANDOBTAININGBIOPSYSPECIMENSASWELLASTHEDESIRETOAVOIDIONIZING radiation in patients with dysphagia. 7E BELIEVE HOWEVER THAT ENDOSCOPY AND BARIUM ESOPHAGOGRAPHY SHOULD BE REGARDEDASCOMPLEMENTARYRATHERTHANCOMPETITIVETECHNIQUESFORTHEEVALUATIONOF PATIENTSWITHDYSPHAGIAANDPOSSIBLE%O%)NSUCHCASES THEBARIUMSTUDYPROVIDES AGLOBALEXAMINATIONTHATCANBEUSEDNOTONLYTODETECTESOPHAGITISORSTRICTURES BUT ALSOTOASSESSSWALLOWINGFUNCTION ESOPHAGEALMOTILITY ANDTHEPRESENCEANDDEGREE OFGASTROESOPHAGEALREmUXDISEASE'%2$ INPATIENTSWITHOTHERCONDITIONSMASQUERADINGAS%O%BASEDONTHECLINICALPRESENTATION;1].

D.A. Katzka (*) $EPARTMENTOF-EDICINE -AYO#LINIC ST3TREET 37 2OCHESTER -. 53! E MAIL+ATZKADAVID MAYOEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_12, © Springer Science+Business Media, LLC 2012

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"ARIUM ESOPHAGOGRAPHY MAY ALSO REVEAL CHARACTERISTIC lNDINGS INCLUDING A RINGED ESOPHAGUS AND A SMALL CALIBER ESOPHAGUS THAT MARKEDLY RAISE THE PRETEST PROBABILITYOF%O%ONENDOSCOPY)NPATIENTSWITHASMALL CALIBERESOPHAGUS THE RADIOGRAPHIClNDINGSMAYINDICATETHENEEDFORUSINGAPEDIATRICENDOSCOPETOTRAVERSETHENARROWEDESOPHAGEALLUMENANDGUIDEPLANNINGFORENDOSCOPICDILATIONOR OTHER THERAPEUTIC INTERVENTIONS )N PATIENTS WITH TIGHT STRICTURES IN THE PROXIMAL ESOPHAGUS THAT PRECLUDE PASSAGE OF THE ENDOSCOPE BARIUM STUDIES ALSO ENABLE ASSESSMENTOFTHEMOREDISTALESOPHAGUSTHATCANNOTBEVISUALIZEDATENDOSCOPY&OR ALL OF THESE REASONS BARIUM STUDIES HAVE AN IMPORTANT ROLE IN THE EVALUATION AND TREATMENTOFPATIENTSWITH%O%/URCHAPTERDESCRIBESTHESTATEOFTHEARTOFBARIUM esophagography in the diagnostic work-up of this disease.

Technique for Performing Barium Esophagography "ARIUMESOPHAGOGRAMSSHOULDBEPERFORMEDASBIPHASICEXAMINATIONSTHATINCLUDE DOUBLE CONTRAST VIEWS WITH A HIGH DENSITY BARIUM SUSPENSION AND SINGLE CONTRAST VIEWSWITHALOW DENSITYBARIUMSUSPENSION;1]. The double-contrast phase is perFORMEDBYOBTAININGUPRIGHT LEFTPOSTERIOROBLIQUE,0/ DOUBLE CONTRASTVIEWSOF THEESOPHAGUSUSINGANEFFERVESCENTAGENT"AROS,AFAYETTE0HARMACEUTICALS ANDA WVHIGH DENSITYBARIUMSUSPENSION% : ($% : %-#OMPANY )NPATIENTS with dysphagia, the cardia and fundus should also be visualized with the patient in a lateral, right side down position for a double-contrast view of the gastric cardia and FUNDUS 4HE SINGLE CONTRAST PHASE IS SUBSEQUENTLY PERFORMED BY OBTAINING PRONE RIGHTANTERIOROBLIQUE2!/ SINGLE CONTRASTVIEWSOFTHEESOPHAGUSUSINGAWV LOW DENSITYBARIUMSUSPENSION%NTROBAR,AFAYETTE0HARMACEUTICALS 4HEDOUBLE CONTRASTVIEWSOPTIMIZEDETECTIONOFESOPHAGITISANDOTHERMUCOSALABNORMALITIES WHEREAS THE SINGLE CONTRAST VIEWS OPTIMIZE ESOPHAGEAL DISTENTION FOR DETECTION OF RINGSORSTRICTURESANDALSOIMPROVEDETECTIONOFHIATALHERNIAS %SOPHAGEALMOTILITYISEVALUATEDBYHAVINGTHEPATIENTTAKEMULTIPLEUSUALLYn INNUMBER SEPARATESWALLOWSOFLOW DENSITYBARIUMINTHEPRONE 2!/POSITION %SOPHAGEAL MOTILITY IS CONSIDERED ABNORMAL WHEN TWO OR MORE OF lVE SEPARATE SWALLOWS FAIL TO SHOW NORMAL PROGRESSION OF THE PRIMARY PERISTALTIC THROUGH THE ESOPHAGUSTOTHEGASTROESOPHAGEALJUNCTION;2]. At the end of the study, patients should routinely be evaluated for GERD by ROTATINGTHEMFROMTHESUPINEPOSITIONINTOTHERIGHTLATERALPOSITIONWHILEASSESSING FORSPONTANEOUS'%2$AND IFNECESSARY EMPLOYINGPROVOCATIVETECHNIQUESTOELICIT '%2$ INCLUDINGAWATERSIPHONTESTORSTRAIGHTLEGRAISINGORA6ALSALVAMANEUVER TOINCREASEINTRAABDOMINALPRESSURE7HENREmUXISOBSERVEDATmUOROSCOPY ATLEAST one radiograph of the esophagus should be obtained during the act of reflux for DOCUMENTATION )NMOSTRADIOLOGYDEPARTMENTS BARIUMESOPHAGOGRAPHYISCURRENTLYPERFORMED USINGDIGITALmUOROSCOPICEQUIPMENTTHATENABLESREVIEWANDINTERPRETATIONOFTHE DIGITALIMAGESATAPICTUREARCHIVINGANDCOMMUNICATIONSSYSTEM0!#3 WORKSTATION

12

Radiographic Diagnosis of Eosinophilic Esophagitis

149

WITHOUT THE NEED FOR CREATION OF HARD COPY RADIOGRAPHS 4HIS TYPE OF SYSTEM HAS MANYADVANTAGESOVERCONVENTIONALmUOROSCOPY ASITDECREASESRADIATIONEXPOSURE TO THE PATIENT EXPEDITES PATIENT THROUGHPUT FACILITATES IMAGE INTERPRETATION AND DECREASESTHEOVERALLCOSTSOFIMAGESTORAGE;].

Findings on Barium Esophagography )TISESTIMATEDTHATASMANYASOFALLPATIENTSWITH%O%HAVENOABNORMALITIES ATENDOSCOPY;4n6=%VENWHENENDOSCOPYISABNORMAL THEMOSTCOMMONlNDINGS AREMUCOSALLESIONS SUCHASLINEARFURROWS ERYTHEMA GRANULARITY ANDWHITEEXUDATES3UCHlNDINGSAREFOUNDATENDOSCOPYINnOFPATIENTSWITH%O%;4, 5], BUTTHISMUCOSALDISEASEISMUCHMOREDIFlCULTTODETECTONBARIUMESOPHAGOGRAphy, which therefore cannot be considered a sensitive test for the diagnosis of EoE. .EVERTHELESS TWOOFTHECLASSIClNDINGSOF%O%ATENDOSCOPYnARINGEDESOPHAGUS ANDASMALL CALIBERESOPHAGUSnCANALSOBEVISUALIZEDATESOPHAGOGRAPHY ANDTHESE lNDINGSAREFELTTOBERELATIVELYSPECIlCSIGNSOF%O%ONBARIUMSTUDIES4HUS A RELATIVELYCONlDENTDIAGNOSISOF%O%CANBEMADEWHENARINGEDESOPHAGUS SMALL CALIBERESOPHAGUS ORBOTHAREDETECTEDONESOPHAGOGRAPHY3TRICTURESINTHEPROXIMAL MIDDLE OR DISTAL THIRDS OF THE THORACIC ESOPHAGUS ARE ALSO A FREQUENT lNDING IN PATIENTSWITH%O% BUTSTRICTURESMAYBECAUSEDBYAVARIETYOFCONDITIONS SOTHEY ARELESSSPECIlCFORTHISDISEASE4HERADIOGRAPHIClNDINGSIN%O%ARECONSIDERED separately in the following sections.

Strictures 3TRICTURES ARE A COMMON lNDING IN %O% HAVING BEEN REPORTED AT ENDOSCOPY IN nOFADULTPATIENTSWITHTHISDISEASE;4, 5, 7="ARIUMESOPHAGOGRAPHYISALSO ANEXCELLENTTECHNIQUEFORDETECTINGSTRICTURES WHICHHAVEBEENREPORTEDINUPTO OFADULTPATIENTSWITH%O%;8=-OSTPATIENTSHAVESEGMENTALSTRICTURES;8n1], but the location of these strictures is variable. In one series, 70% of radiographically DIAGNOSEDSTRICTURESWERELOCATEDINTHEUPPERORMIDTHORACICESOPHAGUS&IG12.1) ;12], whereas in another series 64% were located in the distal thoracic esophagus or ATTHEGASTROESOPHAGEALJUNCTION&IG12.2 ;8=4HEMEANLUMINALDIAMETEROFTHESE STRICTURESISABOUTCMWITHARANGEOFnMM ANDTHEMEANLENGTHISABOUT CMWITHARANGEOFnCM ;8=)NTERESTINGLY STRICTURESINTHEUPPERORMIDTHOracic esophagus tend to be longer than those in the distal thoracic esophagus (see &IGS 12.1 and 12.2 ;8]. In general, esophageal strictures associated with EoE APPEARASLONGSEGMENTSOFSYMMETRICNARROWINGWITHASMOOTHCONTOURANDTAPERED MARGINSSEE&IG12.1 THOUGHOCCASIONALSTRICTURESCANBEMOREFOCAL ASYMMETRIC ORIRREGULAR;8=2ARELY PATIENTSWITH%O%MAYHAVECONCOMITANTSTRICTURESINSUCH

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Fig. 12.1 EoE with a stricture in the upper thoracic ESOPHAGUS3POTIMAGEFROM a double-contrast ESOPHAGOGRAMSHOWSALONG STRICTUREEXTENDINGFROMTHE thoracic inlet to the carina (arrows .OTEHOWTHE STRICTUREHASASMOOTH CONTOURANDTAPEREDPROXIMAL ANDDISTALMARGINSnFEATURES characteristic of strictures in EoE

CASES THEMOREDISTALSTRICTURECOULDBECAUSEDBYSIMULTANEOUSREmUXDISEASE;8]. Most patients with EoE and strictures are found to present with dysphagia. 4HEDIFFERENTIALDIAGNOSISFORSTRICTURESONBARIUMESOPHAGOGRAPHYDEPENDSON THELOCATIONOFTHESTRICTURE/THERCAUSESOFSTRICTURESINTHEUPPERORMIDTHORACIC ESOPHAGUSINCLUDE"ARRETTSESOPHAGUS MEDIASTINALIRRADIATION&IG12.), caustic INGESTION &IG 12.4 AND MEDICATIONS SUCH AS NONSTEROIDAL ANTI INmAMMATORY DRUGS .3!)$S POTASSIUM CHLORIDE AND QUINIDINE ;14, 15= WHEREAS THE MOST COMMONCAUSEOFSTRICTURESINTHEDISTALTHORACICESOPHAGUSISSCARRINGFROMREmUX ESOPHAGITIS&IG12.5 ;14=)NMOSTCASES HOWEVER THECORRECTDIAGNOSISISSUGgested by the clinical history and presentation.

Ringed Esophagus %SOPHAGEALRINGSAREAFREQUENTlNDINGINPATIENTSWITH%O%AVARIETYOFTERMSHAVE been used to describe these rings in the gastroenterology literature, including “corrugation” and “trachealization” of the esophagus as well as the “ringed esophagus”

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Radiographic Diagnosis of Eosinophilic Esophagitis

151

Fig. 12.2 EoE with a stricture in the distal thoracic esophagus. (a 3POTIMAGEFROMADOUBLE CONTRASTESOPHAGOGRAMSHOWSAFOCALSTRICTUREarrow) in the distal esophagus just above the gastroesophageal junction. (b 3POTIMAGEFROMASINGLE CONTRASTESOPHAGOGRAMINTHESAMEPATIENT SHOWSASMOOTH TAPEREDSTRICTUREarrow) in the distal esophagus above a hiatal hernia. Strictures IN THE DISTAL ESOPHAGUS IN PATIENTS WITH %O% TEND TO BE SHORTER THAN THOSE IN THE UPPER OR MID ESOPHAGUSSEE&IG12.1)

;5, 7, 16n18]. The extent and location of these rings are highly variable at endoscopy; THEYCANBECONlNEDTOTHEUPPER MIDDLE ORDISTALTHORACICESOPHAGUSORTHEYCAN HAVEAMOREDIFFUSEDISTRIBUTIONINTHEESOPHAGUS;5=4HESERINGSMAYCOMPROMISE LUMINALDIAMETERTOSUCHADEGREETHATITISDIFlCULTTOADVANCEANENDOSCOPEINTO THEDISTALESOPHAGUS;5]. 4HERINGEDESOPHAGUSMAYBEMANIFESTEDONBARIUMESOPHAGOGRAPHYBYDISTINCTIVERING LIKEINDENTATIONSTHATARESEENASMULTIPLE CLOSELYSPACED CONCENTRICRINGS TRAVERSINGTHELUMEN&IGS12.6n12.8 ;8]. In one study, the rings all occurred in the REGIONOFESOPHAGEALSTRICTURESSEE&IGS12.6 and 12.7 ;8= BUTINANOTHERMORE RECENTSTUDY THESERINGSWEREASSOCIATEDWITHASMALL CALIBERESOPHAGUSSEENEXT SECTION 3MALL #ALIBER %SOPHAGUS ;19]. As on endoscopy, there is considerable VARIATIONINTHELOCATIONANDEXTENTOFRINGFORMATIONONBARIUMSTUDIESINPATIENTS WITH%O%;8, 19=3OMEPATIENTSMAYHAVERINGSWITHOUTANASSOCIATEDSTRICTURESEE &IG12.8). Although the pathogenesis is uncertain, the ringed esophagus should be

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Fig. 12.3 Radiation stricture in the upper thoracic esophagus. This stricture has ASMOOTHCONTOURANDTAPERED PROXIMALANDDISTALMARGINS (arrows .OTESIMILARITYTO THE%O%STRICTUREIN&IG12.1

highly suggestive of EoE on esophagography, particularly if associated with STRICTURESORASMALL CALIBERESOPHAGUS A ringed esophagus has also been described in patients with congenital esophaGEALSTENOSISINWHOMBARIUMSTUDIESORENDOSCOPYREVEALEDCORRUGATEDESOPHAGEAL STRICTURESCONTAININGMULTIPLERINGS&IG12.9 ;20, 21]. In such cases, the rings have BEEN ATTRIBUTED TO ABERRANT EMBRYOLOGIC DEVELOPMENT WITH TRACHEOBRONCHIAL REMNANTSORACTUALCARTILAGINOUSRINGSINTHEWALLOFTHEESOPHAGUS;20, 21]. In retroSPECT HOWEVER WEBELIEVETHATSOMEPATIENTSWITHAPREVIOUSDIAGNOSISOFCONGENITAL ESOPHAGEALSTENOSISHAVEHADUNRECOGNIZED%O%ASTHECAUSEOFTHEIRSYMPTOMSAND THATPATIENTSWITHARINGEDESOPHAGUSANDESOPHAGEALSTRICTURESAREFARMORELIKELY to have EoE as the cause of their disease. 4HEDIFFERENTIALDIAGNOSISOFTHERINGEDESOPHAGUSALSOINCLUDESlXEDTRANSVERSE FOLDSINPATIENTSWITHPEPTICSTRICTURES&IG12.10 ;22=5NLIKETHERINGSIN%O% HOWEVER THESElXEDTRANSVERSEFOLDSAREFURTHERAPART PRODUCINGACHARACTERISTIC STEPLADDERAPPEARANCEDUETOTRAPPINGOFBARIUMBETWEENTHEFOLDS;22]. The feline ESOPHAGUS COULD ALSO CONCEIVABLY BE MISTAKEN FOR THE RINGED ESOPHAGUS OF %O%

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Radiographic Diagnosis of Eosinophilic Esophagitis



Fig. 12.4 Chronic lye STRICTUREINTHEMIDTHORACIC esophagus. This patient has a LONG SOMEWHATASYMMETRIC STRICTUREWITHASMOOTH CONTOURANDTAPEREDMARGINS (arrows). Again note SIMILARITYTOTHE%O%STRICTURE IN&IG12.1

&IG12.11 BUTTHESEDELICATETRANSVERSESTRIATIONSOCCURASATRANSIENTPHENOMENON ANDAREALMOSTALWAYSASSOCIATEDWITHGASTROESOPHAGEALREmUXRATHERTHANSTRICTURE FORMATION;2=&INALLY NONPERISTALTICCONTRACTIONSINTHEESOPHAGUSMAYOCCASIONALLY PRODUCEACORRUGATEDAPPEARANCE BUTTHISFORMOFESOPHAGEALDYSMOTILITYISALSO OBSERVEDASATRANSIENTlNDINGWITHOUTASSOCIATEDSTRICTUREFORMATION

Small-Caliber Esophagus 3INCEITSORIGINALDESCRIPTIONBY6ASILOUPOSIN;24= THESMALL CALIBERESOPHAgus has been recognized as an endoscopic sign of EoE in which there is diffuse loss OFCALIBEROFVIRTUALLYTHEENTIRETHORACICESOPHAGUS&IGS12.12 and 12.1 ;25n0]. )NARECENTSTUDY ITWASFOUNDTHATTHESMALL CALIBERESOPHAGUSOF%O%ISALSOCHARACTERIZED ON BARIUM ESOPHAGOGRAPHY BY LONG SEGMENT NARROWING OF THE THORACIC ESOPHAGUSTHENARROWEDSEGMENTHASAMEANLENGTHOFABOUTCMWITHSMOOTH

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Fig. 12.5 0EPTICSTRICTUREIN the distal esophagus. This patient has a focal stricture (arrow WITHSMOOTH TAPERED MARGINSINTHEDISTAL esophagus just above a hiatal HERNIA.OTESIMILARITYTOTHE %O%STRICTUREIN&IG12.2

UNIFORM CONTOURS AND TAPERED MARGINS THAT MERGE GRADUALLY WITH THE ADJACENT ESOPHAGUS;19=)NTHISSTUDY PATIENTSWITH%O%ALLHADAMEANTHORACICESOPHAGEAL DIAMETER OF  MM OR LESS WHEREAS CONTROL SUBJECTS ALL HAD A MEAN THORACIC ESOPHAGEALDIAMETERGREATERTHANMM SOMMWASAUSEFULTHRESHOLDDIAMETER FOR SUGGESTING THE DIAGNOSIS OF %O% ;19= )N THE SAME STUDY MORE THAN  OF PATIENTSWITHASMALL CALIBERESOPHAGUSONBARIUMSTUDIESWEREFOUNDTOHAVE%O% ONENDOSCOPICBIOPSYSPECIMENS SOTHISlNDINGAPPEARSTOBEARELATIVELYSPECIlC RADIOGRAPHICSIGNOF%O%;19=)TSHOULDBENOTEDTHATTHEPROXIMALEXTENTOFTHE SMALL CALIBERESOPHAGUSONBARIUMSTUDIESISVARIABLETHENARROWEDSEGMENTMAY EXTENDPROXIMALLYTOTHETHORACICINLET AORTICARCH OREVENTHELEFTMAINBRONCHUS WHEREASITUSUALLYEXTENDSDISTALLYTOTHEGASTROESOPHAGEALJUNCTION;19]. 4HESMALL CALIBERESOPHAGUSSHOULDBEDIFFERENTIATEDRADIOGRAPHICALLYFROMSTRICTURESIN%O% WHICHARECHARACTERIZEDBYSHORTER MOREFOCALSEGMENTSOFNARROWING THATHAVEMOREDISCRETEMARGINSSEE&IGS12.1 and 12.2 ;8]. Ring-like indentations

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Radiographic Diagnosis of Eosinophilic Esophagitis

155

Fig. 12.6 EoE with a ringed esophagus. This patient has a SMOOTH TAPEREDSTRICTUREIN the lower third of the thoracic ESOPHAGUS.OTEMULTIPLE distinctive ring-like indentations (arrows) in the region of the stricture. This lNDINGSHOULDBEHIGHLY SUGGESTIVEOF%O%ONBARIUM studies

(i.e., the ringed esophagus) have also been observed in about 60% of patients with a SMALL CALIBER ESOPHAGUS ;19], so the presence of rings should further support the DIAGNOSISOF%O%WHENASMALL CALIBERESOPHAGUSISDIAGNOSEDONBARIUMSTUDIES 4HEDEGREEOFNARROWINGINSOME%O%PATIENTSWITHASMALL CALIBERESOPHAGUSIS QUITESUBTLE HOWEVER SORADIOLOGISTSAREMORELIKELYTODIAGNOSEASMALL CALIBER ESOPHAGUS ON BARIUM EXAMINATIONS IF THEY HAVE A LOW THRESHOLD FOR THIS lNDING when interpreting the studies. 4HESMALL CALIBERESOPHAGUSOF%O%HASBEENREPORTEDONBARIUMSTUDIESINOLDER adolescents and adults, but to our knowledge, not in the pediatric population. We SUSPECT THIS IS BECAUSE BARIUM STUDIES ARE MORE LIKELY TO BE PERFORMED ON ADULT PATIENTS WITH %O% AND ALSO BECAUSE THE SMALL CALIBER ESOPHAGUS PRESUMABLY REPRESENTS AN ADVANCED STAGE OF %O% THAT DEVELOPS AFTER YEARS OF INmAMMATION lBROSIS ANDSCARRING.EVERTHELESS ITREMAINSUNCLEARWHYSOMEPATIENTSDEVELOP SUCH DIFFUSE ESOPHAGEAL DISEASE WHILE OTHERS HAVE MORE LOCALIZED DISEASE MANIfested by rings or strictures.

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Fig. 12.7 EoE with a ringed esophagus. A prone, SINGLE CONTRASTESOPHAGOGRAM SHOWAMILDSTRICTUREINTHE upper thoracic esophagus with subtle ring-like indentations (black arrows) in the region of the stricture. !MMINDIAMETER BARIUMTABLETwhite arrow) is seen to be lodged at the level of the stricture

Other Findings !GRANULARORNODULARAPPEARANCEOFTHEMUCOSAHASBEENDETECTEDONESOPHAGOGRAPHY IN UP TO  OF PATIENTS WITH %O% PRESUMABLY BECAUSE OF EDEMA AND INmAMMATION OF THE MUCOSA &IG 12.14 ;8]. Recently, Schatzki rings have also been reported in children with EoE. In one study, eight patients with EoE had rings THATWEREDEMONSTRATEDONLYONBARIUMSTUDIESDESPITEOTHERTYPICALlNDINGSOF%O% ATENDOSCOPY;1]. Such observations reflect not only the subtle nature of Schatzki RINGS BUTALSOTHEHIGHERSENSITIVITYOFBARIUMSTUDIESINDETECTINGTHESERINGSCOMPAREDTOENDOSCOPY;2]. Although there are no reports of Schatzki rings in adult PATIENTSWITH%O% SUCHRINGSMAYOCCASIONALLYBEENCOUNTEREDONBARIUMSTUDIES SEE&IG12.7). 2ARELY %O%PATIENTSWITHSTRICTURESORASMALL CALIBERESOPHAGUSMAYALSOHAVE ESOPHAGEALINTRAMURALPSEUDODIVERTICULASEE&IG12.1 ;19,  4]. As in other PATIENTS WITH PSEUDODIVERTICULOSIS THE PSEUDODIVERTICULA PRESUMABLY DEVELOP BECAUSEOFCHRONICESOPHAGITISANDSTRICTUREFORMATION4HESEPSEUDODIVERTICULAARE TYPICALLYSEENINPROlLEASTINY mASK SHAPEDOUTPOUCHINGSFROMTHEESOPHAGUS

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Radiographic Diagnosis of Eosinophilic Esophagitis

157

Fig. 12.8 EoE with a ringed esophagus. In this patient, a prone, single-contrast ESOPHAGOGRAMSHOWSTHE distinctive rings (small arrows) of EoE without a DElNITESTRICTUREINTHIS region. Also note a Schatzki ring (large arrow) as a focal ring-like constriction at the gastroesophageal junction just above a hiatal hernia. Schatzki rings have also been described in patients with EoE

!TRUEESOPHAGEALDIVERTICULUMHASALSOBEENDESCRIBEDINONEPATIENTWITH%O% BUT THISlNDINGCOULDHAVERESULTEDFROMMULTIPLEPREVIOUSESOPHAGEALDILATIONPROCEDURES;5="ARIUMSTUDIESMAYALSOREVEALHIATALHERNIAS GASTROESOPHAGEALREmUX ANDESOPHAGEALDYSMOTILITYINPATIENTSWITH%O% BUTSUCHlNDINGSMOSTLIKELYHAVE no relationship to this disease.

Other Radiologic Modalities 4HEREISSCANTEXPERIENCEWITHOTHERRADIOLOGICMODALITIESINTHEDIAGNOSISOF%O%)N two case reports, CT of the chest revealed diffuse thickening of the esophageal wall INPATIENTSWITHTHESMALL CALIBERESOPHAGUSOF%O%;6, 7]. Although experience is

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Fig. 12.9 Congenital esophageal stenosis with a ringed esophagus. This patient has distinctive ring-like constrictions (arrows) thought to be secondary to tracheobronchial REMNANTSWITHCARTILAGINOUS rings in the wall of the ESOPHAGUS.OTESIMILARITYTO the ringed esophagus of EoE

LIMITED ENDOSCOPICULTRASOUND%53 INPATIENTSWITH%O%HASREVEALEDLOSSOFTHE NORMALECHOLAYERSOFTHEESOPHAGUSANDDIFFUSEESOPHAGEALWALLTHICKENINGTHESE lNDINGSMAYBESECONDARYTOTRANSMURALlBROSISORLOCALIZEDTHICKENINGOFTHEMUSCULARISPROPRIA;8=ORSUBMUCOSA;9=)NOTHERSTUDIES %53HASREVEALEDPROMINENT LONGITUDINALFOLDS;40=ANDENLARGEDMEDIASTINALLYMPHNODESTHATWEREFOUNDTOBE REACTIVEWITHEOSINOPHILSONlNENEEDLEASPIRATION;41=.EVERTHELESS THEUTILITYOF %53INPATIENTSWITH%O%REMAINSUNCERTAIN!LSO THERELATIVELYLARGEDIAMETERSOF ENDOSCOPESUSEDFOR%53COULDINCREASETHERISKOFPERFORATIONINPATIENTSWITH%O% because of the high prevalence of strictures and rings in these individuals.

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Radiographic Diagnosis of Eosinophilic Esophagitis

159

Fig. 12.10 &IXEDTRANSVERSE folds in the distal esophagus SECONDARYTOSCARRINGFROM reflux esophagitis. This PATIENTHASAMILDPEPTIC stricture in the distal ESOPHAGUSABOVEASMALL HIATALHERNIA"ARIUMISALSO seen to be trapped between SEVERALlXEDTRANSVERSEFOLDS (arrows) in the region of the STRICTURE4HISlNDINGCOULD BEMISTAKENFORTHERINGED esophagus of EoE

Esophagography for Suspected Esophageal Perforation !DULT PATIENTS WITH %O% COMMONLY UNDERGO DILATION PROCEDURES FOR RELIEF OF dysphagia associated with rings and/or strictures. In the endoscopic literature, the risk of esophageal perforation during these dilation procedures appears to be greater INPATIENTSWITH%O%THANINOTHERPATIENTSWITHESOPHAGEALSTRICTURES0ATIENTSWITH %O% ALSO COMMONLY REPORT CHEST PAIN AFTER DILATION PROCEDURES INCREASING THE endoscopist’s concern about a possible perforation. As a result, EoE patients often undergo esophagography with water-soluble contrast agents to rule out esophageal PERFORATIONINTHISCLINICALSETTING&ORTUNATELY WHENLEAKSOCCURAFTERDILATIONPROCEDURES PATIENTSWITH%O%AREMORELIKELYTOHAVEINTRAMURALDISSECTIONSORSMALL sealed-off leaks than other patients with esophageal perforation. Because of the OFTEN SUBTLE NATURE OF THESE LEAKS THE RADIOLOGIST SHOULD IMMEDIATELY REPEAT THE STUDYWITHHIGH DENSITYBARIUMIFNOLEAKISDETECTEDWITHAWATER SOLUBLECONTRAST agent to increase the radiographic sensitivity for detecting subtle leaks. This approach increases the detection rate of esophageal perforation by 100% as COMPAREDTOADMINISTRATIONOFWATER SOLUBLECONTRASTAGENTSALONE;42].

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Fig. 12.11 &ELINEESOPHAGUSWITHMULTIPLETRANSVERSESTRIATIONSINTHEESOPHAGUSa) The initial DOUBLE CONTRASTVIEWSHOWSMULTIPLE CLOSELYSPACEDTRANSVERSEFOLDSINTHEESOPHAGUSDUETOCONTRACTIONOFTHELONGITUDINALLYORIENTEDMUSCULARISMUCOSAEb !REPEATVIEWMOMENTSLATERSHOWS NOEVIDENCEOFAFELINEESOPHAGUS4HESETRANSIENTTRANSVERSEFOLDSSHOULDNOTBEMISTAKENFORTHE ringed esophagus of EoE

Fig. 12.12 %O%WITHASMALL caliber esophagus. A single-contrast ESOPHAGOGRAMSHOWSLOSSOF distensibility of the entire THORACICESOPHAGUS.OTE HOWTHEREISDIFFUSELUMINAL narrowing without a discernible stricture. This lNDINGISCHARACTERISTICOF EoE

Fig. 12.13 %O%WITHASMALL caliber esophagus. A double-contrast ESOPHAGOGRAMSHOWSLOSSOF caliber of the entire thoracic esophagus indistinguishable FROMTHESMALL CALIBER ESOPHAGUSIN&IG12.12. This patient also has tiny ESOPHAGEALINTRAMURAL pseudodiverticula seen as TINYOUTPOUCHINGSFROMTHE wall of the esophagus

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Fig. 12.14 EoE with a granular esophagus. A double-contrast ESOPHAGOGRAMSHOWS diffuse granularity SECONDARYTOEDEMAAND SPASMOFTHEMUCOSA

Conclusion "ARIUMESOPHAGOGRAPHYCANBEHELPFULINANUMBEROFWAYSFOREVALUATINGPATIENTS WITHSUSPECTED%O%&IRSTANDFOREMOST ITISAGLOBALEXAMINATIONFORPATIENTSWITH dysphagia and can be used not only to diagnose EoE, but also a host of other abnorMALITIES IN THE PHARYNX AND ESOPHAGUS )N SOME PATIENTS THE BARIUM STUDY MAY DEMONSTRATERELATIVELYSPECIlClNDINGSOF%O% SUCHASTHERINGEDESOPHAGUSAND THE SMALL CALIBER ESOPHAGUS 7HEN THE BARIUM STUDY DETECTS SUBTLE STRICTURES OR DIFFUSEESOPHAGEALNARROWINGNOTVISUALIZEDATENDOSCOPY THESElNDINGSNOTONLY MAYEXPLAINTHEPATIENTSSYMPTOMS BUTALSOMAYINDICATETHENEEDFORANESOPHAGEALDILATIONPROCEDURE)N%O%PATIENTSWITHSEVEREDYSPHAGIA THEBARIUMSTUDY MAYALSOREVEALTIGHTSTRICTURESTHATCANNOTBETRAVERSEDBYTHEENDOSCOPEAND IN such cases, enable visualization of the esophagus below the stricture, facilitating TREATMENT PLANNING &INALLY ESOPHAGOGRAPHY HAS A CRITICAL ROLE IN ASSESSING FOR POSSIBLEPERFORATIONWHENESOPHAGEALDILATIONPROCEDURESAREPERFORMEDONTHESE patients.

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Radiographic Diagnosis of Eosinophilic Esophagitis



References  ,EVINE -3 2UBESIN 3% ,AUFER ) "ARIUM ESOPHAGOGRAPHY A STUDY FOR ALL SEASONS #LIN 'ASTROENTEROL(EPATOLn  /TT$* #HEN9- (EWSON%' ETAL%SOPHAGEALMOTILITYASSESSMENTWITHSYNCHRONOUSVIDEO TAPEmUOROSCOPYANDMANOMETRY2ADIOLOGYn  ,EVINE-3 ,AUFER)4HEGASTROINTESTINALTRACTDOSANDDONTSOFDIGITALIMAGING2ADIOLOGY n  -ÓLLER3 0UHL3 6IETH- 3TOLTE-!NALYSISOFSYMPTOMSANDENDOSCOPIClNDINGSIN PATIENTSWITHHISTOLOGICDIAGNOSESOFEOSINOPHILICESOPHAGITIS%NDOSCOPYn  ,UCENDO!* 0ASQUAL 4URRION*- .AVARRO- ETAL%NDOSCOPIC BIOPTIC ANDMANOMETRIClNDINGS IN EOSINOPHILIC ESOPHAGITIS BEFORE AND AFTER STEROID THERAPY A CASE SERIES %NDOSCOPY n  0RASAD '! 4ALLEY .* 2OMERO 9 ET AL 0REVALENCE AND PREDICTIVE FACTORS OF EOSINOPHILIC ESOPHAGITISINPATIENTSPRESENTINGWITHDYSPHAGIAAPROSPECTIVESTUDY!M*'ASTROENTEROL n  #ROESE * &AIRLEY 3+ -ASSON *7 ET AL #LINICAL AND ENDOSCOPIC FEATURES OF EOSINOPHILIC ESOPHAGITISINADULTS'ASTROINTEST%NDOSCn  :IMMERMAN3, ,EVINE-3 2UBESIN3% ETAL)DIOPATHICEOSINOPHILICESOPHAGITISINADULTS THERINGEDESOPHAGUS2ADIOLOGYn  0ICUS$ &RANK0(%OSINOPHILICESOPHAGITIS!*2!M*2OENTGENOLn -ATZINGER-! $ANEMAN!%SOPHAGEALINVOLVEMENTINEOSINOPHILICGASTROENTERITIS0EDIATR 2ADIOLn &ECZKO 0* (ALPERT 2$ :ONCA - 2ADIOGRAPHIC ABNORMALITIES IN EOSINOPHILIC ESOPHAGITIS 'ASTROINTEST2ADIOLn 6ITELLAS+- "ENNETT7& "OVA*' *OHNSON*# #ALDWELL*( -AYLE*%)DIOPATHICEOSINOPHILICESOPHAGITIS2ADIOLOGYn -AHAJAN, 7YLLIE2 0ETRAS2 3TEFFEN2 +AY-)DIOPATHICEOSINOPHILICESOPHAGITISWITH STRICTURE FORMATION IN A PATIENT WITH LONG STANDING EOSINOPHILIC GASTROENTERITIS 'ASTROINTEST %NDOSCn ,EVINE-3'ASTROESOPHAGEALREmUXDISEASE)N'ORE2- ,EVINE-3 EDITORS4EXTBOOKOF GASTROINTESTINALRADIOLOGYRDED0HILADELPHIA 0!%LSEVIERPn ,EVINE-3/THERESOPHAGITIDES)N'ORE2- ,EVINE-3 EDITORS4EXTBOOKOFGASTROINTESTINALRADIOLOGYRDED0HILADELPHIA 0!%LSEVIERPn !L (USSAINI!! 3EMAAN4 %L(AG)!%SOPHAGEALTRACHEALIZATIONAFEATUREOFEOSINOPHILIC ESOPHAGITIS3AUDI*'ASTROENTEROLn "OUSVAROS! !NTONIOLI$! 7INTER(32INGEDESOPHAGUSANASSOCIATIONWITHESOPHAGITIS !M*'ASTROENTEROLn 3IAFAKAS#' 2YAN#+ "ROWN-2 -ILLER4,-ULTIPLEESOPHAGEALRINGSANASSOCIATIONWITH EOSINOPHILIC ESOPHAGITIS n CASE REPORT AND REVIEW OF THE LITERATURE !M * 'ASTROENTEROL n  7HITE3" ,EVINE-3 2UBESIN3% 3PENCER'3 +ATZKA$! ,AUFER)4HESMALL CALIBERESOPHAGUSARADIOGRAPHICSIGNOFIDIOPATHICEOSINOPHILICESOPHAGITIS2ADIOLOGY n +ATZKA$! ,EVINE-3 'INSBERG'' ETAL#ONGENITALESOPHAGEALSTENOSISINADULTS!M *'ASTROENTEROLn /H#( ,EVINE-3 +ATZKA$! ETAL#ONGENITALESOPHAGEALSTENOSISINADULTSCLINICALAND RADIOGRAPHIClNDINGSINSEVENPATIENTS!*2!M*2OENTGENOLn ,EVINE-3 'OLDSTEIN(-&IXEDTRANSVERSEFOLDSINTHEESOPHAGUSASIGNOFREmUXESOPHAGITIS!*2!M*2OENTGENOLn 'OHEL 6+ %DELL 3) ,AUFER ) 2HODES 7( 4RANSVERSE FOLDS IN THE HUMAN ESOPHAGUS 2ADIOLOGYn 6ASILOPOULOS3 -URPHY0 !UERBACH! ETAL4HESMALL CALIBERESOPHAGUSANUNAPPRECIATED cause of dysphagia for solids in patients with eosinophilic esophagitis. Gastrointest Endosc. n

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M.S. Levine and D.A. Katzka

&OX6, .URKO3 &URUTA'4%OSINOPHILICESOPHAGITISITSNOTJUSTKIDSSTUFF'ASTROINTEST %NDOSCn -UNITIZ 6 -ARTINEZ DE (ARO ,& /RTIZ ! ET AL 0RIMARY EOSINOPHILIC ESOPHAGITIS $IS %SOPHAGUSn 0OTTER*7 3AEIAN+ 3TAFF$ +OMOROWSKI2! 3HAKER2 (OGAN7*%OSINOPHILICESOPHAGITIS IN ADULTS AN EMERGING PROBLEM WITH UNIQUE ESOPHAGEAL FEATURES 'ASTROINTEST %NDOSC n !RORA!3 9AMAZAKI+%OSINOPHILICESOPHAGITISASTHMAOFTHEESOPHAGUS#LIN'ASTROENTEROL (EPATOLn 2EMEDIOS- #AMPBELL# *ONES$- +ERLIN0%OSINOPHILICESOPHAGITISINADULTSCLINICAL ENDOSCOPIC HISTOLOGIC lNDINGS AND RESPONSE TO TREATMENT WITH mUTICASONE PROPIONATE 'ASTROINTEST%NDOSCn 3GOUROS3. "ERGELE# -ANTIDES!%OSINOPHILICESOPHAGITISINADULTSWHATISTHECLINICAL SIGNIlCANCE%NDOSCOPYn .URKO 3 4EITELBAUM *% (USAIN + ET AL !SSOCIATION OF 3CHATZKI RING WITH EOSINOPHILIC ESOPHAGITISINCHILDREN*0EDIATR'ASTROENTEROL.UTRn /TT$* #HEN9- 7U7# 'ELFAND$7 -UNITZ(!2ADIOGRAPHICANDENDOSCOPICSENSITIVITYINDETECTINGLOWERESOPHAGEALMUCOSALRING!*2!M*2OENTGENOLn 4SAI#- "UTLER* #ASH"$0SEUDODIVERTICULOSISWITHEOSINOPHILICESOPHAGITISlRSTREPORTED CASE'ASTROINTEST%NDOSCn %NGEL -! 2AITHEL - !MANN + 'REESS ( (AHN %' +ONTUREK 0# 2ARE COINCIDENCE OF EOSINOPHILIC ESOPHAGITIS WITH ESOPHAGEAL STENOSIS AND INTRAMURAL PSEUDODIVERTICULOSIS $IG ,IVER$ISn -ECKLENBURG) 7EBER& &OLWACZNY#3PONTANEOUSRECOVERYOFDYSPHAGIABYRUPTUREOFAN ESOPHAGEALDIVERTICULUMINEOSINOPHILICESOPHAGITIS$IG$IS3CIn (ORIKI. -ARUYAMA- &UJITA9 9ONEKURA4!CASEOFIDIOPATHICEOSINOPHILICESOPHAGITIS WITH #4 lNDINGS SHOWING MARKED THICKENING OF THE ESOPHAGEAL WALL *PN * 'ASTROENTEROL n 2UIZ 2EBOLLO-, !TIENZA 3ANCHEZ2 0EREZ !LONSO0!NEWCASEOFEOSINOPHILICESOPHAGITIS$IS%SOPHAGUSn 3TEVOFF# 2AO3 0ARSONS7 +AHRILAS0* (IRANO)%53 AND HISTOPATHOLOGIC CORRELATES IN EOSINOPHILICESOPHAGITIS'ASTROINTEST%NDOSCn &URUTA + !DACHI + +OWARI + ET AL ! *APANESE CASE OF EOSINOPHILIC ESOPHAGITIS *'ASTROENTEROLn &OX6, .URKO3 4EITELBAUM*% "ADIZADEGAN+ &URUTA'4(IGH RESOLUTION%53INCHILDREN WITHEOSINOPHILIChALLERGICvESOPHAGITIS'ASTROINTEST%NDOSCn 41. Bhutani MS, Moparty B, Chaya CT, Schnadig V, Logrono R. Endoscopic ultrasound-guided lNE NEEDLE ASPIRATION OF ENLARGED MEDIASTINAL LYMPH NODES IN EOSINOPHILIC ESOPHAGITIS %NDOSCOPYSUPPL%n 3WANSON */ ,EVINE -3 2EDFERN 2/ 2UBESIN 3% 5SEFULNESS OF HIGH DENSITY BARIUM FOR DETECTIONOFLEAKSAFTERESOPHAGOGASTRECTOMY TOTALGASTRECTOMY ANDTOTALLARYNGECTOMY!*2 !M*2OENTGENOLn

Chapter 13

Endoscopic Features of Eosinophilic Esophagitis David A. Leiman and Gary W. Falk

Keywords %OSINOPHILIC ESOPHAGITIS s $YSPHAGIA s &OOD IMPACTION s "IOPSY s%NDOSCOPY

Introduction %OSINOPHILICESOPHAGITIS%O% ISACHRONICINmAMMATORYDISORDEROFCHILDRENAND ADULTS4HEDISEASEISDElNEDBYCLINICOPATHOLOGICCRITERIA INCLUDINGSYMPTOMSOF DYSPHAGIAANDFOODIMPACTION ESOPHAGEALBIOPSIESWITHt15 eosinophils per high POWEREDlELDANDLACKOFRESPONSETOANTISECRETORYTHERAPY;1]. Patients with eosinoPHILICESOPHAGITISHAVEAWIDEVARIETYOFENDOSCOPIClNDINGS4ABLE13.1) and the DISEASEDOESNOTHAVEAUNIFORMENDOSCOPICAPPEARANCE)NFACT ONESTUDYSUGGESTED THATONLYOFINDIVIDUALSTHOUGHTTOHAVEEOSINOPHILICESOPHAGITISATTHETIMEOF ENDOSCOPYHADHISTOLOGICCONlRMATIONOFTHEDISEASEANDASUBSETOFPATIENTSMAY ALSOHAVEANENTIRELYNORMALAPPEARINGESOPHAGUS
;2=&URTHERMORE ENDOSCOPIClNDINGSMAYVARYBYAGE;3=%NDOSCOPYPLAYSAKEYROLEINTHEDIAGNOSISOF%O%PATIENTS ANDTHEVARIEDENDOSCOPICFEATURESOFTHISDISEASEARETHEFOCUSOFTHISCHAPTER

'7&ALK*) $EPARTMENTOF-EDICINE (OSPITALOFTHE5NIVERSITYOF0ENNSYLVANIA 0ERELMAN3CHOOL OF-EDICINE 0HILADELPHIA 0! 53! $EPARTMENTOF-EDICINE $IVISIONOF'ASTROENTEROLOGY (OSPITALOFTHE5NIVERSITY OF0ENNSYLVANIA 2AVDIN 3PRUCE3TREET 0HILADELPHIA 0! 53! E MAILGARYFALK UPHSUPENNEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_13, © Springer Science+Business Media, LLC 2012

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166

Table 13.1 %NDOSCOPICFEATURESASSOCIATEDWITHEOSINOPHILICESOPHAGITIS .ORMALENDOSCOPY ,INEARFURROWING Concentric rings White exudates $IMINISHEDVASCULARITY 0ROXIMALSTRICTURES 3MALLCALIBERESOPHAGUS Crepe-paper esophagus Schatzki’s ring Pseudodiverticula )NCREASEDWALLTHICKNESSON%53

Fig. 13.1 .ORMALENDOSCOPICAPPEARANCEOFTHEESOPHAGUS

Endoscopy of the Normal Esophagus 4HENORMALSQUAMOUSEPITHELIUMOFTHEESOPHAGUSAPPEARShPEARLYvWHITEONENDOSCOPICEXAMINATION&IG13.1 ANDTERMINATESATAh: LINEvWHICHSERVESASADEMARCATIONFROMTHESALMON COLOREDCOLUMNAREPITHELIUMOFTHESTOMACH4HEESOPHAGUS ISCHARACTERIZEDBYAlNENETWORKOFSUBEPITHELIALBLOODVESSELSTHATAREMOREEASILY SEENWITHPARTIALAIRINSUFmATIONANDACCENTUATEDWITHlLTERSSUCHASNARROW BAND IMAGING4HEBLOODVESSELSARELINEARLYORIENTEDANDMAYBEMOREAPPARENTINTHE distal esophagus.

 %NDOSCOPIC&EATURESOF%OSINOPHILIC%SOPHAGITIS

167

Endoscopic Features of EoE Linear Furrowing ,INEARFURROWSAREONEOFTHEMOSTCHARACTERISTIClNDINGSOF%O%4HESEAPPEARAS ALINEARPATTERNOFFURROWSTHATTYPICALLYINVOLVETHEFULLLENGTHOFTHEESOPHAGUS 4HEYCANBESEENWITHCONVENTIONALWHITELIGHTENDOSCOPYANDAREFURTHERACCENTUATED WITH NARROW BAND IMAGING &IG 13.2  4HE USE OF CHROMOENDOSCOPY WITH CONTRAST ENHANCING DYE CAN MAKE FURROWS APPEAR MORE DISTINCT AS WELL ;]. /BSERVATIONSWITHENDOSCOPICULTRASONOGRAPHYSUGGESTTHATFURROWSMAYBERELATED TOTHICKENINGOFTHEMUCOSALANDSUBMUCOSALLAYERS;5=&URROWSMAYBESEENEITHER ALONEORINCONJUNCTIONWITHOTHERENDOSCOPICFEATURESOF%O%)TISESTIMATEDTHAT LINEARFURROWSOCCURINnOF%O%PATIENTS;3, , 6n11]. &URROWS HAVE ALSO BEEN DESCRIBED IN BOTH GASTROESOPHAGEAL REmUX DISEASE '%2$ PATIENTSANDNORMALADULTS BUTFURROWSINTHESESETTINGSTENDTOBEMORE FAINT AND LIMITED TO THE DISTAL ESOPHAGUS ;= /VERALL THE PRESENCE OF FURROWS IS HIGHLYSUGGESTIVEOF%O%INBOTHCHILDRENANDADULTSANDISANENDOSCOPIClNDING THATMAYHELPTODISTINGUISH%O%PATIENTSFROM'%2$PATIENTS;3].

Concentric Rings 0ERHAPSTHEMOSTSTRIKINGENDOSCOPIClNDINGOF%O%ISTHATOFMULTIPLECONCENTRIC RINGSANDTERMEDTHERINGED CORRUGATED ORhFELINEvESOPHAGUS&IG13.3 2INGS

Fig. 13.2 %NDOSCOPICAPPEARANCEOFLINEARFURROWS

168

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Fig. 13.3 %NDOSCOPICAPPEARANCEOFCONCENTRICRINGS

Fig. 13.4 %NDOSCOPICAPPEARANCEOFCONCENTRICRINGSWITHLINEARFURROWS

CANAPPEARASTHEONLYlNDINGORMAYBESEENINCONJUNCTIONWITHOTHERENDOSCOPIC lNDINGSOF%O%&IGS13. and 13.5 #ONCENTRICRINGSMAYBEOBSERVEDFOCALLYIN ESOPHAGEALSEGMENTSORMAYINVOLVETHEENTIRELENGTHOFTHEESOPHAGUS!SSUCH THEYAREDISTINCTLYDIFFERENTFROMA3CHATZKISRING WHICHISTYPICALLYFOUNDONLYAT THESQUAMOCOLUMNARJUNCTION7ORKBY$ELLONETALSUGGESTSTHATTHElNDINGOF RINGSISONEOFTHEFEATURESTHATCANDIFFERENTIATE%O%PATIENTSFROM'%2$PATIENTS ;3=4HEETIOLOGYOFTHESEESOPHAGEALRINGSISNOTCOMPLETELYUNDERSTOODANDITIS

 %NDOSCOPIC&EATURESOF%OSINOPHILIC%SOPHAGITIS

169

Fig. 13.5 %NDOSCOPIC APPEARANCE OF CONCENTRIC RINGS WITH LINEAR FURROWS ACCENTUATED WITH NARROW BANDIMAGING

THOUGHTTHATRINGSMAYREPRESENTINTERMITTENTCONTRACTIONOFTHEDEEPMUSCLELAYER ORPOSSIBLYEOSINOPHILICINlLTRATION;12=)NTERESTINGLYTHESERINGSMAYRESOLVEWITH APPROPRIATETHERAPY;9=%STIMATESOFTHEPREVALENCEOFTHERINGEDESOPHAGUSRANGE FROMTOOF%O%PATIENTS;3, 7n10, 13n15].

White Exudate 7HITEEXUDATESCOMEINAVARIETYOFDIFFERENTSHAPESANDSIZES/THERTERMSUSEDFOR white exudates include white specks, pinpoint nodules, patches, and scales. These vary INSIZEFROMTOMMANDARETYPICALLYSCATTEREDALONGTHELENGTHOFTHEESOPHAGUS GIVINGTHEESOPHAGUSASPECKLEDAPPEARANCEANDMAYBEEASILYDISLODGED&IGS13.6 and 13.7 7HITEEXUDATESMAYBEMISTAKENFORCandida esophagitis, but in the setting OFEOSINOPHILICESOPHAGITIS THISlNDINGCORRESPONDSTOCOLLECTIONSOFEOSINOPHILSOR EVENMICROABSCESSESINTHEMUCOSA;15=4HElNDINGISMORECOMMONINCHILDRENTHAN ADULTS;3=4HEPREVALENCEOFWHITEEXUDATESVARIESFROMTO;3, 7n11, 16].

Diminished Mucosal Vascularity 4HENORMALESOPHAGUSHASAWELL DElNEDNETWORKOFSUBEPITHELIALBLOODVESSELS VISIBLE AT THE TIME OF ENDOSCOPY AS DESCRIBED ABOVE BUT MUCOSAL INmAMMATION MAYBEASSOCIATEDWITHALOSSOFTHENORMALVASCULARPATTERN4HISAPPEARANCEMAY BEDUETOEXPANSIONOFTHEBASALLAYEROFTHEMUCOSAACCOMPANIEDBYEDEMA;12].

170

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Fig. 13.6 %NDOSCOPICAPPEARANCEOFWHITEEXUDATE

Fig. 13.7 %NDOSCOPICAPPEARANCEOFWHITEEXUDATESCOMBINEDWITHLINEARFURROWSANDCONCENTRIC RINGSACCENTUATEDBYNARROWBANDIMAGING

)NASTUDYOFADULT%O%PATIENTSBY3TRAUMANNETAL LOSSOFTHENORMALVASCULAR PATTERNWASFOUNDINMAKINGITTHEMOSTFREQUENTENDOSCOPIClNDING;15]. /THERSHAVEDESCRIBEDDECREASEDVASCULARITYINnOF%O%PATIENTS;3, 7, 10]. 7HILE THIS lNDING MAY BE SUBJECTIVE CURRENT HIGH DElNITION WHITE LIGHT ENDOSCOPESALLOWFORMOREACCURATEDETECTIONOFTHISlNDING WHICHMAYPROVIDEACLUE FORTHEPRESENCEOF%O%

 %NDOSCOPIC&EATURESOF%OSINOPHILIC%SOPHAGITIS

171

Fig. 13.8 %NDOSCOPICAPPEARANCEOFTHECREPE PAPERESOPHAGUSACCOMPANIEDBYAMUCOSALRENT )MAGECOURTESYOF%VAN3$ELLON -$ -0(

Strictures &OCAL STRICTURES IN THE ABSENCE OF NARROW CALIBER ESOPHAGUS OR CONCENTRIC RINGS MAYBEENCOUNTEREDINnOF%O%PATIENTS;3, 7n10, 13, 15]. These strictures are TYPICALLYENCOUNTEREDINTHEPROXIMALESOPHAGUS MAYBESUBTLEANDARECHARACTERIZED BY SMOOTH CIRCUMFERENTIAL NARROWING OF THE ESOPHAGUS 3TRICTURES ARE MORE COMMONLYSEENINADULTSTHANINCHILDREN;3, ].

Small Caliber Esophagus 3MALLCALIBERESOPHAGUSISAUNIQUElNDINGIN%O%ANDISDElNEDASANARROWlXED INTERNALDIAMETEROFTHEESOPHAGUS;13=4HISFEATUREMAYNOTBEAPPRECIATEDONENDOSCOPEINSERTION BUTISCHARACTERIZEDBYEXTENSIVELINEARABRASIONSORMUCOSALRENTS BESTSEENUPONWITHDRAWALOFTHEENDOSCOPEORAFTERDILATION;17=4HEPREVALENCEOF SMALLCALIBERESOPHAGUSISESTIMATEDTOBEBETWEENAND;3, 9, 10, 13].

Crepe-Paper Esophagus 4HETERMhCREPE PAPERvESOPHAGUSWASlRSTSUGGESTEDBY3TRAUMANNETALINA CASESERIESOFlVEMEN4HEMUCOSAOFTHEESOPHAGUSISCHARACTERIZEDASFRAGILE DELICATE INELASTIC ANDTEARSWITHLITTLEPRESSURE&IG13.8 ;18].

172

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Schatzki’s Ring 3CHATZKIS RING A THIN DIAPHRAGM LIKE CIRCUMFERENTIAL FOLD OF MUCOSA PROTRUDING INTOLUMENANDLOCATEDATGASTROESOPHAGEALJUNCTIONISPRESENTINnOFTHE general population. It is typically associated with reflux disease but has also been DESCRIBED IN PATIENTS WITH %O% ;19= $ESPITE THESE REPORTS IT REMAINS UNCLEAR IF 3CHATZKISRINGSAREINFACTPARTOFTHESPECTRUMOF%O%$ESAIETALDESCRIBED ADULTSWITHDYSPHAGIAANDFOODIMPACTIONANDFOUNDTHATOFTHOSEWHOMET HISTOLOGICCRITERIAFOR%O%HADA3CHATZKISRING;11]. Gonsalves et al. reported that OFADULTPATIENTSWITH%O%HADINCIDENTALlNDINGSOFA3CHATZKISRING BUTNONE OF THE PATIENTS WITH 3CHATZKIS RINGS HAD SIGNIlCANT MUCOSAL EOSINOPHILIA ;10]. (OWEVER OTHERSHAVEFAILEDTOlNDARELATIONSHIPBETWEEN3CHATZKISRINGSAND%O% ;20]. Thus the data to date suggest that there is no clear relationship between Schatzki’s rings and EoE.

Pseudodiverticulosis !MORERECENTLYDESCRIBEDlNDINGIN%O%ISTHEPRESENCEOFINTRAMURALPSEUDODIVERticulosis. Pseudodiverticulosis is a rare finding in the esophagus characterized by MULTIPLE mASK SHAPED OUTPOUCHINGS IN THE ESOPHAGEAL WALL THAT REPRESENT DILATED EXCRETORYDUCTSOFESOPHAGEALMUCUSGLANDS;21]. These are usually seen in the setTINGMOTORABNORMALITIESASWELLASINCandidaINFECTION CORROSIVEINGESTION STRICTURES 0LUMMERn6INSON AND CARCINOMA ;22]. Pseudodiverticulae have been DESCRIBEDINTWOCASEREPORTSTODATE&IG13.9 ;21, 22].

Normal Endoscopy in EoE )NTERESTINGLY ACOMPLETELYNORMALENDOSCOPYMAYBEENCOUNTEREDINnOF patients with EoE.;2, 3, 7, 1=)NASTUDYOFPATIENTSWITHUNEXPLAINEDDYSPHAGIA AT THE -AYO #LINIC  OF  PATIENTS  WITH A NORMAL APPEARING ESOPHAGUSHAD%O%ONBIOPSIES/VERALL THISlNDINGMAYBEMORECOMMONINTHE PEDIATRICTHANTHEADULTPOPULATION;3].

Endosonographic Findings %NDOSONOGRAPHY HAS BEEN STUDIED IN A LIMITED NUMBER OF %O% PATIENTS TO DATE ! CASE REPORT OF AN ELDERLY MALE BY 3TEVOFF ET AL DESCRIBED CIRCUMFERENTIAL BUT ASYMMETRICTHICKENINGORTHEMUSCULARISPROPRIA;23=&OXETALFOUNDSIGNIlCANT DIFFERENCES IN TOTAL WALL THICKNESS  MM VS  MM COMBINED MUCOSA AND

 %NDOSCOPIC&EATURESOF%OSINOPHILIC%SOPHAGITIS

173

Fig. 13.9 %NDOSCOPICAPPEARANCEOFTHEPSEUDODIVERTICULOSISWITHCONCENTRICRINGS)MAGECOURTESYOF%VAN3$ELLON -$ -0(

SUBMUCOSA THICKNESS  MM VS  MM AND MUSCULARIS PROPRIA THICKNESS MMVSMM BETWEENCHILDRENWITH%O%ANDCONTROLCHILDREN;2]. Wall THICKENINGHASALSOBEENDESCRIBEDINANADULTCASEREPORT;25].

Conclusions and Future Directions $ESPITEINCREASEDAWARENESS UNDERSTANDING ANDEVALUATIONOF%O% STRICTENDOSCOPIC CRITERIAANDTERMINOLOGYFORDElNINGTHEDISEASEREMAINELUSIVE)TSEEMSCLEARTHAT DESPITETHEGROWINGNUMBEROFENDOSCOPICFEATURESIDENTIlEDANDDESCRIBEDABOVE THESEALONEARENOTSUFlCIENTTOMAKETHEDIAGNOSIS3OMEFEATURESOF%O%AREMORE COMMONINCHILDRENNORMAL WHITEPLAQUES ERYTHEMA WHEREASOTHERFEATURESARE MORECOMMONINADULTSCONCENTRICRINGS PROXIMALSTRICTURES CREPEPAPERMUCOSA NARROWCALIBERESOPHAGUS ;3=4HEWIDEVARIETYOFFEATURESDESCRIBEDABOVEMAYBE FOUNDALONEORINCOMBINATIONIN%O%PATIENTS&URTHERMORE ONESTUDYHASSHOWN ONLYOFPATIENTSWITHENDOSCOPIClNDINGSTHOUGHTTOBECOMPATIBLEWITH%O% WILLRECEIVEADIAGNOSISOF%O%ANDASDESCRIBEDABOVE ASUBSETOFPATIENTSWITH%O% WILLHAVEANORMALENDOSCOPY;2=4HEDIAGNOSTICUTILITYOFENDOSCOPICFEATURESOF



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%O%INCREASESWITHTHENUMBEROFFEATURESPRESENTWHENONEFEATUREWASPRESENT %O%WASDIAGNOSEDONLYOFTHETIMEVSnOFTHETIMEWHENMORETHAN ONEFEATURERINGS WASPRESENT;2=4HEINTER ANDINTRAOBSERVERAGREEMENTFORTHE VARIOUSFEATURESDESCRIBEDABOVEHAVENOTBEENEVALUATEDTODATEANDARECLEARLYIN NEEDOFFURTHERSTUDY)TISHOPEDTHATSTANDARDIZEDTERMINOLOGYANDDElNITIONSOF ENDOSCOPIC lNDINGS OF THE ESOPHAGUS IN %O% BECOME PART OF THE NEW CONSENSUS GUIDELINESUNDERDEVELOPMENTATPRESENT

References  &URUTA'4 ,IACOURAS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGYn  0RASAD '! 4ALLEY .* 2OMERO 9 ET AL 0REVALENCE AND PREDICTIVE FACTORS OF EOSINOPHILIC ESOPHAGITISINPATIENTSPRESENTINGWITHDYSPHAGIAAPROSPECTIVESTUDY!M*'ASTROENTEROL n  $ELLON%3 'IBBS7" &RITCHIE+* ETAL#LINICAL ENDOSCOPIC ANDHISTOLOGIClNDINGSDISTINGUISH EOSINOPHILIC ESOPHAGITIS FROM GASTROESOPHAGEAL REmUX DISEASE #LIN 'ASTROENTEROL (EPATOLn  #ROESE * &AIRLEY 3+ -ASSON *7 ET AL #LINICAL AND ENDOSCOPIC FEATURES OF EOSINOPHILIC ESOPHAGITISINADULTS'ASTROINTEST%NDOSCn  &OX6, .URKO3 &URUTA'4%OSINOPHILICESOPHAGITISITSNOTJUSTKIDSSTUFF'ASTROINTEST %NDOSCn  'UPTA3+ &ITZGERALD*& #HONG3+ ETAL6ERTICALLINESINDISTALESOPHAGEALMUCOSA6,%-  A TRUE ENDOSCOPIC MANIFESTATION OF ESOPHAGITIS IN CHILDREN 'ASTROINTEST %NDOSC  n  -ÓLLER3 0ÓHL3 6IETH- ETAL!NALYSISOFSYMPTOMSANDENDOSCOPIClNDINGSINPATIENTS WITHHISTOLOGICALDIAGNOSESOFEOSINOPHILICESOPHAGITIS%NDOSCOPYn  #OHEN -3 +AUFMAN !" 0ALAZZO *0 ET AL !N AUDIT OF ENDOSCOPIC COMPLICATIONS IN ADULT EOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOLn  2EMEDIOS- #AMPBELL# *ONES$- ETAL%OSINOPHILICESOPHAGITISINADULTSCLINICAL ENDOSCOPIC HISTOLOGIClNDINGS ANDRESPONSETOTREATMENTWITHmUTICASONEPROPIONATE'ASTROINTEST %NDOSCn 'ONSALVES . 0OLICARPIO .ICOLAS - :HANG 1 ET AL (ISTOPATHOLOGIC VARIABILITY AND ENDOSCOPIC CORRELATES IN ADULTS WITH EOSINOPHILIC ESOPHAGITIS 'ASTROINTEST %NDOSC  n $ESAI4+ 3TECEVIC6 #HANG#( ETAL!SSOCIATIONOFEOSINOPHILICINmAMMATIONWITHESOPHAGEALFOODIMPACTIONINADULTS'ASTROINTEST%NDOSCn &OX 6, %OSINOPHILIC ESOPHAGITIS ENDOSCOPIC lNDINGS 'ASTROINTEST %NDOSC #LIN . !M n 0OTTER*7 3AEIAN+ 3TAFF$ ETAL%OSINOPHILICESOPHAGITISINADULTSANEMERGINGPROBLEM WITHUNIQUEESOPHAGEALFEATURES'ASTROINTEST%NDOSCn  +APLAN- -UTLU%! *AKATE3 ETAL%NDOSCOPYINEOSINOPHILICESOPHAGITIShFELINEvESOPHAGUS ANDPERFORATIONRISK#LIN'ASTROENTEROL(EPATOLn 3TRAUMANN! 3PICHTIN(0 "UCHER+! ETAL%OSINOPHILICESOPHAGITISREDONMICROSCOPY WHITEONENDOSCOPY$IGESTIONn ,IM*2 'UPTA3+ #ROFlE*- ETAL7HITESPECKSINTHEESOPHAGEALMUCOSAANENDOSCOPIC MANIFESTATION OF NON REmUX EOSINOPHILIC ESOPHAGITIS IN CHILDREN 'ASTROINTEST %NDOSC n

 %NDOSCOPIC&EATURESOF%OSINOPHILIC%SOPHAGITIS

175

6ASILOPOULOS3 -URPHY0 !UERBACH! ETAL4HESMALL CALIBERESOPHAGUSANUNAPPRECIATED CAUSEOFDYSPHAGIAFORSOLIDSINPATIENTSWITHEOSINOPHILICESOPHAGITIS'ASTROINTEST%NDOSC n 3TRAUMANN! 2OSSI, 3IMON(5 ETAL&RAGILITYOFTHEESOPHAGEALMUCOSAAPATHOGNOMONIC ENDOSCOPICSIGNOFPRIMARYEOSINOPHILICESOPHAGITIS'ASTROINTEST%NDOSCn .URKO 3 4EITELBAUM *% (USAIN + ET AL !SSOCIATION OF 3CHATZKI RING WITH EOSINOPHILIC ESOPHAGITISINCHILDREN*0EDIATR'ASTROENTEROL.UTRn 20. Sgouros SN, Bergele C, Mantides A. Schatzki’s rings are not associated with eosinophilic ESOPHAGITIS'ASTROINTEST%NDOSCn %NGEL -! 2AITHEL - !MANN + ET AL 2ARE COINCIDENCE OF EOSINOPHILIC ESOPHAGITIS WITH ESOPHAGEALSTENOSISANDINTRAMURALPSEUDODIVERTICULOSIS$IG,IVER$ISn 4SAI#- "UTLER* #ASH"$0SEUDODIVERTICULOSISWITHEOSINOPHILICESOPHAGITISlRSTREPORTED CASE'ASTROINTEST%NDOSCn 3TEVOFF # 2AO 3 0ARSONS 7 ET AL %53 AND HISTOPATHOLOGIC CORRELATES IN EOSINOPHILIC ESOPHAGITIS'ASTROINTEST%NDOSCn &OX 6, .URKO 3 4EITELBAUM *% ET AL (IGH RESOLUTION %53 IN CHILDREN WITH EOSINOPHILIC hALLERGICvESOPHAGITIS'ASTROINTEST%NDOSCn 25. Bhutani MS, Moparty B, Chaya CT, et al. Endoscopic ultrasound-guided fine-needle aspiraTION OF ENLARGED MEDIASTINAL LYMPH NODES IN EOSINOPHILIC ESOPHAGITIS %NDOSCOPY  3UPPL%n

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Chapter 14

Histologic Features of Eosinophilic Esophagitis Margaret H. Collins

Keywords %OSINOPHILICESOPHAGITISs'ASTROESOPHAGEALREmUXDISEASEs0EDIATRIC s0ATHOLOGY

Introduction %OSINOPHILICESOPHAGITIS%% ISANINCREASINGLYRECOGNIZEDCHRONICINmAMMATORY disorder of the esophagus affecting both adults and children [1–3]. EE shows a STRONGPREDILECTIONFORMALES ANDMAYOCCURINFAMILIES;4]. Esophageal biopsies FROM %% PATIENTS EXHIBIT CHARACTERISTIC HISTOLOGY ;5, 6] (Figs. 14.1–14.3). Gene MICROARRAYANALYSISOFESOPHAGEALBIOPSIESIDENTIlESATRANSCRIPTOMEUNIQUETO%% CHARACTERIZEDBYMARKEDOVEREXPRESSIONOFTHEEOTAXIN GENE WHICHENCODESA CHEMOKINETHATATTRACTSEOSINOPHILSINTOESOPHAGEALEPITHELIUM;7]. Results of an ONGOING GENOME WIDE ASSOCIATION STUDY STRONGLY IMPLICATE THE THYMIC STROMAL LYMPHOPOIETIN 43,0 GENE AS ALSO IMPORTANT IN THE PATHOGENESIS OF %% ;8]. #LINICALANDEXPERIMENTALSTUDIESDEMONSTRATETHATMULTIPLECYTOKINESPARTICIPATE INNUMEROUSASPECTSOFTHISDISEASE;9–16].

M.H. Collins (*) $EPARTMENTOF0ATHOLOGY 5NIVERSITYOF#INCINNATI #INCINNATI#HILDRENS (OSPITAL-EDICAL#ENTER "-, "URNETT!VENUE #INCINNATI /( 53! E MAIL-ARGARETCOLLINS CHMCCORG C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_14, © Springer Science+Business Media, LLC 2012

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M.H. Collins

Fig. 14.1 (a 4HISESOPHAGEALBIOPSYILLUSTRATESMANYOFTHEHISTOLOGICFEATURESOFEOSINOPHILIC ESOPHAGITIS%% 4HEREARENUMEROUSINTRAEPITHELIALEOSINOPHILSINCLUDINGATTHESURFACEtop), the BASALLAYEROFTHEEPITHELIUMISEXPANDEDbar), papillae appear elongated, and intercellular spaces appear dilated (arrow ;HEMATOXYLINANDEOSIN(% ¾=b 4HISESOPHAGEALBIOPSYFROMTHE SAME PATIENT WHOSE BIOPSY IS SHOWN IN a APPEARS NORMAL 4HIS IS A BIOPSY FOLLOWING THERAPY FOR%%)NTRAEPITHELIALEOSINOPHILSWERENOTFOUNDINANYHIGHPOWERlELDINTHEBIOPSY ANDTHE EPITHELIALARCHITECTUREANDINTEGRITYARERESTOREDTONORMAL(% ¾

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Fig. 14.2 (a 4HISBIOPSYINCLUDESTHELAMINAPROPRIAblack arrowATLEFT ANDMUSCULARISMUCOSA (black arrowPOINTINGDOWNINCENTER THATARENOTSEENINMOSTESOPHAGEALBIOPSIES4HELAMINA PROPRIAFORMSADISTINCTLAYERBELOWTHEESOPHAGEALSQUAMOUSEPITHELIUM ANDINTHISCASESHOWS lBROSIS )T ALSO SHOWS MAINLY CHRONIC INmAMMATION THAT INCLUDES PLASMA CELLS white arrow), as well as scattered eosinophils (outlined arrow 4HEDEEPERLAMINAPROPRIACLOSERTOTHEMUSCULARISMUCOSAAPPEARSNORMAL;HEMATOXYLINANDEOSIN(% ¾=b 4HISISACLOSERVIEWOFTHE biopsy in (a 4HEDENSElBROSISOFTHELAMINAPROPRIAISMOREAPPARENT ANDPLASMACELLSwhite arrow) and eosinophils (outlined arrow ARESEENMORECLEARLY!NEXTENSIONOFTHELAMINAPROPRIA FORMINGAPAPILLAISSEENATTHERIGHT!LSOAPPARENTISTHEMARKEDBASALLAYEREXPANSION DILATED INTERCELLULARSPACES ANDNUMEROUSINTRAEPITHELIALEOSINOPHILS(% ¾

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Fig. 14.3 (a 4HISPIECETHATAPPEARSNORMALISFROMTHESAMEBIOPSY THESAMESITEINTHEESOPHAgus, as the piece shown in (b 4HISILLUSTRATIONEMPHASIZESTHEPATCHYNATUREOFTHEINlLTRATEIN EOSINOPHILIC ESOPHAGITIS %% AND THE NEED TO SUBMIT MULTIPLE SAMPLES IF %% IS SUSPECTED TO INCREASETHEDIAGNOSTICYIELD;HEMATOXYLINANDEOSIN(% ¾=b !LTHOUGHSOMEWHATTANGENTIALLY ORIENTED THIS BIOPSY SHOWS MANY OF THE HISTOLOGIC FEATURES OF %% INCLUDED TRAILS OF EXTRACELLULAREOSINOPHILGRANULESarrows )FTHISPIECEWASNOTINCLUDEDINTHESAMPLE THEDIAGNOSISWOULDBEMISSED4HISPATIENTHASINmAMMATORYBOWELDISEASE(% ¾

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Definition %%ISDElNEDASESOPHAGEALEOSINOPHILICINmAMMATIONTHATISREFRACTORYTOANTI REmUX THERAPY OROCCURSINTHEPRESENCEOFNORMALP(MONITORING;17]. It is a clinicopathoLOGICDIAGNOSIS%%CANNOTBEDIAGNOSEDBYCLINICALSIGNSANDSYMPTOMSONLY%% cannot be diagnosed by biopsy only. EE is diagnosed in patients with the appropriate CLINICALSETTINGBYESOPHAGEALBIOPSYTHATSHOWSEOSINOPHILICINmAMMATION !TTENTIONCONTINUESTOBEFOCUSEDONh4(%vNUMBERTHATDElNES%%4HEDIAGNOSISOF%%ISNOTBASEDONTHENUMBERONLYTHECLINICALSETTINGISASIMPORTANTTOTHE DIAGNOSISASTHEBIOPSYHISTOLOGY4HECONSENSUSSTATEMENTRECOMMENDSATHRESHOLD VALUEOFat leastAPEAKCOUNTOFINTRAEPITHELIALEOSINOPHILSINA¾HIGHPOWER lELDHPF INANESOPHAGEALBIOPSYASPARTOFTHEDIAGNOSISOF%%#LINICIANSAND INVESTIGATORSMAYSETAHIGHERTHRESHOLDVALUEFORTHEPEAKEOSINOPHILCOUNT IFTHEY BELIEVE THAT IS APPROPRIATE ;18, 19]. It is not RECOMMENDED THAT A THRESHOLD VALUE lower than 15/hpf is set for the peak esophageal eosinophil count to diagnose EE.

Indeterminate Esophagitis 'UIDELINES FOR DIAGNOSIS AND TREATMENT MAY NOT BE APPLICABLE TO ALL PATIENTS &OR EXAMPLE SOMEPATIENTSWHOAPPEARCLINICALLYTOHAVE%%HAVEESOPHAGEALBIOPSIES that contain eosinophils, but fewer than 15/hpf [20, 21= 4HESE BIOPSIES SHOULD BE CONSIDEREDINDETERMINATEFOR%%&IG14.4). Clinicians and pathologists need to conSULTEACHOTHERABOUTTHESECASES SINCEEACHPROVIDESPARTOFTHEDIAGNOSIS BUTNEITHER supplies the entire diagnosis. In such cases, pathologists should be aware of the patchy NATUREOFTHEINlLTRATESIN%%ANDEXAMINEADDITIONALHISTOLOGICSECTIONS ESPECIALLYIF THE EPITHELIUM AND LAMINA PROPRIA APPEAR ABNORMAL &IG 14.3). In patients whose BIOPSIES ARE INITIALLY INDETERMINATE REPEAT BIOPSIES AT AN APPROPRIATE TIME MAY BE MOREINFORMATIVE4HEGOALISTOTREATEACHPATIENTAPPROPRIATELY TOPROVIDETHETHERAPYTHATANINDIVIDUALPATIENTREQUIRESnTOEXERCISETHEARTOFMEDICINE)NTHESCENARIO INWHICHTHECLINICALSETTINGISSTRONGLYINDICATIVEOF%% BUTTHEBIOPSYISEQUIVOCAL A CLINICIANMAYOPTTOTREATPATIENTSWITHTHOSElNDINGSFOR%% ESPECIALLYIFOTHERTHERAPEUTICOPTIONSHAVEFAILED)NTHISSETTING PATIENTRESPONSETOTHERAPYFOR%%SHOULDBE COMMUNICATED BY THE CLINICIAN TO THE PATHOLOGIST 2EPORTING THE OUTCOME OF CASES SUCHASTHESETOTHELARGERMEDICALCOMMUNITYWILLHELPTOFURTHERDElNETHEDISEASE

Differential Diagnosis %%MAYBECLASSIlEDASAPRIMARYORSECONDARYDISEASE;22=4HEPRIMARYFORMIS OFTENASSOCIATEDWITHALLERGY4HESECONDARYFORMISASSOCIATEDWITHOTHERDISTINCT DISEASES%SOPHAGEALHISTOLOGYDOESNOTDISTINGUISHPRIMARYFROMSECONDARYFORMS )TISIMPORTANTFORPATHOLOGISTSANDCLINICIANSTOREALIZETHATROUTINEESOPHAGEALHISTOLOGYDOESNOTIDENTIFYASPECIlCETIOLOGYFOR%% DOESNOTDISTINGUISHATOPICFROM NONATOPICPATIENTS FAMILIALFROMSPORADICCASES MALESFROMFEMALES ETC

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Gastroesophageal Reflux Disease !MONGTHECAUSESOFSECONDARY%% GASTROESOPHAGEALREmUXDISEASE'%2$ ISTHE MOST IMPORTANT BECAUSE IT IS THE MOST COMMON '%2$ MAY MIMIC PRIMARY %% CLINICALLYANDHISTOLOGICALLY$ISTINGUISHING%%FROM'%2$ISIMPORTANT BECAUSE THETHERAPYFORTHEDISEASESDIFFER&UNDOPLICATIONMAYBEINDICATEDFORSOMEPATIENTS WHOHAVE'%2$ BUTITISNOTINDICATEDFORPATIENTSWHOHAVE%%4HEREFORE GOOD CLINICALPRACTICEISTOBIOPSYTHEESOPHAGUSPRIORTOPERFORMINGFUNDOPLICATIONANDTO CONSIDERTHEDIAGNOSISOF%%IFNUMEROUSINTRAEPITHELIALEOSINOPHILSAREFOUND;23]. )NDEED nOFPATIENTSWHOHAVEREFRACTORY'%2$IE WHODONOTRESPOND TOMEDICALANTI REmUXTHERAPY HAVE%%;24, 25]. 0ATIENTSWHOAREBELIEVEDCLINICALLYTOHAVE'%2$AREOFTENTREATEDEMPIRICALLY WITH MEDICATION AND IF THERE IS SATISFACTORY RESOLUTION OF SIGNS AND SYMPTOMS OF '%2$ ENDOSCOPYWITHBIOPSYISNOTPERFORMED&OREXAMPLE ARECENTSTUDYOFCHILDRENWHOHADSIGNSANDSYMPTOMSOFESOPHAGEALDYSFUNCTION WITHNORMALORABNORMAL P( MONITORING AND A PEAK EOSINOPHIL COUNT t15/hpf reported a substantial RESPONSERATETOPROTONPUMPINHIBITOR00) THERAPY DElNEDASEOSINOPHILSHPFON REPEATESOPHAGEALBIOPSYHOWEVER ONLYOFTHETOTALPOPULATIONOFPATIENTSWHO METTHEINITIALINCLUSIONCRITERIAHADREPEATBIOPSY;26]. Although in the past, intraepiTHELIALEOSINOPHILSWERECONSIDEREDSPECIlCINDICATORSOFABNORMALESOPHAGEALREmUX it is likely that there are few if any intraepithelial eosinophils in esophageal biopsies FROM'%2$PATIENTSWHOHAVENOTBEENTREATEDFORREmUXDISEASE!NOLDERSTUDYIN CHILDREN THAT LINKED REmUX TO INTRAEPITHELIAL EOSINOPHILS IN BIOPSIES ACTUALLY DOCUMENTEDFEWEOSINOPHILSINPATIENTSWITHABNORMALREmUX;27=)NTHATSTUDY VIRTUALLY all patients who had intraepithelial eosinophils, and few eosinophils were reported or ILLUSTRATED HAD ABNORMAL ACID REmUX BUT FEWER THAN HALF OF THE PATIENTS WHO HAD ABNORMALACIDREmUXHADINTRAEPITHELIALEOSINOPHILSINTHEIRESOPHAGEALBIOPSIES !MONGPATIENTSWHOHAVE'%2$ BIOPSIESDEMONSTRATINGt15 eosinophils/hpf occur [28=0ATIENTSWHOHAVETHEHISTOLOGICANDENDOSCOPICFEATURESTHATAREHIGHLY CHARACTERISTIC OF %% INCLUDING LARGE NUMBERS OF INTRAEPITHELIAL EOSINOPHILS WITH ABSCESSESANDFURROWEDESOPHAGEALMUCOSAMAYRESPONDCOMPLETELY CLINICALLYAND HISTOLOGICALLY TOANTI REmUXMEDICATIONS;29, 30=4HESEPATIENTSSHOULDBECONSIDEREDTOHAVE'%2$ ASTHEYDONOTREQUIREADDITIONALTHERAPY4HEPREVALENCEOF BIOPSIESTHATHAVEtEOSINOPHILSHPFAMONGUNTREATED'%2$PATIENTSISUNKNOWN SINCEMOSTDONOTHAVEBIOPSIESOBTAINEDPRIORTOTHERAPY 3TATISTICALLY SIGNIlCANT DIFFERENCES EXIST FOR VARIOUS ASPECTS OF THE ESOPHAGEAL HISTOLOGYOFPATIENTSWHOHAVE'%2$ONLYCOMPAREDTOTHOSEWHOHAVE%%ONLY BUT Fig. 14.4 (a 4HISBIOPSYWASTAKENFROMANADOLESCENTMALEWHOPRESENTEDWITHAFOODIMPACTION (EHADAHISTORYOFALLERGICRHINITISANDOTHERALLERGIES4HEEPITHELIUMISTHICK ANDTHEREISSUPERlCIALEPITHELIALNECROSISarrow 4HELAMINAPROPRIAISlBROTICwhite arrow ANDINmAMEDWITH LYMPHOCYTES PLASMA CELLS AND EOSINOPHILS &EW INTRAEPITHELIAL EOSINOPHILS ARE SEEN outlined arrow 4HISBIOPSYSHOULDBECONSIDEREDINDETERMINATE;HEMATOXYLINANDEOSIN(% ¾= (b 4HE PATIENT WAS TREATED MEDICALLY FOR REmUX DISEASE BUT CONTINUED TO BE SYMPTOMATIC AND REPEAT BIOPSIES SHOWED FEWER EPITHELIAL ALTERATIONS BUT NUMEROUS INTRAEPITHELIAL EOSINOPHILS (arrows PEAKCOUNTHPF CONSISTENTWITHEOSINOPHILICESOPHAGITIS(% ¾

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there is not a histologic characteristic that occurs in one disease but not the other [31]. )T IS TRUE THAT THE HISTOLOGIC CHANGES IN ESOPHAGEAL BIOSPIES ARE GENERALLY MORE MARKEDIN%%COMPAREDTO'%2$ BUTTHEREAREEXCEPTIONS;29, 30, 32]. %%ISADISEASETHATISANTIGEN DRIVEN SHOWSNUMEROUSINTRAEPITHELIALEOSINOPHILS INESOPHAGEALBIOPSIES ANDISNOTAMELIORATEDBYTHERAPYFORREmUX WHEREAS'%2$ ISADISEASETHATINMOSTPATIENTSISRESPONSIVETOACIDSUPPRESSIONASMONOTHERAPY and shows few if any intraepithelial eosinophils in esophageal biopsies. In practice, NOTALLPATIENTSCANBECLEARLYIDENTIlEDASHAVINGEITHERONEORTHEOTHERDISEASE SOME PATIENTS HAVE COMPELLING EVIDENCE OF BOTH DISEASES AND MANY %% PATIENTS REPORTSOME BUTINCOMPLETE CLINICALIMPROVEMENTWITH00)THERAPY;33, 34]. In supPORTOFTHISCLINICALOBSERVATIONISINVITRODATATHATCELLSFROMPRIMARYESOPHAGEAL EPITHELIALCELLCULTURESSIGNIlCANTLYINCREASEEOTAXIN SECRETIONATACIDICP(;15]. 4HEEOTAXIN GENEISTHEMOSTUPREGULATEDGENEINTHE%%TRANSCRIPTOME ISEXPRESSED INESOPHAGEALEPITHELIALCELLS ANDENCODESACHEMOKINETHATISAPOWERFULATTRACTANT for eosinophils [7= #ONVERSELY THERE ARE OBSERVATIONS INDICATING THAT THE USE OF ACID SUPPRESSIVETHERAPYFOR'%2$ALSOMIGHTCONTRIBUTETOTHEDEVELOPMENTOF%% [35=#LEARLY THEINTERACTIONBETWEENPATHOLOGICREmUXANDESOPHAGEALANTIGENSENSITIZATIONMUSTBEEXPLOREDFURTHER)DEALLY FUTURESTUDIESSHOULDINCLUDEPLACEBO CONTROLGROUPS BECAUSETHEPLACEBOEFFECTMAYBEGREATERTHANANTICIPATED;36].

Beyond GERD /THER DISEASES THAT HAVE BEEN ASSOCIATED WITH ESOPHAGEAL BIOPSIES SHOWING THE CHARACTERISTICHISTOLOGYOF%%INCLUDECELIACDISEASEANDIDIOPATHICINmAMMATORY bowel disease [37] (Fig. 14.3 )NPATIENTSWHOARESUSPECTEDTOHAVEPRIMARY%% BIOPSYFROMEXTRA ESOPHAGEALSITESSHOULDBEOBTAINED INCLUDINGTHELOWER')TRACT IFCLINICALLYINDICATED TOUNCOVEREOSINOPHILICDISEASEATOTHERSITES ANDTODISCOVER OTHER PATHOLOGY AT THOSE SITES SUCH AS CELIAC DISEASE OR IDIOPATHIC INmAMMATORY bowel disease.

General Features )N%% THEHISTOLOGICCHANGESARETYPICALLYPATCHYANDTHEREFORE EXAMININGMULTIPLE BIOPSYPIECESINCREASESTHEDIAGNOSTICSENSITIVITYOFENDOSCOPY;34, 38].

Eosinophils 4HECURRENTRECOMMENDATIONISTHATEOSINOPHILSINTHEMOSTINTENSELYINmAMEDAREA INANESOPHAGEALBIOPSYAREENUMERATEDTOGENERATEAPEAKCOUNTOFEOSINOPHILSHPF 4HISISPRACTICALFORDAILYSURGICALPATHOLOGYPRACTICE0EAKVALUESHAVEBEENSHOWN

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TO CORRELATE WELL WITH THE RESULTS OF MORE EXTENSIVE EOSINOPHIL QUANTITATION ;39]. -OREEXTENSIVECOUNTINGMAYBEAPPROPRIATEFORRESEARCHSTUDIES ANDDOCUMENTTHE PATCHYNATUREOFTHEDISEASEINMOSTCASES )TISRECOMMENDEDTHATEOSINOPHILSARECOUNTEDAT¾TOTALMAGNIlCATION4HE AREAONGLASSSLIDESSUBTENDEDBYOBJECTIVESVARIESAMONGMICROSCOPES ANDSUCH VARIABILITYAFFECTSTHETOTALEOSINOPHILCOUNT/PTIMALLY SEQUENTIALBIOPSIESFROMA GIVENPATIENTAREEVALUATEDBYTHESAMEPATHOLOGISTUSINGTHESAMEMICROSCOPE OR ANYDIFFERENCEINTHEAREAOFTHEVARIOUSMICROSCOPESUSEDTOQUANTITATEEOSINOPHILS is taken into account when reporting peak eosinophil counts. Reporting eosinophils as NUMBERUNITAREAISNOTCURRENTLYASTANDARDPRACTICE BUTREPORTINGCOUNTSTHATWAY WOULDHELPTOSTANDARDIZECOUNTSAMONGPATHOLOGISTS %OSINOPHILSMAYBEFOUNDDISPERSEDINTHEEPITHELIUMINCASESOF%% ANDMAY ALSOFORMMICRO ABSCESSESANDLAYERSATTHELUMINALSURFACE;40] (Fig. 14.5 4HESE FEATURESAREFOUNDMOSTOFTENINBIOPSIESTHATARETHEMOSTINTENSELYINmAMED;41].

Degranulation %XTRACELLULARGRANULESAREOFTENSEENIN%%BIOPSIES MOSTLYTHOSETHATAREINTENSELY INmAMED&IG14.3b !TLEASTSOMEDEGRANULATIONMAYBESECONDARYTOMECHANICAL factors [42, 43=.EVERTHELESS EXTRACELLULAREOSINOPHILGRANULESAREBOUNDBYMEMBRANESTHATEXPRESSRECEPTORSANDRELEASEPROTEININRESPONSETOLIGANDBINDING;44, 45=4HESEDATASUPPORTTHECONCEPTTHATEXTRACELLULARGRANULESMAYBEIMPORTANTIN the pathogenesis of eosinophil-related disorders including EE. Antibodies to eosinoPHILGRANULECONTENTS SUCHASMAJORBASICPROTEIN EOSINOPHILPEROXIDASE ANDEOSINOPHIL DERIVED NEUROTOXIN DEMONSTRATE MORE EXTRACELLULAR GRANULES THAN ARE FOUND ON HEMATOXYLIN AND EOSIN (% STAIN ;20, 30, 46, 47= 4HESE ANTIBODIES MAY HELP ULTIMATELYTOCLASSIFYCASESTHATARENOTEASILYCLASSIlED BUTIMMUNOHISTOCHEMISTRY IS NOT CURRENTLY REQUIRED FOR DIAGNOSIS %LECTRON MICROSCOPY OF %% BIOPSIES HAS SHOWNTHATTHEEOSINOPHILGRANULESAREACTIVATED;48].

Epithelial Reactivity %XPANSIONOFTHEBASALLAYERISCOMMONLYFOUNDIN%%&IG14.5 4HEBASALLAYER REMAINSMITOTICALLYACTIVEANDREPLENISHESTHEREMAINDEROFTHEESOPHAGEALSQUAMOUS EPITHELIUMNORMALLY)N%% THEDEGREEOFHYPERPLASIACORRELATESWITHTHENUMBEROF eosinophils [7, 49=4HEPROLIFERATIONMARKER-)" ANTIBODYDEMONSTRATESTHATEPIthelial cell proliferation is increased in both EE and GERD [50]. Epithelial prolifERATIONDIMINISHESFOLLOWINGTHERAPYFOR%%;12, 36, 49]. 4HEREISPERSUASIVEEXPERIMENTALEVIDENCETHATCYTOKINESIMPORTANTINTHEPATHOGENESISOF%%AFFECTESOPHAGEALEPITHELIUM&OREXAMPLE #$ ),TRANSGENICMICE show greater basal layer hyperplasia after allergen challenge than nontransgenic

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Fig. 14.5 (a 4HISBIOPSYOFTHEDISTALESOPHAGUSFROMA YEAR OLDSYMPTOMATICWOMANSHOWS MANYOFTHEFEATURESOFEOSINOPHILICESOPHAGITIS INCLUDINGMARKEDBASALLAYERHYPERPLASIA DILATED INTERCELLULARSPACES ANDNUMEROUSINTRAEPITHELIALEOSINOPHILSTHATARECONCENTRATEDATTHESURFACE A focus of surface layering is seen at the upper left (arrow ;HEMATOXYLINANDEOSIN(% ¾= (b !PIECEFROMTHEPROXIMALESOPHAGUSOBTAINEDATTHESAMEENDOSCOPICPROCEDURESHOWSTHE MICROSCOPICCORRELATEOFWHITESTREAKSORPATCHESSEENONTHEESOPHAGEALMUCOSAATENDOSCOPY EOSINOPHILSADMIXEDWITHSHEDNECROTICEPITHELIALCELLSATTHESURFACE(% ¾

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MICE;14=%PITHELIALHYPERPLASIAINHUMAN%%BIOPSIESISREDUCEDINPATIENTSWHO HAVEBEENTREATEDWITHANANTIBODYTO), ;12]. !NOTHERCYTOKINETHATISOVEREXPRESSEDINHUMAN%%DIRECTLYAFFECTSESOPHAGEAL EPITHELIUM)NTERLEUKIN ),  INCREASESEOTAXIN PRODUCTIONINVITROBYCULTUREDHUMANESOPHAGEALEPITHELIALCELLSINVIVO THEEOTAXIN GENEISUPREGULATED IN%% M2.!LEVELSAREINCREASEDINHUMAN%%BIOPSIES ANDINSITUHYBRIDIZATION DEMONSTRATESEOTAXIN EXPRESSIONINHUMANESOPHAGEALEPITHELIUMIN%%;7, 15]. %OTAXIN ISESSENTIALINTHEPATHOGENESISOF%% BECAUSEITATTRACTSEOSINOPHILSINTO ESOPHAGEALEPITHELIUM4HEUPREGULATIONOFEOTAXIN APPEARSTOBEDIRECTEDATLEAST in part by IL-13. )NHUMAN%% lLAGGRINGENEEXPRESSIONISREDUCEDANDlLAGGRINM2.!LEVELSARE SIGNIlCANTLYDIMINISHEDIN%%ESOPHAGEALBIOPSIES BUTRETURNTONORMALFOLLOWING therapy [7, 15=&ILAGGRINPROTEINPERFORMSANIMPORTANTFUNCTIONINBARRIERPROTECTIONINEPIDERMISANDISDOWNREGULATEDINATOPICDERMATITIS ACONDITIONTHATOCCURS INSOME%%PATIENTS&URTHERMORE ALOSSOFFUNCTIONMUTATIONINTHElLAGGRINGENE ISMOREPREVALENTAMONG%%PATIENTSTHANPATIENTSWITHOUT%%), ACTSDIRECTLYON CULTUREDHUMANESOPHAGEALEPITHELIALCELLSTODECREASETHEEXPRESSIONOFTHElLAGGRIN gene [15=4HESEDATASUGGESTASIGNIlCANT),  MEDIATEDALTERATIONINEPITHELIAL BARRIERINTEGRITYIN%%THATMAYCONTRIBUTETOTHECHRONICNATUREOFTHEDISEASE

Other Cell Types 4HEESOPHAGUSISTHElRSTPARTOFTHE')TRACTTHATENCOUNTERSFOOD.ORMALESOPHAGEAL MUCOSA CONTAINS A VARIETY OF CELL TYPES THAT ARE IMPORTANT FOR IMMUNE COMPETENCE )NSECTIONSOFESOPHAGEALMUCOSALBIOPSIESSTAINEDWITH(% EOSINOPHILSARE THE PREDOMINANT INmAMMATORY CELLS IN %% (OWEVER SPECIAL STAINS OR ANTIBODIES MAYBEREQUIREDTODETECTOTHERCELLTYPESTHATAREALSOINCREASEDINESOPHAGEALEPITHELIUMIN%%

Dendritic Cells -OST%%PATIENTSHAVEEVIDENCEOFALLERGENSENSITIZATION INCLUDINGTOFOOD ANDMAY RESPONDWELLTOANTIGENELIMINATIONDIET;51]. Dendritic cells are antigen-presenting CELLS THAT ARE FOUND IN SKIN AND MUCOSA AND ARE NOT SEEN WITH THE (% STAIN Langerhans cells are epithelial dendritic cells that stain with CD1a antibody (Fig. 14.6 ,ANGERHANSCELLSAREFOUNDINNORMALESOPHAGEALEPITHELIUM ANDNUMBER EXPRESSED PER UNIT volume  Õ MM3 HAVE BEEN REPORTED IN NORMAL ESOPHAGEALBIOPSIESFROMADULTS;52=)NESOPHAGEALBIOPSIESOFADULTSWHOHAVE '%2$  Õ MM3#$A POSITIVECELLSHAVEBEENREPORTED ANONSIGNIlCANT INCREASEFROMNORMAL3IMILARLY INESOPHAGEALBIOPSIESOFADULTSWHOHAVE%% THE

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Fig. 14.6 (a #$AANTIBODYDECORATES,ANGERHANSCELLS DENDRITICCELLS INNORMALESOPHAGEAL EPITHELIUM4HEDENDRITICCELLPROCESSESARENICELYILLUSTRATEDINSOMECELLSarrow #$A ¾  (b) In eosinophilic esophagitis, dendritic cells are also seen (arrow ANDAPPEARMORENUMEROUSIN THISlELDCOMPAREDTOTHElELDFROMANORMALBIOPSYINa #$A ¾

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NUMBER OF #$A POSITIVE CELLS HAS BEEN REPORTED AS  Õ MM3, also a NONSIGNIlCANT INCREASE COMPARED TO NORMAL AFTER THERAPY WITH TOPICAL STEROIDS  Õ MM3 are found [52=)NCONTRAST THENUMBEROF#$A POSITIVECELLS INESOPHAGEALBIOPSIESFROMCHILDRENWHOHAVE%%HASDECREASEDSIGNIlCANTLYFOLLOWINGTOPICALSTEROIDTHERAPY FROMNUMBEREXPRESSEDPERUNITarea ÕMM2 TOÕMM2INTHEDISTALESOPHAGUS ANDÕMM2TOÕMM2 in the PROXIMALESOPHAGUS;53=4HEROLEOFDENDRITICCELLSINTHEGENESISANDMAINTENANCE OF%%SHOULDBEFURTHEREXPLORED

Mast Cells -ASTCELLSAREVIRTUALLYUBIQUITOUS BUTAREGENERALLYNOTEASILYRECOGNIZEDINTISSUE sections without the use of special stains or antibodies (Fig. 14.7). Mast cells parTICIPATEINALLERGICREACTIONS ANDINRESPONSETOCERTAINSTIMULISECRETEPREFORMEDOR NEWLYSYNTHESIZEDMEDIATORS;54]. Mast cell granules contain literally hundreds of SUBSTANCESINCLUDINGTHECYTOKINES), AND), THATAREIMPORTANTINTHEPATHOGENESIS OF %% /THER MEDIATORS CONTAINED IN MAST CELL GRANULES ARE HISTAMINE TRYPTASE CHYMASE ANDCARBOXYPEPTIDASE4RYPTASERELEASEISCONSIDEREDAMARKER OFMASTCELLACTIVATION-EDIATORSRELEASEDBYMASTCELLSCOULDPOTENTIALLYBECOME BIOMARKERSOF%%ANDDISEASEACTIVITY;55]. -ASTCELLSEXPRESSC KIT ATYROSINEKINASERECEPTORENCODEDBYTHEPROTO ONCOGENECKIT ANDACKITGENEMUTATIONCHARACTERIZESSYSTEMICMASTOCYTOSIS3YSTEMIC MASTOCYTOSISCOMMONLYAFFECTSTHEGASTROINTESTINALTRACT') ANDMAYINVOLVEANY SITEINCLUDING RARELY THEESOPHAGUS WITHESOPHAGEALSTRICTURESOCCURRINGINSOME patients [56, 57=)NCASESOFSYSTEMICMASTOCYTOSISTHATHAVETHECHARACTERISTICCKIT MUTATIONANDINVOLVETHE')TRACT THEMASTCELLINlLTRATESMAYBEACCOMPANIEDBY NUMEROUSEOSINOPHILS;58]. 4HENUMBEROFMASTCELLSDETECTEDBYTRYPTASEANTIBODYINTHEEPITHELIUMOFNORMALESOPHAGEALBIOPSIESOFCHILDRENHASBEENVARIABLEREPORTSHAVERANGEDFROMNO TRYPTASE POSITIVECELLSINTHEEPITHELIUMBUTOCCASIONALCELLSINTHELAMINAPROPRIA TOÕMASTCELLSHPF ANDÕMASTCELLSHPFWITHAPEAKCOUNTOFHPF [7, 59, 60=!NTI C KIT#$ DETECTSSIMILARNUMBERSOFINTRAEPITHELIALMASTCELLS INESOPHAGEALEPITHELIUM;60=4HENUMBEROFTRYPTASE POSITIVEMASTCELLSINNORMAL ESOPHAGEALBIOPSIESOFADULTSHASBEENREPORTEDASNUMBERPERUNITarea) 4 ± 0.9/ MM2ANDNUMBERPERUNITvolume  MM3 [52, 61]. )NBOTHCHILDRENANDADULTSWHOHAVE%% MASTCELLSAREINCREASEDINESOPHAGEAL EPITHELIUM;7, 30, 36, 47, 52, 59, 61–64=4HENUMBEROFTRYPTASE POSITIVECELLSIS GREATERIN%%COMPAREDTO'%2$BIOPSIES;30=4HENUMBEROFTRYPTASE POSITIVE MAST CELLS DOES NOT DIFFER IN BIOPSIES OF ATOPIC PATIENTS COMPARED TO NONATOPIC PATIENTS EVENAMONGPATIENTSWHOHAVE%%;64]. )NTRAEPITHELIAL MAST CELL DENSITY CORRELATES WITH EOSINOPHIL DENSITY ;7, 30, 47], basal layer hyperplasia [7], and B-cell density [64=-ASTCELLNUMBERDECREASESWITH topical steroid therapy [36, 52, 63], and following anti-interleukin-5 (IL-5)

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Fig. 14.7 (a 4RYPTASE ANTIBODY STAINS MAST CELLS brown AND IN THIS NORMAL BIOPSY ARE SEEN SCATTEREDINTHELAMINAPROPRIAANDBASALEPITHELIUM4RYPTASE ¾ b 4RYPTASE POSITIVEMAST CELLS APPEAR MORE NUMEROUS IN THIS HIGH POWER lELD FROM AN EOSINOPHILIC ESOPHAGITIS BIOPSY 4RYPTASE ¾

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-EPOLIZUMAB THERAPYINSOMEPATIENTS;12, 65=(OWEVER THENUMBEROFMASTCELLS INPOST THERAPY%%BIOPSIESMAYREMAININCREASEDCOMPAREDTONORMALBIOPSIES INDICATINGPERSISTENTINmAMMATIONANDPOTENTIALLYHYPERACTIVEIMMUNERESPONSES;52]. 3EVERALOBSERVATIONSANDLINESOFEVIDENCEIMPLICATEIMMUNOGLOBULIN%)G% IN THEPATHOGENESISOF%% INCLUDINGTHEPRESENCEOF)G%ANTIGEN SPECIlCANTIBODIESIN THE SERUM OF MANY %% PATIENTS AND THE OVEREXPRESSION OF THE HIGH AFlNITY )G% receptor gene in EE [7, 66=)G%ANTIBODYDOESNOTDECORATECELLSINNORMALESOPHAGEALBIOPSIES BUTNUMEROUS)G% POSITIVECELLSAREFOUNDIN%% ANDNONEORFEWOF THESECELLSAREFOUNDINBIOPSIESFROM'%2$PATIENTS;52, 59, 61, 64]. IgE-bearing MASTCELLSAREMOREPREVALENTIN%%BIOPSIESFROMATOPICCOMPAREDTONONATOPIC%% patients [64= )G% POSITIVE CELLS ARE NOT FOUND IN ESOPHAGEAL BIOPSIES FROM EE patients following therapy [52]. )NTHE%%TRANSCRIPTOME lVEMASTCELLGENESAREHIGHLYINDUCEDINCLUDINGCARBOXYPEPTIDASE TRYPTASE AND&#EPSILON2 THEHIGHAFlNITY)G%RECEPTOR%XPRESSION OFTRYPTASEANDCARBOXYPEPTIDASEGENESCORRELATESWITHMASTCELLNUMBERSINSUPRABASILAR ESOPHAGEAL EPITHELIUM AND BOTH MAST CELL NUMBERS AND M2.! LEVELS OF CARBOXYPEPTIDASEDECREASEWITHTHERAPY;67]. 4HESEDATADEMONSTRATEANIMPORTANTROLEFORMASTCELLSINTHEPATHOGENESISAND CLINICALCOURSEOF%% SUGGESTTHEPOTENTIALFORMASTCELLPRODUCTSTOBEBIOMARKERS OFTHEDISEASE ANDPOTENTIALLYPROVIDETHEBASISFORNOVELTHERAPIESTOTREAT%%

Lymphocytes ,YMPHOIDTISSUEISNORMALLYFOUNDINESOPHAGEALMUCOSA&IG14.8). Intraepithelial LYMPHOCYTESAREALSONORMALLYFOUNDINESOPHAGEALSQUAMOUSEPITHELIUM)N(% STAINS THEY APPEAR TO HAVE IRREGULAR NUCLEI AND ARE REFERRED TO AS SQUIGGLE CELLS )N(% STAINEDSECTIONSOFNORMALESOPHAGEALBIOPSIES THEYAREDESCRIBEDASCOMMON;40=ANDHAVEBEENQUANTIlEDASÕHPFWITHARANGEOFnHPF;7]. )NTRAEPITHELIALLYMPHOCYTESAREINCREASEDIN%%BIOPSIES,YMPHOCYTESARECRITICAL COMPONENTS OF INmAMMATORY AND IMMUNE RESPONSES AND THERE IS SIGNIlCANT CLINICAL AND EXPERIMENTAL DATA THAT SUPPORT A CRUCIAL ROLE FOR LYMPHOCYTES IN THE pathogenesis of EE. Esophageal eosinophil counts correlate with the percentage of PERIPHERALBLOOD4CELLSTHATEXPRESS), IN%%PATIENTS;68=4HE%%TRANSCRIPTOME INCLUDESOVEREXPRESSIONOFGENESEG -)#! -)#" ANDINTERLEUKIN[), ] THATAREKNOWNTOSTIMULATEINTRAEPITHELIAL4 CELLACTIVATION;1, 7=!CTIVATED4CELLS secrete IL-5 and IL-13 [1=,YMPHOCYTE DElCIENTAND4 CELL DElCIENTMICEDONOT DEVELOPEXPERIMENTAL%%;69=%FFECTOR4CELLSAREINCREASEDANDREGULATORY4CELLS ARE DECREASED AMONG TOTAL ESOPHAGEAL CELLS IN ALLERGEN CHALLENGED COMPARED TO SALINE CHALLENGEDMICE;70]. 4 CELLS ARE COMMONLY FOUND IN SMALL NUMBERS IN ESOPHAGEAL EPITHELIUM AND ACTIVATED4CELLSSECRETEBOTH), AND), &IG14.9 )NNORMALADULTESOPHAGEAL BIOPSIES #$ POSITIVE4CELLSHAVENUMBEREDÕMM2 ANDINNORMALPEDIATRICESOPHAGEALBIOPSIESTHEYHAVENUMBEREDÕHPF;53, 61=#$ POSITIVE

192

M.H. Collins

Fig. 14.8 ,YMPHOIDTISSUEISANORMALCOMPONENTOFTHEESOPHAGEALMUCOSA4HEarrow points DOWNWARDTOTHEGERMINALCENTEROFALYMPHOIDFOLLICLEINTHELAMINAPROPRIA4HEEDGESOFTHE FOLLICLE ARE SOMEWHAT CRUSHED AN ARTIFACT RESULTING FROM TISSUE HANDLING HEMATOXYLIN AND EOSIN ¾

Fig. 14.9 .UMEROUS#$ POSITIVE4LYMPHOCYTESbrown ARESEENINTHETHICKENEDEPITHELIUM ANDlBROTICLAMINAPROPRIAINTHISEOSINOPHILICESOPHAGITISBIOPSY#$ ¾

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4CELLSAREINCREASEDIN%%BIOPSIESCOMPAREDTONORMALBIOPSIESAND'%2$BIOPSIES [53, 61, 63, 71=#$ POSITIVECELLSHAVENUMBEREDÕMM2IN%%BIOPSIESFROM ADULTS ÕHPF IN %% BIOPSIES FROM CHILDREN AND ÕHPF RANGE nHPF IN%%BIOPSIESFROMBOTHADULTSANDCHILDREN;53, 61, 71=#$ POSITIVE CELLSAREREDUCEDIN%%BIOPSIESAFTERTOPICALSTEROIDTHERAPYCOMPAREDTOPRETHERAPY biopsies [53, 63]. 3UPPRESSOR4CELLS#$ POSITIVE AREMOREPREVALENTTHANHELPER4CELLS#$ POSITIVE IN NORMAL ESOPHAGEAL EPITHELIUM ;52, 63] (Fig. 14.10  4HE NUMBER OF #$ POSITIVECELLSREPORTEDINNORMALESOPHAGEALBIOPSIESINCHILDRENISÕ hpf [53=)N%% #$ POSITIVECELLSAREINCREASED;36, 49, 52, 53, 63=4HENUMBER OF# POSITIVE4CELLSISALSOREDUCEDFOLLOWINGTOPICALSTEROIDTHERAPY BUTNOTPLAcebo [36, 49, 52, 53, 63]. " CELLS ARE LESS PREVALENT THAN 4 CELLS IN THE NORMAL ESOPHAGUS &IG 14.11). #$ POSITIVE"CELLSARENOTFOUNDINNORMALESOPHAGEALBIOPSIESINADULTS;52, 61= )N CHILDREN #$ POSITIVE " CELLS ARE RARELY DETECTED IN NORMAL ESOPHAGEAL BIOPSIES FROM EITHER ATOPIC OR NONATOPIC PATIENTS #$ POSITIVE " CELLS ARE INCREASEDIN%%BIOPSIES TOASIMILARDEGREEINATOPICANDNONATOPICPATIENTS;64]. )NCHILDREN #$ POSITIVE"CELLSAREINCREASEDINEPITHELIUMANDVASCULARPAPILLAE BUTNOTINLAMINAPROPRIA IN%%PATIENTSCOMPAREDTOCONTROLS;64]. In EE biopsies FROM CHILDREN #$ POSITIVE " CELLS CORRELATE WITH MAST CELL NUMBERS BUT NOT eosinophil counts [64=)NADULTS #$ POSITIVE"CELLSAREINCREASEDTOASIMILAR DEGREEINBOTH%%BIOPSIESÕMM2) [52, 61] and GERD biopsies [52]. )G% POSITIVECELLSAREFOUNDIN%% BUTNOTCONTROLESOPHAGEALBIOPSIES;52, 61, 64=)G% POSITIVECELLSIN%%BIOPSIESMAYBEMASTCELLS;61= AND)G% POSITIVEMAST CELLS ARE INCREASED IN ATOPIC COMPARED TO NONATOPIC %% PATIENTS ;64= (OWEVER SOME #$ NEGATIVE CELLS IN %% BIOPSIES ARE )G% POSITIVE ;64= AND SOME )G% POSITIVE CELLS HAVE THE MORPHOLOGY OF PLASMA CELLS ;62= 4HEREFORE A SUBSET OF )G% POSITIVECELLSIN%%BIOPSIESMAYBEPLASMACELLS STRONGLYIMPLICATING"CELLS INTHEIMMUNEREACTIONSIN%%,OCALIMMUNOGLOBULINCLASSSWITCHINGTO)G%AND )G% PRODUCTION HAS BEEN RECENTLY DEMONSTRATED IN ESOPHAGEAL TISSUE IN %% ;64]. )NCREASED EXPRESSION OF " CELL RELATED GENES IS FOUND IN %% INCLUDING IMMUNOGLOBULIN LAMBDA JOINING  IMMUNOGLOBULIN HEAVY CHAIN DELTA IMMUNOGLOBULIN J polypeptide, and B-cell RAG-associated protein [7, 64=4HEREFORE "CELLSPROBABLY PLAYANIMPORTANTROLEIN%% BUTMAYNOTCONTRIBUTESIGNIlCANTLYTOTHEINITIATION OF %% SINCE " CELL DElCIENT MICE ARE NOT PROTECTED FROM BUT ARE SUSCEPTIBLE TO EXPERIMENTALLY INDUCED%%;69].

Lamina Propria )NCONTRASTTOTHERESTOFTHE')TRACT THELAMINAPROPRIAINTHEESOPHAGUSFORMSA distinct subepithelial layer and projects into the epithelial layer creating papillae (Fig. 14.2  ,AMINA PROPRIA IS NOT PRESENT IN ALL ENDOSCOPIC ESOPHAGEAL BIOPSIES HAMPERINGSTUDYOFTHISLAYER!LTHOUGHTHENORMALCELLCOMPLEMENTOFTHELAMINA

194

M.H. Collins

Fig. 14.10 (a # POSITIVESUPPRESSORCELLSARENORMALLYTHEMOSTABUNDANT4CELLSINTHEESOPHAGUS.UMEROUSCELLSbrown ARESEENNEARALYMPHOIDAGGREGATEINTHELAMINAPROPRIA ANDFEWER ARESEENINTHEOVERLYINGSQUAMOUSEPITHELIUM#$ ¾ b #$ POSITIVE4CELLSAREMORE NUMEROUSINTHETHICKENEDEPITHELIUMANDlBROTICLAMINAPROPRIAINlELDINEOSINOPHILICESOPHAGITISCOMPAREDTONORMAL#$ ¾

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Fig. 14.11 0LASMACELLSoutlined arrows ARETERMINALLYDIFFERENTIATED"CELLS ANDARESEENALONG with eosinophils (arrows INTHISlBROTICLAMINAPROPRIAINEOSINOPHILICESOPHAGITISHEMATOXYLIN ANDEOSIN ¾

PROPRIAISNOTASWELLCHARACTERIZEDASTHEESOPHAGEALEPITHELIALLAYER LYMPHOCYTES ARENORMALCOMPONENTSANDMAYFORMLYMPHOIDAGGREGATESORFOLLICLES&IG14.8). "CELLSAREFOUNDINTHELAMINAPROPRIAOFNORMALBIOPSIES;64]. Mast cells are also FOUNDINLAMINAPROPRIAOFNORMALBIOPSIES;47]. %OSINOPHILSARENOTFOUNDINTHELAMINAPROPRIAOFNORMALPEDIATRICESOPHAGEAL biopsies [47=%OSINOPHILSAREFOUNDINTHELAMINAPROPRIAOFESOPHAGEALBIOPSIESFROM PATIENTSWHOHAVE'%2$ BUTARELESSCOMMONTHANAMONG%%BIOPSIES)NADULTS LAMINAPROPRIAEOSINOPHILSAREFOUNDINOFPATIENTSWHOHAVE%%COMPAREDTO WHOHAVE'%2$;72=)NCHILDREN MEANCOUNTRANGESFROMRANGEn TO RANGEn EOSINOPHILSHPFINTHELAMINAPROPRIAINBIOPSIESOFPATIENTSWHOHAVE %% COMPAREDTOAMEANCOUNTOFn HPFINPATIENTSWHOHAVE'%2$;47, 73]. ,AMINA PROPRIA MAST CELLS DETECTED BY TRYPTASE ANTIBODY HAVE BEEN REPORTED AS  (0–64)/hpf in EE biopsies and 9.5 (7–23)/hpf in GERD biopsies in children [47]. ,AMINAPROPRIAlBROSISOCCURSIN%%ANDMAYBEFOUNDLESSCOMMONLYINOTHER DISORDERS)NADULTS LAMINAPROPRIAlBROSISISFOUNDINOF%%BIOPSIESAND of GERD biopsies [72=)TMAYINCREASEINPREVALENCEOVERTIMEINESOPHAGEALBIOPSIESOFADULTSWHOHAVE%%;74= BUTMAYRESOLVEINCHILDREN;75=,AMINAPROPRIA lBROSIS CORRELATES WITH DYSPHAGIA AND FOOD IMPACTIONS BUT NOT WITH DURATION OF SYMPTOMS INCHILDREN;47=)NCREASEDSTAININGFOR4'&E ANDITSDOWNSTREAMSIGNALINGMOLECULEPHOSPHO 3-!$INLAMINAPROPRIACELLSIN%%BIOPSIESSHOWING lBROSIS INCLUDINGPATIENTSWITHSTRICTURES STRONGLYIMPLICATESTHISSIGNALINGPATHWAYINTHEGENESISOFLAMINAPROPRIAlBROSISIN%%;73=0ATIENTSWHORESPONDTO

196

M.H. Collins

SWALLOWED BUDESONIDE THERAPY WITH REDUCED lBROSIS AND REDUCED STAINING FOR 4'&E ANDPHOSPHO 3-!$ AREMORELIKELYTOHAVEA##GENOTYPEATTHE– POSITIONINTHE4'&EBETA PROMOTERREGION;75=4HISlNDINGSUGGESTSTHATGENOTYPEMAYBEIMPORTANTINTHEGENESISOFLAMINAPROPRIAlBROSIS ), ISALSOIMPORTANTINTHEGENESISOFLAMINAPROPRIAlBROSISIN%%), LEVELS ARE INCREASED IN THE ESOPHAGUS OF %% PATIENTS ),  DElCIENT MICE DEVELOP LESS LAMINAPROPRIAlBROSISTHANWILD TYPEMICE AND#$ ), TRANSGENICMICESHOWED INCREASEDlBROSISCOMPAREDTONONTRANSGENICMICE;14]. !GENOME WIDEMICROARRAYANALYSISOFESOPHAGEALBIOPSIESHASSHOWNINCREASED EXPRESSION OF THE PERIOSTIN GENE ;7= 0ERIOSTIN IS A SECRETED PROTEIN EXPRESSED BY lBROBLASTSTHATINTERACTSWITHCOMPONENTSOFTHEEXTRACELLULARMATRIX0ERIOSTINIS MARKEDLYOVEREXPRESSEDINLAMINAPROPRIAOF%%BIOPSIESCOMPAREDTONORMALBIOPSIES AND ),  AND 4'&E INCREASE PERIOSTIN EXPRESSION IN PRIMARY ESOPHAGEAL lBROBAST CULTURES 0ERIOSTIN INCREASES EOSINOPHIL ADHESION TO lBRONECTIN IN VITRO ANDPERIOSTIN DElCIENTALLERGEN CHALLENGEDMICEHAVEREDUCEDEOSINOPHILSINLUNG and esophagus [76= 4HESE DATA SUGGEST THAT PERIOSTIN PLAYS AN IMPORTANT ROLE IN EOSINOPHILRECRUITMENTFROMTHEVASCULATUREINTOTHELAMINAPROPRIA

Future Directions #LINICALANDEXPERIMENTALSTUDIESHAVEELUCIDATEDMANYASPECTSOFTHEPATHOGENESIS OF%%3TUDIESHAVEFOCUSEDONPRIMARYORALLERGIC%% ANDEFFORTSSHOULDBEMADETO IDENTIFYANYOTHERPATHWAYSTHATMAYBEINVOLVEDINTHEGENESISOF%%ASSOCIATED WITHOTHERDISEASES%XPERIMENTALDATAHAVEPROVIDEDTHEBASISFORCLINICALTRIALS;77]. 4HE GOALS OF THERAPY MUST BE CLARIlED /NE GOAL SHOULD BE TO REDUCE ESOPHAGEAL INmAMMATION BUTTHEDEGREEOFREDUCTIONISNOTYETIDENTIlED-ECHANISMSOFLAMINA PROPRIAlBROSISHAVEBEENIDENTIlED ANDEVIDENCEISEMERGINGTHATITMAYBEREVERSIBLE BUTTHERELATIONSHIPOFLAMINAPROPRIAlBROSISTOESOPHAGEALDYSFUNCTIONAND STRICTUREINPARTICULARSHOULDBEEXPLORED,ITTLEISKNOWNABOUTTHENATURALHISTORYOF EE in children. Gastroenterologists who treat adults should be aware that biopsies SHOWINGALLTHECHARACTERISTICFEATURESOF%%WEREOBTAINEDFROMCHILDRENDECADES ago and interpreted as GERD [78=ITISPOSSIBLETHATADULTSWHOARENOWDIAGNOSED WITH%%HADTHEDISEASEINCHILDHOOD ANDTHENATURALHISTORYWILLBECOMECLEARERBY REPORTINGTHESEPATIENTS4HEGOALOFALLTHESEEFFORTSISTOCURE%%

References  2OTHENBERG -% "IOLOGY AND TREATMENT OF EOSINOPHILIC ESOPHAGITIS 'ASTROENTEROLOGY n  6ANDERHEYDEN!$ 0ETRAS2% $E9OUNG"2 ETAL%MERGINGEOSINOPHILICALLERGIC ESOPHAGITIS)NCREASEDINCIDENCEORINCREASEDRECOGNITION!RCH0ATHOL,AB-EDn  7HITNEY -ILLER#, +ATZKA$ &URTH%%%OSINOPHILICESOPHAGITIS!RETROSPECTIVEREVIEWOF ESOPHAGEAL BIOPSY SPECIMENS FROM  TO  AT AN ADULT ACADEMIC MEDICAL CENTER !M *#LIN0ATHOLn

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 #OLLINS-( "LANCHARD# !BONIA*0 ETAL#LINICAL PATHOLOGIC ANDMOLECULARCHARACTERIZATION OFFAMILIALEOSINOPHILICESOPHAGITISCOMPAREDWITHSPORADICCASES#LIN'ASTROENTEROL(EPATOL n 5. Collins MH. Histopathologic features of eosinophilic esophagitis. Gastrointest Endosc Clin N !Mn  #OLLINS-((ISTOPATHOLOGYASSOCIATEDWITHEOSINOPHILICGASTROINTESTINALDISEASES)MMUNOL !LLERGY#LIN.ORTH!Mn  "LANCHARD# 7ANG. 3TRINGER+& ETAL%OTAXIN ANDAUNIQUELYCONSERVEDGENE EXPRESSION PROlLEINEOSINOPHILICESOPHAGITIS*#LIN)NVESTn  2OTHENBERG-% 3PERGEL*- 3HERRILL*$ ETAL#OMMONVARIANTSATQASSOCIATEWITHPEDIATRICEOSINOPHILICESOPHAGITIS.AT'ENETn  -ISHRA! (OGAN30 "RANDT%" ETAL), PROMOTESEOSINOPHILTRAFlCKINGTOTHEESOPHAGUS *)MMUNOLn 10. Mishra A, Rothenberg ME. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, EOTAXIN  AND34!4 DEPENDENTMECHANISM'ASTROENTEROLOGYn "LANCHARD# -ISHRA! 3AITO !KEI( ETAL)NHIBITIONOFHUMANINTERLEUKIN  INDUCEDRESPIRATORYANDOESOPHAGEALINmAMMATIONBYANTI HUMAN INTERLEUKIN ANTIBODY#!4  #LIN %XP!LLERGYn 3TEIN-, #OLLINS-( 6ILLANEUVA*- ETAL!NTI ), THERAPYFOREOSINOPHILICESOPHAGITIS *!LLERGY#LIN)MMUNOLn "LANCHARD# -INGLER-+ 6ICARIO- ETAL), INVOLVEMENTINEOSINOPHILICESOPHAGITIS TRANSCRIPTOME ANALYSIS AND REVERSIBILITY WITH GLUCOCORTICOIDS * !LLERGY #LIN )MMUNOL n -ISHRA! 7ANG- 0EMMARAJU62 ETAL%SOPHAGEALREMODELINGDEVELOPSASACONSEQUENCE OFTISSUESPECIlC),  INDUCEDEOSINOPHILIA'ASTROENTEROLOGYn 15. Blanchard C, Stucke EM, Burwinkel K, et al. Coordinate interaction between IL-13 and epiTHELIAL CELL DIFFERENTIATION CLUSTER GENES IN EOSINOPHILIC ESOPHAGITIS * )MMUNOL n :HU8 7ANG- -AVI0 ETAL)NTERLEUKIN EXPRESSIONISINCREASEDINHUMANEOSINOPHILIC ESOPHAGITISANDMEDIATESPATHOGENESISINMICE'ASTROENTEROLOGYn &URUTA'4 ,IACOURIS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGYn !CEVES33 .EWBURY2/ $OHIL2 ETAL$ISTINGUISHINGEOSINOPHILICESOPHAGITISINPEDIATRIC PATIENTS CLINICAL ENDOSCOPIC AND HISTOLOGIC FEATURES OF AN EMERGING DISORDER * #LIN 'ASTROENTEROLn 3PERGEL*- "ROWN 7HITEHORN4& "EAUSOLIEIL*, ETAL9EARSOFEOSINOPHLICESOPHAGITIS CLINICALFEATURESANDPROGNOSIS*0EDIATR'ASTROENTEROL.UTRn 0ROTHEROE# 7OODRUFF3! DE0ETRIS' ETAL!NOVELHISTOLOGICSCORINGSYSTEMTOEVALUATE MUCOSAL BIOPSIES FROM PATIENTS WITH EOSINOPHILIC ESOPHAGITIS #LIN 'ASTROENTEROL (EPATOL n  /LIVEIRA # :AMAKHASHARY - -ARCON 0 ET AL %OSINOPHILIC ESOPHAGITIS AND INTERMEDIATE ESOPHAGITISAFTERTRACHEOESOPHAGEALlSTULAREPAIRACASESERIES*0EDIATR3URGn 2OTHENBERG -% %OSINOPHILIC GASTROINTESTINAL DISORDERS %')$  * !LLERGY #LIN )MMUNOL n $ELLON%3 &ARRELL4- "OZYMSKI%- ETAL$IAGNOSISOFEOSINOPHILICESOPHAGITISAFTERFUNDOPLICATIONFORhREFRACTORYREmUXvIMPLICATIONSFORPREOPERATIVEEVALUATION$IS%SOPHAGUS %PUBAHEADOFPRINT0-)$n 0OH#( 'ASIOROWSKA! .AVARRO 2ODRIGUEZ4 ETAL5PPER')TRACTlNDINGSINPATIENTSWITH HEARTBURNINWHOMPROTONPUMPINHIBITORTREATMENTFAILEDVERSUSTHOSENOTRECEIVINGANTIREmUX TREATMENT'ASTROINTEST%NDOSCn 25. Foroutan M, Norouzi A, Molaei M, et al. Eosinophilic esophagitis in patients with refractory GASTROESOPHAGEALREmUXDISEASE$IG$IS3CIn  $RANOVE*% (ORN$3 $AVIS-! ETAL0REDICTORSOFRESPONSETOPROTONPUMPINHIBITORTHERAPY AMONGCHILDRENWITHSIGNIlCANTESOPHAGEALEOSINOPHILIA*0EDIATRn

198

M.H. Collins

 7INTER(3 -ADARA*, 3TAFFORD2* ETAL)NTRAEPITHELIALEOSINOPHILSANEWDIAGNOSTICCRITERION FORREmUXESOPHAGITIS'ASTROENTEROLOGYn 28. Rodrigo S, Abboud G, Oh D, et al. High intraepithelial eosinophil counts in esophageal SQUAMOUSEPITHELIUMARENOTSPECIlCFOREOSINOPHILICESOPHAGITISINADULTS!M*'ASTROENTEROL n .GO 0 &URUTA '4 !NTONIOLI $! ET AL %OSINOPHILS IN THE ESOPHAGUS n PEPTIC OR ALLERGIC EOSINOPHILIC ESOPHAGITIS #ASE SERIES OF THREE PATIENTS WITH ESOPHAGEAL EOSINOPHILIA !M *'ASTROENTEROLn -UELLER3 .EUREITER$ !IGNER4 ETAL#OMPARISONOFHISTOLOGICALPARAMETERSFORTHEDIAGNOSISOFEOSINOPHILICOESOPHAGITISVERSUSGASTRO ESOPHAGEALREmUXDISEASEONOESOPHAGEALBIOPSY MATERIAL(ISTOPATHOLOGYn $ELLON%3 'IBBS7" &RITCHIE+* ETAL#LINICAL ENDOSCOPIC ANDHISTOLOGIClNDINGSDISTINGUISH EOSINOPHILIC ESOPHAGITIS FROM GASTROESOPHAGEAL REmUX DISEASE #LIN 'ASTROENTEROL (EPATOLn 6ANDENPLAS 9 2UDOLPH #$ $I,ORENZO # ET AL 0EDIATRIC GASTROESOPHAGEAL REmUX CLINICAL PRACTICE GUIDELINES JOINT RECOMMENDATIONS OF THE .ORTH !MERICAN 3OCIETY FOR 0EDIATRIC 'ASTROENTEROLOGY (EPATOLOGY AND .UTRITION .!30'(!. AND THE %UROPEAN 3OCIETY FOR 0EDIATRIC'ASTROENTEROLOGY (EPATOLOGY AND.UTRITION%30'(!. *0EDIATR'ASTROENTEROL .UTRn 0ETERSON+! 4HOMAS+, (ILDEN+ ETAL#OMPARISONOFESOMEPRAZOLETOAEROSOLIZED SWALLOWEDmUTICASONEFOREOSINOPHILICESOPHAGITIS$IG$IS3CI%PUBAHEADOFPRINT0-)$ n 3HAH ! +AGALWALLA !& 'ONSALVES . ET AL (ISTOPATHOLOGIC VARIABILITY IN CHILDREN WITH EOSINOPHILICESOPHAGITIS!M*'ASTROENTEROLn -ERWAT 3. 3PECHLER 3* -IGHT THE USE OF ACID SUPPRESSIVE MEDICATIONS PREDISPOSE TO THE DEVELOPMENTOFEOSINOPHILICESOPHAGITIS!M*'ASTROENTEROLn +ONIKOFF-2 .OEL2* "LANCHARD# ETAL!RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED TRIAL OF mUTICASONE PROPIONATE FOR PEDIATRIC EOSINOPHILIC ESOPHAGITIS 'ASTROENTEROLOGY n !TKINS $ &URUTA '4 -UCOSAL IMMUNOLOGY EOSINOPHILIC ESOPHAGITIS AND OTHER INTESTINAL INmAMMATORYDISEASES*!LLERGY#LIN)MMUNOL3 3n  'ONSALVES. 0OLICARPIO .ICOLAS- :HANG1 ETAL(ISTOPATHOLOGICVARIABILITYANDENDOSCOPIC CORRELATESINADULTSWITHEOSINOPHILICESOPAHGITIS'ASTROINTEST%NDOSCn ,AI!, 'IRGIS3 ,IANG9 ETAL$IAGNOSTICCRITERIAFOREOSINOPHILICESOPHAGITISA YEARRETROSPECTIVEREVIEWINAPEDIATRICPOPULATION*0EDIATR'ASTROENTEROL.UTRn 7ALSH36 !NTONIOLI$! 'OLDMAN( ETAL!LLERGICESOPHAGITISINCHILDREN!CLINICOPATHOLOGICSTUDY!M*3URG0ATHOLn #HEUNG+- /LIVER-2 #AMERON$*3 ETAL%SOPHAGEALEOSINOPHILIAINCHILDRENWITHDYSPHAGIA*0EDIATR'ASTROENTEROL.UTRn +ATO - +EPHART '- 4ALLEY .* ET AL %OSINOPHIL INlLTRATION AND DEGRANULATION IN NORMAL HUMANTISSUE!NAT2ECn $E"ROSSE #7 #ASE *7 0UTNAM 0% ET AL 1UANTITY AND DISTRIBUTION OF EOSINOPHILS IN THE GASTROINTESTINALTRACTOFCHILDREN0EDIATR$EVELOP0ATHOLn .EVES*3 0EREZ3!# 3PENCER,! ETAL%OSINOPHILGRANULESFUNCTIONEXTRACELLULARLYASRECEPTOR MEDIATEDSECRETORYORGANELLES0.!3n .EVES*3 2ADKE!, 7ELLER0&#YSTEINYLLEUKOTRIENESACTINGVIAGRANULEMEMBRANE EXPRESSED RECEPTORS ELICIT SECRETION FROM WITHIN CELL FREE HUMAN EOSINOPHIL GRANULES * !LLERGY #LIN )MMUNOLn +EPHART'- !LEXANDER*! !RORA!3 ETAL-ARKEDDEPOSITIONOFEOSINOPHIL DERIVEDNEUROTOXININADULTPATIENTSWITHEOSINOPHILICESOPHAGITIS!M*'ASTROENTEROLn #HEHADE- 3AMPSON(! -OROTTI2! -AGID-3%SOPHAGEALSUBEPITHELIALlBROSISINCHILDRENWITHEOSINOPHILICESOPHAGITIS*0EDIATR'ASTROENTEROL.UTRn *USTINICH#* 2ICCI*R! +ALAFUS$! ETAL!CTIVATEDEOSINOPHILSINESOPHAGITISINCHILDREN ATRANSMISSIONELECTRONMICROSCOPYSTUDY*0EDIATR'ASTROENTEROL.UTRn

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Histologic Features of Eosinophilic Esophagitis

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Chapter 15

Complications Associated with Eosinophilic Esophagitis Stephen E. Attwood and Glenn T. Furuta

Keywords %OSINOPHILIC ESOPHAGITIS s %SOPHAGEAL NARROWINGS s %SOPHAGEAL PERFORATIONSs&OODIMPACTIONs-ALADAPTIVEEATINGBEHAVIOURS

Introduction %OSINOPHILICESOPHAGITISISACHRONICINmAMMATORYDISEASEASSOCIATEDWITHDENSE ESOPHAGEAL EOSINOPHILIA HYPERPLASTIC EPITHELIA AND SUBEPITHELIAL lBROSIS ;1]. As CLINICALRECOGNITIONOFEOSINOPHILICESOPHAGITIS%O% INCREASES SOTOODOOBSERVATIONSIDENTIFYINGCOMPLICATIONSOFTHEDISEASEANDITSTREATMENTS&ORTHEPURPOSESOF THISCHAPTER COMPLICATIONSWILLBEDElNEDASUNFAVOURABLEEVOLUTIONSOFCHRONIC INmAMMATIONORUNTOWARDCONSEQUENCESOFONGOINGTREATMENT)NTHISREGARD PARTIAL ORCOMPLETEESOPHAGEALOBSTRUCTIONDUETOESOPHAGEALNARROWINGSORFOODIMPACTIONANDEATINGDIFlCULTIESARETWOIMPORTANTCOMPLICATIONSOF%O%7ITHRESPECTTO CHRONICTREATMENT THEOVERALLGOALISTORESOLVESYMPTOMSANDPREVENT%O% RELATED COMPLICATIONS "UT TREATMENT ENDPOINTS HAVE NOT BEEN ESTABLISHED AND THUS THE EXACT DURATION FREQUENCY EXPENSE AND TYPE TREATMENTS HAVE NOT BEEN FORMALLY ESTABLISHED"ECAUSEOFTHISLACKOFGUIDELINES CLINICIANSAREPOTENTIALLYFACEDWITH COMPLICATIONSRELATEDTOENDOSCOPICPROCEDURES MEDICALTREATMENTSANDNUTRITIONAL RESTRICTIONS)NTHISCHAPTER WEWILLPROVIDEOURINTERPRETATIONOFTHELITERATUREAND SUMMARYOFOURCLINICALEXPERIENCESOFTHESECOMPLICATIONSINCHILDRENANDADULT patients with EoE.

'4&URUTA*) 'ASTROINTESTINAL%OSINOPHILIC$ISEASES0ROGRAM 4HE#HILDRENS(OSPITAL#OLORADO .ATIONAL*EWISH(EALTH 5NIVERSITYOF#OLORADO$ENVER3CHOOLOF-EDICINE %ASTTH!VE" !URORA #/ 53! E MAILGLENNFURUTA CHILDRENSCOLORADOORG C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_15, © Springer Science+Business Media, LLC 2012

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Complications Associated with EoE in Children and Adults Esophageal Narrowings )NSOMEPATIENTSWITH%O% CHRONICEOSINOPHILICINmAMMATIONCANLEADTOPARTIAL ESOPHAGEALOBSTRUCTIONTHATISMANIFESTBYSYMPTOMSOFFEEDINGDIFlCULTIES DYSPHAGIAANDFOODIMPACTIONANDENDOSCOPICEVIDENCEOFISOLATEDESOPHAGEALSTRICTURES NARROW BORE ESOPHAGUS SMALL CALIBER ESOPHAGUS CREPE PAPER ESOPHAGUS LONGITUDINAL NARROWINGS LONGITUDINAL RENTSLACERATIONS OR MUCOSAL TEARS #LINICAL EXPERIENCESUGGESTSTHATNOTALLPATIENTSDEVELOPTHESEPROBLEMSBUTWHOANDWHEN THEYWILLDEVELOPTHEMANDIDENTIlCATIONOFCONTRIBUTINGFACTORSTOWARDTHEIRDEVELOPMENTAREALLUNCERTAIN)NADDITION ITISNOTYETCLEARWHETHERANYFORMOFTREATMENTCANPREVENTTHEM)NCREASINGCLINICALEXPERIENCEDOCUMENTSCLINICALASPECTSOF THESElBROTICCHANGESOFTHEESOPHAGEALMUCOSA

Pediatrics ! LIMITED BODY OF WORK DOCUMENTS ESOPHAGEAL STRICTURES AND NARROWINGS ASSOCIATED WITH%O%2ADIOGRAPHICSTUDIESWERETHElRSTTODESCRIBEESOPHAGEALSTRICTURESIN%O% ANDIDENTIFYTHEIRPROPENSITYTODEVELOPINTHEPROXIMALESOPHAGUS;2, 3]. Since then, a NUMBEROFCASESERIESHAVEIDENTIlEDESOPHAGEALSTRICTURESOCCURRINGINTHEPROXIMAL MIDDLEANDDISTALESOPHAGUSOFCHILDRENWITH%O%;4–10]. Age at presentation ranges FROMTOYEARSANDLONGSTANDINGHISTORIESOFESOPHAGEALDYSFUNCTIONWITHVOMITING FEEDINGDIFlCULTIESORDYSPHAGIAORPASTMEDICALHISTORIESOFFUNDOPLICATIONARENOT UNUSUALSUGGESTINGTHATTHESELESIONSWEREUNRECOGNIZEDORTHATTHEIRCLINICALIMPACTWAS UNDERESTIMATED4HEDURATIONOFTIMEREQUIREDTOFORMTHESESTRICTURESISNOTKNOWNBUT SOMEINSIGHTSWEREPROVIDEDINACASEREPORTDESCRIBINGA YEAR OLDMANWITHPROGRESSIVESOLIDFOODDYSPHAGIA(ERECEIVEDANORIGINALDIAGNOSISOFEOSINOPHILICGASTROENTERITISYEARSEARLIERATWHICHTIMEHEPRESUMABLYDIDNOTHAVEASTRICTURESUGGESTING THATTHISLESIONTAKESYEARSTODEVELOP;11=&EWSTUDIESHAVEADDRESSEDTHESIZEORFREQUENCYOFESOPHAGEALSTRICTURESIN%O%)NASERIESOFFOURPEDIATRICPATIENTS THEMEAN DIAMETEROFTHESTRICTUREWASMMANDINADULTSMM;12]. 7HETHERMEDICALORNUTRITIONALTREATMENTSPRE ORPOST DILATIONAREBENElCIALIS NOTCERTAINBUTSUPPORTEDBYSOMEANDHASBEENTHEAPPROACHINMOSTPATIENTSINOUR PRACTICE;9, 13, 14=#HRONICDILATIONDOESNOTTREATUNDERLYINGINmAMMATIONASSOCIATED WITH%O%;15–18].

Approach to Child with Suspected Esophageal Narrowing and EoE Personal experiences and discussions with other colleagues support a thorough ASSESSMENT OF CHILDREN IN WHOM ONE SUSPECTS ESOPHAGEAL NARROWINGS ASSOCIATED

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Adults 3TRICTURESINADULTPRESENTATIONOF%O%ARERAREBUTSEEMTOREPRESENTASEVEREVARIANT of this condition. Two patterns of esophageal strictures, isolated stricture and long NARROWCALIBER HAVEBEENSEENINADULTS4HEPRESENCEOFANISOLATEDBUTTIGHTSTRICTURE SEEMS RELATIVELY RARE BUT HAS OCCURRED IN  OF PATIENTS IN PUBLISHED SERIES ;32–34=4HESEPATIENTSHAVEOFTENALREADYADAPTEDTHEIRDIETANDINGESTONLYLIQUIDS ORVERYSOFTFOODS ANDEATVERYSLOWLY3UCHADAPTATIONWITHOUTOVERTSYMPTOMS SUGGESTSTHATTHEIRSTRICTURESDEVELOPEDOVERTIMEALTHOUGHTHEREISNOOBSERVATIONAL proof of this concept.

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4HE SECOND VARIATION IN ADULTS IS THE NARROW OR SMALL CALIBER ESOPHAGUS 4HIS VARIANTSEEMSTOBEASSOCIATEDWITHTHEMOSTSEVEREFORMSOFSWALLOWINGDIFlCULTY ANDASSOCIATEDMALNUTRITION/NESUCHPATIENTOFOURSPRESENTEDTOHERLOCALHOSPITAL ATTHEAGEOFYEARSWHERESHEWASINITIALLYREGARDEDASHAVINGAPSYCHOLOGICAL EATINGDISORDER4HEBARIUMESOPHAGRAMWASALSOINITIALLYMISINTERPRETEDBECAUSE THEOVERALLESOPHAGEALAPPEARANCEDIDNOTSUGGESTASPECIlCSTRICTUREANDTHELACKOF THENORMALDISTENSIONWASNOTSOMETHINGTHELOCALRADIOLOGISTWASSENSITIVETO3EE SECTIONONPEDIATRICEVALUATIONABOVE 4HISPATIENTWASCOMMENCEDONTOTALPARENTERALNUTRITIONANDREFERREDTOTHELOCALSURGICALDEPARTMENTFORMANOMETRYTOSEEIF THEDYSPHAGIAWASAFORMOFACHALASIA.OPREVIOUSENDOSCOPYHADBEENPERFORMED ANDPRIORTOTHEMANOMETRYTESTTHEENDOSCOPYPERFORMEDINOURINSTITUTIONSHOWED ANARROWCALIBERESOPHAGUSTHATWOULDNOTALLOWTHEPASSAGEOFA MMENDOSCOPE "IOPSIESCONlRMED%O%ANDAFTERASHORTCOURSEOFSYSTEMICSTEROIDSSWALLOWING WAS RESTORED .OW  YEARS LATER THAT PATIENT STILL REMAINS MILDLY SYMPTOMATIC WHILEONMEDICALTHERAPY3HEHASRECOVEREDALLHERSTRENGTHANDSUCCESSFULLYDELIVEREDTWOCHILDREN4HISVIGNETTEHIGHLIGHTSTHEPOTENTIALSEVERITYOFSTRICTURE NARROW BORE ESOPHAGUS OR SMALL CALIBRE OESOPHAGUS AND EMPHASIZES THAT A PATIENT MAY APPEAROUTWARDLYNORMALINEVERYOTHERWAYBECAUSEOFCOPINGBEHAVIOURS Another case represents other classical features of a tight stricture with a longer SEGMENTOFNARROWBORESMALLCALIBERESOPHAGUS4HIS YEAR OLDMALEPRESENTED WITHA YEARHISTORYOFASWALLOWINGDISORDER(ISPARENTSHADBEENEXTREMELY SUPPORTIVESINCETHEYlRSTNOTICEDHISDIFlCULTYATTHEAGEOFYEARS!FTERYEARS OF TESTS AND UNHELPFUL TREATMENTS MOSTLY ACID SUPPRESSION HE WAS REFERRED TO A SURGEONWHODESPITEHAVINGTHEDISCIPLINEOFPERFORMINGMANOMETRYANDP(STUDIES DECIDEDTHATINTHEABSENCEOFACIDONTHEP(STUDYHISSTRICTUREMUSTBEPEPTIC ANDPERFORMEDA.ISSENFUNDOPLICATION(ISBARIUMSTUDYATTHEAGEOFISSHOWN IN&IG15.1 ANDREVEALSATIGHTSTRICTUREINTHEJUNCTIONOFTHEUPPERANDMIDDLETHIRD OF ESOPHAGUS A SLIGHTLY DILATED PROXIMAL ESOPHAGUS AND A NARROW CALIBERSMALL CALIBERESOPHAGUSBELOWFORCMINWHICHARECLASSICRINGS4HISPATIENTWASSUBJECTTOA.ISSENFUNDOPLICATIONATTHEAGEOFYEARSWITHOUTANYIMPROVEMENTIN HISSYMPTOMSANDCARRIEDONWITHLIQUIDNUTRITIONUNTILHISTHYEAR $ESPITE NEVER HAVING EATEN A SOLID MEAL OF ANY KIND HE LIVED ON HIGH CALORIE DRINKSANDLIQUIDFOODSUPPLEMENTS HEHADGROWNlTANDSTRONGANDHEPRESENTEDTO OURINSTITUTIONWHENHEHADREACHEDANADULTAGEHAVINGEXHAUSTEDALLOFTHEINVESTIGATIVEPOSSIBILITIESINHISLOCALPEDIATRICFACILITIES7HENHECAMETOOURINSTITUTION THEDIAGNOSISWASOBVIOUSFROMTHEHISTORYANDRADIOLOGY ANDCONlRMEDBYENDOSCOPYANDBIOPSY(EWASTREATEDBYDILATATIONOFHISSTRICTUREFROMTOMMINITIALLY SYSTEMICSTEROIDS FOLLOWEDBYMONTELUKASTMEDICATIONWITHCOMPLETESYMPTOM RESOLUTION RESTORATIONOFNORMALSOLIDINGESTIONAFTERHAVINGNONEFORYEARS4HIRTY MONTHSLATER HEEXPERIENCEDONERECURRENCEOFBOLUSOBSTRUCTIONTHATREQUIREDDILATATIONANDTHEADDITIONOFTOPICALSTEROIDSFORMAINTENANCETHERAPY 4HE REASON FOR THE STRICTURING IN THESE ABOVE PATIENTS HAS NOT BEEN CLEARLY UNDERSTOOD !T ENDOSCOPY THE STRICTURES APPEAR TO BE COVERED WITH HYPERPLASTIC MUCOSAE BUTNOTENDOSCOPICALLYINmAMED ANDNOTOVERTLYlBROTIC)NTHESERIESOF PATIENTSFOLLOWEDLONGITUDINALLYOVERYEARS;32–34= THEREDOESNOTSEEMTOBE

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PROGRESSIONFROMSYMPTOMATICDYSPHAGIATOSTRICTUREANDTHETYPEOFTREATMENTUSED MAY NOT HAVE ANY INmUENCE OVER THE DEVELOPMENT OR PROTECTION FROM STRICTURING 4HEUSEOFTOPICALSTEROIDSMAYREDUCEMUCOSALOREVENSUBMUCOSALlBROSISBUTIS UNLIKELY TO HAVE ANY INmUENCE ON MUSCULAR lBROSIS ;35= 3YSTEMIC STEROIDS MAY REDUCEMUSCULARlBROSISBUTTHEYHAVEGENERALLYBEENUSEDTOTREATTHESEPATIENTSIN THEEARLYPHASEOFTHEIRTREATMENTS ANDONLYSHORTCOURSESAREGIVENTOMINIMIZE SIDEEFFECTSOFLONG TERMUSE)TISNOTCLEARIFTHEUSEOFMONTELUKAST COMMONLY USEDFORTHISCONDITIONINTHE5+ HASANYINmUENCEONTHEDEVELOPMENTOFSTRICTURES0OTENTIALMECHANISMSOFACTIONTHATMAYBERELEVANTTO%O%RELATETOTHEFACT THATMONTELUKASTISALEUKOTRIENE$ ANTAGONISTTHATCANSTABILIZEEOSINOPHILDEGRANULATIONANDTHERELEASEOFLOCALLYNEURO ACTIVEMEDIATORSTHATMAYSTIMULATEMUSCULAR DYSFUNCTION7HETHERTHESEMECHANISMSHAVEANYINmUENCEONTHEPOTENTIALSPORADICDEVELOPMENTOFSTRICTURESISUNKNOWN

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)NONE!MERICANSERIESOFADULTSREPORTEDBY0OTTERETALIN AMUCHHIGHER PROPORTIONOFPATIENTS PRESENTEDWITHRINGS STRICTURESORSMALLCALIBERESOPHAGUS;36=4HEREASONFORTHISMUCHHIGHERINCIDENCEISNOTCLEARBUTCIRCUMSTANCES OFREFERRALPATTERN THELIBERALUSEOFBARIUMSWALLOWSANDREFERRALAFTERRADIOLOGICAL IDENTIlCATION OF STRICTURE MAY SKEW THE PREVALENCE OF STRICTURE !LTHOUGH BARIUM SWALLOWISEXTREMELYUSEFULITSHOULDBEUSEDTOCOMPLIMENT ANDNOTINSTEADOF ENDOSCOPYANDBIOPSYINTHEEVALUATIONOFDYSPHAGIA4HESENSITIVITYANDSPECIlCITY OFTHESETESTSINTHEEVALUATIONOFESOPHAGEALNARROWINGIN%O%ARENOTCERTAINSO THATBOTHTESTSOFFERVALUEINTHEEVALUATIONOFOBSTRUCTIVELESIONS4HEVARIATIONOF STRICTUREPATTERNSEENIN%O%INCLUDESMUCOSALlBROTICRINGS WHICHAREOCCASIONALLY PRONOUNCEDANDCONTRIBUTETODYSPHAGIAATMULTIPLELEVELS;37=4HUS COMMUNICATIONWITHTHERADIOLOGISTSISIMPORTANTSOTHATTHESPECIlCQUESTIONSCANBEANSWERED WITHTHEESOPHAGRAM

Food Impaction #HILDRENANDADULTSWITH%O%CANEXPERIENCEFOODIMPACTION;38–46=/FTENTIMES THISPROBLEMMAYREPRESENTTHElRSTPRESENTATIONOF%O%)TISNOTUNUSUALTOHEAR PATIENTSRECALLPROBLEMSWITHFOODGETTINGSTUCKAFTERSWALLOWINGANDTHATAVARIETY OFDIFFERENTMANEUVERSINCLUDINGJUMPINGUPANDDOWN RAISINGTHEARMSABOVE THE HEAD FORCED GAGGING AND ATTEMPTING TO SWALLOW LIQUIDS HAD BEEN USED TO DISLODGETHEBOLUS/FTENTHESEARESUCCESSFULANDTHUSTHEPATIENTDOESNOTSEEK FURTHERATTENTION BUTEVENTUALLY THEBOLUSREMAINSSTUCKLEADINGTOAVISITTOTHE EMERGENCYROOM7EINITIALLYREPORTEDTHATOFADULTSPRESENTINGTOANEMERGENCYROOMACUTELYWITHFOODIMPACTIONHADlNDINGSCONSISTENTWITH%O%;38]. 3IMILARlNDINGSHAVEBEENREPORTEDINCHILDRENANDADULTSINOTHERSERIES;38–46]. &OODIMPACTIONCANALSOOCCURAFTERTHEDIAGNOSISOF%O%HASBEENOBTAINEDAND LIKELYRELATESTOPOORLYCONTROLLEDINmAMMATION DEVELOPMENTOFANESOPHAGEAL NARROWINGOREXPOSURETOANEWFOODORAERO ALLERGEN4HEMECHANISMSFORFOOD IMPACTIONSARENOTCERTAINBUTINCLUDEISOLATEDORDIFFUSEESOPHAGEALNARROWING OR TRANSIENT CONTRACTION OF THE ESOPHAGEAL MUSCULARIS )N SUPPORT OF THE LATER MECHANISMISTHEOBSERVATIONTHATAFTERBOLUSREMOVAL ANOBSTRUCTINGLESIONMAY NOTBEPRESENT 2EMOVALOFFOODBOLUSIN%O%PATIENTSALSODESERVESCOMMENT&ORANON %O% RELATEDESOPHAGEALFOODIMPACTION ASURGICALAPPROACHTHROUGHARIGIDENDOSCOPE WASPREFERRED WITHTHECITEDADVANTAGETHATRETRIEVALOFSUCHABOLUSWASSAFERFOR THEAIRWAYRATHERTHANWITHAmEXIBLESCOPE(OWEVER INPATIENTSWITH%O% USING A2OTHNETOROTHERRETRIEVALDEVICEORPLACINGANOVERTUBEOVERAmEXIBLEENDOSCOPE AREALTERNATIVEWAYSTOPROTECTTHEAIRWAYINSUCHCASESANDTHERISKOFPERFORATION AT A THERAPEUTIC ENDOSCOPY FOR BOLUS OBSTRUCTION IS LIKELY REDUCED ;16–18, 47]. 7HETHER THIS SHOULD BE PERFORMED BY A GASTROENTEROLOGIST FAMILIAR WITH mEXIBLE ENDOSCOPY ORWHETHEROTOLARYNGOLOGIST DEPENDSONLOCALEXPERTISE EQUIPMENTAND AWARENESSOFTHERELATIVELYHIGHFREQUENCYOF%O%ASACAUSEOFBOLUSOBSTRUCTIONAND ITSATTENDANTRISKOFPERFORATION;19, 30, 38, 48=7HENAPEDIATRICGASTROENTEROLOGISTS

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PERFORMSESOPHAGEALFOREIGNBODYREMOVAL ITISTYPICALLYPERFORMEDUNDERGENERAL ANESTHESIA WITH INTUBATION AND mEXIBLE ENDOSCOPY TO PROTECT THE SMALLER AIRWAY ANATOMY

Perforation Spontaneous perforation. Spontaneous perforation of the esophagus in EoE is rare WITHTHESEVERITYRANGINGFROMAFULL"OERHAAVESRUPTURE;44, 49–51], to partial TEARS ;49= TO CIRCUMFERENTIAL DISSECTIONS ;52–54= 3OME %O% PATIENTS MAY HAVE RELATIVEFRAGILEESOPHAGEALWALLSDUETOEOSINOPHILICINmAMMATIONANDTHUSMAYBE at special risk of perforation secondary to pill ingestions. Drug-induced perforaTIONHASBEENSUGGESTEDINRELATIONTOPARACETAMOLUSEINAPATIENTWITH%O%;55]. ! WIDE RANGE OF MANAGEMENT STYLES HAS BEEN REPORTED FOR THESE SPONTANEOUS PERFORATIONS ! FULL "OERHAAVE TYPE RUPTURE REQUIRES IMMEDIATE THORACOTOMY AND REPAIR OR REPLACEMENT OF THE ESOPHAGUS ! REPORT FROM ,IGUORI ET AL DESCRIBES A  YEAR OLDMANWITHA YEARHISTORYOFMILDDYSPHAGIAFOLLOWEDBYSUDDENFOOD IMPACTIONWHODEVELOPEDSPONTANEOUSDISSECTIONOFTHEESOPHAGEALMUCOSAANDAN ASSOCIATED PNEUMOMEDIASTINUM ;53= 4HIS PATIENT WITH PREVIOUSLY UNDIAGNOSED %O%WASMANAGEDBYSURGICALRESECTIONINTHEACUTESETTING4HISREPORTALLOWEDAN INTERESTINGPATHOLOGICALSTUDYOFTHETRANSMURALEFFECTOF%O%)NCONTRAST PATIENTS WITHKNOWN%O%HAVEBEENMANAGEDDIFFERENTLY&ORINSTANCE ONEREPORTDESCRIBED APATIENTWITHAN YEARHISTORYOF%O%WHODEVELOPEDAPERFORATIONWITHEVIDENCE OFANAIRLEAKWHOWASMANAGEDCONSERVATIVELY WITHOUTANYPROCEDURALINTERVENTION 4HEPATIENTWASSUPPORTEDWITHPARENTERALNUTRITIONANDANTIBIOTICS;54=&INALLY A FURTHERVARIATIONON%O%MANAGEMENTWASTHEUSEOFSTENTFORACIRCUMFERENTIALDISSECTIONWITHOUTEVIDENCEOFTRANSMURALPERFORATION;52].

Maladaptive Eating Behaviours $URINGTHECOURSEOFCHRONICINmAMMATIONASSOCIATEDWITH%O% ANUMBEROFOBSERVATIONSSUGGESTTHATTHEPATIENTUNDERGOESADAPTIVEBEHAVIOURSTHATAREDIRECTEDAT LIMITINGSYMPTOMSSUCHASPAIN DYSPHAGIAANDVOMITING3EESECTIONONPEDIATRIC EVALUATION ABOVE  )N YOUNG CHILDREN THESE ADAPTIVE BEHAVIOURS OFTENTIMES LIMIT FOODINGESTIONANDCANLEADTOMALNUTRITION;20, 56–61]. In older children and adults, THESE ADAPTIVE BEHAVIOURS OR COPING STRATEGIES MAY LEAD TO ALTERED EATING HABITS THATSIGNIlCANTLYALTERLIFESTYLES Pediatric. #LINICALEXPERIENCEANDALIMITEDAMOUNTOFRESEARCHSUPPORTTHEOBSERVATIONS THAT CHILDREN WITH %O% EXHIBIT AT LEAST TWO FORMS OF MALADAPTIVE FEEDING BEHAVIOUR;20=&IRST CHILDRENWHOEXPERIENCEPAINORDISCOMFORTWITHFEEDINGAND OR SWALLOWING MAY LEARN TO LIMIT THE INGESTION OF CALORIES AND MICRONUTRIENTS

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ADEQUATETOSUSTAINGROWTHANDDEVELOPMENT-OSTOFTEN WHENTHEINmAMMATIONIS RESOLVED ORIGINALPATTERNSOFEATINGWILLRETURNANDCHILDRENWILLREGAINTHEIRGROWTH )NSOMECIRCUMSTANCES THEINGESTIONOFADEQUATENUTRITIONREMAINSLIMITEDNECESSITATINGTHEUSEOFNASOGASTRICORGASTROSTOMYTUBESUPPLEMENTATION)NOUREXPERIENCE IT ISRAREFORTHESEINTERVENTIONSTOBENECESSARYBUTTHEYHAVEBEENUTILIZEDINSOMECIRCUMSTANCES4HESECONDTYPEOFMALADAPTIVEBEHAVIOURCONCERNSTHEDEVELOPMENTOF FEEDINGDIFlCULTIES&EEDINGDIFlCULTIESCANBECATEGORIZEDASDELAYEDADVANCEMENTOF NORMALEATINGSKILLSORDEVELOPMENTOFLEARNEDDYSFUNCTIONALEATINGBEHAVIOURS BOTH OFWHICHCANDEVELOPASARESULTOFANESOPHAGEALINSULT;20, 59=4HElRSTPROBLEM DELAYEDADVANCEMENTOFNORMALEATINGSKILLS ISPORTRAYEDINA YEAR OLDCHILDWITH %O%WHODOESNOTADVANCETHROUGHTHENORMALDEVELOPMENTALMILESTONESOFBEING ABLETOEATMORETEXTUREDFOODS4HEPATIENTCONTINUESTOEATSOFTFOODSANDDOESNOT PROGRESSTOINGESTMOREHIGHLYTEXTUREDFOODS!NEXAMPLEOFTHESECONDPROBLEM DEVELOPMENTOFLEARNEDDYSFUNCTIONALEATINGBEHAVIOURS ISPORTRAYEDINTHE YEAR OLD CHILDWHOREFUSESTOEATPREVIOUSLYACCEPTEDTYPICALLYHIGHTEXTUREFOODSLIKELYASA RESULTOFACCOMMODATINGTOANINmAMEDESOPHAGUS)NOURRECENTSTUDY LEARNEDMALADAPTIVEFEEDINGBEHAVIOURSWEREIDENTIlEDINCHILDRENWITHEOSINOPHILICGASTROINTESTINALDISEASES%')$S ANDFEEDINGDIFlCULTIES;20=%XAMPLESOFTHISBEHAVIOUR INCLUDEFOODREFUSAL LOWVOLUMEORVARIETYOFINTAKE SPITTINGFOODOUT GRAZING LACK OFMEALTIMESTRUCTUREANDREQUIRINGPROMPTINGTOEAT)MPORTANTLY BOTHOFTHESEPATTERNSMAYPERSISTEVENWHENMUCOSALINmAMMATIONRESOLVES;20]. Together, these kind OFEATINGPATTERNSCANBEEXTREMELYDISRUPTIVETOFAMILYMEALS CREATEFRUSTRATIONIN PARENTnCHILDDYNAMICSAND INALIMITEDNUMBEROFCASES LEADTOMALNUTRITION Adults. 4HEDIFlCULTIESEXPERIENCEDBYADULTSWHENEATINGMANIFESTTHEMSELVESIN THEIRINABILITYTOEATOUTINRESTAURANTSANDTHEIRANXIETYABOUTTHERISKOFTHECHOKING EPISODES OF BOLUS OBSTRUCTION 4HESE FEARS MAY HAVE MARKED EFFECTS BY ISOLATING PATIENTSSOCIALLY ANISSUECLEARLYDESCRIBEDBYTHEACCOUNTOF3TRAUMANNETALINHIS NATURALHISTORYOF%O%;34]. In this description, he also notes the need for patients to ALTERTHEIRWORKINGLIFE EVENTOTHEPOINTOFNEEDINGTOCHANGECAREERSSOTHATTHEY CANADAPTTOTHEIREATINGDIFlCULTIES;51].

Psychological Impacts 5NMEASURED COSTS ASSOCIATED WITH %O% INCLUDE PSYCHOLOGICAL IMPACTS RELATED TO COPING WITH A CHRONIC DISEASE UNDERGOING REPEATED THERAPEUTIC EVALUATIONS AND ACCOMMODATINGTONECESSARYTREATMENTS#OPINGWITHACHRONICDISEASECANBRING SIGNIlCANTDISRUPTIONTOANYFAMILYANDTHISISPOTENTIALLYCOMPOUNDEDIN%O%BY REPEATEDSKINTESTEVALUATIONS ENDOSCOPICPROCEDURESANDANESTHESIA)NADDITION MALNUTRITIONANDSOCIALISOLATIONRELATEDTOFOODRESTRICTIONORSIDEEFFECTSFROMCORTICOSTEROIDCARRYUNTOLDCOSTS3EE#HAP;62].

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Complications Associated with Treatment Medical Treatment Corticosteroid side effects. !NUMBEROFSTUDIESDOCUMENTTHEEFlCACYANDSAFETY OF TOPICAL CORTICOSTEROIDS IN THE TREATMENT OF ALLERGIC DISEASES INCLUDING ASTHMA ATOPIC DERMATITIS ALLERGIC RHINITIS AND MOST RECENTLY %O% 3IDE EFFECTS THAT HAVE BEENREPORTEDINASSOCIATIONWITHTOPICALSTEROIDTREATMENTFOR%O%INCLUDEESOPHAGEAL #ANDIDAAND(ERPESINFECTIONANDONECASEOFCATARACTS;63–66]. Other potential, BUTUNREPORTED SIDEEFFECTSOFTOPICALSTEROIDSINPATIENTSWITH%O%INCLUDEDIABETES LONGITUDINALGROWTHDELAY SYSTEMICINFECTIONOREPITHELIALATROPHY;67=4HESYSTEMIC EFFECTSOFTOPICALSTEROIDSIN%O%AREMINIMIZEDBECAUSEOFTHELIMITEDSYSTEMICABSORPTIONTHATOCCURSBECAUSEOFlRSTPASSHEPATICMETABOLISM

Surgical Treatment Inappropriate surgery when EoE diagnosis is delayed. 4HEINAPPROPRIATEPERFORMANCE OFA.ISSENFUNDOPLICATIONFORASSUMED'%2$WHENTHEPATIENTISACTUALLYSUFFERING FROM %O% HAS BEEN A RECURRING THEME 4HE PRECISE PREVALENCE OF THIS PROCEDURE IN PATIENTSWITH%O%ISHARDTOESTIMATEBUTANUMBEROFCASESERIESREPORTTHISOCCURRENCE INATLEASTTENPATIENTS;24, 68–70]. Clinical experiences and these series note that in PATIENTSWITH%O% ANTI REmUXOPERATIONSPROVIDENOSUSTAINABLESYMPTOMRELIEF )NSOMEPRACTICES THEPRESENCEOFSUITABLESYMPTOMS THEOBSERVATIONOFENDOSCOPIC INmAMMATION OR THE PRESENCE OF HIATUS HERNIA IS SUFlCIENT JUSTIlCATION FOR FUNDOPLICATIONFOR'%2$)NTHEAUTHORSEXPERIENCES THEUSEOFSYMPTOMSALONETO DISTINGUISH%O%FROM'%2$ISDIFlCULTATBEST ANDENDOSCOPICFEATURESASSOCIATED WITH %O% ARE NON SPECIlC )N THIS LIGHT PRIOR TO PERFORMING FUNDOPLICATION THE AUTHORS WILL ROUTINELY USE P(IMPEDANCE MONITORING TO INSURE THAT PATHOLOGICAL REmUX IS PRESENT )N OUR PRACTICE THE ROUTINE USE OF P( PROBE NOT ONLY IDENTIlES PATIENTSWHOSHOULDUNDERGOFUNDOPLICATIONFORRECALCITRANT'%2$ BUTALSOPERMITS THEIDENTIlCATIONOFTHOSEPATIENTSWHOMAYHAVE%O%ASANETIOLOGYFORTHEIRSYMPTOMS)F'%2$ LIKESYMPTOMSPERSIST DESPITEPROTONPUMPTREATMENT ANDANORMAL PH MONITORING OF THE DISTAL ESOPHAGUS IS RECORDED WHEN THE PATIENT IS OFF PROTON PUMPTREATMENT THEDIAGNOSISOF%O%ISHIGHLYLIKELY;1=7HETHERNON ACIDREmUXIS ACONTRIBUTINGCAUSEOF%O%ISUNCERTAINBUTATLEASTTWOSTUDIESHAVESHOWNTHATNON ACIDREmUXISNOTINCREASEDINATLEASTTWOSTUDIESOFCHILDRENWITH%O%;71, 72].

Perforation Perforation as a complication of dilation. 3TRAUMANN ET AL HAVE HIGHLIGHTED THERISKOFDILATIONOFSTRICTURESIN%O%INTHEIRSERIES PERFORATIONOCCURREDMORE OFTEN WITH THE USE OF RIGID ENDOSCOPY COMPARED TO mEXIBLE ENDOSCOPY ;34].

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211

Fig. 15.2 "ARIUMESOPHAGRAMOFAPATIENTFOLLOWINGRIGIDESOPHAGOSCOPYFORREMOVALOFAFOOD BOLUSOBSTRUCTION SHOWINGASUBMUCOSALDISSECTIONANDPARTIALPERFORATION

!MONG OTHER THINGS THIS REPORT HIGHLIGHTS THE PROBLEM OF PRACTICE ORGANIZATION REFERRALPATTERNSMAYSENDPATIENTSWITH%O% RELATEDESOPHAGEALSTRICTURESTOSUBspecialty surgeons who are not always aware of the EoE diagnosis and attendant POTENTIALPREDISPOSITIONTOPERFORATE)NTHE53! THISMOSTCOMMONLYOCCURSINTHE EMERGENCY ROOM SETTING WHERE A PATIENT PRESENTS ACUTELY WITH AN ESOPHAGEAL OBSTRUCTION PRACTICE ORGANIZATIONS MAY EITHER ROTATE THE RESPONSIBILITY OF ENDOSCOPICMANAGEMENTBETWEENGASTROENTEROLOGISTANDSURGEONORSOLELYREFERTOTHE SURGEON)NTHE5+REFERRALTOANEAR NOSEANDTHROATSURGEON2HYNOLARYNGOLOGIST RARELYIFEVERRESULTSINADIAGNOSISOF%O%)NTHESECIRCUMSTANCES WHENTHESURGEONISNOTAWAREOF%O% THEUNDERLYINGFRAGILEMUCOSAMAYBEATINCREASEDRISKOF perforation with the use of a rigid endoscope. )NASUBSEQUENTREPORT 3TRAUMANNETALFURTHEREMPHASIZEDTHEIMPORTANCEOFPERFORMINGAmEXIBLEENDOSCOPY INSTEADOFARIGIDENDOSCOPY IN%O%PATIENTS;44]. In THIS SERIES THEY IDENTIlED THE OCCURRENCE OF ESOPHAGEAL PERFORATION IN TWO OF TEN PATIENTSUNDERGOINGRIGIDENDOSCOPIESCOMPAREDWITHOFWHOUNDERWENTmEXIBLE ENDOSCOPIES&IG15.2 3EVERALRECENTSTUDIESEXAMINEDPRACTICALASPECTSOFESOPHAGEALDILATIONWITHmEXIBLEENDOSCOPESINOVER%O%PATIENTS;16–18, 47]. These STUDIESREPORTTHATDILATIONISSAFEWHENPERFORMEDCAUTIOUSLYANDDESPITEPOST PROCEDUREPAIN ITISWELLRECEIVEDBYMOSTPATIENTS;16]. Reported that in a study of 70 DILATIONSPERFORMEDINADULTSWITH%O% COMPLICATIONSOFMUCOSALTEARSANDPAIN WEREPREDICTEDBYYOUNGERPATIENTAGEVSYEARS ANDINCREASEDNUMBEROF DILATIONSVS ;17=#OMPARED%O%PATIENTSTREATEDWITHDILATIONALONETO PATIENTSTREATEDWITHDILATIONANDTOPICALSTEROIDSANDIDENTIlEDNOSIGNIlCANT

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DIFFERENCES IN LUMINAL DILATION OR DURATION OF RESPONSE  VS  MONTHS DILATION ALONEVSDILATIONANDTREATMENT ;17=.OPERFORATIONSWEREREPORTED!USEFULOVERVIEWOFTHERISKOFPERFORATIONINDISCUSSEDBY*ACOBSETALINARECENTREVIEW;31]. Perforation related to the simple passage of the endoscope. 4HIS PROBLEM LIES SOMEWHEREBETWEENSPONTANEOUSPERFORATIONANDTHATDUETODILATATION4HECOMPLICATIONISRELATIVELYRARE;47, 73–75=#OHENETALIDENTIlEDMUCOSALLACERATIONS PERFORATIONS INADULTSWITH%O%UNDERGOINGENDOSCOPY4HEMEANAGEOFTHE PATIENTSWASYEARSANDDILATIONSHADBEENPERFORMEDINSIXOFTHEPATIENTSWHO DEVELOPEDCOMPLICATIONS!GAINTHEDECISIONONMANAGEMENTDEPENDSONTHEDEGREE OFPERFORATION THETIMEOFDISCOVERYANDTHEEXTENTOFTHELEAKWITHTHEREPORTED CASESBEINGSUCCESSFULLYMANAGEDBYESOPHAGECTOMYORCONSERVATIVEAPPROACHES

Muscular Involvement in EoE Leiomyomatosis of the Esophageal Wall ! CASE OF ESOPHAGEAL LEIOMYOMATOSIS WITH EOSINOPHILIA WAS REPORTED FROM OUR GROUPBY-ORRISETALTHATSHOWEDVERYSIMILARPATHOLOGYTOTHECASEOF,IGUORI ETALDESCRIBEDABOVE;53, 76=)NOURCASEITWASNOTKNOWNIFTHEDEVELOPMENTOF THIS COMPLICATION WAS A DIRECT RESULT OF MUCOSAL ESOPHAGEAL EOSINOPHILIA BUT THE DYSPHAGIAWHICHOCCURREDINTHIS YEAR OLDMALEWASSEVEREANDTHEPATHOLOGYOF THESECTIONOFESOPHAGEALWALLREMOVEDATSURGERYWASREMARKABLYSIMILARTOTHAT SEENINTHECASEOFRESECTEDESOPHAGUSAFTERPERFORATIONDESCRIBEDBY,IGUORIETAL 4HECIRCUMSTANCEOFFULLTHICKNESSEOSINOPHILICINlLTRATIONINEOSINOPHILICESOPHAGITISWASlRSTRAISEDBY.ICHOLSONETALINANDALTHOUGHTHEIRPAPERDESCRIBEDTHE POTENTIALFORAhCOMMONALLERGICINmAMMATORYPROlLEvVERYFEWOTHERCASESHAVE BEENREPORTED;77=)NTHECASEOF-ORRISETAL THEPATIENTHADNODETECTABLEMUCOSAL DISEASEANDATTHETIMETHEREWASNOREASONTOLINKHISCONDITIONWITH%O%;76=(IS INTRACTABLEDYSPHAGIAWASTHOUGHTTOBEBENIGNTUMOURON#4SCAN BUTATSURGERY BYTHORACOTOMYTHEDIFFUSENATUREOFHISESOPHAGEALWALLSWELLINGWASNOTTYPICALOF MALIGNANCY AND AFTER RESECTING A  CM WIDE STRIP OF FULL THICKNESS MUSCLE FROM ALONGAPPROXIMATELYCMOFOESOPHAGEALMYOTOMY ANDWITHSUITABLEREASSURANCE FROMFROZENSECTIONPATHOLOGY THEESOPHAGUSWASPRESERVEDANDTHEPATIENTSWALLOWEDCOMFORTABLYFORMANYYEARSAFTER

Esophageal Muscular Inflammation )TWOULDBEOFGREATFUNCTIONALINTERESTTOKNOWIFTHEEOSINOPHILICINVOLVEMENTOF MUSCLELAYERSWASACOMMONPHENOMENONIN%O%OFTHEMUCOSA4HECASEREPORT

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OF&ASSANPUBLISHEDONLYINANABSTRACTDESCRIBINGAMYOlBROBLASTICTUMORASAN ADVERSEOUTCOMEOF%O%MAYBEASIMILARCONDITION;78=4HEWORKOF+ORSAPATI ETALSUGGESTSTHATTHEOUTERLAYERSOFESOPHAGEALLONGITUDINALMUSCLESHOWGREATER DEGREESOFDYSFUNCTIONBUTWEDONOTKNOWIFTHISISSECONDARYTOMEDIATORSRELEASED FROMMUCOSALORSUBMUCOSALEOSINOPHILSORITISDUETOEOSINOPHILINlLTRATIONOFTHE MUSCLEWALLS;79]. At least four other studies utilizing endoscopic ultrasound and MOTILITY TRACINGS SUPPORT EXTENSION OF THE EOSINOPHILIA TO THE MUSCULAR LAYERS IN CHILDREN AND ADULTS ;12, 80–83= &URTHER RESEARCH IN THIS AREA WOULD BE OF GREAT INTERESTANDMETHODSOFBIOPSYOFTHEDEEPERLAYERSPERHAPSTHROUGH%53MIGHTBE VERYREVEALING ASLONGASTHEYCANBEPERFORMEDSAFELY

Summary 4HELISTOFCOMPLICATIONSOFEOSINOPHILICESOPHAGITISGROWSASCLINICALEXPERIENCE WITHDIAGNOSISANDTREATMENTINCREASES!WARENESSOFCOMPLICATIONSISVERYIMPORTANTGIVENTHEPOTENTIALSERIOUSNESSOFTHEIRCONSEQUENCES0RECAUTIONSTOAVOIDPRECIPITATING THEM DURING THERAPY ARE PARAMOUNT TO THE CARING PHYSICIANS &ROM A PATIENTSPERSPECTIVE 7HETHERTHElRSTPRESENTINGWITH%O%ISCHRONICDYSPHAGIAOR ACUTE BOLUS OBSTRUCTION THE LIKELIHOOD OF SERIOUS COMPLICATIONS APPEARS TO BE SMALLTHISBEINGSAID THEMOSTIMPORTANTASPECTOFCAREOFTHEPATIENTWITHAPOSSIBLE COMPLICATIONOF%O%ORITSTREATMENTISATTENTIONTOWARDPREVENTION Acknowledgements 'LENN 4 &URUTA ACKNOWLEDGES THE INSIGHTFUL GUIDANCE AND EXPERTISE OF 6ICTOR&OX $AN!TKINS .ANCY#RESKOFF-AUNEAND!NGELA(AASINTHEDEVELOPMENTANDWRITING of this chapter.

References  ,IACOURAS#! &URUTA'4 (IRANO) !TKINS$ !TTWOOD3% "ONIS0! "URKS!7 #HEHADE- #OLLINS-( $ELLON%3 $OHIL2 &ALK'7 'ONSALVES. 'UPTA3+ +ATZKA$! ,UCENDO!* -ARKOWITZ*% .OEL2* /DZE2$ 0UTNAM0% 2ICHTER*% 2OMERO9 2UCHELLI% 3AMPSON (! 3CHOEPFER! 3HAHEEN.* 3ICHERER3( 3PECHLER3 3PERGEL*- 3TRAUMANN! 7ERSHIL "+ 2OTHENBERG-% !CEVES335PDATEDCONSENSUSRECOMMENDATIONSFORCHILDRENANDADULTS *!LLERGY#LIN)MMUNOL*UL  E%PUB!PR0-)$  &ECZKO 0 (ALPERT 2 :ONCA - 2ADIOGRAPHIC ABNORMALITIES IN EOSINOPHILIC ESOPHAGITIS 'ASTROINTEST2ADIOLn  0ICUS$ &RANK0(%OSINOPHILICESOPHAGITIS!*2!M*2OENTGENOLn  !CEVES33 .EWBURY2/ $OHIL2 "ASTIAN*& "ROIDE$(%SOPHAGEALREMODELINGINPEDIATRIC EOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOLn  !CEVES 33 .EWBURY 2/ $OHIL 2 3CHWIMMER * "ASTIAN *& $ISTINGUISHING EOSINOPHILIC ESOPHAGITISINPEDIATRICPATIENTSCLINICAL ENDOSCOPIC ANDHISTOLOGICFEATURESOFANEMERGING DISORDER*#LIN'ASTROENTEROLn  "INKOVITZ ,! ,ORENZ %! $I ,ORENZO # +AHWASH 3 0EDIATRIC EOSINOPHILIC ESOPHAGITIS RADIOLOGIClNDINGSWITHPATHOLOGICCORRELATION0EDIATR2ADIOLn

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Chapter 16

IgE- and Non-IgE-Mediated Food Allergy Scott H. Sicherer

Keywords %OSINOPHILIC ESOPHAGITIS s &OOD ALLERGIES s )MMUNOLOGIC RESPONSES s!LLERGYPATCHTESTS

Introduction &OODALLERGYISGENERALLYDElNEDASANIMMUNE MEDIATEDADVERSERESPONSETOFOOD [1= )N CONTRAST NONIMMUNE ADVERSE REACTIONS TO FOODS INCLUDE INTOLERANCE FOR EXAMPLELACTOSEINTOLERANCE ANDPHARMACOLOGICRESPONSES FOREXAMPLETACHYCARDIA FROM CAFFEINE OR mUSHING AND PRURITUS FROM SCOMBROID lSH POISONING 4HE IMMUNOLOGICRESPONSESRESPONSIBLEFORFOODALLERGIESAREOFTENCATEGORIZEDAS)G% ANTIBODY MEDIATED CELL MEDIATED NON )G% OR CAUSED BY COMBINED IMMUNE RESPONSE&OOD INDUCEDEOSINOPHILICESOPHAGITISISTYPICALLYCONSIDEREDTOBETHE RESULT OF OR RELATED TO BOTH CELLULAR AND )G% ANTIBODY RESPONSES 4HIS CHAPTER FOCUSES UPON THE FULL SPECTRUM OF FOOD ALLERGIC DISORDERS WITH LESS EMPHASIS ON EOSINOPHILIC ESOPHAGITIS 4ABLE 16.1 LISTS VARIOUS TYPES OF ADVERSE REACTIONS TO FOODSWITHEXAMPLES 4HERE ARE A NUMBER OF IMPORTANT REASONS FOR CONSIDERING A DIAGNOSIS OF FOOD ALLERGYINTHOSEWHOHAVEORMAYHAVEEOSINOPHILICESOPHAGITIS&OODISANIMPORTANTTRIGGERFOREOSINOPHILICESOPHAGITIS;2=#OEXISTINGFOODALLERGY ORATLEASTPOSITIVE TESTS FOR FOOD SPECIlC )G% OR POSITIVE ALLERGY PATCH TESTS TO FOODS ;3] are FREQUENTLYREPORTED)NREPORTSOFCHILDRENANDADULTSWITHEOSINOPHILICESOPHAGITIS GENERALLY OVER  HAVE POSITIVE TESTS FOR FOOD SPECIlC )G% ;4–7]. Additionally,

S.H. Sicherer (*) $EPARTMENTOF0EDIATRICS -OUNT3INAI3CHOOLOF-EDICINE *AFFE&OOD!LLERGY)NSTITUTE 'USTAVE,,EVY0LACE  .EW9ORK .9 53! E MAILSCOTTSICHERER MSSMEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_16, © Springer Science+Business Media, LLC 2012

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S.H. Sicherer Table 16.1 'ENERALOVERVIEWOFADVERSEREACTIONSTOFOODSWITHEXAMPLES &OODALLERGYIMMUNERESPONSES )G% MEDIATEDEG ANAPHYLAXIS .OT)G% MEDIATEDCELLMEDIATED EG FOODPROTEIN INDUCEDENTEROCOLITIS -IXED)G%NON )G%EG EOSINOPHILICGASTROINTESTINALDISEASE ATOPICDERMATITIS )NTOLERANCENONALLERGICHYPERSENSITIVITYANDPHARMACOLOGICRESPONSES ,ACTOSEINTOLERANCELACTASEDElCIENCY #AFFEINEJITTERINESS 4OXINS "ACTERIALFOODPOISONING 3COMBROIDINDARK MEATlSH MAYMIMICALLERGY .EUROLOGICANDPSYCHOLOGICALPSYCHIATRIC !URICULOTEMPORALSYNDROMEFACIALmUSHWITHSALIVATION 'USTATORYRHINITISRHINITISFROMSPICYORHOTFOODS !NOREXIANERVOSAANDFOODAVERSIONS

n OF THOSE WITH EOSINOPHILIC ESOPHAGITIS HAVE ANAPHYLACTIC FOOD ALLERGIES [8–11= 4HUS IDENTIlCATION AND MANAGEMENT OF )G% MEDIATED FOOD ALLERGY IS AN IMPORTANT COMPONENT OF CARE FOR MANY PATIENTS WITH EOSINOPHILIC ESOPHAGITIS !DDITIONALLY ATOPIC DISEASE SUCH AS ATOPIC DERMATITIS AND ASTHMA ARE COMMON CO MORBIDITIESAMONGTHOSEWITHEOSINOPHILICESOPHAGITISANDMAYALSOBERELATED TOFOODALLERGIESINSOMEPATIENTS;12=,ASTLY VARIOUSFOOD ASSOCIATEDGASTROINTESTINALDISORDERSMAYNEEDTOBECONSIDEREDINTHEDIFFERENTIALDIAGNOSISOFTHOSEWITH POSSIBLEEOSINOPHILICESOPHAGITIS

Pathophysiology &OODALLERGYISPRESUMEDTOBETHERESULTOFAFAILURETOACHIEVE ORALOSSOF ORAL TOLERANCE4HISDEFECTISTHOUGHTTOOCCURDUETOIMMUNEDYSREGULATIONASSOCIATED WITH ORAL EXPOSURE TO FOOD PROTEINS ALLERGENS  !LTERNATIVELY A NONORAL ROUTE OF EXPOSUREMAYABROGATETOLERANCE&OREXAMPLE ORALALLERGYSYNDROMEPOLLEN FOOD RELATED SYNDROME A TYPE OF FOOD ALLERGY DISCUSSED FURTHER BELOW RESULTS WHEN RESPIRATORY SENSITIZATION TO PROTEIN IN BIRCH TREE POLLEN RESULTS IN ORAL SYMPTOMS UPONINGESTIONOFHOMOLOGOUSPROTEINSINSPECIlCFRUITS;13]. 3YMPTOMSASSOCIATEDWITH)G%ANTIBODY MEDIATEDREACTIONSTOFOODSARETYPICALLYSUDDENINONSET OCCURRINGWITHINMINUTESTOAFEWHOURSAFTEREXPOSURE4HESE PATIENTS TYPICALLY HAVE FOOD SPECIlC )G% ANTIBODIES THAT CAN BE DEMONSTRATED BY ALLERGYSKINPRICKTESTS304 ORSERUMTESTS#ELL MEDIATEDFOODALLERGIES PRIMARILY AFFECTINGTHEGUT CAUSECHRONICSYMPTOMSWHERETHEONSETMAYBEDELAYEDBYHOURS ORDAYSORMAYBECHRONIC4ESTSFORFOOD SPECIlC)G%AREGENERALLYNEGATIVE ANDIN SOMECASESRESEARCHERSHAVEDEMONSTRATEDPOSITIVETESTSOFDELAYEDTYPEHYPERSENSITIVITYUSINGPATCHTESTINGPLACEMENTOFTHEFOODONTHESKINUNDERACHAMBER FOROVERHWITHEVALUATIONOFTHERESPONSEFORSEVERALDAYSAFTERREMOVAL ;14].

 )G% AND.ON )G% -EDIATED&OOD!LLERGY

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"OTHEOSINOPHILICESOPHAGITISANDFOOD ASSOCIATEDATOPICDERMATITISARECONSIDERED TOBEOFMIXED)G%NON )G%ETIOLOGYANDSTUDIESHAVERELATEDFOOD RESPONSIVENESS TOPOSITIVETESTSFORFOOD SPECIlC)G%ANDORPATCHTESTING;15, 16]. )MMUNE RESPONSES ARE PRIMARILY DIRECTED TO PROTEINS IN FOODS 2ELATIVELY FEW PROTEIN FAMILIES ACCOUNT FOR THE VAST MAJORITY OF ALLERGIC REACTIONS ;17]. Allergic REACTIONSTOEGG MILK PEANUT TREENUTS lSH SHELLlSH WHEAT ANDSOYACCOUNTFOR MOSTSIGNIlCANTFOODALLERGIES ALTHOUGHANYFOODMAYTRIGGERANALLERGICRESPONSE [18= 4HESE FOOD ALLERGENS SHARE A NUMBER OF COMMON FEATURES THEY ARE WATER SOLUBLEGLYCOPROTEINS nK$AINSIZEANDARERELATIVELYSTABLETOHEAT ACID AND PROTEASES(OWEVER RECENTSTUDIESSUGGESTTHATTHECARBOHYDRATEMOIETYOFCERTAIN GLYCOPROTEINS MAY PLAY A SIGNIlCANT ROLE IN THE ALLERGENICITY OF SPECIlC FOODS 0LATTS -ILLSANDCOLLEAGUESIDENTIlEDADULTSWHOREPORTEDURTICARIA ANGIOEDEMA ORANAPHYLAXISnHAFTERINGESTINGBEEF LAMB ORPORK;19=4HESEPATIENTSWERE FOUND TO HAVE POSITIVE SKIN TESTS AND SERUM )G% ANTIBODIES TO GALACTOSE ALPHA   GALACTOSE THECARBOHYDRATEMOIETYOFTHESEMAMMALIANGLYCOPROTEINS4HISISTHE lRSTDEMONSTRATIONOF)G%ANTIBODIESDIRECTEDATACARBOHYDRATEEPITOPELEADINGTO CLINICALSYMPTOMSANDMAYREPRESENTSENSITIZATIONTOTICKBITEANTIGENSFROMSPECIES INTHEREGIONSWHERETHESEPATIENTSWEREOBSERVED

Epidemiology 4HEEPIDEMIOLOGYOFEOSINOPHILICESOPHAGITISISCONSIDEREDIN#HAPSAND(ERE WEFOCUSUPONGENERALESTIMATESOFFOODALLERGYPREVALENCE5NFORTUNATELY DElNITIVESTUDIESAREFEWANDESTIMATESVARYBYSTUDYDESIGNANDOTHERFACTORS#ONSIDERING ALLERGY TO MILK EGG PEANUT AND SEAFOOD IN A META ANALYSIS OF  STUDIES SELF REPORTEDALLERGYRANGEDFROMTOWHILEESTIMATESFROMSTUDIESUSINGMORE DElNITIVETESTSSUCHASMEDICALLYSUPERVISEDFEEDINGSESTIMATEDRATESOFn [20=)NAMETA ANALYSISINCLUDINGPOPULATION BASEDSTUDIESFOCUSINGONALLERGY TOFRUITSANDVEGETABLESEXCLUDINGPEANUT ;21= ONLYINCLUDEDSUPERVISEDFEEDING TESTSANDESTIMATESOFALLERGYVARIEDWIDELYFROMTOFORFRUITSANDTREENUTS TOTOFORVEGETABLESANDUNDERFORWHEAT SOY ANDSESAME &OODALLERGYPREVALENCERATESVARYBYAGE CULTURALDIET ANDMANYOTHERFACTORS !#$#REPORTINDICATEDANRISEINCHILDHOODFOODALLERGYFROMTO WITHANESTIMATEDOFCHILDRENCURRENTLYAFFECTED;22=3TUDIESINTHE53 ANDTHE5+HAVEINDICATEDATLEASTADOUBLINGINTHERATEOFPEANUTALLERGYINYOUNG children within the past decade [23, 24=%XTRAPOLATIONFROMA53STUDYINDICATES APPROXIMATELY EMERGENCYROOMVISITS;25=AND EPISODESOFANAPHYlaxis [26=FROMFOODSEACHYEAR&ATALITIESAREPRIMARILYREPORTEDFROMALLERGICREACTIONSTOPEANUTSANDTREENUTS APPEARTOBEASSOCIATEDWITHDELAYEDTREATMENTWITH EPINEPHRINEANDOCCURMOREOFTENINTEENAGERSANDYOUNGADULTSWITHASTHMAANDA PREVIOUSLY DIAGNOSED FOOD ALLERGY ;27= !LLERGY TO ADDITIVES AND PRESERVATIVES THOUGHOFTENSUSPECTED AREUNCOMMON ;28='ENETICRISKFACTORSFORFOOD ALLERGYINCLUDEAFAMILYORPERSONALHISTORYOFATOPICDISORDERSASTHMA ATOPICDERMATITIS ALLERGICRHINITIS FOODALLERGY 

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3TUDIESTOADDRESSTHEREASONSFORTHEAPPARENTINCREASEDPREVALENCEOFFOOD ALLERGIES HAVE FOCUSED PRIMARILY ON PEANUT (YPOTHESES INCLUDE THE hHYGIENE HYPOTHESISvWHERELACKOFEXPOSURETOMICROBESRESULTSINIMMUNEDYSREGULATION CHANGESINTHECOMPONENTSOFTHEDIETINCLUDINGANTIOXIDANTS FATS ANDNUTRIENTS SUCHASVITAMIN$THATMAYALTERIMMUNEFUNCTION THEUSEOFANTACIDSRESULTING IN EXPOSURE TO MORE INTACT PROTEIN VARIOUS FORMS OF FOOD PROCESSING EG FOR PEANUTROASTINGANDEMULSIlCATIONTOPRODUCEPEANUTBUTTERCOMPAREDTOFRIEDOR BOILEDPEANUT ANDTIMINGOFINGESTIONSUCHASEXPOSURETHATISTOOEARLYINLIFE OREXTENSIVELYDELAYING;29, 30=4HELATTERHYPOTHESISPOSESTHATORALEXPOSUREIS TOLERANCE INDUCING AND LACK OF ORAL EXPOSURE MAY RESULT IN THE OPPORTUNITY TO EXPERIENCE SENSITIZING EXPOSURES BY NONORAL ROUTES %VIDENCE SUPPORTING THIS HYPOTHESISISPROVIDEDBYASTUDYSHOWINGPEANUTALLERGYRATESINASCHOOLAGE COHORT OF )SRAELI *EWISH CHILDREN TO BE  COMPARED TO A COHORT OF *EWISH CHILDRENINTHE5+WHERETHERATEWASABOUTTENFOLDHIGHERp IN THE CONTEXT OF DATA SHOWING CONSUMPTION OF PEANUT AT AGES n MONTHS WAS GIN)SRAELCOMPAREDTOGINTHE5+p ;31]. A case–control study ADDITIONALLYFOUNDTHATPEANUTALLERGYWASASSOCIATEDWITHHOUSEHOLDPEANUTCONSUMPTIONRATHERTHANMATERNALORINFANTPEANUTCONSUMPTION;32=(OWEVER RANDOMIZED CONTROLLED TRIALS ARE NEEDED TO CONlRM THE HYPOTHESIS THAT EARLIER INGESTIONOFPEANUTISPROTECTIVE

Clinical Disorders IgE-Mediated Disorders )G% MEDIATEDFOOD ALLERGICREACTIONSTYPICALLYRESULTINSYMPTOMSSOONAFTERINGESTIONOFTHEFOOD4HEORGANSYSTEMS AFFECTEDANDTHESPECIlCSYMPTOMPATTERNS SOMETIMESRELATEDTOTHEROUTEOFCONTACTORSENSITIZATION FURTHERDElNETHESPECIlC DISORDERSTHATRESULTFROMTHESEMECHANISMS4HEDISORDERSGENERALLYRESULTFROMTHE RELEASEOFMEDIATORS SUCHASHISTAMINEANDPLATELET ACTIVATINGFACTOR FROMEFFECTOR CELLS EG MAST CELLS AND BASOPHILS AFTER FOOD SPECIlC )G% ANTIBODIES ARE CROSS LINKEDTHROUGHINTERACTIONWITHTHETRIGGERPROTEINSONTHESURFACESOFTHEEFFECTOR CELLS4HESYMPTOMSANDDISORDERSINCLUDE Urticaria and/or angioedema. 5RTICARIA PRURITIS ANDmUSHINGARECOMMONSKIN MANIFESTATIONSOFFOODALLERGY EITHERALONEORINCOMBINATIONWITHOTHERSYMPTOMS;1=4HERASHMAYOCCURANYWHERE THOUGHAREASONTHEFACEAREMOSTCOMMONLY AFFECTED ! LOCALIZED FORM OF URTICARIA contact urticaria DESCRIBES THE OBSERVATIONTHATDIRECTSKINCONTACTWITHTHEFOODRESULTSINHIVES&ORASPECIlC PATIENT AFOODTHATTRIGGERSCONTACTURTICARIAMAYBETOLERATEDWHENINGESTEDWITHout direct skin contact. Chronic urticariaISTYPICALLYDESCRIBEDASAPERIODWITH WEEKSORMOREOFFREQUENTURTICARIATHISDISORDERISNOTCOMMONLYASSOCIATED WITHFOODALLERGY

 )G% AND.ON )G% -EDIATED&OOD!LLERGY

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Gastrointestinal anaphylaxis. 4HIS TERM IS USED TO DESCRIBE ISOLATED ACUTE GASTROINTESTINALRESPONSESSUCHASNAUSEA PAIN VOMITINGANDORDIARRHEAINDUCED BY )G% MEDIATED MECHANISMS 'ASTROINTESTINAL ANAPHYLAXIS IS UNCOMMON BUT GASTROINTESTINAL SYMPTOMS COMMONLY ACCOMPANY OTHER ORGAN SYSTEM MANIFESTATIONSOFACUTE )G%ANTIBODY MEDIATEDREACTIONSTOFOODS Pollen-food allergy syndrome (oral allergy syndrome). 4HISDISORDERISAFORMOF CONTACTALLERGYWHERETHEPRIMARYSYMPTOMSOCCURINTHEOROPHARYNXANDLIPS;33]. )NITIALSENSITIZATIONTOPOLLENPROTEINSMAYRESULTINSYMPTOMSWHENHOMOLOGOUS PROTEINSINPARTICULARSPECIlCRAWFRUITSVEGETABLESAREINGESTED&OREXAMPLE THE BIRCHPOLLENPROTEIN "ETV SHARESHOMOLOGYWITHAPPLE -ALD!DDITIONALRELATIONSHIPSWITHBIRCH POLLENPROTEINSINCLUDEOTHER2OSACEAEFAMILY FRUITSSUCHAS PEACHANDPLUMANDVEGETABLESSUCHASCARROT!NOTHERRELATIONSHIPISBETWEENRAGWEEDPOLLENPROTEINANDPROTEINSINMELONSSUCHASCANTALOUPEANDHONEYDEW)TIS ESTIMATEDTHATOFPOLLEN ALLERGICPERSONSMAYBEAFFECTED3YMPTOMSARETYPICALLYMILDANDSELF LIMITEDWITHORALPRURITUSANDMILDANGIOEDEMA BUTPROGRESSION TOASYSTEMICREACTIONMAYOCCUR#AUSALPROTEINSAREPRESUMABLYHEAT LABILESINCE COOKINGTHEFOODTYPICALLYABOLISHESREACTIONS4HESYMPTOMPATTERNMUSTBEDISTINGUISHEDFROMMILDORALREACTIONSTOSTABLEPROTEINSANDORALREACTIONSTHATMAYBEA lRSTSYMPTOMOFAMOREPROGRESSIVEALLERGICRESPONSE4HESELFSAMEFOODSCAUSING THISORALSYNDROMEMAYINDUCESYSTEMICREACTIONSINPERSONSREACTIVETOSTABLEPROTEINSINTHEMEG LIPIDTRANSFERPROTEINS 0ERSONSWITHEOSINOPHILICESOPHAGITIS OFTENHAVEPOLLENALLERGIESANDTHEROLEOFBOTHRESPIRATORYEXPOSURETOTHEPOLLENS ANDOFORAL TOPICALEXPOSURETOPOLLEN RELATEDPROTEINSINRAWFRUITSORVEGETABLES HASNOTBEENFULLYELUCIDATED Asthma and Allergic Rhinitis. #HRONICASTHMAANDCHRONICALLERGICRHINITISARENOT TYPICALLYSOLELYATTRIBUTABLETOFOODALLERGY(OWEVER NASALRESPIRATORYSYMPTOMSOF RHINORRHEA CONGESTION ANDPRURITUSORASTHMASYMPTOMSSUCHASCOUGHANDWHEEZING MAY ACCOMPANY SYSTEMIC ALLERGIC REACTIONS FROM INGESTED FOOD ALLERGENS )NHALATIONOFAIRBORNEALLERGENICFOODPROTEINSMAYALSOINDUCERESPIRATORYREACTIONS EITHERINANOCCUPATIONALSETTING EG BAKERSASTHMAFROMWHEAT ORWHENSTABLE PROTEINSBECOMEAEROSOLIZEDDURINGCOOKINGORPROCESSING;34]. Anaphylaxis. /UTSIDEOFMEDICALSETTINGS FOODISTHEMOSTCOMMONTRIGGEROFANAPHYLAXIS ASERIOUSSYSTEMICALLERGICREACTIONTHATISRAPIDINONSETANDMAYCAUSE death [35=3YMPTOMSCANVARYANDMAYAFFECTANYOFACOMBINATIONOFORGANSYSTEMSAMONGTHESKIN RESPIRATORYTRACT GASTROINTESTINALTRACT ANDCARDIOVASCULARSYSTEM 3YMPTOMS MAY ALSO INCLUDE AN AURA OF hIMPENDING DOOM v AND UTERINE CONTRACTIONS 7HILE A VARIETY OF MILD SYMPTOMS SUCH AS URTICARIA AND ABDOMINAL PAINMAYOCCUR LIFE THREATENINGSYMPTOMSINCLUDELARYNGEALEDEMA SEVEREASTHMA ANDCARDIOVASCULARCOMPROMISE&ATALITIESARERARE BUTHAVEBEENASSOCIATEDWITH DELAYED TREATMENT CO MORBID CONDITIONS SUCH AS ASTHMA AND REACTIONS TO FOODS SUCH AS PEANUT TREE NUTS lSH SHELLlSH AND MILK ;27]. Anaphylaxis is a clinical DIAGNOSIS2EACTIONSMAYFOLLOWABIPHASICCOURSEWITHINITIALSYMPTOMSWANING WITHRECURRENCEOFSEVERESYMPTOMSnHLATER ORLONGER!SUB TYPEOFFOOD INDUCED

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anaphylaxis is food-associated, exercise-induced anaphylaxis [36=4HISDISORDERIS CHARACTERIZEDBYANAPHYLAXISOCCURRINGONLYWHENEXERCISEFOLLOWSINGESTIONOFA SPECIlCFOODORFOODS THATISOTHERWISETOLERATED4HESYNDROMEOFEXERCISE RELATED FOODANAPHYLAXISHASBEENATTRIBUTEDTOAVARIETYOFSPECIlCFOODS MOSTCOMMONLY WHEATANDCELERY BUTSOMEINDIVIDUALSEXPERIENCEANAPHYLAXISWITHEXERCISEAFTER ANYMEAL

Non-IgE-Mediated (Cell Mediated) Disorders 3IMILARTOTHE)G% ASSOCIATEDDISORDERS THESEDISORDERSMAYALSOAFFECTVARIOUSTARget organs [37=(OWEVER SYMPTOMSTHATAREASSOCIATEDWITHEXPOSURETENDTOOCCUR CHRONICALLYDURINGAPERIODOFINCLUSIONOFTHEFOODINTHEDIETORSUBACUTELY HOURS ORMOREAFTERANINGESTION-OSTOFTHEDISORDERSINTHISCATEGORYAFFECTTHEGASTROINtestinal tract. Contact dermatitis. %CZEMATOUSERUPTIONSFROMDIRECTSKINCONTACT OFTENINOCCUPATIONALSETTINGS REPRESENTATYPE)6HYPERSENSITIVITYRESPONSE&IXEDRAISED ERYTHEMATOUSERUPTIONS SIMILARTOlXEDDRUGERUPTIONS HAVERARELYBEENATTRIBUTEDTO FOODS Dermatitis herpetiformis. 4HISISAPAPULOVESICULARSKINRASHASSOCIATEDWITHCELIAC DISEASECAUSEDBYANIMMUNERESPONSETOGLUTEN Heiner’s syndrome or milk-induced pulmonary hemosiderosis. 4HISRARECONDITION ISASSOCIATEDWITHPRECIPITATING)G' ANTIBODIESTOCOWSMILK3YMPTOMSINCLUDE ANEMIA PULMONARY INlLTRATES RECURRENT PNEUMONIA AND GROWTH FAILURE WHICH RESOLVEWITHMILKELIMINATION Dietary protein proctocolitis/allergic eosinophilic proctocolitis. )NFANTS WITH THIS DISORDERAPPEARGENERALLYHEALTHYBUTEXPERIENCEMUCOUSY BLOODYSTOOLS4HEDISORDERISATTRIBUTEDTOANIMMUNERESPONSEDIRECTED MOSTCOMMONLY AGAINSTCOWS MILKPROTEIN4HEMEANAGEATDIAGNOSISISAPPROXIMATELYDAYS WITHARANGEOF DAYTOMONTHS;38, 39=5NLIKEBLEEDINGASSOCIATEDWITHPERIRECTALlSSURESWHERE STREAKSOFBLOODAPPEARONFORMEDSTOOL THEPATTERNOFBLEEDINGMOREOFTENRESULTS INSTOOLTHATHASAMIXTUREOFFROTHYMUCOUSANDBLOOD!BOUTOFCASESOCCUR INBREASTFEDINFANTSWHERETHEIMMUNERESPONSERESULTSFROMMATERNALINGESTIONOF THEFOODALLERGEN USUALLYCOWSMILK WHICHISPASSEDINIMMUNOLOGICALLYRECOGNIZABLEFORMINTOTHEBREASTMILK)NFORMULA FEDINFANTS THEREACTIONISASSOCIATEDWITH COWSMILKOR LESSCOMMONLY SOY;40–42=%NDOSCOPICEXAMINATIONISUSUALLYNOT NEEDEDFORDIAGNOSTICPURPOSESBUT WHENPERFORMED SHOWSPATCHYERYTHEMA FRIABILITY AND A LOSS OF VASCULARITY GENERALLY LIMITED TO THE RECTUM BUT SOMETIMES extending throughout the colon [43=(ISTOLOGICALLY HIGHNUMBERSOFEOSINOPHILS nPERHIGH POWERlELD OREOSINOPHILICABSCESSESARESEENINTHELAMINAPROPRIA CRYPTEPITHELIUM ANDMUSCULARISMUCOSA;38, 44=4HEEOSINOPHILSAREFREQUENTLY ASSOCIATEDWITHLYMPHOIDNODULESLYMPHONODULARHYPERPLASIA ;38, 45].

 )G% AND.ON )G% -EDIATED&OOD!LLERGY

225

4HE FREQUENCY OF FOOD ALLERGY CAUSING RECTAL BLEEDING IN INFANTS HAS NOT BEEN EXTENSIVELYSTUDIED8ANTHAKOSETAL;46=PERFORMEDCOLONOSCOPYANDBIOPSYON INFANTSPRESENTINGWITHRECTALBLEEDINGANDPROVEDEOSINOPHILICCOLITISIN  4HEREMAINDERHADNORMALBIOPSIES ORNONSPECIlCCOLITIS 4HISGROUP RECOMMENDEDDIETARYELIMINATIONFORTHOSEWITHEOSINOPHILICCOLITISANDTHEMAJORITYHADRESOLUTIONWITHINnWEEKS(OWEVER THERELATIONSHIPOFCOWSMILKPROTEINTOSYMPTOMSWASNOTPROVENBYRE CHALLENGEINTHATSTUDY!RVOLAETAL;47] EXAMINED  INFANTS PRESENTING WITH RECTAL BLEEDING )NFANTS WERE RANDOMIZED TO EITHERAVOIDCOWSMILKPROTEINORMAINTAINTHEIRCURRENTDIET4HEGROUPSWERESIMILARWITHREGARDTODURATIONANDSEVERITYOFBLEEDING$URINGFOLLOW UP COWSMILK ALLERGYWASDIAGNOSEDINOFTHEINFANTSANDFORTHESECOWSMILKALLERGICINFANTS THEREWASAREDUCEDLENGTHOFBLEEDINGIFTHEYHADBEENRANDOMIZEDTOANELIMINATION DIET AT STUDY OUTSET !TOPIC DERMATITIS AND CONlRMED INmAMMATION OF THE COLONICMUCOSAWEREASSOCIATEDWITHPERSISTENCEOFCOWSMILKALLERGYUPTOTHEAGE OFYEAR4HESESTUDIESINDICATETHATFOODALLERGYMAYNOTBEACOMMONCAUSEOF RECTALBLEEDINGIN INFANTSUNLESSTHEREAREADDITIONALSIGNSOFALLERGY(OWEVER A SURVEYOFPEDIATRICGASTROENTEROLOGISTSSHOWEDTHATPRESCRIBEEMPIRICDIETARY trials [46= )N COWS MILK OR SOY FORMULA FED INFANTS SUBSTITUTION WITH A PROTEIN HYDROLYSATEFORMULACANBEUNDERTAKEN-ANAGEMENTINBREASTFEDINFANTSREQUIRES MATERNALRESTRICTIONOFCOWSMILKORPOSSIBLYSOY EGG OROTHERFOODS;40]. Because THEREISGENERALLYNORISKOFASEVEREREACTION THEFOODSCANBEGRADUALLYREINTRODUCEDINTOTHEDIETEITHERASATRIALTOPROVEACAUSALRELATIONSHIPORMONTHSAFTERWARDSTOMONITORFORRESOLUTIONOFTHEALLERGY Food protein-induced enterocolitis syndrome (FPIES). 4HISDRAMATICBUTUNCOMMONDISORDERINCLUDESASYMPTOMCOMPLEXOFPROFUSEVOMITINGANDDIARRHEAUSUALLY DIAGNOSED IN THE lRST MONTHS OF LIFE AND MOST COMMONLY ATTRIBUTABLE TO AN IMMUNERESPONSETOCOWSMILKORSOY;48="OTHTHESMALLANDLARGEINTESTINESARE INVOLVEDINTHEINmAMMATORYPROCESS7HENTHECAUSALPROTEINREMAINSINTHEDIET CHRONICSYMPTOMSCANINCLUDEBLOODYDIARRHEA POORGROWTH ANEMIA HYPOALBUMINEMIA ANDFECALLEUKOCYTES ANDTHEILLNESSMAYPROGRESSTODEHYDRATIONANDHYPOTENsion [49, 50=2EMOVALOFTHECAUSALPROTEINLEADSTORESOLUTIONOFSYMPTOMSBUT RE EXPOSURERESULTSINACHARACTERISTICDELAYED APPROXIMATELYH ONSETOFVOMITING LETHARGY ELEVATIONOFTHEPERIPHERALBLOODPOLYMORPHONUCLEARLEUKOCYTECOUNT ANDPOSSIBLYREDUCEDTEMPERATURE THROMBOCYTOSIS HYPOTENSION DEHYDRATION ACIDEMIA ANDMETHEMOGLOBINEMIA;51, 52=4HEDRAMATICNATUREOFTHEPRESENTATION OFTENRESULTSINEVALUATIONSFORSEPSISORSURGICALDIAGNOSES;53= ANDADELAYINlNAL DIAGNOSISUNTILMORETHANONEEPISODEOCCURS;52="ASEDUPONSTUDIESINTHE53AND Israel [54–56= APPROXIMATELYHALFOFINFANTSWITHCOWSMILKREACTIONSALSOREACTTO SOYANDAMONGCHILDRENREACTINGTOMILKSOY ABOUTREACTTOADDITIONALPROTEINS SUCHASRICEOROAT3ENSITIVITYTOMILKWASLOSTINANDTOSOYINOFTHE PATIENTSAFTERYEARSFROMTHETIMEOFPRESENTATION)NADDITION SOMEPATIENTSMAINTAINTHEIRALLERGYBEYONDTHEAGEOFYEARS;57=!RETROSPECTIVESTUDYOFCHILDREN FROM !USTRALIA EVALUATED OVER A SPAN OF  YEARS SHOWED RICE  CHILDREN SOY  ANDMILK TOBETHEMOSTCOMMONTRIGGERSANDSENSITIVITYWASLOSTBYTHEAGE

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OFYEARSTORICEANDSOYINABOUT;52=)NACOHORTOF+OREANINFANTSWITH MILKSOY&0)%3 RESOLUTIONRATESWEREFORMILKANDFORSOYBYMONTHS OFAGEANDALLWERETOLERANTBYMONTHS;58]. 6ARIOUSSTUDIESHAVEIMPLICATED4.& ALPHAASAMEDIATOROFINTERESTINTHISDISorder [59–62]. Chung et al. [62=DEMONSTRATEDTHATTHETYPE BUTNOTTYPE RECEPTORFOR4'& BETAWEREDECREASEDINDUODENALBIOPSYSPECIMENSINPATIENTSWITH &0)%3COMPAREDTOCONTROLS!NALYSISOFHUMORALFEATURESINMILK INDUCEDENTEROCOLITIS SHOWS MILK PROTEIN SPECIlC )G! BUT VERY LOW LEVELS OF SPECIlC )G' AND )G' ANDTHISHASBEENTHEORIZEDTOBEPATHOGENICBECAUSE)G'MIGHTOTHERWISE BLOCKCOMPLEMENT lXINGANTIBODIES;63=3PECIlC)G%ISSOMETIMESNOTEDASWELL ANDMAYBEAMARKEROFPERSISTENCE;51]. 4HE DIAGNOSIS OF &0)%3 RESTS ON CLINICAL AND CHALLENGE CRITERIA -OST PATIENTS WOULDNOTUNDERGOAFORMALCHALLENGEDURINGINFANCYBECAUSETHEDIAGNOSISBECOMES SELF EVIDENTAFTERELIMINATIONOFTHECAUSALPROTEIN ANDFREQUENTLYPATIENTSEXPERIENCEINADVERTENTRE EXPOSURE PROVINGTHEIRSENSITIVITYBEFOREADIAGNOSTICTESTFEEDING)TMUSTBEAPPRECIATEDTHATCHRONICINGESTION ORRE EXPOSURETOTHECAUSALFOOD CANRESULTINACLINICALPICTURETHATISSEVEREANDMAYMIMICSEPSIS)NAREVIEWOF INFANTSHOSPITALIZEDWITHTHISDISORDER -URRAYAND#HRISTIE;64=REPORTEDINFANTS WHOPRESENTEDWITHACIDEMIAMEANP( ANDMETHEMOGLOBINEMIA&OLLOW UP MEDICALLYSUPERVISEDFEEDINGMAYBEPERFORMEDATINTERVALSTODETERMINETOLERANCE DRAMATIC REACTIONS INCLUDING SHOCK CAN OCCUR SO SPECIALIST CARE IS NEEDED 2E EVALUATION FOR THE DEVELOPMENT OF ANTIGEN SPECIlC )G% ANTIBODY BEFORE CHALLENGEMAYBEHELPFULBECAUSEAFEWCHILDRENMAYCONVERTTO)G% MEDIATEDREACTIONS OVER TIME AND EXPERIENCE MORE PERSISTENT SYMPTOMS AND ACUTE ALLERGIC REACTIONS [51=0ATCHTESTINGWASPERFORMEDINONESMALLSTUDYANDSHOWEDSENSITIVITY ANDSPECIlCITY;14=ADDITIONALSTUDIESARENEEDEDTOCONlRMTHESEPROMISING RESULTS!BOUTHALFOFPOSITIVECHALLENGESREQUIRETREATMENTUSUALLYINTRAVENOUSmUIDS [51=)NVIEWOFTHEPRESUMEDPATHOPHYSIOLOGY CORTICOSTEROIDSHAVEBEENADMINISTEREDFORSEVEREREACTIONS4HEROLEOFEPINEPHRINEFORTREATMENTISNOTKNOWN BUTIT SHOULDBEAVAILABLEFORSEVERECARDIOVASCULARREACTIONS Dietary protein enteropathy. 4HISDISORDERISCHARACTERIZEDBYPROTRACTEDDIARRHEA VOMITING MALABSORPTION AND FAILURE TO THRIVE !DDITIONAL FEATURES MAY INCLUDE ABDOMINAL DISTENTION EARLY SATIETY EDEMA HYPOPROTEINEMIA AND PROTEIN LOSING enteropathy [65=3YMPTOMSUSUALLYBEGININTHElRSTSEVERALMONTHSOFLIFE DEPENDINGONTHETIMEOFEXPOSURETOTHECAUSALPROTEINS4HEDISORDERWASDESCRIBEDPRIMARILYFROMTHESTOSANDWASCOMMONLYATTRIBUTEDTOCOWSMILKPROTEIN BUTHASNOTBEENDESCRIBEDINTHELITERATUREFORMANYYEARS;66–69]. A decrease in PREVALENCEWASDOCUMENTEDIN&INLAND;70] and Spain [71=ANDATTRIBUTEDTOARISE INBREASTFEEDINGANDORTHEUSEOFADAPTEDINFANTFORMULA0RESENTATIONSOFEOSINOPHILICGASTROENTERITISWITHPROTEINLOSINGENTEROPATHYSHAREMANYFEATURESWITHPREVIOUSDESCRIPTIONSOFTHISDISORDER;72, 73]. Celiac disease. "ECAUSE CELIAC DISEASE OR GLUTEN SENSITIVE ENTEROPATHY IS THE RESULTOFANIMMUNERESPONSETOGLUTENSFROMWHEAT BARLEY RYE ANDRELATEDPROTEINS IT IS SOMETIMES CONSIDERED AMONG ALLERGIC GASTROINTESTINAL DISORDERS 4HE DISORDER AFFECTS APPROXIMATELY  OF THE POPULATION AND IS CHARACTERIZED BY

 )G% AND.ON )G% -EDIATED&OOD!LLERGY

227

INmAMMATORYINJURYTOTHESMALLINTESTINALMUCOSA;74–76=4HECLASSICPRESENTATION OCCURSININFANTSAFTERWEANING ATTHETIMEWHENCEREALSAREINTRODUCEDINTOTHE DIET 3YMPTOMS PARTLY REmECT MALABSORPTION WITH PATIENTS EXHIBITING FAILURE TO THRIVE ANEMIA AND MUSCLE WASTING !DDITIONAL SYMPTOMS INCLUDE DIARRHEA ABDOMINALPAIN VOMITING BONEPAIN ANDAPHTHOUSSTOMATITIS#HRONICINGESTION OFGLUTEN CONTAININGGRAINSINCELIACPATIENTSISASSOCIATEDWITHINCREASEDRISKOF ENTEROPATHY ASSOCIATED4CELLLYMPHOMA#ELIACDISEASEISASSOCIATEDWITHAUTOIMMUNE DISORDERS AND )G! DElCIENCY %NDOSCOPY OF THE SMALL BOWEL IN ACTIVE CELIACDISEASETYPICALLYREVEALSTOTALVILLOUSATROPHYANDEXTENSIVECELLULARINlLTRATE -ORE THAN  OF PATIENTS ARE (,! $1 WITH THE REMAINDER BEING (,! $1;74, 77='LIADINISONEOFTHEFEWSUBSTRATESFORTISSUETRANSGLUTAMINASE WHICHDEAMIDATESSPECIlCGLUTAMINESWITHINGLIADIN CREATINGEPITOPESTHAT BINDEFlCIENTLYTO$1GUT DERIVED4CELLS;78=4HEACTIVATIONOF$1OR$1 RESTRICTED4CELLSINITIATESTHEINmAMMATORYRESPONSE;76=%LIMINATIONOFGLIADIN FROMTHEDIETRESULTSINADOWNREGULATIONOFTHE4CELL INDUCEDINmAMMATORYPROCESS AND NORMALIZING OF THE MUCOSAL HISTOLOGY 4ESTS FOR )G! ANTI ENDOMYSIAL ANTIBODYUSINGTISSUETRANSGLUTAMINASE ARESENSITIVEn ANDSPECIlCn  WITHEXCELLENTPOSITIVEn ANDNEGATIVEn PREDICTIVEVALues [76, 79].

“Mixed” IgE/Non-IgE-Mediated Disorders Atopic dermatitis. 3TUDIESUSINGDOUBLE BLIND PLACEBO CONTROLLEDORALFOODCHALLENGES SHOW THAT APPROXIMATELY ONE IN THREE YOUNG CHILDREN WITH MODERATE TO SEVEREATOPICDERMATITISHASFOODALLERGY;80=4HEREISSOMECONTROVERSYABOUTTHE ROLE OF CHRONIC INGESTION IN INCREASING SKIN INmAMMATION AS OPPOSED TO HAVING FOODALLERGYASACO MORBIDCONDITIONAMONGTHOSEWITHATOPICDERMATITIS;81–83]. (OWEVER STUDIESHAVENOTEDmARINGOFATOPICDERMATITISSOMETIMESASSOCIATEDWITH POSITIVETESTSFORDELAYEDTYPEHYPERSENSITIVITYRATHERTHANTESTSFORFOOD SPECIlC IgE [16=-OSTSTUDIESREVEALTHATFOOD SPECIlC)G%ANTIBODYISDETECTABLETOTHE FOODSTHATCAUSESYMPTOMS"ECAUSEOFTHECHRONICNATUREOFTHEDISORDER ANDITS WAXING AND WANING COURSE IT IS DIFlCULT TO ASSOCIATE SYMPTOMS WITH PARTICULAR FOODSBYHISTORYALONE3TUDIESINCHILDRENIDENTIFYTHATOVEROFREACTIONSARE ATTRIBUTEDTOMILK EGG WHEAT ANDSOY)TISLESSCOMMONTOVERIFYAROLEFORMEATS FRUITS ORVEGETABLES;80]. Allergic eosinophilic esophagitis/gastroenteritis. 4HESE DISORDERS COVERED EXTENSIVELYINTHISBOOKANDTHEREFORENOTDELINEATEDFURTHERHERE AREALSOASSOCIATEDWITH FOODSWITHSOMEEVIDENCEOFBOTH)G% ANDCELL MEDIATEDMECHANISMS;2]. Additional disorders not clearly linked to food allergy. !NUMBEROFPUBLICATIONS HAVEADDRESSEDTHEPOSSIBILITYOFFOODALLERGYORNONALLERGICRESPONSESTOFOODSASA TRIGGERFORREmUX;84], constipation [85= ORINFANTILECOLIC;86]. Additional studies ARENEEDEDTODElNETHESEPOTENTIALRELATIONSHIPS&OODALLERGYISNOTCONSIDEREDA CAUSEOFBEHAVIORALSYMPTOMS;87].

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Diagnosis 4HE DIAGNOSTIC MODALITIES TO IDENTIFY FOOD ALLERGIES IN PERSONS WITH EOSINOPHILIC ESOPHAGITISAREREVIEWEDIN#HAP(EREWEFOCUSONPRINCIPLESOFGENERALDIAGNOSISOFFOODALLERGY&IG16.1 4HECLINICALEVALUATIONOFANADVERSEREACTIONTO FOODDEPENDSUPONACAREFULHISTORYANDPHYSICALEXAMINATIONTODETERMINETHETYPE OFADVERSERESPONSEANDWHATFOODS MAYBERESPONSIBLE;87]. Based upon the hisTORY ADVERSEREACTIONSTOFOODSMIGHTBEALTOGETHERRULEDOUTFOREXAMPLE ADIAGNOSISOFVIRAL INDUCEDURTICARIA ORNONALLERGICADVERSEREACTIONSMIGHTBEGIVENGREATER CONSIDERATIONFOREXAMPLE LACTOSEINTOLERANCERESULTINGINDIARRHEA )MPORTANTFACTORSTOCONSIDERINCLUDETHETYPESOFSYMPTOMS THECHRONICITY REPRODUCIBILITY AND ALTERNATIVEREASONSFORSYMPTOMS)FSYMPTOMSINDICATEANONIMMUNERESPONSEIS LIKELY ADDITIONALEVALUATIONWOULDFOLLOWTHESPECIlCSUSPICION&OREXAMPLE LACTOSEINTOLERANCEMAYBECONlRMEDTHROUGHBREATHHYDROGENTESTING)FAFOODALLERGY ISLIKELY THEPATTERNOFILLNESSANDLISTOFPOSSIBLETRIGGERSMAYDISCLOSEWHETHERAN )G%ORNON )G%ASSOCIATEDDISORDERISLIKELYANDWILLESTABLISHWHATTYPEOFTESTING MAYBEAPPROPRIATE&ORCHRONICDISORDERSSUCHASATOPICDERMATITISANDEOSINOPHILIC GASTROENTERITIS THEIDENTIlCATIONOFSUSPECTFOODSISDIFlCULTBECAUSEFOODISINGESTED THROUGHOUT THE DAY AND SYMPTOMS ARE OFTEN CHRONIC WITH A WAXING AND WANING COURSE4HEPERIODICNATUREOFTHESYMPTOMSMAYRESULTINMISLEADINGCOINCIDENTAL ASSOCIATIONSWITHFOODS3YMPTOMDIARIESAREHELPFULBUTRARELYDIAGNOSTIC)NADDITION INDIVIDUALSWITHTHESEDISORDERSOFTENTESTPOSITIVETOMULTIPLEFOODSTHATMAY NOTBECAUSINGILLNESS#AREINSELECTINGANDINTERPRETINGTHETESTSISPARAMOUNT &ORDETERMINATIONOFFOOD SPECIlC)G%ANTIBODIES PRICKSKINTESTS034S PERFORMEDUSINGAPROBETOINTRODUCEFOODPROTEINTOTHESUPERlCIALSKINLAYER ORSERUM TESTS AREGENERALLYSENSITIVE^n ANDSPECIlC^n ;37=034S GENERALLYPERFORMEDBYALLERGISTS AREUSEDONRASH FREESKINWHILETHEPATIENTISAVOIDING ANTIHISTAMINES INTRADERMAL SKIN TESTS SHOULD NOT BE USED 4HOUGH COMMERCIAL EXTRACTSAREAVAILABLEFORPERFORMINGPRICKSKINTESTSFORMANYFOODS FRESHEXTRACTS PARTICULARLYWHENTESTINGFRUITSANDVEGETABLESWHOSEPROTEINSAREPRONETODEGRADATION MAYBEMORESENSITIVE)F)G%ANTIBODYSPECIlCFORTHEFOODPROTEINISPRESENT AWHEALANDmAREWILLOCCURTHATISCOMPAREDTOPOSITIVEHISTAMINE ANDNEGATIVE SALINE GLYCERINE CONTROLS034SARECONSIDEREDPOSITIVEIFTHEREISAMEANWHEAL DIAMETEROFMMORGREATER AFTERSUBTRACTIONOFTHESALINECONTROL!NOTHERMEANS TO DETECT FOOD SPECIlC )G% ANTIBODY IS A SERUM TEST !LTHOUGH THE TERM h2!34v RADIOALLERGOSORBENTTEST ISOFTENUSED THETERMISANTIQUATEDANDINACCURATEBECAUSE MODERNASSAYSTYPICALLYDONOTUSERADIOLABELS6ARIOUSASSAYSYSTEMSARECOMMERCIALLYAVAILABLEANDTHEIRRESULTSMAYNOTBEINTERCHANGEABLE;88=2ESULTSMAYBE EXPRESSED IN A VARIETY OF MEASUREMENTS UNITS COUNTS CLASSES THAT ARE ALSO NOT INTERCHANGEABLEANDWHILEINCREASINGSCORESORCONCENTRATIONSOFFOOD SPECIlCANTIBODYGENERALLYCORRELATEWITHINCREASINGRISKOFALLERGY THEREARENOABSOLUTEVALUES THATAREENTIRELYDIAGNOSTICOFANALLERGY &OR PROPER DIAGNOSIS IT IS THEREFORE CRUCIAL TO CONSIDER THAT A POSITIVE 034 OR SERUM)G%TESTMERELYINDICATESTHATFOOD SPECIlC)G%ISPRESENTITDOESNOTITSELF CONlRMANALLERGY)NALIMITEDNUMBEROFSTUDIESOFAFEWFOODSININFANTSANDOR

 )G% AND.ON )G% -EDIATED&OOD!LLERGY

229

Fig. 16.1 General approach to diagnosis

CHILDREN DIAGNOSTICVALUESASSOCIATEDWITHVERYHIGHt PREDICTIVEVALUESFOR REACTIONSHAVEBEENDETERMINED THOUGHNOTUNIVERSALLYCONlRMED!STUDYUSING 034SINYOUNGCHILDRENREVEALEDTHATWHENWHEALSWEREPARTICULARLYLARGEtMM FORMILKANDPEANUT ANDtMMFOREGG CLINICALREACTIONSWEREVIRTUALLYCERTAIN [89=3TUDIESDETERMININGTHECONCENTRATIONOFSPECIlC)G%ANTIBODYMEASUREDUSING APARTICULARMETHOD#!0 2!34&%)!®OR5NI#AP®OR)MMUNO#!0® reported in K5A, SHOWEDAFOOD SPECIlC)G%CONCENTRATIONOFtK5A/L to egg, tTOMILK and tTOPEANUTWEREPREDICTIVEFORAREACTIONAMONG YEAR OLDCHILDREN [90=&ORCHILDRENUNDERAGEYEARS THEVALUESWHEREMOSTREACTEDWERELOWEREG tK5A,FOREGGORMILK 4HESERESULTSHAVENOTBEENUNIVERSALLYCONlRMED;18, 87]. )T MUST BE EMPHASIZED THAT DIAGNOSTIC CONCENTRATIONS ARE UNDETERMINED FOR OTHER

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FOODS ALLERGIC DISORDERS OR AGE GROUPS ;91= &OOD SPECIlC )G% MAY BE DETECTED DESPITETOLERANCEOFAFOOD ORMAYREMAINDETECTABLE BUTTYPICALLYDECLINES ASA FOOD ALLERGY RESOLVES /BTAINING hPANELSv OF FOOD ALLERGY TESTS WITHOUT CONSIDERATION FOR THE HISTORY IS NOT A GOOD PRACTICE BECAUSE NUMEROUS IRRELEVANT POSITIVE RESULTSMAYOCCUR4HEHISTORYISCRUCIALBECAUSETESTSAREEXPECTEDTOBENEGATIVE WHEN THE PATHOPHYSIOLOGY OF THE RESPONSE IS CONSISTENT WITH NON )G% MEDIATED REACTIONS THUS A NEGATIVE TEST MAY NONETHELESS BE CONSISTENT WITH AN ALLERGY ! NEGATIVE TEST IS MORE RELIABLE IN EXCLUDING AN )G% MEDIATED ALLERGIC REACTION (OWEVER ACUTEANAPHYLACTICREACTIONSMAYALSOOCCASIONALLYOCCURDESPITEANEGATIVETEST SOCAUTIONISNEEDEDWHENEVALUATINGAPATIENTWITHACONVINCINGHISTORY DESPITEANEGATIVETEST;92]. .EITHERTHESIZEOFTHE034NORLEVELOF)G%INSERUMUSEFULLYPREDICTSTHETYPEOR SEVERITY OF REACTION !DDITIONAL DIAGNOSTIC TESTS ARE BEING RESEARCHED !NOTHER POTENTIALPITFALLISTHATFOODSWITHHOMOLOGOUSPROTEINSCANRESULTINTESTSTHATARE POSITIVEAMONGFOODSWHILEANINDIVIDUALISNOTTRULYCLINICALLYALLERGICTOALLOFTHE hCROSS REACTIVEvFOODS&OREXAMPLE OFTHOSEWITHPEANUTALLERGY ALEGUME CANTOLERATEOTHERBEANSANDYETWILLHAVEPOSITIVETESTSTOMULTIPLEBEANS4HE RATESOFCLINICALCROSS REACTIVITYVARYAMONGFOODS BEINGHIGHAMONGlSHANDSHELLlSHANDLOWFORGRAINSANDLEGUMES;93]. 4HE!TOPY0ATCH4EST!04 WHICHISPERFORMEDBYPLACINGTHEFOODALLERGENON THESKINUNDEROCCLUSIONFORHANDASSESSINGFORADELAYEDRASHATnHSHOWS SOMEPROMISEFORNON )G% MEDIATEDDISORDERSORTHOSEWITHMIXEDETIOLOGIESINCLUDINGEOSINOPHILICESOPHAGITIS-ORESTUDIESARENEEDEDTODETERMINEUTILITY;87]. &OREVALUATIONOFTHEROLEOFFOODALLERGYINCHRONICDISEASE THEAMELIORATIONOF SYMPTOMSDURINGDIETARYELIMINATIONOFSUSPECTEDFOODSPROVIDESPRESUMPTIVEEVIDENCEOFCAUSALITY%LIMINATIONDIETSCANBEUNDERTAKENBYREMOVINGADElNEDFOOD SUSPECTEDTOBECAUSINGSYMPTOMS REMOVINGALLBUTADElNEDGROUPOFFOODSTHAT ARERARELYALLERGENICOLIGOANTIGENICDIET ORBYGIVINGANELEMENTALDIETOFONLYA HYPOALLERGENIC EXTENSIVELY HYDROLYZED FORMULA OR A NONALLERGENIC AMINO ACID BASEDFORMULA4HEELEMENTALDIETPROVIDESTHEMOSTDElNITIVETRIAL4HETYPEOF ELIMINATIONDIETSELECTEDWILLDEPENDUPONTHECLINICALSCENARIO APRIORIREASONING CONCERNINGOFFENDINGFOODS ANDTHERESULTSOFTESTSFOR)G%ANTIBODY4HELENGTHOF TRIALDEPENDSUPONTHETYPEOFSYMPTOMSTHATHAVEBEENOBSERVED BUTnWEEKS ISUSUALLYTHERANGEREQUIRED!DIETITIANMAYBENEEDEDTOENSURENUTRITIONALSUFlCIENCY OF TRIAL DIETS &OR BREAST FED INFANTS MATERNAL DIETARY ELIMINATION IS REQUIRED7HENAFOODTOWHICH)G%HASBEENDEMONSTRATEDISREMOVEDFROMTHE DIETDURINGACHRONICDISORDER ITISPOSSIBLEFORRE INTRODUCTIONTOINDUCESEVERE REACTIONSSOCAUTIONISNEEDEDANDRISKSBENElTSNUTRITIONAL SOCIAL IMMUNOLOGIC SHOULDBECONSIDERED;94, 95]. 7HENHISTORYANDSIMPLETESTSHAVENOTCONlRMEDANALLERGY ORWHENTOLERANCE ISSUSPECTEDAFTERAPERIODOFAVOIDANCE ANORALFOODCHALLENGE/&# MAYBENEEDED TO CONlRM CLINICAL ALLERGY ;95= !N ORAL FOOD CHALLENGE IS PERFORMED BY FEEDING GRADUALLY INCREASING AMOUNTS OF THE SUSPECTED FOOD UNDER PHYSICIAN OBSERVATION OVERHOURSORDAYS/&#SAREPERFORMEDEITHEROPENLYORBLINDEDBYHIDINGTHEFOOD IN ANOTHER FOOD OR OPAQUE CAPSULES 4HE DOUBLE BLIND PLACEBO CONTROLLED ORAL

 )G% AND.ON )G% -EDIATED&OOD!LLERGY

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Table 16.2 #OMMONLYUSEDDIAGNOSTICTESTSANDTHEIRFEATURES 4EST &EATURES Medical history $ElNESPRIORPROBABILITYOFFOODALLERGYCOMPAREDTOOTHERCAUSES ANDEXAMINATION FORSYMPTOMS %LUCIDATESLIKELYPATHOPHYSIOLOGYTOPROVIDEINSIGHTONTESTING)G% MEDIATEDORNOT $ETERMINES ALONGWITHUNDERSTANDINGOFEPIDEMIOLOGY THECHANCEOF SPECIlCFOODS BEINGIMPLICATED %LIMINATIONDIET

)NTHECONTEXTOFCHRONICSYMPTOMS MAYIMPLICATEAFOODORGROUPOF FOODSASCONTRIBUTINGTOREACTIVITYDISEASE 5NLIKELYTOBEANISOLATEDMEANSTODIAGNOSEASPECIlCCULPRITFOOD

0RICKSKINTESTS

0ROVIDESEVIDENCEOFSENSITIZATION NOTNECESSARILYINTRINSICALLYDIAGNOSTIC (see text) #ORRELATIONOFINCREASINGSIZEWITHINCREASINGRISKOFCLINICALALLERGY

3ERUMFOOD SPECIlC)G%

0ROVIDESEVIDENCEOFSENSITIZATION NOTNECESSARILYINTRINSICALLYDIAGNOSTIC (see text) #ORRELATIONOFINCREASINGCONCENTRATIONWITHINCREASINGRISKOFCLINICALALLERGY

-EDICALLYSUPERVISEDFEEDINGISTHEBESTTESTFORTOLERANCE 2ISKOFREACTIONANDTIMECONSUMING $OUBLE BLIND PLACEBO CONTROLLEDFORMATISCONSIDEREDTHEhGOLDSTANDARDv FORDIAGNOSIS !DDITIONAL TYPES OF TESTS ARE REVIEWED IN THE TEXT !DDITIONAL DETAILS ABOUT TEST ADVANTAGES AND PITFALLSAREDELINEATEDINTHETEXT /RALFOOD challenge

FOODCHALLENGEISTHEMETHODLEASTPRONETOBIASANDISCONSIDEREDTHEhGOLDSTANDARDv TODIAGNOSEFOODALLERGY)NTHISFORMAT ATESTFOODISHIDDENINANOTHERFOODANDTHE PATIENTANDOBSERVERDONOTKNOWWHENTHEYARERECEIVINGACTIVEORPLACEBODOSES FEEDINGSOFTHETRUEORPLACEBOCHALLENGEFOODSARESEPARATEDBYHOURSORDAYS 4HE/&#CANBEUSEDTOEVALUATEANYTYPEOFSUSPECTEDADVERSERESPONSETOFOODS BECAUSEITISNOTDEPENDENTUPONANYPARTICULARPATHOPHYSIOLOGY4HEPROCEDUREIS MOSTOFTENNEEDEDWHENSEVERALFOODSAREUNDERCONSIDERATION TESTSFORSPECIlC)G% AREPOSITIVEANDELIMINATIONRESULTEDINRESOLUTIONOFSYMPTOMSORWHENTESTSCANNOT BEDEPENDEDUPONTOCONlRMADIAGNOSIS SUCHASNON )G% MEDIATEDDISORDERS4HE CHALLENGE SETTING ALSO PROVIDES A SAFE MEANS TO INTRODUCE FOODS THAT WERE HIGHLY SUSPECTEDTOCAUSESEVEREREACTIONSDESPITENEGATIVESKINTESTSOR)G%TESTS0ARTICULARLY IN)G% MEDIATEDREACTIONSANDENTEROCOLITISSYNDROME CAREMUSTBETAKENBECAUSE THE/&#CANRESULTINSEVEREREACTIONS4HESUPERVISINGCLINICIAN USUALLYANALLERGIST MUSTHAVEMEDICATIONSANDSUPPLIESFORRESUSCITATIONIMMEDIATELYAVAILABLETOMANAGE REACTIONS #HALLENGES MAY BE OPTIONAL OR CONTRA INDICATED IN CERTAIN CIRCUMSTANCESANDRISKSOFTHECHALLENGEMUSTBEWEIGHEDAGAINSTTHESOCIALANDNUTRITIONAL DElCITSOFCONTINUEDAVOIDANCE2ECENT SEVEREANAPHYLAXISTOANISOLATEDINGESTION WITHAPOSITIVETESTFORSPECIlC)G%ANTIBODYTOTHECAUSALFOODISONEEXAMPLEOFA RELATIVECONTRAINDICATIONBECAUSETHISSCENARIOREPRESENTSCONlRMATIONOFACONVINCING HISTORY .EGATIVE CHALLENGES SHOULD ALWAYS BE FOLLOWED BY A SUPERVISED OPEN FEEDING OF A RELEVANT PORTION OF THE TESTED FOOD IN ITS COMMONLY PREPARED STATE !SUMMARYOFDIAGNOSTICTESTS THEIRUTILITY ANDLIMITATIONSANDLISTEDIN4ABLE16.2.

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4HEREAREAHOSTOFTESTSTHATHAVEBEENTOUTEDFORTHEDIAGNOSISOFFOODALLERGY BUTHAVENEVERBEENFOUNDUSEFULINBLINDEDSTUDIES4HESEINCLUDEMEASUREMENTOF IgG4ANTIBODY PROVOCATION NEUTRALIZATIONDROPSPLACEDUNDERTHETONGUEORINJECTED TODIAGNOSEANDTREATVARIOUSSYMPTOMS ANDAPPLIEDKINESIOLOGYMUSCLESTRENGTH testing) [87].

Management %XPERIMENTAL THERAPIES DESIGNED TO INDUCE TOLERANCE OR REDUCE REACTION SEVERITY SUCH AS ORAL IMMUNOTHERAPY INJECTION IMMUNOTHERAPY USING MODIlED PROTEINS MONOCLONALANTIBODIESTOBLOCKIMMUNERESPONSESANDOTHERSTRATEGIESAREUNDER INVESTIGATION;96=(OWEVER THECURRENTMAINSTAYOFTREATMENTISAVOIDANCEOFTHE FOODANDPREPARATIONFORTREATMENTINTHEEVENTOFANACCIDENTALINGESTIONLEADINGTO an allergic reaction, including anaphylaxis. $IETARYMANAGEMENTOFFOODALLERGYISFRAUGHTWITHNUTRITIONALANDOTHERPITFALLS #HAPTERREVIEWSDIETARYTREATMENTFOREOSINOPHILICESOPHAGITISSEVERALPRINCIPLES OFGENERALDIETARYMANAGEMENTOFFOODALLERGYAREREVIEWEDHERE!VOIDANCEOFTHE ALLERGENREQUIRESCAREINSHOPPING MEALPREPARATION ANDOBTAININGMEALSOUTSIDEOF THE HOME 2EGARDING LABELING OF COMMERCIAL FOOD PRODUCTS MANY COUNTRIES HAVE ENACTED LABELING LAWS WHERE SPECIlED ALLERGENS MUST BE DISCLOSED IF THEY ARE AN INTENDEDINGREDIENT)NTHE53 THISINCLUDESMILK EGG WHEAT SOY PEANUT TREENUTS lSH AND#RUSTACEANSHELLlSH!DVISORYLABELINGINTHE53ISNOTREGULATED ANDMANUFACTURERSMAYVOLUNTARILYINDICATEIFTHEREISAPOSSIBILITYOFINCLUSIONOFUNINTENDED ALLERGENSWITHSTATEMENTSSUCHAShMAYCONTAINPEANUTSv;97=#AREMUSTBEEXERCISEDFORRESTAURANTMEALSBECAUSECROSSCONTACTWITHALLERGENSDURINGPREPARATION ANDHIDDENINGREDIENTS MAYTRIGGERREACTIONS)NDIVIDUALSLIVINGWITHFOODALLERGIES SHOULD BE INSTRUCTED ABOUT INFORMING OTHERS ABOUT THEIR ALLERGY AND REVIEWING THE ABOVE MENTIONEDCONCERNS;98=&ORCHILDREN DIETARYMANAGEMENTINSCHOOLSREQUIRES PLANNINGANDCOMMUNICATIONTOESTABLISHMEANSOFALLERGENAVOIDANCEAVOIDFOOD SHARINGANDSCHOOLPROJECTSUSINGFOODS ANDRECOGNITIONTREATMENTOFREACTIONS )N THE EVENT OF AN ALLERGIC REACTION ANTIHISTAMINES MAY BE REQUIRED TO REDUCE ITCHINGRASH(OWEVER FORPATIENTSEXPERIENCINGMORESEVERESYMPTOMSOFANAPHYLAXIS PROMPT ADMINISTRATION OF EPINEPHRINE IS THE INDICATED TREATMENT ;35, 99]. 'UIDELINESFORDETERMININGTHOSEWHOSHOULDHAVEACCESSTOTHISMEDICATIONINTHE FORMOFAUTOINJECTORSAREUNDERSCRUTINY BUTCANDIDATESINCLUDEFOOD ALLERGICPATIENTS WITHPREVIOUSSEVEREREACTIONS ALLERGYTOFOODSCOMMONLYCAUSINGSEVEREREACTIONS ANDFOOD ALLERGICPATIENTSWITHUNDERLYINGASTHMA)TISESSENTIALTOPERIODICALLYREVIEW THEINDICATIONSANDTECHNIQUEOFADMINISTRATIONOFSELF INJECTABLEEPINEPHRINEBECAUSE MISTAKESARECOMMON0ATIENTSMUSTBEINSTRUCTEDTHATFOLLOWINGTHEADMINISTRATIONOF THE MEDICATIONS PROMPT TRANSPORTATION TO AN EMERGENCY FACILITY IE AMBULANCE SHOULDBESOUGHTWITHPROLONGEDOBSERVATIONH SINCERECURRENCEOFSEVERESYMPTOMSISPOSSIBLE0ATIENTSSHOULDOBTAINMEDICALEMERGENCYBRACELETSIDENTIFYINGTHEIR ALLERGY ANDBEREMINDEDTOUPDATEEXPIREDANDEXPENDEDEPINEPHRINEINJECTORS&OR CHILDREN ANIMPORTANTCOMPONENTOFTHESCHOOLANDCAMPMANAGEMENTOFFOODALLERGY

 )G% AND.ON )G% -EDIATED&OOD!LLERGY

233

ISTOHAVEAWRITTENEMERGENCYACTIONPLANINPLACE MEDICATIONSREADILYAVAILABLEAND SCHOOLPERSONNELTRAINEDINRECOGNIZINGANDTREATINGREACTIONS&ORCHILDRENWITHFOOD PROTEIN INDUCEDENTEROCOLITISSYNDROME INTRAVENOUSHYDRATIONANDSYSTEMICSTEROIDS HAVEBEENRECOMMENDEDFORTHERAPY;48].

Natural History -OST ^ CHILDREN LOSE THEIR SENSITIVITY TO MOST ALLERGENIC FOODS EGG MILK WHEAT SOY WITHINTHElRSTnYEARSOFLIFE;100=2ECENTSTUDIESFROMAREFERRAL CENTERPRESENTSLOWERRESOLUTIONRATESFORMILKANDEGGALLERGYTHANPASTSTUDIESSUCH THATAMAJORITYOFCHILDRENWERENOTEDTOCONTINUETOHAVETHEALLERGYATSCHOOLAGE BUTMOSTEXPERIENCEDRESOLUTIONBYADOLESCENCE;101, 102]. In contrast, adults with FOODALLERGYMAYHAVELONG LIVEDSENSITIVITY3ENSITIVITYTOPEANUT TREENUTS AND SEAFOOD IS RARELY LOST 4HE NOTION THAT PEANUT AND TREE NUT ALLERGY IS PERMANENT DERIVES INPART FROMTHEOBSERVATIONTHATITISANALLERGYTHATAFFECTSADULTSHOWEVER ITHASBECOMEAPPARENTTHATABOUTOFPEANUTALLERGICCHILDRENUNDERAGEYEARS ANDABOUTOFTHOSEWITHTREENUTALLERGYMAYACHIEVETOLERANCEBYSCHOOLAGE [103, 104=0ROCTOCOLITISSYNDROMETYPICALLYRESOLVESINTHElRSTYEAROFLIFE&OOD PROTEIN INDUCED ENTEROCOLITIS USUALLY RESOLVES WITHIN THE lRST  YEARS ;48] and eosinophilic esophagitis tends to persist [10].

Conclusions &OODALLERGIESARECOMMON APPEARTOBEINCREASINGINPREVALENCE ANDACCOUNTFOR AVARIETYOFACUTEANDCHRONICDISEASEMANIFESTATIONS!LTHOUGHFOODSAREACOMMON TRIGGER OF EOSINOPHILIC ESOPHAGITIS PERSONS WITH %O% MAY ALSO EXPERIENCE OTHER MANIFESTATIONS OF FOOD ALLERGY 5NDERSTANDING THE UNDERLYING MECHANISMS AND KNOWINGTHECOMMONTRIGGERSAIDSINSELECTIONANDINTERPRETATIONOFDIAGNOSTICTESTS 4REATMENTINCLUDESDIETARYAVOIDANCEANDTREATMENTOFREACTIONSTRIGGEREDBYACCIDENTALINGESTION2E EVALUATIONISNECESSARYBECAUSEMOSTFOODALLERGIESTHATDEVELOP INCHILDHOODMAYRESOLVELATER&UTURETHERAPIESMAYSUPPLANTAVOIDANCEANDREACTIONARYTREATMENTSOFALLERGICREACTIONSTHATARETHECURRENTMAINSTAYOFTREATMENT

References 3ICHERER 3( 3AMPSON (! &OOD ALLERGY * !LLERGY #LIN )MMUNOL  3UPPL   S116–25. ,IACOURAS #! 3PERGEL *- 2UCHELLI % 6ERMA 2 -ASCARENHAS - 3EMEAO % ET AL %OSINOPHILICESOPHAGITISA YEAREXPERIENCEINCHILDREN#LIN'ASTROENTEROL(EPATOL  n

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Chapter 17

Allergic and Atopic Features of Children with Eosinophilic Esophagitis Janet L. Beausoleil and Terri Brown-Whitehorn

Keywords %OSINOPHILICESOPHAGITISs!LLERGIESs!TOPICDISEASESs!TOPYs4OPICAL corticosteroids

Introduction 4HEINCREASEDINCIDENCEOFEOSINOPHILICESOPHAGITISHASMIRROREDTHERISEINALLERGIES OVERTHEPASTDECADE%OSINOPHILICESOPHAGITISSHARESMANYFEATURESOFOTHERATOPIC DISEASES4HEINmAMMATORYCELLSANDCYTOKINESSECRETEDARESIMILARTOWHATISSEENIN THECLASSICATOPICDISORDERSSUCHASASTHMA ALLERGICRHINITIS ANDATOPICDERMATITIS "OTHENVIRONMENTALANDFOOD SPECIlC)G%ISPRESENTINTHEMAJORITYOFPATIENTSWITH EOSINOPHILICESOPHAGITIS!SWITHOTHERATOPICDISORDERS IMPROVEMENTOCCURSWITH ELIMINATION OF THE OFFENDING ALLERGEN OR WITH THE USE OF TOPICAL CORTICOSTEROIDS 0ATIENTSWITHEOSINOPHILICESOPHAGITISHAVEAHIGHERPREVALENCEOFTHESEOTHERATOPIC DISORDERS ASWELLASAFAMILYHISTORYOFATOPY4AKENTOGETHER THISIMPLIESASTRONG correlation between allergy, atopy, and eosinophilic esophagitis.

Atopy and Allergy !TOPYISAGENETICPREDISPOSITIONTOWARDTHEDEVELOPMENTOFIMMEDIATEHYPERSENSITIVITY REACTIONSAGAINSTCOMMONENVIRONMENTALANTIGENS!LLERGYISAMOREBROADTERM ANDREFERSTOANABNORMALIMMUNERESPONSETOFOREIGNPROTEINS ANDCANREFERTO

J.L. Beausoleil (*) $EPARTMENTOF0EDIATRICS $IVISIONOF!LLERGYAND)MMUNOLOGY 4HE#HILDRENS(OSPITALOF0HILADELPHIA TH3TREETAND#IVIC#ENTER"LVD 0HILADELPHIA 0!    53! E MAIL*ANET COMCASTNET C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_17, © Springer Science+Business Media, LLC 2012

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*,"EAUSOLEILAND4" 7HITEHORN

BOTH IMMEDIATE )G% MEDIATED AND DELAYED NON )G% MEDIATED HYPERSENSITIVITY REACTIONS0OLLENS MOLDSPORES PETDANDER ANDDUSTMITESMAYTRIGGERALLERGICRHINOCONJUNCTIVITIS ATOPICDERMATITIS ORASTHMA$RUGSANDSTINGINGINSECTSCANTRIGGERANAPHYLAXIS&OODPROTEINS SUCHASMILK EGG SOY PEANUT ANDWHEATCANLEAD TOAVARIETYOFREACTIONS INCLUDING)G% MEDIATEDREACTIONSSUCHASHIVESORANAPHYLAXIS CELLMEDIATEDIMMUNEREACTIONSSUCHASCOLITIS ORMIXED)G% MEDIATEDAND NON )G% MEDIATED REACTIONS THAT ARE SEEN IN ATOPIC DERMATITIS OR EOSINOPHILIC esophagitis. 4HEPRESENCEOFATOPYINANINDIVIDUALCANBEDElNEDINVARIOUSWAYSELEVATED TOTAL)G% PHYSICIANDIAGNOSISOFANATOPICDISEASESUCHASALLERGICRHINITISORATOPIC DERMATITIS ORTHEPRESENCEOFSPECIlC)G%TOAFOODORAEROALLERGENTHROUGHSKIN prick or serological testing). In general, atopic diseases are associated with an EXPANSIONOFTHE4HCELLPOPULATIONANDSUBSEQUENTSECRETIONOFCYTOKINESSUCHAS ),  ),  AND), THATFAVOR)G%SYNTHESISANDEOSINOPHILIA

Prevalence of Atopic Diseases in Eosinophilic Esophagitis Patients $ATA FROM THE  #$# .ATIONAL (EALTH )NTERVIEW 3URVEY .()3 3UMMARY (EALTH 3TATISTIC FOR 53 #HILDREN REPORT A  PREVALENCE OF ASTHMA IN 5NITED 3TATESCHILDREN)NTHISSAMEREPORT THEPREVALENCEOFHAYFEVERWAS RESPIRATORYALLERGIESWERE ANDOTHERALLERGIESWERE;1]. In addition, approxiMATELYOFCHILDRENINTHE5NITED3TATESAREAFFECTEDBYATOPICDERMATITIS;2]. 4HEMAJORITYOFPATIENTSWITHEOSINOPHILICESOPHAGITISAREATOPIC! YEARFOLLOW UP FROM 0HILADELPHIA OF OVER  PEDIATRIC EOSINOPHILIC ESOPHAGITIS PATIENTS SHOWEDTHATTWOTHIRDSOFTHECHILDRENWEREATOPIC SIGNIlCANTLYHIGHERTHANWHAT WOULDBEEXPECTEDINTHEGENERALPOPULATION4WOHUNDREDANDTHIRTY ONEOFTHESE PATIENTSHADASTHMA HADALLERGICRHINITIS ANDHADATOPICDERMATITIS ;3=2EPORTSFROM#INCINNATIALSODEMONSTRATEAHIGHPREVALENCEOF ENVIRONMENTAL  AND FOOD ALLERGIES  IN CHILDREN WITH EOSINOPHILIC ESOPHAGITIS;=4ABLE17.1 )NOFTHEIRPATIENTSWITHEOSINOPHILICESOPHAGITIS HADASTHMA HADALLERGICRHINITIS HADECZEMA HADFOOD INDUCED ANAPHYLAXIS AND  HAD ALLERGIC CONJUNCTIVITIS ;5= !MONG  CHILDREN FROM )NDIANAPOLIS  PATIENTS  HAD A PERSONAL HISTORY OF ATOPY   OF THEMWEREDIAGNOSEDWITHASTHMAREACTIVEAIRWAYDISEASE BUTONLY HAD ECZEMAAND HADRHINITIS;6=)NAREPORTOFPEDIATRICPATIENTSIN/REGON HADFOODALLERGYONEITHERSKINPRICKOR)G%RADIOALLERGOSORBENTTESTS!TOPIC DISEASESWERECOMMON WITHAINCIDENCEOFASTHMA INCIDENCEOFALLERGIC RHINITIS AND  INCIDENCE OF ATOPIC DERMATITIS 4HE INCIDENCE OF ACTUAL FOOD INDUCEDANAPHYLAXISWASNOTREPORTED;7=4HISVARIATIONINTHERATEOFATOPYAMONG CHILDRENWITHEOSINOPHILICESOPHAGITISINTHE5NITED3TATESCOULDREPRESENTREGIONAL DIFFERENCES SELECTIONBIAS ORDIAGNOSTICDIFFERENCES/FNOTE GASTROENTEROLOGISTS

 !LLERGICAND!TOPIC&EATURESOF#HILDRENWITH%OSINOPHILIC%SOPHAGITIS Table 17.1 %NVIRONMENTALANDFOODSENSITIZATIONINPATIENTSWITH%% Age (years) 3EX 304S Allergens <5 >5–10 >10 Male &EMALE Food Patient tested (N) 30 17    Positive 25 11 10   Environmental Patient tested (N) 20 12 11 33 10 Positive 13 10 11   Food and environmental Patient tested (N) 17 11 11 30 9 Both positive 11 7 8 19 7 Food negative, 2 2 3 5 2 ENVIRONMENTPOSITIVE Food positive, 2 2 0  0 ENVIRONMENTNEGATIVE Both negative 2 0 0 2 0



4OTALPATIENTS 61    39    

REPORTEDONTHOSEWITHLOWERPREVALENCEOFALLERGY WHILETHEOTHERSWEREREPORTED BYALLERGISTnIMMUNOLOGISTS )N !USTRALIA A SIMILAR INCREASE IN ATOPY AMONG CHILDREN WITH EOSINOPHILIC ESOPHAGITIS HAS BEEN REPORTED )N  CASES IN %ASTERN !USTRALIA  HAD ATOPIC ECZEMA  HAD ALLERGIC RHINITIS AND  HAD ASTHMA 4HIS IS SIGNIlCANTLY INCREASEDCOMPAREDTOTHEGENERALPOPULATIONIN!USTRALIA WITHHAVINGATOPIC ECZEMA HAVINGALLERGICRHINITIS ANDHAVINGASTHMA;8]. In a world-wideWEB BASEDREGISTRYOFSURVEYRESPONDENTS INCLUDINGFROMTHE5NITED3TATES FROM#ANADA FROM%NGLAND FROM#HINA ANDFROM)SRAEL AINCIDENCE OFALLERGICRHINOCONJUNCTIVITIS INCIDENCEOFASTHMA INCIDENCEOFECZEMA AND  INCIDENCE OF FOOD INDUCED ANAPHYLAXIS WAS REPORTED IN PATIENTS WITH EOSINOPHILICESOPHAGITIS4HEMAJORITYOFTHERESPONDENTSWEREPARENTSOFAFFECTED CHILDREN ;9=4ABLE17.2).

Presence of Atopic Family History in Eosinophilic Esophagitis Patients !SIGNIlCANTNUMBEROFPATIENTSWITHEOSINOPHILICESOPHAGITISHAVEAFAMILYHISTORY OFATOPY/NESTUDYREPORTEDAPREVALENCEOFALLERGICRHINITISINANDASTHMAIN INIMMEDIATEFAMILYMEMBERS;9=)NANOTHERSTUDY OUTOF OF PEDIATRICEOSINOPHILICESOPHAGITISPATIENTSHADAlRSTDEGREERELATIVEWITHASTHMA ALLERGIC RHINITIS OR ATOPIC DERMATITIS ;10= 4HE CALCULATED SIBLING RISK IS  TIMES HIGHERTHANTHEGENERALPOPULATION;11].

Table 17.2 0REVALENCE OFATOPICDISEASEINCHILDRENWITHEOSINOPHILICESOPHAGITIS Portland, Philadelphia. Cincinnati, Location/year Oregon 2009 Pennsylvania 2008 Ohio 2007 # Patients with EoE 20 620 89 Age (years) 0.2–19.5 9.1 ± 3.1 Õ !STHMA    Allergic rhinitis    !TOPICDERMATITIS    Food allergy/ POSITIVEALLERGY ANAPHYLAXIS ANAPHYLAXIS anaphylaxis testing Queensland, Australia 2007  0.3–16    ANAPHYLAXIS

Indianapolis, Indiana 2007  0.2–19.5    5NKNOWN

7ORLD7IDE 7EB 39 8 ± 12    ANAPHYLAXIS

 *,"EAUSOLEILAND4" 7HITEHORN

 !LLERGICAND!TOPIC&EATURESOF#HILDRENWITH%OSINOPHILIC%SOPHAGITIS



Food Allergy and Eosinophilic Esophagitis &OODALLERGYAFFECTSAPPROXIMATELYOFYOUNGCHILDRENINTHE5NITED3TATES 4HEMOSTCOMMONFOODSARECOWSMILK EGG PEANUT WHEAT SOY TREENUTS lSH ANDSHELLlSH!LTHOUGHAFAMILYHISTORYOFATOPICDISORDERSISARISKFACTOR ENVIRONMENTALFACTORSMODULATETHEEXPRESSIONOFFOODALLERGY;12=4HEEXPRESSION OFFOODALLERGYCANBECLASSIlEDACCORDINGTOIMMUNEMECHANISM)G%MEDIATED NON )G% MEDIATED OR MIXED OR ACCORDING TO THE AFFECTED ORGAN SYSTEM SKIN RESPIRATORYTRACT GASTROINTESTINALTRACT SYSTEMIC )G% MEDIATEDGASTROINTESTINALALLERGICDISORDERSINCLUDEORALALLERGYSYNDROMEANDGASTROINTESTINAL ANAPHYLAXIS #ELL MEDIATED GASTROINTESTINAL DISORDERS INCLUDE FOOD PROTEIN INDUCED ENTEROCOLITIS FOOD PROTEIN INDUCED PROCTOCOLITIS AND FOOD PROTEIN INDUCEDENTEROPATHY;12]. Alternatively, eosinophilic esophagitis appears to be DUETOAMIXED)G%ANDNON )G% MEDIATEDIMMUNEMECHANISM!FTERAPPROPRIATETESTINGINTHESEDISORDERS THEDIAGNOSISISCONlRMEDBYIMPROVEMENTAFTER ELIMINATIONOFTHEOFFENDINGFOODSAND WHENAPPROPRIATE RECURRENCEWITHRE CHALLENGETOTHEIMPLICATEDFOODS 4HESTRONGESTEVIDENCEFORFOODALLERGYASACAUSEOFEOSINOPHILICESOPHAGITIS COMESFROMTHECLINICALRESPONSEOFPATIENTSWHOAREPLACEDONRESTRICTEDORELEMENtal diets. In 1995, ten children were described with persistent gastroesophageal REmUX AND ESOPHAGEAL EOSINOPHILIA REFRACTORY TO PHARMACOLOGIC TREATMENT 3IX OF THESE PATIENTS HAD ALSO RECEIVED .ISSEN FUNDOPLICATIONS ! DRAMATIC DECREASE IN ESOPHAGEALEOSINOPHILIAANDCLINICALSYMPTOMSWASOBSERVEDINALLPATIENTSWHEN PLACEDONA WEEKTRIALOFANELEMENTALFORMULA%IGHTPATIENTSDEMONSTRATEDCOMPLETERESOLUTION;13=&URTHERWORKBYOTHERSHASCONlRMEDELEMENTALDIETSTOBE SUCCESSFUL WITHAREPORTEDSUCCESSRATEASHIGHAS;10=)NADDITION OF CHILDRENHAVEBEENREPORTEDTOIMPROVEONSPECIlCELIMINATIONDIETSOFFOODSIDENTIlEDBYSKINPRICKTESTINGANDPATCHTESTING;1=)MPROVEMENTHASALSOBEENREPORTED AFTERIMPLEMENTATIONOFANEMPIRICSIX FOODELIMINATIONDIET0ATIENTSWITHEOSINOPHILICESOPHAGITISREMOVEDMILK SOY EGG WHEAT NUTS ANDSEAFOODFROMTHEIRDIET FORWEEKS3IGNIlCANTDECREASEINESOPHAGEALEOSINOPHILSLESSTHANPER(0& OCCURREDINOFTHEPATIENTSCOMPAREDTOOFTHEPATIENTSWHOIMPROVEDON ANELEMENTALDIET;15=4ABLE17.3). )NEOSINOPHILICESOPHAGITIS FOODSMOSTCOMMONLYIMPLICATEDARESIMILARTOOTHER FORMSOFFOODALLERGY WITHMILK EGG WHEAT SOY ANDPEANUTACCOUNTINGFORMORE THAN HALF OF THE CAUSATIVE FOODS IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS ;3] (Fig. 17.1). 4HE MAJORITY OF PATIENTS WITH EOSINOPHILIC ESOPHAGITIS HAVE EVIDENCE OF )G% MEDIATEDSENSITIZATIONTOFOODBASEDONINVITROSPECIlC)G%ORSKINPRICKTESTING 0OSITIVESKINTESTINGTOTHESEFOODSISCOMMON WITHONEREPORTOFPOSITIVESKIN TESTTOEGGANDPEANUT TOSOY ANDTOCOWSMILK;5=(OWEVER THEREPORTED INCIDENCEOFACTUALFOOD INDUCEDANAPHYLAXISHASBEENVARIABLE4WOLARGEPEDIATRIC EOSINOPHILIC ESOPHAGITIS POPULATIONS IN THE 5NITED 3TATES HAVE REPORTED THE INCIDENCE OF ANAPHYLAXIS AS  ;10= AND  ;5= )N AN !USTRALIAN COHORT OF 



*,"EAUSOLEILAND4" 7HITEHORN

Table 17.3 %FFECTOFDIETARYAVOIDANCEINCHILDRENWITHEOSINOPHILICESOPHAGITIS 3YMPTOMS Study Diet IMPROVED %LEMENTAL 100 +ELLYETAL;13] 3PERGELETAL;1] %LIMINATIONBASEDONSKIN 75 prick and patch testing %LEMENTAL 97 ,IACOURASETAL;10] +AGALWALLAETAL;15] %MPIRICSIX FOODELIMINATION 97 +AGALWALLAETAL;15] %LEMENTAL 100

$ECREASE in eosinophils 100 75 97  88

Fig. 17.1 4HEMOSTCOMMONFOODTRIGGERSOFEOSINOPHILICESOPHAGITISCONlRMEDBYENDOSCOPY AFTERFOODALLERGYTESTING

CONSECUTIVE EOSINOPHILIC ESOPHAGITIS PATIENTS REFERRED TO A PEDIATRIC ALLERGIST AN EVENHIGHERRATEHASBEENREPORTED WITHOFPEDIATRICEOSINOPHILICESOPHAGITIS HAVING PHYSICIAN DIAGNOSED ANAPHYLAXIS 4HIS NUMBER IS ONE HUNDRED TIMES THAT REPORTEDINTHEGENERALPOPULATIONIN!USTRALIA;8].

Aeroallergens and Eosinophilic Esophagitis 4HEREISEVIDENCETOSUGGESTTHATAEROALLERGENSMAYPLAYACAUSATIVEROLEINTHE DEVELOPMENTOFEOSINOPHILICESOPHAGITIS!SWILLBEDISCUSSEDLATER INTRANASAL exposure to Aspergillus fumigatusCANINDUCEESOPHAGEALEOSINOPHILIAINMICE !SEASONALVARIATIONINTHECASESOFNEWLYDIAGNOSEDEOSINOPHILICESOPHAGITISIN

 !LLERGICAND!TOPIC&EATURESOF#HILDRENWITH%OSINOPHILIC%SOPHAGITIS



CHILDRENHASBEENDESCRIBED WITHFEWERCASESBEINGDIAGNOSEDINTHEWINTER A SEASONOFLOWOUTDOORALLERGENEXPOSURECOMPAREDTOSPRING SUMMER ANDFALL ;6=)NADATABASEOFCHILDRENWITHEOSINOPHILICESOPHAGITIS POLLEN ALLERGIC PATIENTSHADASEASONALVARIATIONINTHEIRDISEASE CONlRMEDBYBIOPSY ANDAN ADDITIONALHADAPOTENTIALSEASONALINmUENCE CORRELATINGWITHASPRINGORFALL POLLENSEASON&OODALLERGIESWERESTILLTHEPRIMARYCAUSEOFDISEASEINALLBUT ONEOFTHESEPATIENTS(OWEVER EXACERBATIONOFDISEASEWASDOCUMENTEDDURING THE SPRING OR FALL POLLEN SEASON &ULL DISEASE CONTROL WAS ACHIEVED ON PROPER DIETARYAVOIDANCEDURINGNON POLLENSEASONS;3=&ROMTHESAMEINSTITUTION ONE FEMALEWASREPORTEDWITHATEMPORALASSOCIATIONWITHEOSINOPHILICESOPHAGITIS ANDPOLLENEXPOSURE4HISPATIENTHADMILDTONOESOPHAGITISINTHEWINTER AND MODERATETOSEVEREESOPHAGITISDURINGPOLLENSEASONS&IGS17.2 and 17.3 ;16]. In Australia, a positive relationship between increasing patient age and degree OF AEROALLERGEN SENSITIZATION AND A NEGATIVE RELATIONSHIP BETWEEN INCREASING PATIENT AGE AND FOOD ALLERGEN SENSITIZATION WAS FOUND ;8= 4HIS SUGGESTS THAT AEROALLERGENSENSITIZATIONMAYPLAYAMOREIMPORTANTROLEINADOLESCENTSWITH EOSINOPHILIC ESOPHAGITIS COMPARED TO YOUNGER CHILDREN (OWEVER SINCE THIS WASBASEDONSKINPRICKANDPATCHTESTINGONLY THECLINICALRELEVANCEOFTHESE lNDINGSISNOTCLEAR

Increase in Eosinophilic Esophagitis and Other Atopic Diseases in the General Population 4HEREPORTEDPREVALENCEOFALLERGICDISEASESASTHMA ALLERGICRHINITIS ATOPICDERMATITIS ANDFOODALLERGY ASWELLASEOSINOPHILICESOPHAGITISHASINCREASEDOVERTHE LASTFEWDECADES4HEREPORTEDPREVALENCEOFASTHMAROSEFROMINTO IN;17=4HEPREVALENCEOFPEDIATRICATOPICDERMATITISROSEFROMIN TOIN;18=ANDTHEPREVALENCEOFALLERGICRHINITISINTHE5NITED3TATESNOW APPROACHES  ;19= !N ESTIMATED n OF THE POPULATION IN INDUSTRIALIZED COUNTRIESHASATOPICDERMATITIS FOODALLERGY ORALLERGICRHINITIS;20]. Although the PREVALENCEOFEOSINOPHILICESOPHAGITISDOESNOTAPPROACHTHATOFOTHERATOPICDISEASES THENUMBERSARECLEARLYONTHERISE;21=4HEDISEASEHASBEENREPORTEDIN EVERYCONTINENTEXCEPT!FRICA)N7ESTERN!USTRALIA AN FOLDINCREASEINCASES BETWEEN  AND  HAS BEEN REPORTED ;22= !T 4HE #HILDRENS (OSPITAL OF 0HILADELPHIA THERE WAS A  FOLD INCREASE IN NEWLY DIAGNOSED EOSINOPHILIC ESOPHAGITISCASESINA YEARPERIOD FROMCASESINTOCASESIN;10]. 4HISNUMBERFURTHERINCREASEDINTONEWCASES;3] (Fig. 17. 4HEREARE LIKELYTOBEOTHERCASESUNDIAGNOSED WITHANESTIMATEDnOFPEDIATRICPATIENTS WITH POORLY CONTROLLED GASTROESOPHAGEAL REmUX THOUGHT TO HAVE EOSINOPHILIC ESOPHAGITIS;23–25].



*,"EAUSOLEILAND4" 7HITEHORN

Fig. 17.2 %OSINOPHILSINBIOPSY%SOPHAGEALBIOPSYSPECIMENSOBTAINEDINTHESPRINGANDWINTER .UMEROUSEOSINOPHILSANDHYPERPLASIAOFTHEBASALLAYERWERESEENINTHEBIOPSYOBTAINEDIN-AY 4HEINmAMMATIONHADENTIRELYSUBSIDEDBY&EBRUARY ANDTHESQUAMOUSEPITHELIUMHADANORMAL appearance

 !LLERGICAND!TOPIC&EATURESOF#HILDRENWITH%OSINOPHILIC%SOPHAGITIS



Fig. 17.3 %OSINOPHILSHIGH POWERlELDPLOTTEDAGAINSTMONTHOFBIOPSY0OLLENSEASONSAREINDICATED in grayMID -ARCHTO*UNEANDMID !UGUSTTO/CTOBER

Year of Diagnosis 140 120

Patients

100 80 60 40 20 6 20 0

5 20 0

4 20 0

3

20 0

20 0

2

1 20 0

0 20 0

9 19 9

8 19 9

7 19 9

19

96

0

Year Total

PA-NJ-DE

Fig. 17.4 4HEINCIDENCEOFNEWCASESOFEOSINOPHILICESOPHAGITISDIAGNOSEDONANANNUALBASIS PA–NJ–DE0ENNSYLVANIA .EW*ERSEY AND$ELAWARE



*,"EAUSOLEILAND4" 7HITEHORN

Fig. 17.5 %SOPHAGEALEOSINOPHILIAINEPICUTANEOUSLYSENSITIZEDMICEa 4HEEOSINOPHILLEVELIN THEESOPHAGUSOFMICESENSITIZEDWITH/6!ORA. fumigates (+) or control vehicle (−). Mice were EXPOSEDTOEPICUTANEOUSANTIGENFORWEEKFOLLOWINGARESTPERIODOFWEEKS THISPROCEDUREWAS REPEATEDOVERTHECOURSEOFWEEKS/6! ANDWEEKSA. fumigatus 4WODAYSFOLLOWINGTHE LAST DAY OF EPICUTANEOUS ANTIGEN EXPOSURE MICE WERE EXPOSED TO INTRANASAL ALLERGEN OR CONTROL

 !LLERGICAND!TOPIC&EATURESOF#HILDRENWITH%OSINOPHILIC%SOPHAGITIS



Link Between Allergen Sensitization and Eosinophilia in the Skin, Lung, and Esophagus in Murine Models 3ENSITIZATION IN MICE CAN LEAD TO ALLERGIC INmAMMATION IN THE SKIN AIRWAY AND ESOPHAGUSDEPENDINGONTHEROUTEOFEXPOSURE!MOUSEMODELWASABLETOLINK ASTHMAANDEOSINOPHILICESOPHAGITIS)NTHISMODEL REPEATEDINTRANASALEXPOSURETO A. fumigatus produced eosinophilia in both the airway and the esophagus, but not THESTOMACHORSMALLINTESTINE/RALEXPOSUREOFTHESAMEALLERGENDIDNOTLEADTO EOSINOPHILIAINTHEAIRWAYORTHEESOPHAGUS;26=)NANOTHERSTUDY MICEWERESENSItized to A. fumigatusOROVALBUMINEPICUTANEOUSLY WHICHLEDTOATOPICDERMATITIS like skin changes without esophageal changes. Following a single intranasal CHALLENGE TO THE SAME ALLERGEN THESE MICE DEVELOPED SIGNIlCANT EOSINOPHILIC ESOPHAGITIS;27] (Fig. 17.5).

Similar Pathophysiology in Eosinophilic Esophagitis and Other Atopic Diseases 4H DRIVEN INmAMMATION IS PRESENT IN THE END ORGANS OF ATOPIC CONDITIONS 4HE INmAMMATORYCELLSFOUNDINPATIENTSWITHASTHMA ALLERGICRHINITIS ATOPICDERMATITIS AND)G% MEDIATEDFOODALLERGIESARESIMILARTOTHOSEFOUNDINPATIENTSWITHEOSINOPHILICESOPHAGITIS!CTIVATIONOFMASTCELLSBYCROSSLINKINGOFALLERGEN SPECIlC)G% LEADSTOANINCREASEIN4HCELLS EOSINOPHILS ANDNEUTROPHILS%OSINOPHILSAREFOUND INNASALSECRETIONSOFTHOSEWITHALLERGICRHINITIS;28=4HCELLSANDEOSINOPHILSARE FOUNDINASTHMAANDEARLYLESIONSOFATOPICDERMATITIS;29, 30=4HEESOPHAGUSOF PATIENTS WITH EOSINOPHILIC ESOPHAGITIS HAVE  TIMES THE DENSITY OF EOSINOPHILS COMPAREDTOCONTROLSANDSIGNIlCANTLYHIGHERLEVELSOF4CELLSANDMASTCELLSCOMPAREDTOPATIENTSWITHGASTROESOPHAGEALREmUX;31]. 4H CYTOKINES SUCH AS ),  ),  AND ),  ARE PRESENT IN ATOPIC DISEASES INCLUDINGEOSINOPHILICESOPHAGITIS;32] (Fig. 17.6 4HCHEMOKINESANDTHEIRRECEPTORSAREALSOIMPORTANTINATOPICDISEASESINCLUDINGEOSINOPHILICESOPHAGITIS4HE GENEENCODINGFOREOTAXIN ACHEMOKINEIMPORTANTFORTRAFlCKINGOFEOSINOPHILS was highly induced in patients with eosinophilic esophagitis. A single nucleotide POLYMORPHISMWASASSOCIATEDWITHINCREASEDSUSCEPTIBILITYTOEOSINOPHILICESOPHAGITIS;33=!NOTHERMOLECULETHATMAYBEASSOCIATEDWITHTHEDEVELOPMENTOFATOPIC DISEASESISlLAGGRIN-UTATIONSINlLAGGRINLEADTOINCREASEDATOPICDERMATITISAND

Fig. 17.5 (continued) SALINE 3!,  $ATA ARE EXPRESSED AS MEANÕ3%- WITH  MICEGROUP **PCOMPAREDWITHCONTROLORSALINEGROUPb %OSINOPHILSWEREIDENTIlEDBYIMMUNOSTAININGWITHANTI MAJORBASICPROTEIN2EPRESENTATIVEEOSINOPHILSAREINDICATEDBYarrows3IGNIlCANT EOSINOPHILIAWASOBSERVEDINTHE/6!GROUPBUTNOTINTHECONTROLGROUP%OSINOPHILSWEREOBSERVED MAINLYINTHELAMINAPROPRIA,0 BUTOCCASIONALEOSINOPHILSWEREOBSERVEDINEPITHELIAL% OR MUSCLELAYERS- , LUMEN/RIGINALMAGNIlCATIONUPPERlGURES ¾LOWERlGURE ¾

250

*,"EAUSOLEILAND4" 7HITEHORN

Fig. 17.6 4H DRIVENINmAMMATIONISPRESENTINTHEEND ORGANSOFATOPICCONDITIONS4HCYTOKINES SUCHAS),  ),  AND),  AREPRESENTINATOPICDISEASESINCLUDINGEOSINOPHILICESOPHAGITIS !CTIVATIONOFMASTCELLSBYCROSSLINKINGOFALLERGEN SPECIlC)G%RELEASESMEDIATORSANDCYTOKINES LEADINGTOALLERGICINmAMMATIONINCLUDINGANINCREASEINEOSINOPHILS

POSSIBLY ASTHMA AND ALLERGIC RHINITIS ;3= )N ADDITION FUNCTIONAL IMPAIRMENT IN lLAGGRINEXPRESSIONMAYBEASSOCIATEDWITHEOSINOPHILICESOPHAGITIS;35]. )N ATOPIC DISEASES CHRONIC INmAMMATION MAY LEAD TO MORE lXED STRUCTURAL CHANGESREFERREDTOASREMODELING)NSOMEASTHMATICS THICKENINGOFTHEBRONCHIAL MUCOSAMAYLEADTOAPERMANENTDECLINEINLUNGFUNCTION;36=)NATOPICDERMATITIS LICHENIlCATIONOFTHESKINMAYOCCUR;30=3IMILARLY INEOSINOPHILICESOPHAGITIS A NARROWINGORSTRICTUREMAYOCCURINTHEESOPHAGUS;3, 10]. Patients with untreated EOSINOPHILICESOPHAGITISHAVEBASEMENTMEMBRANETHICKENINGANDINCREASEDVASCULARACTIVATIONSIMILARTOCHANGESSEENINASTHMATICAIRWAYREMODELING;37].

Summary -OSTCHILDRENWITHEOSINOPHILICESOPHAGITISHAVEEVIDENCEOFCONCOMITANTASTHMA ALLERGICRHINITIS ATOPICDERMATITIS ANDOR)G% MEDIATEDFOODALLERGY!LLATOPICCONditions, including eosinophilic esophagitis, are thought to be chronic and on the rise. "OTHTHEUNDERLYINGPATHOPHYSIOLOGYANDCURRENTAPPROACHESTOMANAGEMENTARE SIMILAR&UTURERESEARCHINALLATOPICDISEASESISIMPORTANTASTHEMOREWELEARN THE MOREWEWILLBEABLETOHELPOURPATIENTS

 !LLERGICAND!TOPIC&EATURESOF#HILDRENWITH%OSINOPHILIC%SOPHAGITIS

251

References  "LOOM " #OHEN 2! &REEMAN ' .ATIONAL #ENTER FOR (EALTH 3TATISTICS 3UMMARY HEALTH STATISTICS FOR 53 CHILDREN .ATIONAL (EALTH )NTERVIEW 3URVEY  6ITAL (EALTH 3TAT  n  !KDIS#! !KDIS- "IEBER4 ETAL$IAGNOSISANDTREATMENTOFATOPICDERMATITISINCHILDRENAND ADULTS %UROPEAN !CADEMY OF !LLERGOLOGY AND #LINICAL )MMUNOLOGY!MERICAN !CADEMY OF !LLERGY !STHMAAND)MMUNOLOGY02!#4!,,#ONSENSUS2EPORT!LLERGY n  3PERGEL * "ROWN 7HITEHORN 4& "EAUSOLEIL *, ET AL  YEARS OF EOSINOPHILIC ESOPHAGITIS CLINICALFEATURESANDPROGNOSIS*0EDIATR'ASTROENTEROL.UTRn  .OEL 2* 0UTNAM 0% 2OPTHENBERG -% %OSINOPHILIC ESOPHAGITIS . %NGL * -ED n  !SSAAD!( 0UTNAM0% #OLLINS-( ETAL0EDIATRICPATIENTSWITHEOSINOPHILICESOPHAGITIS AN YEARFOLLOW UP*!LLERGY#LIN)MMUNOLn  7ANG&9 'UPTA3+ &ITZGERALD*&)STHEREASEASONALVARIATIONINTHEINCIDENCEORINTENSITYOF allergic eosinophilic esophagitis in newly diagnosed children? J Clin Gastroenterol.  n  %ROGLU9 ,U( 4ERRY! ETAL0EDIATRICEOSINOPHILICESOPHAGITISSINGLE CENTEREXPERIENCEIN NORTHWESTERN53!0EDIATR)NT n  3UGNANAM++ #OLLINS*4 3MITH0+ ETAL$ICHOTOMYOFFOODANDINHALANTALLERGENSENSITIZATIONINEOSINOPHILICESOPHAGITIS!LLERGYn  'UAJARDO * 0LOTNICK , &ENDE * ET AL %OSINOPHIL ASSOCIATED GASTROINTESTINAL DISORDERS AWORLD WIDE WEBBASEDREGISTRY*0EDIATRn ,IACOURAS#! 3PERGEL*- 2UCHELLI% ETAL%OSINOPHILICESOPHAGITISA YEAREXPERIENCEIN CHILDREN#LIN'ASTROENTEROL(EPATOLn 2OTHENBERG-% 3PERGEL*- 3HERRILL*$ ETAL#OMMONVARIANTSATQASSOCIATEWITHPEDIATRICEOSINOPHILICESOPHAGITIS.AT'ENET n 3ICHERER 3( 3AMPSON (!  &OOD ALLERGY * !LLERGY #LIN )MMUNOL  3UPPL 3n 13. Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroeSOPHAGEAL REmUXIMPROVEMENTWITHANAMINOACID BASEDFORMULA'ASTROENTEROLOGY n 3PERGEL*- "EAUSOLEIL*, -ASCARENHAS- ETAL4HEUSEOFSKINPRICKTESTSANDPATCHTESTSTO IDENTIFYCAUSATIVEFOODSINEOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOL n +AGALWALLA!& 3ENTONGO4! 2ITZ3 ETAL%FFECTOFSIX FOODELIMINATIONDIETONCLINICALAND HISTOLOGICOUTCOMESINEOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOLn &OGG-) 2UCHELLI% 3PERGEL*-0OLLENANDEOSINOPHILICESOPHAGITIS;LETTER=*!LLERGY#LIN )MMUNOL n "RIM3. 2UDD2! &UNK2( ETAL!STHMAPREVALENCEAMONG53CHILDRENINUNDERREPRESENTEDMINORITYPOPULATIONS!MERICAN)NDIAN!LASKA.ATIVE #HINESE &ILIIPINO AND!SIAN )NDIAN0EDIATRICS En ,AUGHTER$ )STVAN*! 4OFTE3* ETAL4HEPREVALENCEOFATOPICDERMATITISIN/REGONSCHOOLCHILDREN*!M!CAD$ERMATOL n 0LAUT - 6ALENTINE -$ #LINICAL PRACTICE !LLERGIC RHINITIS . %NGL * -ED   n +IYOHARA # 4ANAKA + -IYAKE 9 'ENETIC SUSCEPTIBILITY TO ATOPIC DERMATITIS !LLERGOL )NT  n /RENSTEIN 32 3HALABY 4- $I ,ORENZO # ET AL 4HE SPECTRUM OF PEDIATRIC EOSINOPHILIC ESOPHAGITIS BEYOND INFANCY A CLINICAL SERIES OF  CHILDREN !M * 'ASTROENTEROL  n #HERIAN3 3MITH.- &ORBES$!2APIDLYINCREASINGPREVALENCEOFEOSINOPHILICOESOPHAGITIS IN7ESTERN!USTRALIA!RCH$IS#HILD n

252

*,"EAUSOLEILAND4" 7HITEHORN

"LANCHARD# 7ANG. 2OTHENBERG-%%OSINOPHILICESOPHAGITISPATHOGENESIS GENETICS AND THERAPY*!LLERGY#LIN)MMUNOL n  -ARKOWITZ*% 3PERGEL*- 2UCHELLI% ETAL%LEMENTALDIETISANEFFECTIVETREATMENTFOREOSINOPHILICESOPHAGITISINCHILDRENANDADOLESCENTS!M*'ASTROENTEROL n &OX6, .URKO3 &URUTA'4%OSINOPHILICESOPHAGITISITSNOTJUSTKIDSSTUFF'ASTROINTEST %NDOSC n -ISHRA! (OGAN30 "RANDT%" ETAL!NETIOLOGICROLEFORAEROALLERGENSANDEOSINOPHILSIN EXPERIMENTALESOPHAGITIS*#LIN)NVEST n !KEI(3 -ISHRA! "LANCHARD# ETAL%PICUTANEOUSANTIGENEXPOSUREPRIMESFOREXPERIMENTALEOSINOPHILICESOPHAGITISINMICE'ASTROENTEROLOGY n $URHAM324HEINmAMMATORYNATUREOFALLERGICDISEASE#LIN%XP!LLERGY3UPPL n 2OBINSON$ (AMID1 9ING3 ETAL0REDOMINANT4H LIKEBRONCHOALVEOLAR4 LYMPHOCYTES POPULATIONINATOPICASTHMA.%NGL*-EDn "IEBER4!TOPICDERMATITIS.%NGL*-ED n ,UCENDO!* .AVARRO- #OMAS# ETAL)MMUNOPHENOTYPICCHARACTERIZATIONANDQUANTIlCATIONOFTHEEPITHELIALINmAMMATORYINlLTRATEINEOSINOPHILICESOPHAGITISTHROUGHSEROLOGYAN ANALYSISOFTHECELLULARMECHANISMSOFTHEDISEASEANDTHEIMMUNOLOGICCAPACITYOFTHEESOPHAGUS!M*3URG0ATHOL n 3TRAUMANN! "AUER- &ISCHER" ETAL)DIOPATHICEOSINOPHILICESOPHAGITISISASSOCIATEDWITH A4(  TYPEALLERGICINmAMMATORYRESPONSE*!LLERGY#LIN)MMUNOL n "LANCHARD# 7ANG. 3TRINGER+& ETAL%OTAXIN ANDAUNIQUELYCONSERVEDGENE EXPRESSION PROlLEINEOSINOPHILICESOPHAGITIS*#LIN)NVEST n 7EIDINGER3 /3ULLIVAN- )LLIG4 ETAL&ILAGGRINMUTATIONS ATOPICECZEMA HAYFEVER AND ASTHMAINCHILDREN*!LLERGY#LIN)MMUNOL nE 2OTHENBERG -% "IOLOGY AND TREATMENT OF EOSINOPHILIC ESOPHAGITIS 'ASTROENTEROLOGY  n (OSHINO- .AKAMURA9 3IM* ETAL"RONCHIALSUBEPITHELIALlBROSISANDEXPRESSIONOFMATRIX METALLOPROTEINASE  IN ASTHMATIC AIRWAY INmAMMATION * !LLERGY #LIN )MMUNOL  n !CEVES 33 .EWBURY 2/ $OHIL 2 ET AL %SOPHAGEAL REMODELING IN PEDIATRIC EOSINOPHILIC ESOPHAGITIS*!LLERGY#LIN)MMUNOL n

Chapter 18

Atopic and Allergic Features of Adults with Eosinophilic Esophagitis Javed Sheikh and Katherine N. Cahill

Keywords !LLERGEN EXPOSURE s !TOPY s 0ATHOPHYSIOLOGY OF %O% s 3KIN PRICK TESTINGs3PECIlC)G%TESTING

Introduction !LLERGENEXPOSUREHASBEENWELLDOCUMENTEDTOHAVEAROLEINTHEPATHOGENESISOF PEDIATRICEOSINOPHILICESOPHAGITIS%O% !CASESERIESOFPEDIATRICPATIENTS DEMONSTRATED A DRAMATIC CLINICAL RESPONSE TO AN ELEMENTAL DIET AND SUBSEQUENT CLINICALRELAPSEUPONREINTRODUCTIONOFFOODS)NTHEADULTPOPULATION ITHASBEEN HYPOTHESIZED THAT ALLERGEN EXPOSURE PLAYS A ROLE IN THE PATHOPHYSIOLOGY OF ADULT %O% SUPPORTED BY HIGH RATES OF PERSONAL AND FAMILY HISTORY OF ATOPY !LTHOUGH PUBLISHEDREPORTSOFSUCCESSFULRESOLUTIONOFCLINICALSYMPTOMSOREOSINOPHILICINlLTRATESONBIOPSYASTHERESULTOFFOODORAEROALLERGENSIDENTIlEDTHROUGHANYOFTHE BELOWMEASURESDISCUSSEDARELIMITEDINADULTS THEREISINCREASINGEVIDENCEFORA ROLEFORFOODANDAEROALLERGENSINTHEPATHOPHYSIOLOGYOFADULT%O%ANDAPOTENTIAL FORFUTUREDIAGNOSTICANDTHERAPEUTICIMPLICATIONS

*3HEIKH*) #ENTERFOR%OSINOPHILIC$ISORDERS "ETH)SRAEL$EACONESS-EDICAL#ENTER (ARVARD-EDICAL3CHOOL /NE"ROOKLINE0LACE 3UITE "ROOKLINE -! 53! E MAILJSHEIKH BIDMCHARVARDEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_18, © Springer Science+Business Media, LLC 2012

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*3HEIKHAND+.#AHILL

Background /VERTHEPASTYEARS ALLERGENEXPOSUREHASBEENWELLDOCUMENTEDTOHAVEAROLE IN THE PATHOGENESIS OF PEDIATRIC EOSINOPHILIC ESOPHAGITIS %O%  7HEN CHILDREN WITH LONG STANDING REmUX FAILED TO RESPOND TO ANTI REmUX THERAPIES ATTENTION SHIFTEDTOWARDAPOSSIBLEROLEFORALLERGENSASTHECAUSEOFTHEDENSEEOSINOPHILIC INlLTRATESFOUNDONENDOSCOPICBIOPSIESOFTHEESOPHAGUS)NACASESERIESOF PEDIATRICPATIENTSDEMONSTRATEDADRAMATICCLINICALRESPONSETOANELEMENTALDIET ANDSUBSEQUENTCLINICALRELAPSEUPONREINTRODUCTIONOFFOODS;1=3INCETHATTIME FOODSENSITIZATIONHASBEENSHOWNTOBEPRESENTINOFPEDIATRIC%O%PATIENTS ;2=!SWESHIFTOURATTENTIONTOTHEADULTPOPULATION ITHASBEENHYPOTHESIZEDTHAT ALLERGENEXPOSUREPLAYSAROLEINTHEPATHOPHYSIOLOGYOFADULT%O%(IGHRATESOF PERSONAL AND FAMILY HISTORY OF ATOPY REPEATEDLY DEMONSTRATED IN CASE SERIES OF ADULTPATIENTS PROVIDESUPPORTINGCLUES7ITHFEWEPIDEMIOLOGICALSTUDIES REPORTS OFELIMINATIONDIETOUTCOMES ANDNOLARGE SCALESYSTEMATICALLERGYTESTINGOFTHE ADULT%O%POPULATIONPUBLISHEDTODATE AROLEFORFOODALLERGYINTHEADULTPOPULATIONISNOTCLEAR#HILDRENANDADULTSAREKNOWNTOHAVEDIFFERENTCLINICALPRESENTATIONSOF%O% ANDTHENATURALHISTORYOFFOODALLERGYISONETHATDECREASESWITHAGE SUGGESTING THERE MAY BE MORE THAN FOOD ALLERGY AT PLAY IN THE ADULTS #LINICAL HISTORIESOFSIGNIlCANTALLERGICRHINITIS CASEREPORTSOFSEASONALVARIATIONINSYMPTOMSEVERITY MOUSEMODELSOF%O%TRIGGEREDBYAEROALLERGENEXPOSUREANDINCOMPLETERESPONSETOELIMINATIONDIETSINTHEADULTPOPULATIONHAVEPROMPTEDFURTHER EVALUATIONINTOTHEROLEAEROALLERGENASCOMPAREDTOFOODALLERGEN EXPOSUREHAS in adult EoE. )NTHEPEDIATRICLITERATURECLINICALOBSERVATIONSUPPORTSTHATEOSINOPHILICESOPHAGITISREPRESENTSASPECTRUMOFCLINICALPRESENTATIONS;3=4HISSPECTRUMISANCHOREDON ONEENDBYATOPICINDIVIDUALSANDNON ATOPICONTHEOTHER!TTHEONEEXTREME THE PROFOUNDLYATOPICPEDIATRICPATIENTPRESENTSINEARLYCHILDHOODWITHACONSTELLATION OFATOPICFEATURESINCLUDINGASTHMA ATOPICDERMATITIS ANDFOODANDENVIRONMENTAL ALLERGYASSOCIATEDWITHEOSINOPHILICESOPHAGITISTHATRESPONDSTOANELEMENTALDIET 2EINTRODUCTIONOFANYFOODCAUSESAmAREINSYMPTOMS4HEIRCO OCCURRINGATOPIC CONDITIONSAREOFTENQUITESEVEREANDDONOTRESPONDTODIETARYMODIlCATIONALONE /NTHEOTHEREXTREME ARETHENON ATOPICPATIENTSWHOLACKEVIDENCEOFFOODALLERGY ONFORMALTESTING DONOTRESPONDTOANELEMENTALDIET ANDOFTENRESPONDTOTOPICAL CORTICOSTEROIDTREATMENT$ISCONTINUATIONOFSWALLOWEDCORTICOSTEROIDSOFTENRESULTS INARELAPSE)NBETWEEN THELARGESTNUMBEROFPATIENTSPRESENTWITHAFEWFOODALLERGIES ASSOCIATED WITH MILD ATOPIC ASTHMA ECZEMA ANDOR ENVIRONMENTAL ALLERGEN SENSITIVITY AND ARE USUALLY SUCCESSFULLY TREATED WITH AN ELIMINATION DIET 4HE PRESENCE OF A SIMILAR SPECTRUM IN ADULTS HAS NOT YET BEEN ESTABLISHED BUT IS SUGGESTEDBYANUMBEROFADULT%O%CASESERIESWHICHHIGHLIGHTTHATMANYBUTNOTALL PATIENTS CARRY THE ATOPIC PHENOTYPE TO VARYING LEVELS OF SEVERITY AND HAVE DOCUMENTEDSENSITIZATIONTOFOODANDAEROALLERGENSWHENTESTED;4–7]. 4HISCHAPTERFOCUSESONTHEALLERGICPHENOTYPICOFTHEADULTWITH%O%THEOVERLAP WITHTHEPEDIATRICPOPULATION ANDINDIVIDUALCASEREPORTS CASESERIES ANDCLINICAL

 !TOPICAND!LLERGIC&EATURESOF!DULTSWITH%OSINOPHILIC%SOPHAGITIS

255

TRIALSTHATFOCUSDIRECTLYONTHEADULTWITH%O%ANDTHEUNIQUEALLERGICQUALITIESTHIS POPULATION DEMONSTRATES )N THIS EMERGING BODY OF LITERATURE YOU WILL lND SOUND EVIDENCEFORAROLEOFFOODANDAEROALLERGENSINTHEPATHOGENESISOFADULT%O%

Demographics !DULTPATIENTSWITH%O%COULDBEARBITRARILYCLASSIlEDINTOTWOCATEGORIES THElRST CONSISTINGOFPEDIATRICPATIENTSWITH%O%WHOHAVEBROUGHTTHEIRCHILDHOODDISEASE CHARACTERISTICSANDASSOCIATEDFOODALLERGYINTOADULTHOOD)NTHESECONDCATEGORY AREADULTPATIENTSWITHSYMPTOMSTHATBEGANAFTERAGE-OSTPUBLISHEDSTUDIESTO DATEDONOTDISTINGUISHBETWEENTHESETWOGROUPSWHENREPORTINGDEMOGRAPHICDATA )NAREVIEWOFALLADULTSERIESOFPATIENTSWITH%O% MALEPREDOMINANCEISUNIVERSAL WITHTHEAVERAGERATIOOFTOANDAPEAKINCIDENCEAROUNDTHEFOURTHTOlFTH DECADE OF LIFE ;5, 8, 9= 7HEN REVIEWING RACIAL AND ETHNIC DISTRIBUTION ONE ADULT STUDYOFPATIENTSFROMA#INCINNATI/(TEACHINGHOSPITALSHOWEDANOVERWHELMINGPREDOMINANCEINTHEWHITEPOPULATIONATOF ;10=)NOURUNPUBLISHEDPOPULATIONOFADULTPATIENTS THEPREDOMINANCEINTHEWHITEMALEPOPULATION WITHPEAKINCIDENCEINTHEIRFOURTHDECADEOFLIFEHOLDSTRUE7EFOUNDAMALETO FEMALERATIOOFTO WERESELF IDENTIlEDASWHITE ANDMEDIANAGEATONSET OF SYMPTOMS WAS  4HE DEMOGRAPHICS OF ADULT %O% PATIENTS ARE OUTLINED IN 4ABLE18.1.

Family History 4HECURRENTLITERATUREISLIMITEDTOSELF REPORTINGSTATISTICSFORRATESOFATOPYAMONG FAMILYMEMBERSOFADULTSWITH%O%!DULTPATIENTSREPORTHIGHRATESOFFOODALLERGY ASTHMA ALLERGICRHINITIS ANDATOPICDERMATITISAMONGTHEIRFAMILYMEMBERS&AMILY HISTORYOFATOPYINASERIESOFADULTPATIENTSWASAPPROXIMATELY;6]. Our data INALARGERPOPULATIONSUPPORTAHIGHERRATEOFFAMILIALATOPICDISEASEATWHICHIS MORECONSISTENTWITHRATESFOUNDINTHEPEDIATRICPOPULATIONOFn;11]. Most DATAPUBLISHEDARELIMITEDBYLACKOFCLINICALVALIDATIONOFTHESESELF REPORTS!STHE DISEASEPREVALENCEHASINCREASEDANDMOREATTENTIONHASBEENPAIDTODIFFERENTIATING REmUX ESOPHAGITIS FROM %O% BY PATHOLOGISTS AND ENDOSCOPISTS SELF REPORTING OF FAMILYMEMBERSWITH%O%HASINCREASEDOVERTHEPASTYEARS3TRAUMANNETALINTHEIR FOLLOW UPOFADULTPATIENTSWITH%O% FOUNDlVECASESINVOLVINGTWOFAMILIESWITH %O%;6=/NECASESERIESINREPORTEDTHREEADULTSIBLINGSWITH%O%;12] and a secONDCOMMUNICATIONIDENTIlEDTWOADULTS FATHERAGEDANDDAUGHTERAGED DIAGNOSED WITH %O% WHO BOTH REPORTED LONG STANDING DYSPHAGIA FOR  AND  YEARS RESPECTIVELY;13=.OELETALINREPORTEDOFTHEIRPEDIATRICPOPULATIONOF PATIENTSHADAlRSTDEGREERELATIVEWITH%O%;14=)NPEDIATRICPATIENTS HADA SIBLINGWITH%O%HADAPARENTWITH%O%ORHISTORYOFANESOPHAGEALSTRICTURE;11].

Study Year Croese et al. 2003 0ASHAETAL 2007 3TRAUMANNETAL 2003 #AHILLAND3HEIKHc 2010 a 0HYSICIANDIAGNOSED B Any respiratory allergy c $ATAUNPUBLISHEDTODATE # = no data

.OOF patients 31 42 30 93

Table 18.1 !LLERGICCHARACTERISTICSOFADULTEOSINOPHILICESOPHAGITISPATIENTS Age Male gender .OOF Study Year patients Mean Range .O  Croese et al. 2003 31 34.0 14–77 24 77 0ASHAETAL 2007 42 44.0 21–74 31 74 2OY 'HANTAETAL 2008 23 35.2 18–57 14 61 3IMONETAL 2005 31 37.0 18–66 25 81 3TRAUMANNETAL 2003 30 33.4 6–65 22 73 0ENlELDETAL 2010 26 41.4 20–74 17 65 #AHILLAND3HEIKHc 2010 93 41.0 19–78 69 74

Any OF OF OF OF

!LLERGICRHINITIS # # # #

Any !LLERGICRHINITIS OF # OF # OF 18 OFa -OSTCOMMON OF 17B OF OF OF 66 &AMILYHISTORYOFATOPY

0ERSONALHISTORYOFATOPY

!STHMA 12 5 # #

!STHMA # 15 6 # # 9 25

Atopic DERMATITIS # # # #

Atopic DERMATITIS # # 1 # 3 3 18

Food allergy # # # #

Food allergy 7 # # # 4 # 18

EoE # # 5 #

EoE # # # # # # #

256 *3HEIKHAND+.#AHILL

 !TOPICAND!LLERGIC&EATURESOF!DULTSWITH%OSINOPHILIC%SOPHAGITIS

257

Personal History of Atopy )NBOTHTHEPEDIATRICANDTHEADULTPOPULATIONWITH%O% ANOVERLAPWITHATOPICDISEASE INDEPENDENT OF CAUSE IS CLEAR )NCIDENCE OF PERSONAL HISTORY OF ASTHMA ATOPIC DERMATITIS OROTHEREXTRA ESOPHAGEALALLERGYRANGESFROMTO WITHASTHMA ANDALLERGICRHINITISBEINGMOSTOFTENASSOCIATED;4, 8=)NASYSTEMATICREVIEWOF ADULT%O%PAPERSPUBLISHEDBETWEENAND OFPATIENTS#) n HADASSOCIATEDATOPICORALLERGICDISEASE;9=)NAMORERECENTSERIESOF ADULTPATIENTSWITH%O%WHOWEREREFERREDFORANDCOMPLETEDALLERGYEVALUATION HADCONCOMITANTATOPICDISORDERSWITHALLERGICRHINITISBEINGTHEMOSTCOMMON ATFOLLOWEDBYASTHMAAT;4=4HECHALLENGEWITHINTERPRETINGTHISINFORMATION IS THAT %O% PATIENTS WHO FOLLOW THROUGH WITH ALLERGY EVALUATION MAY BE BIASEDTOWARDSEEKINGCAREBYTHEPRESENCEOFOTHERALLERGICSYMPTOMS3ELF REPORTED ATOPYWASFOUNDINOF ADULT%O%PATIENTS AGAINWITHALLERGICRHINITIS BEINGTHEMOSTCOMMONLYREPORTED INACASESERIESFROM3WITZERLANDIN;7]. )N ACASESERIESOFADULTSHADSELF REPORTEDRATESOFATOPYORALLERGYIN ANDASTHMAIN;9=#LINICIAN DOCUMENTEDATOPICDISEASEWASFOUNDINOF ADULTPATIENTSINACASESERIESFROM;5=)NTHISSTUDY ALLATOPICSWEREFOUNDTO HAVEALLERGICRHINITISWITHSIXDIAGNOSESOFASTHMAANDONEOFATOPICDERMATITIS)N OURSERIESOFADULTPATIENTSWHOCOMPLETEDALLERGYEVALUATION HADAPERSONAL HISTORY OF ATOPIC DISEASE WITH ALLERGIC RHINITIS BEING THE MOST PREVALENT AT  4ABLE18.1SUMMARIZESTHESElNDINGS

Food Allergens !CONNECTIONBETWEEN%O%ANDFOODALLERGENSWASlRSTDESCRIBEDAFTERANAMINO ACID DIETWASSUCCESSFULINELIMINATINGSYMPTOMSINACASESERIESOFTENPEDIATRICPATIENTS ;1=4WOSUBSEQUENTSTUDIESINTHEPEDIATRICPOPULATIONSUPPORTAROLEFORFOODANTIGENSINTHEPATHOGENESISOF%O%-ARKOWITZETALINEVALUATEDTHEUSEOFELEMENTALDIETSAND+AGALWALLAETALINEMPLOYEDEMPIRICALELIMINATIONOFMILK SOY WHEAT EGG PEANUT ANDSEAFOODINTHEDIETSIXFOODELIMINATIONDIET ;2, 15]. .INETYlVETONINETYEIGHTPERCENTOFPEDIATRIC%O%PATIENTSWEREFOUNDTORESPOND TOANELEMENTALDIETEVENINABSENCEOFIDENTIlCATIONOFTHESPECIlCOFFENDINGFOOD ANTIGENS;2, 11=4HEEXTENTTOWHICHFOODANTIGENSARERESPONSIBLEFORSYMPTOMS ANDPATHOLOGIClNDINGSOFTHEADULT%O%POPULATIONISNOTCLEAR4HISISDUEPRIMARILYTOALACKOFDIETARYMODIlCATIONSTUDIESTHATHAVEDEMONSTRATEDCLINICALIMPROVEMENT)NANEGATIVESTUDY 3IMONETALREMOVEDWHEAT RYE ANDBARLEYFORWEEKS FROMTHEDIETOFSIXADULTPATIENTSWHODEMONSTRATEDSENSITIZATION ANDDOCUMENTED NOCLINICALIMPROVEMENTINSYMPTOMS;16='ONSALVESETALINUSEDTHESAME EMPIRICSIX FOODELIMINATIONDIETAS+AGALWALLAETALANDFOUNDTHATONLYOF THEADULTPOPULATIONSTUDIEDVERSUSOFTHEPEDIATRICPOPULATIONSHOWEDACLINICALRESPONSE;17=)N THEYPUBLISHEDPRELIMINARYDATAFROMADULTPATIENTS

258

*3HEIKHAND+.#AHILL

WHOCOMPLETEDASIXFOODELIMINATIONDIETWITHREPORTINGDECREASESINSYMPTOM SCORES ANDHISTOLOGICALIMPROVEMENTIN;18=4HESESTUDIESSUGGESTASMALLER ROLEFORFOODALLERGYINADULT%O%ASCOMPAREDWITHTHEPEDIATRICPOPULATION BUT certainly do not exclude it entirely. (ISTORICALLY THE DElNITIVE DIAGNOSIS OF FOOD ALLERGY IS MADE THROUGH DIRECT OBSERVEDFOODCHALLENGETHATRESULTSINANIMMEDIATEHYPERSENSITIVITYREACTION SUCH ASURTICARIA ANGIOEDEMA VOMITING ORDIARRHEAWITHINMINUTESTOHOFINGESTION ;19=6ERYFEWPATIENTSINEITHERTHEPEDIATRICORADULT%O%POPULATIONDEMONSTRATE SUCHAREACTION YETCLEARLYTHEIR%O%CANOFTENBETREATEDTHROUGHDIETARYAVOIDANCE OF THE OFFENDING FOOD ANTIGENS  /NE GOOD EXAMPLE OF THIS COMES FROM A CASE REPORTFROM3PAINOFA YEAR OLDMALEWITHAHISTORYOFALLERGICRHINOCONJUNCTIVITISANDSENSITIZATIONTODUSTMITEANDGRASSPOLLEN WHOWASDIAGNOSEDWITH%O% AFTERYEARSOFREmUX DYSPHAGIA ANDEPIGASTRICPAINSYMPTOMS;20=!LLERGYEVALUATIONINCLUDINGSKINPRICKTESTING304 TOFOODlSH SHELLlSH NUTS LEGUMES WHEAT mOUR EGG MILK ALMOND APPLEPEEL APPLEPULPANDPEAR ANDAEROALLERGENSDOG AND CAT DANDER DUST MITE !LTERNARIA ASPERGILLUS GRASSES TREES WEEDS OLIVE CYPRESS LATEX AND!NISAKIS ANDPRICK PRICKTESTINGTOEGGWHITE EGGYOLK MILK ANDAPPLEPEELANDPULPWEREPERFORMED)NADDITIONTOPOSITIVEDUSTMITE GRASS AND OLIVERESULTSON304 PRICK PRICKTESTINGWASPOSITIVEFOREGGWHITE3ERUM SPECIlC )G% TESTING WAS ALSO POSITIVE FOR EGG WHITE CLASS   $ESPITE THESE lNDINGS THE PATIENT HAD NOT SELF IDENTIlED ANY CHANGE IN HIS SYMPTOMS WITH EGGS OR ANY EGG CONTAINING FOODS 4REATMENT WITH AN EGG FREE DIET -ONTELUKAST AND +ETOTIFEN RESULTEDINSYMPTOMRESOLUTION 4HECURRENTHYPOTHESISOFTHEMECHANISMOFFOODSENSITIVITYIN%O%ISTHOUGHTTO BEACOMBINATIONOF)G% MEDIATEDASDEMONSTRATEDBYSERUMSPECIlC)G%OR304 ANDDELAYEDNON )G% MEDIATEDASMIGHTBEDEMONSTRATEDBYFOODATOPYPATCHTESTING HYPERSENSITIVITYRESPONSES#LINICALOBSERVATIONSOFPATIENTSWITHNEGATIVE304 RESULTSTOFOODSDESPITESYMPTOMSWITHREINTRODUCTIONINDIETSERVEDASACLUETOA NON )G%MEDIATEDPROCESS!FEWSTUDIESHAVEHIGHLIGHTEDTHEOBSERVATIONOFNON )G%MEDIATEDREACTIONSTOFOODS THATWERENOTDEMONSTRATEDTHROUGH304WHICH RESULTINSYMPTOMATICIMPROVEMENTONCEELIMINATED 4HEREAREMANYCHALLENGESINEVALUATINGTHEROLEOFFOODANTIGENSFORBOTHTHE INDIVIDUAL AS WELL AS THE ADULT %O% POPULATION AS A WHOLE AND SUBSEQUENTLY ELUCIDATING THE ROLE OF FOOD ANTIGENS IN THE PATHOPHYSIOLOGY OF ADULT %O% IS COMPLEX7ITHEVIDENCETOSUPPORTBOTHAN)G%ANDANON )G%MEDIATEDPATHWAY FORFOODANTIGENS THECLINICALCOMMUNITYOFTENSTRUGGLESTOIDENTIFY EVENAFTER PERFORMINGANEXHAUSTIVESEARCH WHICHFOODORFOODSARETRIGGERINGTHECASCADE OFCYTOKINESTHATEVENTUALLYLEADTOEOSINOPHILICINlLTRATIONOFTHEESOPHAGUS$UE TO A LACK OF STANDARDIZED METHODS FOR ESTABLISHING RESPONSIBLE FOOD ANTIGENS IN ADULTS THE LARGE NUMBER OF POTENTIAL OFFENDING AGENTS OR COMBINATIONS THEREOF POORADULTCOMPLIANCEWITHELIMINATIONDIETS APOSSIBLEROLEOFAEROALLERGENSTHAT ISNOTBEINGADDRESSED ANDADISEASEPROCESSTHATMAYBELESSFOODRESPONSIVEIN THEADULTPATIENT WEAREFARFROMUNDERSTANDINGTHEROLEOFFOODANTIGENEXPOSURE in adult EoE.

 !TOPICAND!LLERGIC&EATURESOF!DULTSWITH%OSINOPHILIC%SOPHAGITIS

259

Food Skin Prick Testing 3KIN PRICK TESTING 304 IS USED TO IDENTIFY )G% MEDIATED SENSITIZATION AND IS GENERALLYCONSIDEREDTHEMORESENSITIVETESTFORDETERMININGATRUEALLERGENOVER SPECIlC)G%TESTING;14, 19=)TISCURRENTLYTHERECOMMENDEDMEANSOFPERFORMING ALLERGYEVALUATIONINADULT%O%PATIENTS;21=!REVIEWOFTHEPUBLISHEDSTUDIES EMPLOYING304TOFOODSREVEALSTHEREISNOTONEESTABLISHEDPANELOFFOODSUSED IN EVALUATION AND 304 IS OFTEN NOT SUFlCIENT TO IDENTIFY ALL POSSIBLE FOOD sensitizations. )N ONE OF THE EARLIEST SERIES EVALUATING THE USE OF 304 IN ADULT %O% PATIENTS 3IMONETALEVALUATEDADULT%O%PATIENTSFROM3WITZERLANDINWHOUNDERWENT304TOFOODALLERGENS!,+$ENMARK ANDTHREENATIVEPROBESFROMWHEAT GRAIN RYEGRAIN ANDSOYMILK ASWELLASEVALUATIONOFSPECIlC)G%LEVELSTOCOWS MILK EGGWHITE WHEATmOUR RYEmOUR ANDGLUTEN;7=.INETEENOFPATIENTSHAD POSITIVE304TOFOODALLERGENSOFTHOSEHAD304REACTIONSTOCROSS REACTING AEROALLERGENS,OOKINGSPECIlCALLYATWHEATANDRYERESULTS OFWEREIDENTIlED ASSENSITIZEDTOEITHERORBOTHTHROUGH304ANDSPECIlC)G%RESULTS%IGHTPATIENTS HADPOSITIVE304RESULTSTOEITHERORBOTHFOODS ANDOFTHEHADASPECIlC )G% RESPONSETOEITHERORBOTHFOODS&IFTEENOFTHEWERENOTEDTOBECROSS SENSITIZED TOGRASSPOLLENON304)NAFOLLOW UPSTUDY SIXOFTHESEPATIENTSWHOWEREIDENTIlEDONTHEBASISOFSPECIlC )G%TESTINGRESULTSTOBESENSITIZEDTOWHEATORRYEBUT NOTPOSITIVEON304UNDERWENTANUNSUCCESSFULELIMINATIONDIET;16]. !MORERECENTSTUDYOFADULT%O%PATIENTSREFERREDBYTHEIRGASTROENTEROLOGIST FORALLERGYEVALUATIONUNDERWENT304TOASTANDARDPANELOFFOODSPLUSANYOTHER FOODSTOWHICHCLINICALHISTORYSUPPORTEDAREACTION;4=(ALFOFTHEPATIENTS HAD A POSITIVE RESULT TO ONE OR MORE FOODS TESTED EGG WHITE  COWS MILK  SOYBEAN PEANUT %NGLISHWALNUT WHEAT SHRIMP  HALIBUT ANDOTHERSBASEDONSUPPORTINGCLINICALHISTORYALMOND "RAZIL NUT PISTACHIO lLBERTNUT ANDCANTALOUPE 4HEREWASNOMENTIONOFTHEUSEOFTHESE DATATODIRECTANELIMINATIONDIETANDORSYMPTOMORPATHOLOGICRESPONSETOFOOD ELIMINATION )NAPRELIMINARYREPORTONTHEUSEOFASIXFOODELIMINATIONDIETMILK EGG SOY WHEAT NUTS ANDSEAFOOD INADULTPATIENTS PATIENTSWEREREPORTEDTO HAVECOMPLETEDTHETRIAL;18=!LLPATIENTSUNDERWENT304TOFOODANDAEROALLERGENSPRIORTOTHESTARTOFTHEEMPIRICSIXFOODELIMINATIONDIETWITHHAVINGA POSITIVE304TOFOODANDTOAEROALLERGENS!FTERWEEKSOFTHEELIMINATION DIET THEY HAD A  DECREASE IN SYMPTOM SCORES AND A  IMPROVEMENT ON HISTOLOGY /N REINTRODUCTION THE MOST COMMON FOOD TRIGGERS WERE MILK AND WHEAT AND THESE FOOD TRIGGERS WERE ONLY PREDICTED  OF THE TIME BY 304 results. )NADULT%O%PATIENTSEVALUATEDWITHFOOD304 ONEHALFTOTWOTHIRDSDEPENDING ONTHEPOPULATIONSTUDIED SHOWEDATLEASTONEFOODSENSITIZATIONSEE4ABLE18.2). 4HEREPORTS ALTHOUGHLIMITEDINNUMBER ONUSEOFTHESETOSUCCESSFULLYDIRECTELIMINATIONDIETSSHOWONLYMODESTSUCCESS

Table 18.2 &OODALLERGENCHARACTERISTICSOFADULTSWITHEOSINOPHILICESOPHAGITIS Age Study Year .OOFPATIENTS Mean 2OY 'HANTAETAL 2008 23 35.2 3IMONETAL 2005 31 37 0ENlELDETAL 2010 26 41.4 2ESULTSOFSPECIlCFOODALLERGENS Study 7HEAT Rye %GGWHITE #OWSMILK 0EANUT 2OY 'HANTAETAL OF OF OF OF OF 0ENlELDETAL OF # OF OF OF # = no data 3OYBEAN OF OF

Range 18–57 18–66 20–74 7ALNUT OF OF

3HRIMP # OF

Food sensitization 0OSITIVE2!34 OF # #

/THER # OF

&ISH # OF

0OSITIVE304 # OF OF

260 *3HEIKHAND+.#AHILL

 !TOPICAND!LLERGIC&EATURESOF!DULTSWITH%OSINOPHILIC%SOPHAGITIS

261

Food Specific IgE Testing 4HEREHASBEENATTENTIONTOWARDTHEUSEOFSPECIlC)G%TESTING INCOMPLEMENTTOOR INPLACEOF304 INHOPESOFMOREFULLYEVALUATINGTHENUMEROUSPOTENTIALFOODSENSITIZATIONSINADULT%O%ANDTHENBETTERGUIDINGTREATMENTTHROUGHELIMINATIONDIETS /NEARGUMENTFORTHEUSEOFSPECIlC)G%TESTINGISTHEEASEANDLARGENUMBEROFTESTS THATCANBEPERFORMED INAPOPULATIONTHATTENDSTOHAVEGREATERVARIABILITYINTHEIR DIET;5=/NECASESERIESOFADULTPATIENTSWHOUNDERWENTFOOD ALLERGENSPECIlC TESTINGREPORTEDRESULTSFROMSPECIlC)G%TESTINGTOCOMMONFOODSANDSPICES;5]. 3PECIlC)G%TESTINGWASGUIDEDBYAFOODLISTFROMWHICHPATIENTSSELF IDENTIlED FOODSTHEYATEMOSTOFTENANDTHOSEWHICHCAUSESYMPTOMEXACERBATION.INETEEN OF  HAD ONE OR MORE POSITIVE FOOD SPECIlC )G% WITH A MEDIAN OF lVE MEAN Õ ANDARANGEOFn4HEFOODSMOSTCOMMONLYSENSITIZEDTOWEREWHEAT ANDCARROTS ANDONIONSANDTOMATOES &OLLOWINGCLOSELYBEHINDWERE COW MILK EGG WHITE SESAME SEED BANANA AND APPLE AT  .OTABLE WAS THE ABSENCEOFSENSITIZATIONTOlSHORSHELLlSH ONEOFTHEMOSTCOMMONFOODALLERGENS INTHEADULTPOPULATION.OINFORMATIONONEFFECTOFELIMINATIONDIETFOLLOWINGTHE DETERMINATIONOFFOODSENSITIZATIONORCONTROLPOPULATIONFORCOMPARISONOFSENSITIZATIONRATESWASOFFEREDINTHISSTUDY )NASMALLSERIESOFSIXADULT%O%PATIENTSIDENTIlEDBYSPECIlC)G%RESULTSTOHAVE SENSITIZATIONTOWHEATANDRYE ADOUBLE BLINDPLACEBO CONTROLLEDFOODCHALLENGEAND ANELIMINATIONDIETWEREPERFORMED;16=4HEFOODCHALLENGEREVEALEDONEPATIENTOF THESIXWHOHADPROVOCATIONOFDYSPHAGIAWITHSOLIDWHEATINGESTIONONTHEBLINDED FOODCHALLENGE&OLLOWINGA WEEKELIMINATIONDIET ONEPATIENTREPORTEDADECREASE INFREQUENCYOFDYSPHAGIAATTACKSBUTINTHEABSENCEOFHISTOLOGICALIMPROVEMENTON REPEATBIOPSY WHILETHEREMAINDERSAWNOCHANGEINTHEIRSYMPTOMS.OTABLY THIS ONEPATIENTALSOWASFOUNDTOHAVEPOSITIVE304REACTIONSTOBOTHWHEATANDRYEBUT DIDNOTDEVELOPSYMPTOMSONTHEBLINDEDFOODCHALLENGE4HEAUTHORSCONCLUDEDTHAT SENSITIZATIONTOFOODALLERGENSISNOTAMAJORCAUSEOFSYMPTOMSINADULT%O%ANDTHAT ELIMINATIONDIETSARELESSHELPFULINADULTSTHANINTHEIRPEDIATRICCOUNTERPARTS4HE AUTHORSSUGGESTEDTHATACROSS REACTIONWITHGRASSPOLLENEXTRACTSMAYHAVELEDTOFALSE POSITIVERESULTSASALLOFTHEPATIENTSENROLLEDALSOWERESENSITIZEDTOGRASSPOLLENON 304ORSPECIlC)G%RESULTS'IVENTHESMALLSAMPLEOFADULTPATIENTSANDSHORTDURATION OF THE ELIMINATION DIET WE FEEL THAT THESE lNDINGS SHOULD BE INTERPRETED WITH CAUTION WHEN THINKING ABOUT THE ROLE OF SPECIlC )G% TESTING IN THE EVALUATION AND SUBSEQUENTTREATMENTOFTHEADULT%O%PATIENT!NECDOTALREPORTSFROMOTHERSSUGGEST THATSPECIlC)G%TESTINGISOFLOWYIELDINIDENTIFYINGCAUSATIVEAGENTSOF%O%;22]. /NEMAJORCHALLENGEWITHTHEUSEOFSPECIlC)G%RESULTSISWHICHONESANDHOWMANY TOTEST)NTHESTUDYBY2OY 'HANTA POSITIVETESTSRANGEDFROMTO !NOTHERCONSIDERATIONFORTHEFAILUREOFTHERYEANDWHEATELIMINATIONDIETINTHE STUDYFROM3IMONETALISINCOMPLETEIDENTIlCATIONOFFOODALLERGENSTHROUGH 304ANDSPECIlC )G%TESTING3TUDIESFROMTHEPEDIATRICPOPULATIONHAVESHOWNTHAT NOTALLFOODSAREIDENTIlEDBY304ALONEANDTHEUSEOFATOPYPATCHTESTING!04 IS NECESSARYTOEVALUATEFORFOODANTIGENSRESPONSIBLEFORADELAYED TYPEHYPERSENSITIVITYREACTION;22, 23].

262

*3HEIKHAND+.#AHILL

Atopy Patch Testing -ORERECENTEVIDENCETOSUPPORTAROLEOFNON )G%MEDIATEDIMMUNERESPONSEHAS LEADCLINICIANSTOEVALUATEADULT%O%PATIENTSWITH!04TOFOODANTIGENS!04IS PRIMARILY USED BY NON 53 CLINICIANS IN THE EVALUATION OF ATOPIC DERMATITIS PATIENTS TO IDENTIFY POSSIBLE DELAYED TYPE HYPERSENSITIVITY REACTIONS &OODS ARE APPLIEDTOTHESKINUNDEROCCLUSIONUNDERASMALLDISCANDLEFTINPLACEFORATLEAST H WITHSUBSEQUENTREADINGSTOLOOKFORDELAYEDONSETSKINREACTIONS3UPPORT FORTHEUSEOF!04COMESFROMAFEWCLINICALTRIALSWHICHHAVEDOCUMENTEDTHAT PATIENTSWITHNEGATIVE304MAYHAVEAPOSITIVE!04TOAPARTICULARFOODANTIGEN !STUDYOFPEDIATRICPATIENTSFOUNDTHATMOSTPATIENTSHADPOSITIVEREACTIONS ON304AND!04 WITHDIFFERENTFOODSREACTINGONTHEDIFFERENTTESTS;23=4HIS COMBINATION METHOD WAS ABLE TO IDENTIFY THE CAUSATIVE FOOD IN APPROXIMATELY OFPATIENTSWHOWOULDCLINICALLYANDPATHOLOGICALLYRESPONDTOANELIMINATIONDIET4HESUCCESSOF304AND!04TESTINGRISESTOIFYOUINCLUDETHOSE WHORESPONDEDCLINICALLYBUTHADONLYAPARTIALPATHOLOGICRESPONSE/FTHEFOOD TESTSFOUNDTOBEPOSITIVEON304 ONLYWEREALSOPOSITIVEON!04)TIS NOTED HOWEVER THATLARGE304REACTIONSOFMMWERENOTREPEATEDON!04IN THISSTUDY)NTHEADULT%O%POPULATIONDATAONTHEUSEOF!04ARELIMITEDTOANECDOTALEVIDENCE)NOUREVALUATIONOFPATIENTSWITH%O% !04HASBEENRESERVED FORPATIENTSWITHNEGATIVE304ANDSPECIlC)G%TESTINGORINCOMPLETESYMPTOM RESOLUTIONAFTERFOODSPECIlCELIMINATIONDIETS ANDINTHEPATIENTSEVALUATED THE YIELD HAS BEEN LOW WITH ONLY THREE POSITIVE RESULTS WITH UNCLEAR CLINICAL SIGNIlCANCEOFTHESElNDINGSTODATE 

Environmental Allergens &OODALLERGENSENSITIZATIONINTHEPEDIATRIC%O%POPULATIONISESTABLISHEDTOBEVERY HIGH#ONTINUEDINVESTIGATIONINTHEADULTPOPULATIONSUGGESTSTHATTHEREISAROLEOF FOODALLERGENSENSITIZATION BUTLOWERTHANINTHEPEDIATRICPOPULATION(OWEVER ALARGER ROLEFORAEROALLERGENSINTHEADULT%O%POPULATIONCOMPAREDTOTHEPEDIATRICPOPULATION HASAGROWINGBODYOFEVIDENCE)THASBEENPROPOSEDTHATTHEhATOPICMARCHvISIMPORTANTINPATHOPHYSIOLOGYOFADULT%O% ITSEVALUATION ANDTREATMENT)NACASESERIESOF PEDIATRIC%O%PATIENTS AGEMONTHSTOYEARS WHOUNDERWENT304TOFOODAND AEROALLERGENSAND!04TOSELECTFOODALLERGENS APOSITIVERELATIONSHIPBETWEENRATESOF AEROALLERGENSENSITIZATIONBASEDON304RESULTSANDAGE ANDANEGATIVERELATIONSHIP BETWEENFOODSENSITIZATIONBASEDON304AND!04RESULTSANDAGEWEREIDENTIlED;24]. $ATASUPPORTINGTHISCONTINUEDTRENDWITHAGEINTHEADULT%O%POPULATION ALTHOUGH ESTABLISHEDFOROTHERATOPICDISEASES HAVENOTYETBEENPUBLISHED -ORERECENTLYAPOTENTIALROLEFORENVIRONMENTALALLERGENSINTHEPATHOGENESIS OFADULTEOSINOPHILICESOPHAGITISHASBEENRAISED0ATIENTREPORTSOFSYMPTOMSTHAT mUCTUATEWITHTHESEASONSANDPREDOMINATEINSPRINGANDFALL ANDTHEINCREASEIN

 !TOPICAND!LLERGIC&EATURESOF!DULTSWITH%OSINOPHILIC%SOPHAGITIS

263

FOODIMPACTIONANDDIAGNOSISINTHESPRINGMONTHSSUPPORTTHECONCEPTOFAN ENVIRONMENTAL ALLERGEN EXPOSURE AS A POSSIBLE TRIGGER FOR %O% ;25, 26]. HistoLOGICALSTUDIESHAVEDEMONSTRATEDTHATPATIENTSWITHALLERGICRHINITISHAVEHIGHER NUMBERS OF EOSINOPHILS PER HIGH POWER lELD IN THEIR ESOPHAGUS DURING POLLEN SEASONASCOMPAREDWITHBIOPSIESPERFORMEDOUTOFTHEPOLLENSEASON;27=4ENOF ADULTPATIENTSWITHALLERGICRHINITISDURINGPOLLENSEASON OFWITHGASTROESOPHAGEALREmUXDISEASE'%2$ ANDZEROOFHEALTHYCONTROLSHADEOSINOPHILS PRESENTINTHEIRESOPHAGUS!LTHOUGHTHEINCIDENCEOFPATIENTS WITHEOSINOPHILS PRESENTINTHEESOPHAGUSWASNOTDIFFERENTBETWEENTHOSEWITHALLERGICRHINITISOR THOSEWITH'%2$THENUMBEROFEOSINOPHILSTRENDEDTOWARDBEINGHIGHERINTHE ALLERGICRHINITISPOPULATION!CASEREPORTOFA YEAR OLDFEMALEWHOPRESENTED WITHSYMPTOMATICANDBIOPSYPROVENEXACERBATIONSOF%O%DURINGTHEPOLLENSEASONANDRESOLUTIONOFSYMPTOMSDURINGTHEWINTERISPARTICULARLYINTERESTING;25]. 3HE HAD A HISTORY OF ASTHMA AND ALLERGIC RHINITIS WHEN SHE DEVELOPED REmUX SYMPTOMSTHATWERENOTRESPONSIVETOAGGRESSIVEMEDICALTHERAPY)NITIALBIOPSY IN-AYWASCONSISTENTWITH%O%ANDREPEATBIOPSYIN&EBRUARY ATIMEOFSYMPTOM IMPROVEMENT SHOWED ONLY RARE EOSINOPHILS 2EPEATED BIOPSIES IN !UGUST $ECEMBER AND*ULYOFSUBSEQUENTYEARSREVEALEDTHESAMEPATTERN304AND!04 TO FOODS WERE NEGATIVE 304 TO AEROALLERGENS WERE POSITIVE FOR MULTIPLE TREES GRASSES RAGWEED ASPERGILLUS CAT DOG AND DUST MITE !NOTHER INTERESTING CASE REPORTISTHATOFA YEAR OLDMANWHOPRESENTEDWITHDYSPHAGIATOLIQUIDSAND SOLIDSANDWASFOUNDTOHAVEGREATERTHANEOSINOPHILSPER(0&ONBIOPSY304 AND !04 WERE PERFORMED AND REVEALED SENSITIZATION TO MULTIPLE TREES GRASS MOLDS DUSTMITES ANDCATDANDERWITHANEGATIVEFOODPANEL;28=)NASERIESOF ADULTPATIENTSDIAGNOSEDWITH%O% THEMAJORITYOFPATIENTSWEREDIAGNOSEDIN THESPRINGANDSUMMERSEASONS WITH-AYAND*UNEHAVINGTHEHIGHESTNUMBEROF %O%DIAGNOSESMADEVIAENDOSCOPY;26]. !DDITIONALLY THEREAREMOUSEMODELSTHATSUPPORTTHEROLEOFAEROALLERGENSINTHE DEVELOPMENTOF%O%-ISHRAETALSHOWEDMICEEXPOSEDTOINTRANASALRESPIRATORY allergen (Aspergillus fumigates DEVELOP ESOPHAGEAL EOSINOPHILS FREE EOSINOPHIL GRANULES ANDEPITHELIALCELLHYPERPLASIA;29]. Intragastric or oral allergen exposure WASINSUFlCIENTTOPROMOTETHESECHANGESINTHEESOPHAGUS4HEROLEOFAEROALLERGEN SENSITIVITYIN%O%MIGHTALSOBESUPPORTEDBYSTUDIESINADULTSWHERETHEONSETOF SYMPTOMATIC ENVIRONMENTAL ALLERGY HAS BEEN SHOWN TO PRECEDE THE ONSET OF %O% SYMPTOMS;7].

Environmental Skin Prick Testing 304ISSTANDARDOFCAREFORTHEEVALUATIONOFAEROALLERGENSINTHEADULTANDPEDIATRIC POPULATION BUTTHEPLACEITHASINEVALUATIONOFTHEADULTPATIENTWITH%O%HASLIMITEDSUPPORTINGEVIDENCE3TRAUMANNETALREPORTEDRATESOFAEROALLERGENSENSITIZATIONOFOVERPATIENTS INTHEIRSERIESOFADULTPATIENTS;6=0ENlELDETAL PERFORMEDAEROALLERGEN304EVALUATIONONASUBSETOFPATIENTSINACASESERIESOF

264

*3HEIKHAND+.#AHILL

ADULTSWITH%O%REFERREDONFORALLERGYEVALUATIONONANADHOCBASISBYTHEIR GASTROENTEROLOGIST;4=4HESUBPOPULATIONWASSELECTEDBASEDONCOEXISTINGALLERGIC RHINITISANDORASTHMAWHOHADNOTPREVIOUSLYUNDERGONEAEROALLERGENTESTINGATAN OUTSIDEINSTITUTION&OURTEENOF PATIENTSTESTEDHADONEORMOREPOSITIVE 304304RESULTSINCLUDEDCAT DOG COCKROACH DUSTMITE Dermatophagoides farinae and Dermatophagoides pteronyssinus) MOLD SPORES  TREE MIX  GRASS  WEED MIX  INCLUDING RAGWEED  3EE 4ABLE18.3FORASUMMARYOFAEROALLERGENSENSITIZATIONINADULT%O%PATIENTS 4HEREPORTSWEHAVEATOURCENTEROFADULTPATIENTSWITH%O%WHOHAVEUNDERGONE 304TOAEROALLERGENSHAVEBEENLIMITEDTOTHOSEWITHCONCOMITANTALLERGICRHINITISOR ASTHMA 4HIS HAS BEEN BASED ON THE ASSUMPTION THAT 304 TO AEROALLERGENS IN THE ABSENCEOFUPPERORLOWERAIRWAYSYMPTOMSISOFLOWYIELDINREVEALINGCLINICALLY MEANINGFUL SENSITIZATIONS IN RHINITIS AND ASTHMA 7ITH MORE DATA TO SUPPORT THAT AEROALLERGENSMAYPLAYADIRECTROLEINPRODUCINGEOSINOPHILICINmAMMATIONINTHE ESOPHAGUS MORECOMPREHENSIVETESTINGOF%O%PATIENTSWITHOUTAIRWAYSYMPTOMS WILLNEEDTOBECARRIEDOUTINALARGECLINICALTRIAL5NTILTHISISPERFORMED WEWILL CONTINUETOHAVEANINCOMPLETEUNDERSTANDINGOFANYROLEAEROALLERGENSHAVEINTHE PATHOGENESISOFADULT%O%

Environmental Specific IgE Testing !LTHOUGH 304 IS CONSIDERED STANDARD OF CARE IN THE EVALUATION OF AEROALLERGENS UNLESSOTHERWISECONTRAINDICATED ONESTUDYEVALUATEDTHEUSEOFSPECIlC)G%TESTINGFORAEROALLERGENSINASUBSETOFPATIENTS2OY 'HANTAETALLOOKEDATADULTS WITH%O%ANDAHISTORYOFALLERGICRHINITISWHOUNDERWENTSPECIlC)G%EVALUATIONFOR AEROALLERGENS4HEPANELSINCLUDEDTHECOMMONTREE GRASS ANDWEEDPOLLENSOFTHE NORTHEASTERN5NITED3TATES CATANDDOGDANDER ANDDUSTMITE4HOSEWITHNEGATIVE )G% RESULTS UNDERWENT SKIN PRICK TESTING WITH THE SAME ENVIRONMENTAL PANEL AND CONlRMEDTHENEGATIVERESULTS%IGHTEENOFTHEPATIENTSHADATLEASTONEPOSITIVE RESULTWITHOFTHESEPATIENTSHAVINGAPOSITIVERESULTINTHREEORMOREOFTHETESTED CATEGORIES4HEIRRESULTSSUGGESTEDTHATADULT%O%PATIENTSWITHENVIRONMENTALALLERGENS AREPOLYSENSITIZED;5]. $ESPITETHEABOVEDATAFROMBOTH304ANDSPECIlC)G%TESTING THEREHAVENOTBEEN ANYCLINICALTRIALSTODATEDEMONSTRATINGTHATAEROALLERGENAVOIDANCERESULTSINDISEASE MODIlCATIONINADULTORPEDIATRICPATIENTSWITH%O%;30=)NADDITION THEUSEOFIMMUNOTHERAPYORMEDICALTREATMENTFORAEROALLERGENSHASNOTYETBEENWELLSTUDIED

Role of Allergen Avoidance and Implications for Treatment )NTHEADULTPOPULATIONWITH%O% REPORTSOFSUCCESSFULRESOLUTIONOFCLINICALSYMPTOMS OR EOSINOPHILIC INlLTRATES ON BIOPSY AS THE RESULT OF AVOIDANCE OF FOOD OR AEROALLERGENSIDENTIlEDTHROUGHANYOFTHEABOVEMEASURESDISCUSSEDARELIMITED;18]

All weeds # = no data

a

Table 18.3 !EROALLERGENCHARACTERISTICSOFADULTSWITHEOSINOPHILICESOPHAGITIS Aeroallergen Age sensitization .OOF patients RAST 304 tested Mean Range All POSITIVE POSITIVE Study Year 2OY 'HANTA 2008 21 35.2 18–57 18 18 # et al. 3IMONETAL 2005 30 37 18–66 23 # # 0ENlELDETAL 2010 15 41.4 20–74 14 # 14 # 11

OF 13 # 14a

3PECIlCAEROALLERGENS 4IMOTHY and "IRCH ryegrass Ragweed 17 16 16 # OF

Dust MITE 15

# 10 cat 8 dog

0ET dander 15

# OF

#OCKROACH #

# OF

Molds #

 !TOPICAND!LLERGIC&EATURESOF!DULTSWITH%OSINOPHILIC%SOPHAGITIS 265

266

*3HEIKHAND+.#AHILL

OR UNSUCCESSFUL ;16= IN THE PUBLISHED LITERATURE /NE CASE FROM  REPORTED SYMPTOMIMPROVEMENTANDDECREASEINPERIPHERALBLOODEOSINOPHILIAWITHTHEELIMINATIONOFEGG ANDTREATMENTWITH-ONTELUKASTAFTERPRICK PRICKTESTINGAND304 IDENTIlEDEGGWHITEANDDUSTMITE GRASS ANDOLIVESENSITIZATIONFROMTHEDIETOFA  YEAROLDMALEPATIENT;20=4OOURKNOWLEDGETHEREARENOLARGESTUDIESREPORTING THEEFlCACYOFANELIMINATIONDIETGUIDEDBY304RESULTSALONE(OWEVER ITISTHE CLINICALEXPERIENCEOFTHEAUTHORSTHATIDENTIlCATIONTHROUGH304OFFOODALLERGENS FORINDIVIDUALPATIENTSANDSUBSEQUENTINITIATIONOFELIMINATIONDIETSISSUCCESSFUL FOR SOME PATIENTS AND A WORTHY ATTEMPT PRIOR TO SUBJECTING A PATIENT TO LIFE LONG SWALLOWEDCORTICOSTEROIDS4HEDATAONTHESUCCESSOFAEROALLERGENIDENTIlCATION AVOIDANCE ANDTREATMENTISVERYLIMITEDANDISINCONCLUSIVETODATE-ANYSTUDIES HAVEDOCUMENTEDTHATTHETYPICALADULTPATIENTWITH%O%ISSENSITIZEDTOAEROALLERGENSSEE4ABLE18.3 WHICHTYPICALLYPREDATESTHEONSETOFTHEIR%O%SYMPTOMS;7]. 4HEIDEAOFCROSSSENSITIZATIONBETWEENAEROALLERGENSANDFOODALLERGENSASACAUSATIVEMODELFOR%O%HASALSOBEENRAISED;4, 5, 16=)TREMAINSACHALLENGETOTEASE OUTTHEINTERPLAYBETWEENAEROALLERGENANDFOODALLERGENSENSITIZATION ANDDESIGNINGLARGETRIALSOFADULTSWHOHAVEUNDERGONECOMPREHENSIVEFOODANDAEROALLERGEN TESTING FOLLOWED BY A COMBINATION OF INTERVENTION MEASURES WILL BE NECESSARY IN ORDERTOESTABLISHTHEBESTTREATMENTPLANFOROURADULTPATIENTS )N ACONSENSUSSTATEMENTPUBLISHEDINGastroenterologyRECOMMENDEDA COMPLETEEVALUATIONBYAWELL INFORMEDALLERGISTINCLUDING304FORFOODANDAEROALLERGENSFORALLADULT%O%PATIENTS;21=7ITHSTUDIESANDCASEREPORTSDOCUMENTING THECLEARBENElTOFFOODALLERGENAVOIDANCEINSOMEADULTPATIENTSWITH%O%ANDAN EMERGING BODY OF LITERATURE THAT CLEARLY DOCUMENTS THE PRESENCE OF AEROALLERGEN SENSITIZATION WEHAVEAMODESTAMOUNTOFEVIDENCETOBASEARECOMMENDATIONFOR ROUTINEFOODANDAEROALLERGENTESTINGINTHEADULTPATIENTWITH%O%

Summary %O%ISANINmAMMATORYDISORDERCHARACTERIZEDBYEOSINOPHILICINlLTRATIONINTOTHE LAMINAPROPRIAOFTHEESOPHAGUS%O%PRESENTSINBOTHCHILDRENANDADULTSWITHDIFFERENTCLINICALFEATURES)TWASlRSTDIAGNOSEDANDISWELLCHARACTERIZEDINTHEPEDIATRICPOPULATION)NTHEADULTPOPULATION CURRENTKNOWLEDGEONTHEROLEOFFOODAND AEROALLERGENSISLIMITEDTOCASEREPORTS RETROSPECTIVECASESERIES ANDAFEWPROSPECTIVE TRIALS 4HE ADULT POPULATION DEMONSTRATES HIGH RATES OF FAMILIAL AND PERSONAL ATOPY WHICHISNOTLIMITEDTOFOOD/BSERVATIONALDATAHAVESUGGESTEDASEASONAL VARIATION IN SYMPTOMS AND DIAGNOSIS ;25, 26= ! GROWING NUMBER OF CASE SERIES DEMONSTRATETHATAEROALLERGENSANDFOODALLERGENSCO OCCURINTHEADULTWITH%O% ;4, 5, 7=!LTHOUGHPUBLISHEDREPORTSOFSUCCESSFULRESOLUTIONOFCLINICALSYMPTOMS OREOSINOPHILICINlLTRATESONBIOPSYASTHERESULTOFFOODORAEROALLERGENSIDENTIlED THROUGHANYOFTHEABOVEMEASURESDISCUSSEDARELIMITEDINADULTS THEREISGROWING EVIDENCEFORAROLEFORFOODANDAEROALLERGENSINTHEPATHOPHYSIOLOGYOFADULT%O% ANDAPOTENTIALFORFUTUREDIAGNOSTICANDTHERAPEUTICIMPLICATIONS

 !TOPICAND!LLERGIC&EATURESOF!DULTSWITH%OSINOPHILIC%SOPHAGITIS

267

References  +ELLY +* ,AZENBY !* 2OWE 0# 9ARDLEY *( 0ERMAN *! 3AMPSON (! %OSINOPHILIC ESOPHAGITISATTRIBUTEDTOGASTROESOPHAGEALREmUXIMPROVEMENTWITHANAMINOACID BASEDFORMULA'ASTROENTEROLOGY n  -ARKOWITZ*% 3PERGEL*- 2UCHELLI% ,IACOURAS#!%LEMENTALDIETISANEFFECTIVETREATMENT FOR EOSINOPHILIC ESOPHAGITIS IN CHILDREN AND ADOLESCENTS !M * 'ASTROENTEROL   777–82.  0UTNAM0%%OSINOPHILICESOPHAGITISINCHILDRENCLINICALMANIFESTATIONS'ASTROINTEST%NDOSC #LIN.!M nVII  0ENlELD*$ ,ANG$- 'OLDBLUM*2 ,OPEZ2 &ALK'74HEROLEOFALLERGYEVALUATIONIN ADULTSWITHEOSINOPHILICESOPHAGITIS*#LIN'ASTROENTEROL n  2OY 'HANTA3 ,AROSA$& +ATZKA$!!TOPICCHARACTERISTICSOFADULTPATIENTSWITHEOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOL n  3TRAUMANN! 3PICHTIN(0 'RIZE, "UCHER+! "EGLINGER# 3IMON(5.ATURALHISTORYOF PRIMARY EOSINOPHILIC ESOPHAGITIS A FOLLOW UP OF  ADULT PATIENTS FOR UP TO  YEARS 'ASTROENTEROLOGY n  3IMON$ -ARTI( (EER0 3IMON(5 "RAATHEN,2 3TRAUMANN!%OSINOPHILICESOPHAGITIS ISFREQUENTLYASSOCIATEDWITH)G% MEDIATEDALLERGICAIRWAYDISEASES*!LLERGY#LIN)MMUNOL  n  +ATZKA$!$EMOGRAPHICDATAANDSYMPTOMSOFEOSINOPHILICESOPHAGITISINADULTS'ASTROINTEST %NDOSC#LIN.!M nVIII  0ASHA3& $I"AISE*+ +IM(* ETAL0ATIENTCHARACTERISTICS CLINICAL ENDOSCOPIC ANDHISTOLOGIC lNDINGS IN ADULT EOSINOPHILIC ESOPHAGITIS A CASE SERIES AND SYSTEMATIC REVIEW OF THE MEDICALLITERATURE$IS%SOPHAGUS n !SSAAD!( 0UTNAM0% #OLLINS-( ETAL0EDIATRICPATIENTSWITHEOSINOPHILICESOPHAGITIS AN YEARFOLLOW UP*!LLERGY#LIN)MMUNOL n ,IACOURAS#! 3PERGEL*- 2UCHELLI% ETAL%OSINOPHILICESOPHAGITISA YEAREXPERIENCEIN CHILDREN#LIN'ASTROENTEROL(EPATOL n 0ATEL 3- &ALCHUK +2 4HREE BROTHERS WITH DYSPHAGIA CAUSED BY EOSINOPHILIC ESOPHAGITIS 'ASTROINTEST%NDOSC n -EYER '7 %OSINOPHILIC ESOPHAGITIS IN A FATHER AND A DAUGHTER 'ASTROINTEST %NDOSC   .OEL2* 0UTNAM0% 2OTHENBERG-%%OSINOPHILICESOPHAGITIS.%NGL*-ED  940–1.  +AGALWALLA !& 3ENTONGO 4! 2ITZ 3 ET AL %FFECT OF SIX FOOD ELIMINATION DIET ON CLINICAL AND H ISTOLOGICOUTCOMESINEOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOL n  3IMON$ 3TRAUMANN! 7ENK! 3PICHTIN( 3IMON(5 "RAATHEN,2%OSINOPHILICESOPHAGITIS INADULTSnNOCLINICALRELEVANCEOFWHEATANDRYESENSITIZATIONS!LLERGY n 'ONSALVES.&OODALLERGIESANDEOSINOPHILICGASTROINTESTINALILLNESS'ASTROENTEROL#LIN.ORTH !M nVI 'ONSALVES. 9ANG' $OERmER" 2ITZ3 $ITTO!- (IRANO)!0ROSPECTIVE#LINICAL4RIAL OF 3IX &OOD %LIMINATION $IET AND 2EINTRODUCTION OF #AUSATIVE !GENTS IN !DULTS WITH %OSINOPHILIC%SOPHAGITIS%% 'ASTROENTEROLOGY3UPPL ! n "ERNSTEIN), ,I*4 "ERNSTEIN$) ETAL!LLERGYDIAGNOSTICTESTINGANUPDATEDPRACTICEPARAMETER!NN!LLERGY!STHMA)MMUNOL3UPPL 3n !NTON 2EMIREZ * %SCUDERO 2 #ACERES / &ERNANDEZ "ENITEZ - %OSINOPHILIC ESOPHAGITIS !LLERGOL)MMUNOPATHOL-ADR  n &URUTA'4 ,IACOURAS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGY n 3PERGEL *- %OSINOPHILIC ESOPHAGITIS IN ADULTS AND CHILDREN EVIDENCE FOR A FOOD ALLERGY COMPONENTINMANYPATIENTS#URR/PIN!LLERGY#LIN)MMUNOL n

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Chapter 19

Allergy Testing in Eosinophilic Esophagitis Antonella Cianferoni and Jonathan Spergel

Keywords &OOD ALLERGY s !LLERGY TESTING s 3KIN TESTING s 0ATCH TESTING s%OSINOPHILICESOPHAGITIS

Introduction: Allergy Testing !TOPY AND ALLERGIC RESPONSES HAVE BEEN STRONGLY IMPLICATED IN THE ETIOLOGY OF %OSINOPHILIC%SOPHAGITIS%O% BASEDONSEVERALLINESOFEPIDEMIOLOGICAL MOLECULARBIOLOGYANDCLINICALANDEVIDENCES  &ROM AN EPIDEMIOLOGIC PROSPECTIVE THE PREVALENCE OF %O% IS THE HIGHEST AND CONTINUESTORISEINTHEWESTERNCOUNTRYMIRRORINGTHEDEMOGRAPHICSOFATOPIC disease [1–5].  3UBSTANTIALEVIDENCEISACCUMULATINGTHAT%O%ISASSOCIATEDWITH4HELPERCELL 4H  TYPE IMMUNE RESPONSES THE TYPE OF 4 HELPER CELL POLARIZATION SEEN IN ALLERGICINDIVIDUALS )NPARTICULAR ELEVATEDLEVELSOFEOSINOPHIL ACTIVE4HCYTOKINES;EG INTERLEUKIN),  ),  AND), =ASWELLASMASTCELLSAREPRESENTIN THEESOPHAGUSOF%O%PATIENTS;6–8=)NADDITION EXPERIMENTALANIMALMODELSOF %O%CANBEINDUCEDINMICEBYALLERGENEXPOSURE ASWELLASBYOVER EXPRESSION OF4HCYTOKINES), AND),  ;9–12=#OLLECTIVELY THESEDATADEMONSTRATEAN INTIMATECONNECTIONBETWEENTHEDEVELOPMENTOFEOSINOPHILICINmAMMATIONIN THERESPIRATORYTRACTANDESOPHAGUSNOTONLYINRESPONSETOEXTERNALALLERGICTRIGGERSBUTALSOTOINTRINSIC4HCYTOKINES  #LINICALLYUPTOOFPATIENTSWITH%O%HAVEBEENREPORTEDTOBEATOPICBASED ONTHECOEXISTENCEOFATOPICDERMATITIS!$ ALLERGICRHINITIS!2 FOODALLERGY

J. Spergel (*) $EPARTMENTOF0EDIATRICS $IVISIONOF!LLERGYAND)MMUNOLOGY 4HE#HILDRENS(OSPITAL OF0HILADELPHIA TH3TREETAND#IVIC#ENTER"LVD 0HILADELPHIA 0! 53! E MAILSPERGEL EMAILCHOPEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_19, © Springer Science+Business Media, LLC 2012

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&! ANDORASTHMAANDTHEPRESENCEOFALLERGICANTIGENSENSITIZATIONBASEDON SKINPRICKTESTINGORMEASUREMENTOFPLASMAANTIGEN SPECIlC)G%;13]. It is interESTING TO NOTE THAT PATIENTS WITH %O% SOMETIMES REPORT SEASONAL VARIATIONS IN THEIR SYMPTOMS ANDOR SEASONAL CHANGES IN ESOPHAGEAL EOSINOPHIL LEVELS ;14]. %VENMOREIMPORTANTLY MOSTPATIENTSBECOMESYMPTOMFREEANDTHEESOPHAGEAL LESIONS GREATLY IMPROVE ON ALLERGEN FREE ELEMENTAL DIETS PROVIDING SUPPORTIVE EVIDENCETHATFOOD ALLERGENSARETRIGGERINGTHEDISEASE;4, 15].

EoE and Atopic Diseases !TOPYINVOLVESANEXAGGERATEDIMMUNERESPONSETOCOMMONENVIRONMENTALALLERGENS !TOPICDISEASES SUCHASASTHMA !2 &! OR!$ HAVECOMMONFEATURESINmAMMATION OFTENEOSINOPHILIC HYPERRESPONSIVENESSTOSTIMULI REMODELINGOFTISSUES AND4H cellular production [16–19]. 7EANDOTHERSHAVEREPORTEDTHATTHEPREVALENCEOFATOPYAMONGCHILDRENAND ADULTSWITH%O%ISGREATERTHANINTHEGENERALPOPULATION)NDEEDINPATIENTSWITH %O% ATOPYHASBEENREPORTEDWITHAPREVALENCEBETWEENAND;4, 20–24=VS ONLY  OF ADULTS AND CHILDREN IN THE GENERAL POPULATION IN WESTERN COUNTRIES [25–27]. !TOURINSTITUTION A YEARFOLLOW UPOFMORETHANPEDIATRICPATIENTSWHO HAD %O% SHOWED THAT TWO THIRDS HAD EVIDENCE OF OTHER ALLERGIC DISEASE APPROXIMATELYTHREEFOLDGREATERTHANTHEGENERALPOPULATION;4=$ATAFROM#INCINNATIALSO INDICATED A HIGH PREVALENCE OF ENVIRONMENTAL  AND FOOD ALLERGIES  IN CHILDRENWHOHAD%O%;23=3IMONETALHAVEDESCRIBEDASIMILARPATTERNOFINCREASED ATOPYINADULTPATIENTSWHOHAD%O%/FTHESEADULTPATIENTSWHOHAD%O%  EXPERIENCEDASTHMA !$ OR!2;28=4HEREPORTEDINCIDENCEOFACTUALFOOD INDUCED ANAPHYLAXISHASBEENBETWEENAND;4, 21, 23, 24= WITHANINCIDENCESIMILAR TOTHEONEREPORTEDIN!$;29= WHICHHASASIMILARMECHANISMSUGGESTINGANON )G% MEDIATEDREACTIONORMIXEDREACTIONSFORBOTHDISEASES

EoE and Food Allergens &OODSHAVEBEENSHOWNTOBETHECAUSEOF%O%THROUGHTHEUSEOFELIMINATIONDIETS OR ELEMENTAL FORMULAS ;4, 15= %LEMENTAL DIETS HAVE DEMONSTRATED RESOLUTION OF SYMPTOMSANDNORMALIZATIONOFBIOPSIESINGREATERTHANOFTHEPATIENTS;4, 13]. 3UCH EFlCACY OF THE ELEMENTAL DIET WAS ORIGINALLY REPORTED BY +ELLY ET AL WHO EXAMINEDTENCHILDRENWHOHADPERSISTENTGASTROESOPHAGEALREmUXDISEASE'%2$ ANDESOPHAGEALEOSINOPHILIAREFRACTORYTOPHARMACOTHERAPYANDOR.ISSENFUNDOPLICATION AS A TREATMENT OF MEDICALLY RESISTANT '%2$ &OLLOWING A  WEEK TRIAL OF ELEMENTAL FORMULA A SIGNIlCANT DECREASE IN ESOPHAGEAL EOSINOPHILS AND CLINICAL SYMPTOMS WAS OBSERVED IN ALL OF THE PATIENTS WITH EIGHT PATIENTS DEMONSTRATING COMPLETERESOLUTION;15=!TOURINSTITUTION INOURLASTPUBLISHEDREPORTOF%O%

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PATIENTS TREATED WITH AN ELEMENTAL DIET  ACHIEVED SYMPTOM RESOLUTION AND ESOPHAGEALBIOPSYNORMALIZATION;4, 13= WHICHREMAINSCONSISTENTINOURCURRENT POPULATIONOFNEARLY%O%PATIENTS"ECAUSEOFTHEPOORPALATABILITYOFELEMENTAL FORMULAS ELIMINATIONDIETSBASEDONSKINPRICKTESTS304S ANDATOPYPATCHTESTS !04S ;30, 31=ORREMOVALOFTHEMOSTCOMMONFOODALLERGENS;32=HAVEBEENTRIED WITHRATESOFIMPROVEMENTOFn)NDEEDTHEUSEOFSPECIlCELIMINATIONDIETS OF FOODS IDENTIlED BY SKIN PRICK TESTING AND PATCH TESTING LED TO IMPROVEMENT IN OFCASES;13=+AGALWALLAETAL;32= DEMONSTRATEDIMPROVEMENTOF%O%AFTER IMPLEMENTATIONOFANEMPIRICSIX FOODELIMINATIONDIET!FTERA WEEKELIMINATION OFSIXMOSTCOMMONFOODALLERGENSMILK SOY EGG WHEAT PEANUTS TREENUTS AND SEAFOOD FROMTHEDIETSOF%O%PATIENTS THEYFOUNDSIGNIlCANTIMPROVEMENTIN  OF PATIENTS ON THE SIX FOOD ELIMINATION GROUP AS COMPARED WITH AN  RESPONSEINCHILDRENTREATEDWITHANELEMENTALDIET(OWEVER REMOVALOFTHEMOST COMMONFOODALLERGENSDIDNOTREDUCEEOSINOPHILSTOANORMALRANGEEOSINOPHILS(0& ;32=WHEREASELIMINATIONDIETSWHENEFFECTIVEBASEDON304AND!04 TESTING REDUCE COUNTS TO  EOSINOPHILS(0& ;30, 31= AND ELEMENTAL DIETS ;13] REDUCEDEOSINOPHILCOUNTSTOANORMALRANGEOFEOSINOPHILS(0& 4HEMECHANISMUNDERLYINGTHEIMMUNOLOGICREACTIONTOFOODSIN%O%ISNOTONLY )G%MEDIATEDBUTALSOCELLMEDIATED ASINATOPIC!$)NDEED AFTERINGESTIONOFTHE OFFENDINGFOOD SYMPTOMSMAYDEVELOPWITHINH ASWITHANAPHYLAXISORCERTAIN TYPEOF!$ CANBEDELAYEDSEVERALHOURS ASREPORTEDBY+ELLYETAL;15= OREVEN DAYSORMONTHS-OREOVER +ELLYETAL;15=DEMONSTRATEDTHATTHEINTRODUCTIONOF SKINTESTnNEGATIVEFOODSINTOTHEDIETCOULDINDUCECLINICALDISEASE4OHELPADDRESS THISISSUE WEHAVEUSEDPATCHTESTINGASATOOLFORIDENTIFYINGDELAYED CELL MEDIATED ALLERGICREACTIONSIN%O%)NPEDIATRICPATIENTS THISTESTINGMETHOD ALONGWITHSKIN PRICKTESTING HASBEENSHOWNTOBEEFFECTIVEINGUIDINGMANAGEMENT4HECOMBINATIONOFSKINPRICKANDPATCHTESTINGHADANEGATIVEPREDICTIVEVALUEOFnFOR FOODSEXCEPTMILK WHEREASTHEPOSITIVEPREDICTIVEVALUEWASGREATERTHAN FORTHEMOSTCOMMONFOODSCAUSING%O%;33]. 4HELINKBETWEENFOODSAND%O%ISNOTASCLEARINADULTPATIENTSBECAUSELIMITED DATAEXISTREGARDINGTHEUSEANDEFlCACYOFELEMENTALANDELIMINATIONDIETS)NONE STUDY SIXADULTSWITH%O%ANDSENSITIZATIONSHOWNBYSKINTESTSPOSITIVITY TOWHEATRYE WHEAT FAILED TO RESPOND TO ANTIGEN REMOVAL ;34= (OWEVER THESE PATIENTS WERE ALSOSENSITIZEDTOGRASSPOLLEN WHICHCANACCOUNTFORTHEWHEATRYESENSITIZATION DUETOCROSSREACTIVITY-OREOVER ASERIESOFCASEREPORTSPUBLISHEDINANABSTRACT FORMINDICATETHATDIETMAYBEHELPFULINADULTS&OREXAMPLE 'ONSALVESREPORTEDA RESPONSERATEINADULTSONASIXFOODELIMINATIONDIETANDNEARRESOLUTION ONANELEMENTALDIET;35].

EoE and Aeroallergens 3OMEEVIDENCESUGGESTSTHATAEROALLERGENSMAYPLAYACAUSATIVEROLEINTHEDEVELOPMENTOF%O%INHUMANS!SEASONALVARIATIONINCASESOFNEWLYDIAGNOSED%O%HAS BEEN DESCRIBED WITH FEWER CASES BEING DIAGNOSED IN THE WINTER WHEN THE AIR

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contains less pollen [36= $URING POLLEN SEASON THERE IS AN INCREASED NUMBER OF EOSINOPHILSINPATIENTSWITH!2COMPAREDTONORMALCONTROLS ALTHOUGHTHENUMBER OFEOSINOPHILSOBSERVEDWASLOWERTHANVALUESTYPICALLYSEENINPATIENTSWHOHAVE EoE [14=)NOUR%O%POPULATION WEHAVECONlRMEDSEASONALPOLLENVARIATIONIN PATIENTS WITHWORSENINGSYMPTOMSANDESOPHAGEALEOSINOPHILIADURINGPOLLEN SEASONS &OOD ALLERGIES WERE STILL THE PRIMARY CAUSE OF DISEASE IN THESE PATIENTS (OWEVER DURINGPOLLENSEASONINTHESPRINGORFALL ANEXACERBATIONOFDISEASECONlRMEDBYBIOPSY WASDOCUMENTED&ULLDISEASECONTROLWASACHIEVEDONLYDURING NON POLLENSEASONSANDONPROPERDIETARYTHERAPY;4=!LTHOUGHDIRECTDEPOSITIONOF POLLENSONTOTHEESOPHAGEALMUCOSAISONEPOTENTIALMECHANISMFORINmAMMATION EXPERIMENTALEVIDENCEPOINTSTOWARDOTHERPOTENTIALMECHANISMSSUCHASEOTAXIN SECRETIONUPONAEROALLERGENSTIMULATIONRESULTINGINEOSINOPHILMIGRATIONINTOTHE ESOPHAGUS)NDEED EOTAXINISOVER EXPRESSEDINPATIENTSWITH%O%ANDDURINGTHE POLLENSEASONTHEYMAYHAVEEXCESSIVEPRODUCTIONTHATFACILITATESTHERECRUITMENTOF EOSINOPHILSINTHEESOPHAGUS;37=)NTERESTINGLY INTRANASALSTEROIDTHERAPYHASBEEN SHOWNTODECREASENASALSECRETIONOFEOTAXININPATIENTSWHOHAVE!2;38=(ENCE AGGRESSIVETREATMENTOF!2WITHTOPICALSTEROIDSISHIGHLYRECOMMENDEDINAPATIENT WITH%O%;39].

Allergic Evaluation of EoE Patients History (ISTORYISVERYIMPORTANTINMANAGEMENTOF%O%4HEPATIENTSHISTORYMUSTFOCUS ON POSSIBLE TRIGGERS OR SEASONAL VARIATION OF %O% 4HE PATIENT NEEDS TO BE ASKED SPECIlCALLYIFANYFOODSEEMSTOTRIGGERTHE%O%-ANYTIMES PATIENTSINTUITIVELY AVOIDFOODSTHATMAYEXACERBATETHEIRDISEASE SOEVENIFTHEPATIENTCANNOTCITEANY OFFENDINGFOODS THECAREGIVERALSONEEDSTOASKIFTHEPATIENTISLIMITINGTHEINTAKE OFANYPARTICULARFOOD;4="ECAUSEOFTHEHIGHRATEOFALLERGICRHINITIS ASTHMA ANDOR ECZEMAIN%O%PATIENTS ACOMPLETEEVALUATIONBYAWELL INFORMEDALLERGISTFORFOOD ALLERGYANDOTHERATOPICDIATHESESISRECOMMENDED;40].

Skin Prick Testing for Antigen Sensitization 3KINPRICKTESTINGFORFOODSANDENVIRONMENTALALLERGENSSHOULDBECONSIDEREDSO THAT POTENTIAL ALLERGENS AND THE ATOPIC STATUS OF %O% PATIENTS ARE IDENTIlED 3KIN PRICKTESTSSHOULDBEPERFORMEDUSINGCOMMERCIALLYAVAILABLEEXTRACTS5SINGANEEDLE THE OPERATOR SHOULD PRICK THROUGH A DROP OF THE EXTRACT WHICH WILL BE THEN ABSORBED 0OSITIVE HISTAMINE AND NEGATIVE DILUENT CONTROLS NEED ALSO BE USED

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2EACTIONSNEEDTOBERECORDEDONTHEBASISOFTHELARGESTDIAMETERINMILLIMETERS OFTHEWHEALANDmAREATMIN!WHEALOFMMGREATERTHANTHENEGATIVECONTROL ISCONSIDEREDPOSITIVE&IFTEENSTUDIESINVOLVINGCASESERIESANDCASEREPORTS HAVEEXAMINEDSKINPRICKTESTINGIN%%PATIENTS)NADULTS POSITIVESKINTESTSTO FOODALLERGENSHAVEBEENDIFlCULTTOELICIT WHEREASPOSITIVESKINTESTSTOENVIRONMENTAL ALLERGENSAREMOREFREQUENTLYFOUNDTHANPOSITIVEREACTIONSTOFOODANTIGENS;28]. In PEDIATRIC PATIENTS MORE COMPREHENSIVE STUDIES HAVE BEEN REPORTED ;4, 30]. !PPROXIMATELYTWOTHIRDSOFPATIENTSHAVEPOSITIVESKINTESTSTOATLEASTONEFOOD ALLERGEN4HEMOSTCOMMONFOODSREPORTEDTOBEPOSITIVEBYSKINPRICKTESTSINCLUDED COMMONFOODALLERGENSnCOWSMILK EGGS SOY WHEATnINADDITIONTOPOTATO CORN CHICKEN RICE ANDBEEF0EANUTSANDNUTSWEREREPORTEDPOSITIVEINASMALLSUBGROUP OFPATIENTS !SHISTORYISOFTENNOTENOUGHTODELINEATEWHICHFOODMAYBEIMPLICATEDINTRIGGERING%O% LARGEFOODPANELSARERECOMMENDEDTHATSHOULDINCLUDEALLTHEFOODS SUSPECTEDBYHISTORY PLUSTHECOMMONFOODALLERGENSnCOWMILK EGGS PEANUTS SOY WHEATnASWELLASREPRESENTATIVEMEMBERSOFCLASSESOFFOODSINCLUDINGGRAINS OAT RYE BARELY CORN RICE MEATSCHICKEN BEEF TURKEY PORK SEAFOODSEAFOOD AND lSH MIX FRUITS APPLE PEACH AND VEGETABLES CARROTS POTATO  )F THERE IS A CLINICALHISTORYOF%O%TRIGGEREDBYVEGETABLEANDORFRUITTHATCOMEBACKNEGATIVE BY304USINGCOMMERCIALLYAVAILABLEEXTRACTS THEPRICKBYPRICKTECHNIQUEUSING FRESHVEGETABLESANDORFRUITSHOULDBETRIED ASTHECOMMERCIALLYAVAILABLEEXTRACTS MAYCONTAINDEGRADEDALLERGENS;41=!LLFOODSTHATAREPOSITIVESHOULDBEELIMINATED FROM THE DIET 4HOSE THAT ARE NEGATIVE FROM THIS PANEL SHOULD BE TESTED AS !TOPY0ATCH4ESTS

Atopy Patch Testing in EoE !TOPYPATCHTESTING!04 HASBEENUSEDFORTHEDIAGNOSISOFNON )G% CELL MEDIATED IMMUNERESPONSESINWHICH4CELLSARETHOUGHTTOPLAYAPROMINENTROLE)NDEED THEIRROLEISWELLESTABLISHEDINTHEEVALUATIONOFCONTACTDERMATITIS)NTHEEVALUATIONOFFOODALLERGY !04HASBEENMOSTEXTENSIVELYSTUDIEDIN!$!FTERTHElRST CONTROLLEDTRIALONPATCHTESTINGINECZEMAPUBLISHEDIN;42= SEVERALSTUDIES HAVEFOUNDTHAT!04ISBETTERINIDENTIFYINGLATEREACTIONSAND')REACTIONSINCHILDRENWITHATOPICDERMATITIS;43–45=!04INVOLVESPROLONGEDCONTACTOFTHEALLERGENTOTHESKINWITHTHEGOALOFMIMICKINGASIMILARIMMUNERESPONSETO!$)N FACT BIOPSY SPECIMENS OF THE PATCH TEST SITES TYPICALLY SHOW AN INITIAL 4H CELL INlLTRATION FOLLOWED BY A PREDOMINANCE OF 4H CYTOKINES AND EOSINOPHILS ;46] SIMILARTOTHEBIOPSYlNDINGSTHATHAVEBEENOBSERVEDINTHESKINOFATOPICDERMATITISPATIENTSINACUTEANDCHRONICLESIONS;18=4HEFOODTOBETESTEDISTYPICALLY PLACEDINALUMINUMCUPS&INN#HAMBERSON3CANPORE!LLERDERM,ABORATORIES )NC0ETALUMA #! ANDTHENAPPLIEDTOUNINVOLVEDAREASOFTHEPATIENTSBACKINTHE  MMCHAMBERS;30=3IMILARTOPATCHTESTINGFORCONTACTDERMATITIS A HOCCLUSION

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TIMEISUSED ANDTHEPATCHESARESUBSEQUENTLYREADATHAFTERREMOVALOFTHE &INNCHAMBER EXAMININGFORERYTHEMA PAPULES ANDINDURATION;47, 48=!NYFOOD CANBEASSESSEDWITHPATCHTESTING ALTHOUGHCOWSMILK EGG WHEAT ANDSOYHAVE BEENSTUDIEDMOSTEXTENSIVELY;33=7EHAVEUSED!04DIAGNOSISOFFOODALLERGIES IN%O%EXTENSIVELY;30, 33=7EEXAMINEDCHILDRENINOURLASTPUBLISHEDSERIES ONTHISTOPICWITHBIOPSYSPECIMEN DIAGNOSED%O% ANDELIMINATEDFOODSBASEDON POSITIVESKINTESTANDATOPYPATCHTEST7EFOUNDTHATOFTHEPATIENTSHADRESOLUTIONOFTHEIRESOPHAGEALBIOPSYABNORMALITIESBASEDONTHESERESULTSINCLUDING THATREQUIREDELEMENTALFORMULASBECAUSEOFTHEMULTIPLEPOSITIVEFOODALLERGIES 'REATERTHANOFTHEPOPULATIONRESPONDEDTOANELEMENTALDIET;13] sugGESTINGTHATPATIENTSWHOFAILEDTESTINGDIDNOTHAVETHECORRECTFOODSIDENTIlED 4HESAMEPANELOFFOODUSEDIN304SHOULDBEUSED LESSTHOSEFOODSTHATCAME BACKPOSITIVEAT304 4HECOMBINED POSITIVEVALUESOF304AND!04SHOULDGUIDETHEDIAGNOSISOF FOODALLERGY7EHAVECALCULATEDTHEPOSITIVEANDNEGATIVEPREDICTIVEVALUES006 AND.06 OFTHESINGLEANDCOMBINEDTESTINGANDFOUNDTHATTHECOMBINATIONOFTHE TWOTESTSYIELDEDTHEBEST006AND.06;49=)NDEED WHENWEEXAMINEDASUBGROUPOFPATIENTSINWHOMWECOULDDElNITIVELYIDENTIFYTHEFOODSTHATWERECAUSING THEDISEASEANDCALCULATEDTHENEGATIVEPREDICTIVEVALUES.06S POSITIVEPREDICTIVE VALUES 006S SPECIlCITY AND SENSITIVITY FOR 304 AND !04 !LL PATIENTS IN THIS COHORTHAD%O%ONTHEBASISOFEOSINOPHILSPER(0&AFTERATLEASTMONTHTREATMENTWITHAPROTONPUMPINHIBITOR4HEGROUPUSEDFORSTATISTICALEVALUATIONWERE PATIENTSFORWHOMWECOULDIDENTIFYTHEINDIVIDUALFOODSTHATCAUSED%O%ONTHE BASISOFTHEFOLLOWING  2EMOVALOFANINDIVIDUALFOODLEDTONORMALESOPHAGEALBIOPSYEOSINOPHILS (0& ANDOR  !DDITIONOFANINDIVIDUALFOODLEDTOINCREASEDESOPHAGEALEOSINOPHILSGREATER THANEOSINOPHILS(0& ONBIOPSYAFTERAPREVIOUSLYNORMALBIOPSY 4HISSUBGROUPWASSIMILARTOOURENTIRE%O%COHORTOFPATIENTSWHOHAVE UNDERGONE!04AND304(OWEVER THESEPATIENTSHADBIOPSIESnMONTHSAFTER SINGLE FOOD INTRODUCTION OR REMOVAL OF AN INDIVIDUAL FOOD 4HE MOST COMMON FOODSFOR!04INTHEENTIRECOHORTANDTHESUBCOHORTWERETHESAMEMILK WHEAT CORN BEEF EGG POTATO CHICKEN SOY BARLEY OAT ANDRICE4HE006SAND.06S ALONGWITHSPECIlCITYANDSENSITIVITYWERECALCULATEDONTHEBASISOFIDENTIlCATION OFSINGLEFOODSCAUSINGINCREASEDEOSINOPHILSINBIOPSIES4HEVALUESARELISTEDFOR THEMOSTCOMMONFOODSIN4ABLES19.1 and 19.2-ILKANDEGGWERETHEMOST COMMONFOODSCAUSING%O%INANDPATIENTS RESPECTIVELY4HE006FOR304 WASGREATERTHANFORMILK EGG BEEF ANDPEANUT4HISISBETTERTHANTRADITIONALSKINTESTINGFOR)G% MEDIATEDREACTIONS WITH006REPORTEDAROUND;50]. 4HE PREDICTIVE VALUE FOR !04 RANGED FROM  FOR BEEF TO  FOR POTATO 4HE SPECIlCITYFOR!04RANGEDFROMTO LOWERTHANTHEREPORTEDFOR!04IN ATOPICDERMATITIS!$ ;51=,IKEALLALLERGYTESTING 304AND!04ARENOTPERFECT BUTSERVEASAGUIDEFORDIETEVALUATION

Table 19.1 0REDICTIVEVALUESFOR304AND!04 304 Food 006 .06 3PECIlCITY 3ENSITIVITY Milk (n = 46) 95.7 57.7 42.3 97.6 Egg (n = 39) 84.8 75.4 65.1 90.2 Soy (n = 28) 70.0 68.9 37.8 89.5 7HEATn = 26) 77.8 64.7 18.9 96.5 Corn (n = 26) 57.1 71.3 13.8 95.4 "EEFn = 23) 81.8 74.7 30.0 96.9 #HICKENn = 15) 50.0 83.3 26.3 93.3 2ICEn = 14) 50.0 85.6 13.3 97.5 0OTATOn = 11) 60.0 89.9 25.0 97.6 0EANUTn = 10) 77.8 97.6 77.8 97.6 Oat (n = 9) 33.3 90.1 10.0 97.6 Barley (n = 9) 42.9 90.8 27.3 95.2 nNUMBEROFPATIENTSWITHPOSITIVECHANGEINBIOPSYAFTERDIETMODIlCATION !04 006 83.3 78.3 66.7 74.2 65.8 94.4 66.7 59.1 53.8 75.0 47.4 90.0 .06 58.7 82.8 87.3 83.9 93.9 87.0 95.7 96.9 94.6 97.6 98.5 98.7

3PECIlCITY 43.5 62.1 66.7 71.9 89.3 65.4 80.0 86.7 63.6 60.0 90.0 90.0

3ENSITIVITY 90.2 91.4 87.3 85.5 78.0 98.4 91.7 87.5 92.1 98.8 87.0 98.7

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Table 19.2 0REDICTIVEVALUESFORTHECOMBINATIONOF304AND!04 #OMBINED304AND!04 Food 006 .06 3PECIlCITY Milk 92.0 40.9 63.9 Egg 84.8 87.5 86.7 Soy 73.7 92.9 87.5 7HEAT 76.5 90.0 81.3 Corn 63.4 92.5 86.7 "EEF 85.2 92.5 82.1 #HICKEN 62.5 98.6 93.8 Apple 57.1 97.7 66.7 2ICE 60.9 100.0 100.0 0OTATO 61.1 97.4 84.6 0EANUT 71.4 100.0 100.0 Oat 50.0 100.0 100.0 Barley 73.3 100.0 100.0

3ENSITIVITY 81.8 85.7 83.9 87.1 76.6 93.9 88.5 96.6 88.8 91.4 95.2 89.4 95.2

"ECAUSE%O%ISMOSTLIKELYAMIXED)G%ANDNON )G%FOOD MEDIATEDREACTION THECOMBINATIONOF304AND!04INTHEMANAGEMENTOF%O%HASBEENFOUNDTO BEEFFECTIVEANDINDEEDTHECOMBINATIONOFTHETWOTESTINGMETHODSHADANEXCELLENT .06 n FOR ALL FOODS EXCEPT MILK WHICH WAS VERY LOW AT  4ABLE19.2 4HE006WASGREATERTHANFORTHEMOSTCOMMONFOODSMILK EGG ANDSOY BUTDROPPEDOFFASTHEFOODBECAMEALESSCOMMONCAUSEOF%O% 3IMILARLY THESENSITIVITYFORIDENTIlCATIONOFFOODSCAUSING%O%RANGEDFROM TO DEPENDINGONTHEFOOD4HEREFORE THECOMBINATIONOF304AND!04IN DESIGNINGADIETPLANHASAHIGHSUCCESSRATEFORFOODELIMINATIONORFOODREINTRODUCTIONIN%O%WITHTHEEXCEPTIONOFMILK-ILKS.06WASUNACCEPTABLYLOW SUGGESTINGTHATANEGATIVETESTTOMILKON304AND!04DOESNOTRULEOUTMILK triggering EoE.

Assessment of Atopy by Analysis of Blood Samples Peripheral eosinophil count. /VERALL nOFADULTSANDnOFCHILDREN HADELEVATEDPERIPHERALEOSINOPHILCOUNTSBUTUSUALLYONLYMODESTLYELEVATEDLESS THANTWOFOLD )NALLSTUDIES THEREWASAHIGHPERCENTAGEOFCONCURRENTALLERGICSENSITIZATION ANDITISLIKELYTHATCONCURRENTALLERGICDIATHESESINCONJUNCTIONWITH%O% PLAYAROLEINTHEELEVATEDEOSINOPHILCOUNTSFOUNDINTHESEPATIENTS/NESTUDYDEMONSTRATED THAT PERSISTENT BLOOD EOSINOPHILIA CORRELATED WITH PERSISTENT DYSPHAGIA [52=)NANOTHERSTUDY THEDEGREEOFELEVATIONOFSERUMEOSINOPHILSCORRELATEDWITH THE SEVERITY OF %O% ;53= &OLLOWING TREATMENT WITH mUTICASONE  OF PATIENTS DEMONSTRATED DECREASED BLOOD EOSINOPHIL COUNTS ;54= )N ANOTHER STUDY OF ORAL CORTICOSTEROIDS MOSTPATIENTSDEMONSTRATEDDECREASEDBLOODEOSINOPHILSFOLLOWING

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277

TREATMENT;55=(OWEVER THEREARENOSTUDIESTHATDElNETHE006SANDTHE.06SOF BLOODEOSINOPHILIAANDHASMAJORITYOF%O%PATIENTS VARIATIONINTHEIREOSINOPHILIA CANBEDUETOCHANGESINOTHERATOPICDISEASES-OREOVER MOSTOFTHECITEDSTUDIES INVOLVEONLYFEWPATIENTSANDHADSIGNIlCANTAMOUNTOFVARIABILITYINTHEDElNING LEVEL FOR hPERIPHERAL EOSINOPHILIAv RANGE OF EOSINOPHILS REPORTED AS ABNORMAL RANGEDFROMGREATERTHANEOSINOPHILSPERMM3TOGREATERTHANEOSINOPHILS PER MM3  (ENCE ROUTINE CHECKING OF BLOOD EOSINOPHILS IS NOT RECOMMENDED IN CHILDRENWITH%O%

Total IgE 3IMILARTOPERIPHERALBLOODEOSINOPHILIA ONLYFEWSTUDIESWITHALIMITEDNUMBEROF PATIENTSHAVEREPORTEDTHETOTALLEVELOF)G%ANDTHEDElNINGCRITERIAFORABNORMAL VALUES VARIED AMONG STUDIES THUS MAKING BROAD CONCLUSIONS DIFlCULT /VERALL nOFPEDIATRIC%O%PATIENTSANDnOFADULT%O%PATIENTSHADELEVATED TOTAL)G%LEVELS;8, 28, 33, 52, 54, 55=4HEHIGHRATEOFCONCURRENTATOPICDIATHESES INTHESEPATIENTSSUGGESTSTHATELEVATED)G%LEVELSWERELIKELYNOTLINKEDSPECIlCALLY TO%O%.OPUBLISHEDSTUDIESDOCUMENTWHETHERORNOTTOTAL)G%CANSERVEASASURROGATEMARKERFORDISEASEPROGRESSIONORRESOLUTION HENCEWEARENOTCURRENTLYROUTINELYMEASURINGTHEIRLEVELS

Food-Specific IgE #URRENTLYTHEREARENOPOSITIVEORNEGATIVEPREDICTIVEVALUESFORFOOD SPECIlC)G% LEVEL TESTING IN %O% )NDEED ONLY A LIMITED NUMBER OF STUDIES HAVE USED SPECIlC SERUM)G%INTHEEVALUATIONOFFOODALLERGYINCHILDRENWITH%O%;56–58=.OSTUDIES WEREABLETODESIGNASUCCESSFULFOODSPECIlC BASEDELIMINATIONDIETBASEDONTHE FOODSPECIlCSERUM)G%LEVELS(ENCE INVITROFOODALLERGYTESTINGISNOTSUPPORTED INTHEEVALUATIONOF%O%PATIENTSATTHISTIME ANDEMPIRICFOODTESTINGSHOULDUTILIZE SKINPRICKTESTS)NCASEOFIMPOSSIBILITYOFPERFORMINGSKINTESTSPECIlC)G%FOR EXAMPLE SEVEREATOPICDERMATITISORUNABLETOSTOPANTIHISTAMINES CANSUBSTITUTE FORSKINTESTING

Food-Specific IgG &OOD SPECIlC)G'ISPARTOFANORMALPHYSIOLOGICALRESPONSETOFOODANDISNOTUSEFUL IN TESTING FOR ANY ALLERGY )T IS NOT RECOMMEND BY ANY OF THE NATIONALINTERNATIONAL allergy societies [59= 4HERE IS NO EVIDENCE FOR USING OTHER METHODS INCLUDING

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LYMPHOCYTEPROLIFERATION BASOPHILRELEASE FACIALTHERMOGRAPHY GASTRICJUICEANALYSIS CYTOTOXICASSAYS ELECTRODERMALTEST ORMEDIATOR2ELEASE!SSAY,%!0DIET 

Aeroallergen-Specific IgE !LTHOUGHTHEPRESENCEOFALLERGICRHINITISISCITEDINMULTIPLESTUDIES ONEADULTSTUDY SPECIlCALLY DELINEATES THE PRESENCE OF ANTIGEN SPECIlC )G% TO SPECIlC ALLERGENS GRASS APOTENTIALCROSS REACTINGALLERGENTOWHEATANDRYE INAPATIENTWITH%O% ANDSYMPTOMS;28=(OWEVER SEVERALSTUDIESPOINTTOTHEROLEOFAEROALLERGENIN %O%)NFACT AEROALLERGENSHAVEBEENSHOWNTOLEADTOESOPHAGEALEOSINOPHILIA;14] and EoE [39=INTWODIFFERENTSTUDIES)NADDITION 3UGNANMANFOUNDANINCREASED SENSITIZATIONTOAEROALLERGENSWITHOLDERPATIENTS;24=&INALLY THEREAPPEARSTOBE SEASONALITYINTHEDIAGNOSISOF%O%WITHINCREASEDDIAGNOSISINTHEPOLLENSEASON 'IVENTHEHIGHRATEOFOTHERALLERGICDIATHESESn IN%O%PATIENTSANDTHE POTENTIALOFAEROALLERGENSTOHAVEAROLEINTHEINSTIGATIONOF%O% ITISIMPORTANTTO EVALUATE %O% PATIENTS FOR AEROALLERGEN SENSITIVITY %VALUATION SHOULD BE DONE VIA 304ORSERUM SPECIlC)G% ALTHOUGH304AREGENERALLYCHEAPERANDMORESENSITIVE INTHEDIAGNOSISOFAEROALLERGENSENSITIVITY;60, 61].

Conclusion 4HEREISSTRONGCLINICALANDMECHANISTICEVIDENCETHATALLERGIESPLAYAKEYROLEINTHE %O%&OOD!LLERGIESHAVEBEENFOUNDTOBECONSISTENTTRIGGERINTHEMAJORITYOFBOTH PEDIATRICANDADULTPATIENTS(OWEVER THEFOODALLERGIESARENOThCLASSICvFOODALLERGIESASTHEYARENOT)G% MEDIATEDASTHESYMPTOMSAREDELAYEDANDREMOVALOF)G% POSITIVEFOODSDONOTLEADTORESOLUTIONOFSYMPTOMSANDNORMALIZATIONOFBIOPSIES 4HEREFORE %O%APPEARSTOBEAMIXED)G%ANDNON )G%MEDIATEDFOODREACTION 4HETESTINGFORALLERGIESINPARTICULARFOODALLERGIESISNOTPERFECT3KINTESTING ANDATOPYPATCHTESTINGCANHAVEBOTHFALSEPOSITIVEANDNEGATIVES"UT INGENERAL IFAFOODISNEGATIVEONBOTHSKINANDATOPYPATCHTESTING ITISUNLIKELYTHATFOODIS CAUSINGDISEASEWITHTHEEXCEPTIONOFMILK7EUSE304AND!04TOGUIDEUSIN DEVELOPINGATREATMENTPLAN&IG19.1 )FHISTORYANDORSKINTESTCONlRMENVIRONMENTALALLERGIES THEYSHOULDBETREATEDAGGRESSIVELYWITHINHALEDNASALSTEROIDS TO MINIMIZETHEPOTENTIALFACILITATIONOF%OSINOPHILSRECRUITMENTINTHEESOPHAGUS DUE TOACONCOMITANTAIRWAYSINmAMMATIONANDCONSEQUENTEOTAXINPRODUCTION !SPERTHEFOODALLERGY ANEXTENSIVE304AND!04PANELSHOULDBEPERFORMED ANDATRIALOFFOOD SPECIlCELIMINATIONDIETSHOULDBETRIED0ATIENTSSHOULDBERE SCOPED AFTERWEEKS7HEN%O%ISINCLINICALREMISSIONIE NOSYMPTOMS FOODSHOULDBE REINTRODUCEDEITHERINDIVIDUALLYORASSELECTGROUPS&OOD SPECIlCELIMINATIONDIETS AREEQUALLYEFFECTIVEINCAUSING%O%REMISSION)FFOOD SPECIlCDIETISNOTEFFECTIVE ALTERNATIVETHERAPIESSUCHAS%LEMENTALDIETORPHARMACOLOGICALTHERAPYSHOULDBE explored (Fig. 19.1).

 !LLERGY4ESTINGIN%OSINOPHILIC%SOPHAGITIS

279

Fig. 19.1 &LOWCHARTOF%O%ALLERGICEVALUATIONANDTREATMENTDECISIONS

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282

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/RENSTEIN 32 3HALABY 4- $I ,ORENZO # ET AL 4HE SPECTRUM OF PEDIATRIC EOSINOPHILIC ESOPHAGITISBEYONDINFANCYACLINICALSERIESOFCHILDREN!M*'ASTROENTEROL*UN  1422–30. #ROESE * &AIRLEY 3+ -ASSON *7 ET AL #LINICAL AND ENDOSCOPIC FEATURES OF EOSINOPHILIC ESOPHAGITISINADULTS'ASTROINTEST%NDOSC/CT n 3TAPEL3/ !SERO2 "ALLMER 7EBER"+ ETAL4ESTINGFOR)G'AGAINSTFOODSISNOTRECOMMENDEDASADIAGNOSTICTOOL%!!#)4ASK&ORCE2EPORT!LLERGY*UL n 3ISTEK$ 4SCHOPP*- 3CHINDLER# ETAL#LINICALDIAGNOSISOFCURRENTASTHMAPREDICTIVEVALUE OF RESPIRATORY SYMPTOMS IN THE 3!0!,$)! STUDY 3WISS 3TUDY ON !IR 0OLLUTION AND ,UNG $ISEASESIN!DULTS%UR2ESPIR*&EB n 4SCHOPP*- 3ISTEK$ 3CHINDLER# ETAL#URRENTALLERGICASTHMAANDRHINITISDIAGNOSTICEFlCIENCYOFTHREECOMMONLYUSEDATOPICMARKERS)G% SKINPRICKTESTS AND0HADIATOP 2ESULTS FROMRANDOMIZEDADULTSFROMTHE3!0!,$)!3TUDY3WISS3TUDYON!IR0OLLUTIONAND ,UNG$ISEASESIN!DULTS!LLERGY*UN n

Chapter 20

Esophageal Dilation for Eosinophilic Esophagitis Matthew Bohm and Joel E. Richter

Keywords %SOPHAGEALDILATIONs0ROTONPUMPINHIBITORSs%SOPHAGEALREMODELING s%LEMENTALDIETS

Introduction %OSINOPHILICESOPHAGITIS%O% ISACHRONICINmAMMATORYDISORDEROFTHEESOPHAGUS CHARACTERIZEDBYTHEPROTONPUMPINHIBITOR REFRACTORYACCUMULATIONOFEOSINOPHILS INTHEESOPHAGEALEPITHELIUMINTRAEPITHELIALEOSINOPHILS(0& INCOMBINATION WITHARANGEOFSYMPTOMSINCLUDINGDYSPHAGIA FOODIMPACTION CHESTPAIN ABDOMINAL PAIN AND VOMITING ;1–3= 4HE CLINICAL MANIFESTATIONS OF %O% VARY WITH AGE #HILDRENUNDERTHEAGEOFYEARSCOMMONLYPRESENTWITHFEEDINGDISORDERSCHILDRENUNDERTHEAGEOFPRESENTWITHVOMITING ABDOMINALPAIN ORVAGUEGASTROESOPHAGEALREmUXDISEASE'%2$ SYMPTOMSANDPATIENTSOVERTHEAGEOFHAVE SIMILARPRESENTATIONTOADULTS;1=.EARLYALLADULTSCOMPLAINOFSOLIDFOODDYSPHAGIA WITHMANYBEINGhSLOWEATERSvWHOMETICULOUSLYCHEWTHEIRFOOD-ORETHAN GIVEAHISTORYOFFOODIMPACTION 4HEENDOSCOPICFEATURESOF%O%SUGGESTACHRONICDISEASEPROGRESSINGFROMTHE INmAMMATORYFEATURESOFFURROWS MICROABSCESSES ANDPLAQUESSEENPREDOMINANTLY INPEDIATRICPATIENTSTOESOPHAGEALREMODELINGCHARACTERIZEDBYTHENARROWCALIBER ESOPHAGUS STRICTURES ANDRINGFORMATIONMORECOMMONLYSEENINADULT%O%PATIENTS 4HEMOSTEFlCACIOUSTREATMENTFORTHESEEARLYINmAMMATORYCHANGESANDTHEIRASSOCIATED

J.E. Richter (*) $EPARTMENTOF-EDICINE 3ECTIONOF'ASTROENTEROLOGY 4EMPLE5NIVERSITY3CHOOLOF-EDICINE ."ROAD3TREET 0ARKINSON0AVILION 0HILADELPHIA 0! 53! E MAILJRICHTER TEMPLEEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_20, © Springer Science+Business Media, LLC 2012

283

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-"OHMAND*%2ICHTER

SYMPTOMS ARE ANTI INmAMMATORY MEDICATIONS SWALLOWED mUTICASONE BUDESONIDE PREDNISONE ORRESTRICTIVEANDELEMENTALDIETS;4–18]. On the other hand, adult EoE PATIENTSESOPHAGEALCHANGESTYPICALLYSHOWALESSERDEGREEOFACTIVEINmAMMATION ANDMORElBROTICCHANGESDUETOCOLLAGENDEPOSITIONINTHEEPITHELIUMANDLAMINA PROPRIA)NTREATINGADULT%O%PATIENTS ESOPHAGEALDILATIONISOFTENNECESSARYTOCORRECTTHISlXEDSTENOSISCAUSEDBYESOPHAGEALREMODELING$ILATIONRELIEVESTHEMAJOR SYMPTOMOFSOLIDFOODDYSPHAGIAANDALLEVIATESTHEFEAROFFOODIMPACTIONWHICH IMPROVESQUALITYOFLIFE0OTENTIALSIDEEFFECTSOFTOOAGGRESSIVEDILATIONAREOFCONCERN BUTTHELONG TERMRELIEFSEEMSTOOUTWEIGHTHESECOMPLICATIONS This chapter will review the underlying pathophysiology producing strictures ANDREMODELING REVIEWINDETAILTHEAVAILABLECASESERIES DISCUSSTHEROLEANDTECHNIQUEOFESOPHAGEALDILATIONINTHEMANAGEMENTOFADULT%O%PATIENTSANDITSPOTENTIALCOMPLICATIONS

Pathophysiology 4HESTRUCTURALCHANGESOFTHEESOPHAGUSARISEFROMACASCADEOFEVENTSTHATBEGINS WITHANINmUXOFINmAMMATORYCELLS MOSTIMPORTANTLYEOSINOPHILSINTOTHEMUCOSA OFTHEESOPHAGUS WHERENORMALLYTHEYARERARELYOBSERVED4HESECHANGESAREDISCUSSED IN MORE DETAIL EARLIER IN THIS BOOK )N ADDITION TO THE LOCAL INmAMMATORY PROCESSCAUSEDBYEOSINOPHILSANDMAJORBASICPROTEIN-"0 SOMEBELIEVE'%2$ CAUSESACID PEPTICDAMAGETOTHEEPITHELIALTIGHTJUNCTIONSINCREASINGPERMEABILITY ANDLEADINGTOTHERECRUITMENTANDEXPOSURETOINmAMMATORYCELLS INCLUDINGEOSINOPHILS;19–24=4OBEYAND"ARLOWETALlRSTDESCRIBEDIN'%2$PATIENTSTHEDAMAGE ACIDANDPEPSINDOTOTHETIGHTJUNCTIONSBETWEENEPITHELIALCELLS;23, 24]. The increased PERMEABILITYALSOALLOWSDEEPERPENETRATIONOFGASTRICACIDCAUSINGFURTHERINJURY AND TISSUE DAMAGE LEADING TO STRUCTURAL CHANGES lBROSIS WHICH MAY AFFECT THE lower esophageal sphincter (LES) and peristalsis. 4HE CHRONIC EXPOSURE TO INmAMMATORY CELLS FROM EITHER ALLERGIC MEDIATORS OR ACIDREmUXLEADSTOLAMINAPROPRIAANDSUBEPITHELIALlBROSISONMICROSCOPICEXAMINATIONANDANARROWEDLUMEN STRICTURES ANDRINGSONENDOSCOPY-ISHRAETALlRST REPORTED AN IMPRESSIVE ACCUMULATION OF COLLAGEN IN THE EPITHELIAL MUCOSA BASAL LAYER AND LAMINA PROPRIA IN THE ESOPHAGUS OF %O% PATIENTS AS WELL AS MICE WITH EXPERIMENTAL%O%COMPAREDTOCONTROLS;19–21=4HEINDUCTIONOFCOLLAGENDEPOSITIONWASDEPENDENTON), ANDEOTAXINASMICETHATWEREDEVOIDOFTHESECYTOKINES DIDNOTDISPLAYCOLLAGENDEPOSITIONINTHEIRESOPHAGUS,ATER !CEVESETALEXAMINEDESOPHAGEALBIOPSIESFORREMODELINGINSEVENCHILDRENWITH%O%AVERAGEAGE YEARS ALLMALE SEVENCHILDRENWITH'%2$AVERAGEAGEYEARS MALE ANDSEVENCHILDRENTHATWERENORMALCONTROLSAVERAGEAGEYEARS MALE ;25=4HEYFOUNDINCREASEDLEVELSOFSUBEPITHELIALlBROSISANDINCREASEDEXPRESSION OF4'& BANDITSSIGNALINGMOLECULEPHOSPHO 3-!$COMPAREDWITHPATIENTS WITH'%2$ANDNORMALCONTROLPATIENTS!LLSEVENPATIENTSWITH%O%DEMONSTRATED SUBEPITHELIALlBROSISFOURSEVERE THREEMODERATE ONHEMATOXYLIN EOSINSTAINING

 %SOPHAGEAL$ILATIONFOR%OSINOPHILIC%SOPHAGITIS

285

Fig. 20.1 4HEPATHOGENESISOF%O%SARISESFROMEITHER'%2$ DIETARY ORAIRBORNEALLERGENSORA COMBINATIONOFTHETWO4HISlGUREILLUSTRATESTHEPROGRESSIVEEVOLUTIONOF%O%FROMAPREDOMINANTLYINmAMMATORYPROCESSEARLYONINPEDIATRICPATIENTSLEADINGTORINGS ESOPHAGEALNARROWING ANDSTRICTUREFORMATIONSEENLATERINTHEDISEASEINTHEADULTPOPULATION

ANDORTRICHROMESTAINING)NTERESTINGLY THETWOYOUNGESTPATIENTSWITH%O%AGES lVEANDSIX HADNOSTRICTURESASOPPOSEDTOTHEOLDER%O%CHILDRENWHOMALLHAD STRICTURES RANGE n BUT NONE HAD ESOPHAGEAL RINGS (OWEVER EVEN THE TWO PATIENTSWITH%O%WITHOUTSTRICTURESHADINCREASEDlBROSISCOMPAREDWITHPATIENTS WITH'%2$ANDNORMALPATIENTS SUGGESTINGTHATTHEREMODELINGPROCESSISOCCURRINGEVENINTHEABSENCEOFSTRICTUREFORMATION 5LTIMATELY THESUBEPITHELIALlBROSISLEADSTOESOPHAGEALSTRICTURES RINGS ANDA NARROWCALIBERLUMENWHICHSERVESASAMARKERFORDISEASECHRONICITY4HEONGOING INmAMMATORY RESPONSE AND MORE IMPORTANTLY THE lBROTIC CHANGES PRODUCE THE CHRONICSYMPTOMSOFSOLIDFOODDYSPHAGIAANDFOODIMPACTIONCHARACTERIZINGTHE ADULTPRESENTATIONOF%O%4HUS FROMCHILDHOODTOADULTHOOD THERESEEMSTOBEA PROGRESSIVEPROCESSCAUSEDBYTHEEOSINOPHILINlLTRATIONTHATBEGINSWITHINmAMMATIONANDULTIMATELYLEADSTOlBROSIS&IG20.1).

Current Case Series 4HEREARENUMEROUSPEDIATRIC%O%PROSPECTIVECASEREPORTS COMPARISONTREATMENT STUDIES ANDEVENAPLACEBO CONTROLLEDTRIAL BUTTHESESTUDIESRARELYINVOLVEESOPHAGEAL DILATION -OST MEDICAL TREATMENTS ARE ANTI INmAMMATORY DRUGS TARGETING THE REDUCTION OF MUCOSAL EOSINOPHILIA BUT SUSTAINED CLINICAL REMISSION IS INFREQUENT AFTERTHERAPYISSTOPPED%VENTHEADVOCATESOFSTEROIDTHERAPYFOR%O%HAVEFOUND THAT MUCOSAL EOSINOPHILIA AND DYSPHAGIA SYMPTOMS RETURN TO BASELINE IN AT LEAST

286

-"OHMAND*%2ICHTER

 OF CASES OVER THE SUBSEQUENT n MONTHS AFTER STOPPING ANTI INmAMMATORY DRUGS;10–18=)NADULTS TREATMENTSTUDIESARESCARCEANDNEARLYALLARECASESERIES (OWEVER LONG TERMCLINICALRESOLUTIONOFDYSPHAGIASYMPTOMSHASBEENREPORTED WITHESOPHAGEALDILATIONAND00)THERAPY4ABLE20.1 ;26–36]. 4HE lRST CASE SERIES TREATING %O% PATIENTS WITH ESOPHAGEAL DILATION APPEARED BEFORETHEDISEASEWASWELLKNOWNINADULTS-ORROWETALCONDUCTEDARETROSPECTIVE STUDYOFPATIENTSMALESMEDIANYEARS DIAGNOSEDWITHWHATTHEYCALLED hRINGEDESOPHAGUSvTREATINGTHEMWITHSERIALESOPHAGEALDILATIONS;26=/FTHESEPATIENTS  REPORTEDHEARTBURN  PATIENTSHADAPRIORFOODIMPACTION  HADREmUXONABARIUMSWALLOWSTUDYAND HADEROSIVEESOPHAGITISATTHE TIMEOFENDOSCOPY;26]. The characteristic endoscopic appearance was a poorly disTENSIBLE ESOPHAGUS WITH MULTIPLE CONCENTRIC RINGS LOCATED IN THE MID ESOPHAGUS CAUSINGSIGNIlCANTSTENOSIS%SOPHAGEALBIOPSIESSHOWEDEXTENSIVEMUCOSALEOSINOPHILIAASSOCIATEDWITHBASALCELLHYPERPLASIAANDPROLONGATIONOFRETEPEGSTHELATTER lNDINGS AT THAT TIME CONSIDERED PATHOGNOMONIC OF EARLY '%2$ -OST PATIENTS REQUIRED SEVERAL SESSIONS OF ESOPHAGEAL DILATION WITH 3AVORY BOUGIE GRADUALLY INCREASINGDILATORSIZETOAGOALDIAMETEROFnMM.OPERFORATIONSOCCURRED BUT DEEPMUCOSALTEARSWERECOMMONWITHSEVERALPATIENTSREQUIRINGTEMPORARYNARCOTIC ANALGESIAAFTERDILATION4ELEPHONEFOLLOW UPWASPERFORMEDONAVERAGEMONTHS ÕMONTHS LATERWITH PATIENTSREPORTINGTHATTHEIRDYSPHAGIAIMPROVED DRAMATICALLY 5SING THE FOLLOWING DYSPHAGIA SCALE NO DYSPHAGIA LESS THAN ONCEAMONTH SEVERALTIMESAMONTH SEVERALTIMESAWEEK EVERYDAY NOT EVERYMEALANDEVERYMEAL THEAVERAGEPATIENTSCOREIMPROVEDFROMTO !FTERTHEINITIALSERIESOFDILATIONSANDTHEADDITIONOF00)THERAPY ONLYONEPATIENT REQUIREDREPEATDILATIONS4HISPATIENTWASSUBSEQUENTLYTREATEDWITHORALPREDNIsone and did well. 4WO YEARS AFTER THE -ORROW STUDY WAS PUBLISHED 3TRAUMANN ET AL REPORTED THEIR PROSPECTIVE CASE SERIES OF  ADULT %O% PATIENTS AVERAGE AGE  YEARS  MALES WITHINTERMITTENTSOLIDFOODDYSPHAGIAFOLLOWEDFORANAVERAGEYEARS;27]. 4HE DECISION TO DILATE WAS BASED ON THE FREQUENCY AND SEVERITY OF DYSPHAGIA SYMPTOMSWITHTHEACTUALDILATIONTECHNIQUENOTREPORTED3UCCESSWASEVALUATED WITHTWODIFFERENTSCALESAFREQUENCYSCALEWHERENOATTACKSDURINGTHELAST YEAR ORATTACKSYEAR ATTACKMONTHS ATTACKMONTH ATTACK WEEK AND AT LEAST  ATTACKDAY AND AN INTENSITY SCALE WHERE SWALLOWING UNHINDEREDANDWITHOUTPAIN SLIGHTRETCHINGDISAPPEARINGSPONTANEOUSLYSPONTANEOUSANTEROGRADEREMOVAL SHORTPERIODSOFOBSTRUCTIONNECESSITATINGINTERVENTION SUCH AS DRINKING DEEP BREATHING OR RETCHING INDUCED ANTEROGRADE REMOVAL LONGER LASTINGOBSTRUCTIONONLYREMOVABLEBYVOMITINGFORCEDRETROGRADE REMOVAL AND CONTINUOUS COMPLETE OBSTRUCTION NOT REMOVABLE BY THE PATIENTREQUIRINGENDOSCOPICINTERVENTION 0ATIENTSSUSTAININGATLEASTONEATTACK OFDYSPHAGIAPERWEEKFREQUENCYSCORESAND ANDTHOSEWITHSEVEREATTACKS INTENSITYSCORESAND WERETREATEDWITHESOPHAGEALDILATION/VERALL  PATIENTSREQUIREDESOPHAGEALDILATION3EVENHADASINGLEDILATIONANDFOURREQUIRED REPEATDILATIONS3IXPATIENTSREPORTEDBEINGFREEOFDYSPHAGIAPOST PROCEDUREAND FOURREPORTEDAREDUCTIONINTHEIRSYMPTOMS$YSPHAGIAIMPROVEMENTLASTED

Dilation

Dilation

$ILATIONAND00)

Dilation

Dilation Dilation

Dilation

Dilation

$ILATIONAND00)

3TRAUMANNETAL;27]

#ROESEETAL;28]

0OTTERETAL;35]

#ANTUETAL;29]

:IMMERMANETAL;30] 0ASHAETAL;34]

3CHOEPFERETAL;33]

3CHOEPFERETAL;32]

"OHMAND2ICHTER;36] Case study

Retrospective study

Case study

Retrospective study Case study

Case study

Case study

Case study

Case study

10 Adults

63 Adults

10 Adults

8 Adults 13 Adults

2 Adults

13 Adults

17 Adults

11 Adults

3 Adults, 2 adolescents

Dilation

6ASILOPOULOSETAL;31] Case study

.OOFPATIENTS 19 Adults

Table 20.1 3UMMARYOFESOPHAGEALDILATIONREPORTS 2EFERENCE &ORMOFTREATMENT 4YPEOFSTUDY -ORROWETAL;26] $ILATIONAND00) Case study

#LINICALLYIMPROVED ATYEARAVERAGE&5

#LINICALLYIMPROVED

#LINICALLYIMPROVED !DULTSIMPROVED clinically )MPROVEDCLINICALLY

)MPROVEDCLINICALLY

#LINICALLYIMPROVED

#LINICALLYIMPROVED ATYEAR&5 )MPROVEDCLINICALLY

#LINICALLYIMPROVED

/UTCOME )MPROVEDCLINICALLY

#OMPLICATIONS 3EVERALMUCOSALTEARS NOPERFORATIONS -UCOSALTEARNO PERFORATIONS 3EVERALMUCOSALTEARS NOPERFORATIONS MUCOSALTEARS NOPERFORATIONS -UCOSALTEAR NOPERFORATIONS -UCOSALTEAR NOPERFORATIONS Not reported -UCOSALTEARS NOPERFORATIONS /DYNOPHAGIA NOPERFORATIONS #HESTPAIN NOPERFORATIONS -UCOSALTEAR NOPERFORATIONS

 %SOPHAGEAL$ILATIONFOR%OSINOPHILIC%SOPHAGITIS 287

288

-"OHMAND*%2ICHTER

Fig. 20.2 4HISGRAPHCOMPARESTHEINTENSITYOFDYSPHAGIAANDMAXIMUMEOSINOPHILS(0&BETWEEN THETIMEOFDIAGNOSISANDFOLLOW UPOF%O%PATIENTS&ORALLPATIENTS BASELINELEVELSOFDYSPHAGIA AND EOSINOPHILIC INlLTRATION WERE  AT TIME ZERO 4HE TRENDS AT FOLLOW UP SHOWED A MARKED DECREASE IN EOSINOPHILIC INlLTRATION AND ONLY A SLIGHT DECREASE IN DYSPHAGIA 4HUS THE IMPROVEMENTINEOSINOPHILICINlLTRATIONDIDNOTCORRELATEWITHANIMPROVEMENTINDYSPHAGIA&ROM 3TRAUMANN! 3PICHTIN(0 ETAL'ASTROENTEROLOGYn WITHPERMISSION

FROM  TO  MONTHS AVERAGE  MONTHS  )T WAS NOT REPORTED IF PATIENTS WERE USINGOTHERTHERAPIES SUCHAS00)S3EVEREMUCOSALTEARINGOCCURREDFREQUENTLY BUT NO PERFORATIONS WERE NOTED 4HE AVERAGE EOSINOPHILIC INlLTRATION OVER THE OBSERVATIONPERIODDECREASEDSIGNIlCANTLYINTHEPROXIMALTOHPF ANDDISTAL ESOPHAGUSTOHPF &IG20.2 )NADDITION THEBASALZONEHYPERPLASIAAND THEPAPILLARYSIZEDECREASEDOVERTIME)NTERESTINGLY HISTOLOGICALEXAMINATIONOF THE SUBEPITHELIAL COMPARTMENTS SHOWED AN IMPRESSIVE INCREASE IN lBROUS TISSUE WITHTHICKENINGANDALTERATIONOFTHEARCHITECTUREOFTHESELAYERSINPATIENTS 4HE PATIENTS WITH MORE DENSE EOSINOPHILIC INlLTRATION  EOSHPF AND MORE PRONOUNCEDESOPHAGEALNARROWINGATBASELINEENDOSCOPYSHOWEDATRENDOFMORE ATTACKSANDNEEDFORDILATION.ODYSPLASIAORCANCERWASDETECTEDDURINGTHECAREFULFOLLOW UPOFTHESEPATIENTS 0ASHAETALCONDUCTEDARETROSPECTIVEREVIEWOFADULT%O%PATIENTSMEN MEANAGEYEARS ;34=4HEPREDOMINANTSYMPTOMWASSOLIDFOODDYSPHAGIAAND PATIENTSHADAHISTORYOFFOODIMPACTION%IGHTEENPATIENTSUNDERWENTESOPHAGEALDILATIONMEANTWODILATIONS RANGEn RANGINGFROMTOMM%LEVENOF THE PATIENTSAVAILABLEFORFOLLOW UPHADIMPROVEMENTOFTHEIRSYMPTOMS /FTHESE HADBALLOONANDONEHADBOUGIEDILATION&IVEPATIENTSWEREDILATEDTO ADIAMETEROFMM FOURDILATEDTOMM ANDTHREEDILATEDTOMM4HEREMAINING PATIENT WAS DILATED WITH A &R -ALONEY BOUGIE /NE THIRD OF THE PATIENTS HAD SUPERlCIALMUCOSALTEARS BUTNOPERFORATIONSOCCURRED

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#ROESE ET AL PERFORMED A RETROSPECTIVE REVIEW OF  PATIENTS WITH %O% ALL #AUCASIANMENMEANAGEYEARS ;28]. Esophageal dilations were done in 17 ADULTPATIENTSMEANDILATIONS RANGEn 4HISPROVIDEDRELIEFOF PATIENTSCHESTPAIN DYSPHAGIA ANDDYSPEPSIASYMPTOMS-UCOSALTEARSOCCURREDIN  PATIENTSBUTNOPERFORATIONSOCCURRED 0OTTERETALPERFORMEDESOPHAGEALDILATIONINADULT%O%PATIENTS"OUGIENAGE WASPERFORMEDBYPASSAGEOFPOLYVINYLlLIFORMDILATORSUNDERmUOROSCOPICMONITORINGINATHROUGH THE SCOPEBALLOONDILATORWASUSEDINONEPATIENT;35]. The DILATIONSRANGEDFROM&RTO&RWITHAMEANOF&RDEPENDINGONRESISTANCE ANDMOREIMPORTANTLYMUCOSALDISRUPTION,ONGITUDINALMUCOSALTEARSOCCURREDIN PATIENTS-ODERATECHESTPAINWASEXPERIENCEDBYMOSTPATIENTS4HEREWERE NOESOPHAGEALPERFORATIONSDESPITEEXTENSIVEESOPHAGEALTRAUMA)MPROVEMENTWAS SEENINPATIENTSATTHE MONTHFOLLOW UP 3CHOEPFER ET AL REPORTED A RETROSPECTIVE SERIES OF TEN ADULT %O% PATIENTS WITH SYMPTOMATICESOPHAGEALSTENOSISUNRESPONSIVETOTOPICALCORTICOSTEROIDS;33]. Nine OFTHEPATIENTSRECEIVEDSWALLOWEDmUTICASONEnMGDAY ANDONEPATIENTRECEIVED SWALLOWED BUDESONIDE  MGDAY FOR AT LEAST  WEEKS 4WO PATIENTS WERE CONCOMITANTLYRECEIVINGORALSTEROIDS%IGHTPATIENTSHADASINGLEESOPHAGEALSTRICTURE ONEPATIENTHADTWOSTRICTURES ANDANOTHERHADTHREESTRICTURES4HEMEANSTRICTURE LENGTHMEASUREDBYENDOSCOPYWASCMRANGEnCM !LLPATIENTSWEREDILATED USING3AVORYBOUGIESINMILLIMETERINCREMENTSAVERAGENUMBERDILATIONSRANGE nSESSIONS 4HEMEANDIAMETERAFTERDILATIONWASMMRANGEnMM  4HEPROGRESSIONOFBOUGIEDIAMETERPERSESSIONWASLIMITEDTOMMORLESSTOPREVENTCOMPLICATIONS"OUGIENAGELEDTOPROMPTSYMPTOMRELIEF4HEAVERAGEDECREASE INDYSPHAGIASCOREWASnNODYSPHAGIA ABLETOEATSOLIDFOOD SEMISOLIDSONLY LIQUIDSONLY COMPLETEDYSPHAGIA %VERYPATIENTHADADECREASEIN THEIRDYSPHAGIASCOREBYATLEASTONEPOINT!LLPATIENTSHADVISIBLEMUCOSALTEARSAFTER UPPER ENDOSCOPY DILATION BUT NO PERFORATIONS OCCURRED 4RANSIENT POST PROCEDURAL ODYNOPHAGIA OCCURRED IN SEVEN PATIENTS WHICH RESOLVED IN ALL PATIENTS BY  DAYS $URINGTHEFOLLOW UPPERIODMEANMONTHSRANGEnMONTHS ALLPATIENTSWERE ASYMPTOMATICWITHTHEAVERAGEDYSPHAGIASCOREREMAININGAT )NTHELARGESTSTUDYTODATE 3CHOEPFERETALUTILIZINGACOMBINEDDATABASEFROM 3WITZERLANDAND.ORTHWESTERN(OSPITALIN#HICAGO RECENTLYREPORTEDARETROSPECTIVE REVIEW OF  ADULT %O% PATIENTS DIVIDED INTO TWO COHORTS THAT UNDERWENT ESOPHAGEAL DILATION ;32= #OHORT  COMPRISED  ADULT %O% PATIENTS  MALE AVERAGE AGE  YEARS TREATED ONLY WITH ESOPHAGEAL DILATION !LL PATIENTS COMPLAINEDOFSOLIDFOODDYSPHAGIA HADAHISTORYOFPRIORFOODIMPACTION  WERETAKING00)SANDREPORTEDAHISTORYOFALLERGIES!LLPATIENTSHADSTOPPED ANTI INmAMMATORY MEDICATIONS FOR A MINIMUM OF  MONTHS PRIOR TO ESOPHAGEAL DILATION&ORTY FOURPATIENTS WEREDIAGNOSEDWITHFOCALESOPHAGEALSTRICTURES THREEPATIENTSHADASMALLCALIBERESOPHAGUS ANDAMONGTHEREMAINING  PATIENTS  THE LENGTH OF ESOPHAGEAL NARROWING WAS NOT DESCRIBED &ORTY SIXPATIENTSWEREDILATEDWITH3AVARYBOUGIESAND BYTHROUGH THE SCOPE BALLOONS4HEREWASAMEDIANOFTWOESOPHAGEALDILATIONSWITHANIMPROVEMENT OFESOPHAGEALDIAMETERFROMANAVERAGEOFnMMp < 0.001). This corresponded

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WITH AN IMPROVEMENT IN THE DYSPHAGIA SCORE FROM AN AVERAGE SCORE OF n (p  NO DYSPHAGIA ABLE TO EAT SOLID FOOD SEMISOLIDS ONLY LIQUIDSONLY COMPLETEDYSPHAGIA !FTERDILATION OFPATIENTSREPORTED COMPLETERESOLUTIONOFTHEIRDYSPHAGIAANDCOMPLAINEDOFONLYMINORSWALLOWINGDIFlCULTIES$YSPHAGIACOMPLAINTSSLOWLYRETURNEDONAVERAGEMONTHS AFTERDILATION BUTWERESTILLDYSPHAGIA FREEAFTERMONTHSORLONGER.EARLY HALF OF THE PATIENTS EXPERIENCED MODERATE TO SEVERE PAIN FOLLOWING ESOPHAGEAL DILATION BUT THERE WERE NO PERFORATIONS HOSPITALIZATIONS OR SEVERE BLEEDING #HESTDISCOMFORTPERSISTEDFORDAYINOFPATIENTS UPTODAYSINAND DAYSORMOREIN!LLPATIENTS REGARDLESSOFTHEIRLEVELOFDISCOMFORTPOST PROCEDURE WEREWILLINGTOUNDERGOFURTHERESOPHAGEALDILATIONS2EVIEWOFSERIAL ESOPHAGEAL BIOPSIES n ALLOWED THE INVESTIGATOR TO ASSESS THE INmUENCE OF ESOPHAGEALDILATIONONMUCOSALHISTOLOGY!SPREVIOUSLYREPORTED THEREWASNO STRIKINGCHANGEININTRAEPITHELIALEOSINOPHILINlLTRATIONINTHEIRSERIALESOPHAGEAL BIOPSIES'IEMSASTAINSOFESOPHAGEALTISSUESBEFOREANDAFTERDILATIONSDETECTED AN INCREASE IN SUBEPITHELIAL COLLAGEN DEPOSITION IN PATIENTS WITH LONGER DISEASE duration. #OHORTMALESMEANAGEYEARS INCLUDEDADOLESCENTANDADULT%O% PATIENTSTREATEDWITHTHECOMBINATIONOFDILATIONANDANTI EOSINOPHILICMEDICALTHERAPY 4HE ANTI EOSINOPHILIC TREATMENTS INCLUDED TOPICAL STEROIDS  SYSTEMIC STEROIDS  IMMUNOMODULATORS ANDMONTELUKAST %SOPHAGEALDIAMETERWASRETRIEVED INDILATEDPATIENTSWITHHAVINGAPRE DILATIONDIAMETERMMAND MM&OCALSTRICTURESWERESEENIN PATIENTS EXTENSIVESTRICTURESIN  PATIENTS ANDSTRICTUREDETAILSWERENOTRECORDEDIN PATIENTS%IGHTY PERCENTOFTHEPATIENTSWEREDILATEDWITH3AVARYBOUGIESANDWITHTHROUGH THE SCOPEBALLOONS0ATIENTSUNDERWENTANAVERAGEOFTWODILATIONSRANGEn WITHTHE AVERAGE ESOPHAGEAL DIAMETER INCREASING FROM  TO  MM 0OST DILATION THE MEAN DYSPHAGIA SCORE DECREASED FROM  TO  p  .O MAJOR COMPLICATIONS OCCURRED,ONG TERMFOLLOW UPWASNOTREPORTEDINTHISCOHORT4HEREFORE BOTHCOHORTS SEEMEDTOHAVEASIMILARRESPONSETOESOPHAGEALDILATION 7ERECENTLYREPORTEDAPROSPECTIVEFOLLOW UPOFTENADULT%O%PATIENTSTREATED PRIMARILYWITHESOPHAGEALDILATION;36=!LLPATIENTSUNDERWENTAFOLLOW UPPHONE INTERVIEW OFlCEVISIT REPEATENDOSCOPYWITHBIOPSIESANDPHOTOGRAPHS ANDCOMPREHENSIVEALLERGYTESTINGTWOPATIENTSPHONEINTERVIEWSONLY /FTHETENPATIENTS EIGHTMEN TWOWOMENBETWEENTHEAGESOFANDYEARS EIGHTHADESOPHAGEAL DILATIONAVERAGEMMRANGEnMM ATTHEIRBASELINEVISIT.INEPATIENTS WEREINITIALLYTREATEDWITHA00) USUALLYINTHEMORNINGONEPATIENTWASTREATED WITHARESTRICTIVEDIETANDONEPATIENTWASTREATEDWITHPRNSWALLOWEDmUTICASONEAS WELLASA00)!TFOLLOW UP NINEPATIENTSWERESTILLTAKING00)SANDONEPATIENTWAS ONARESTRICTIVEDIETATTEMPTINGTOELIMINATESOY WHEAT ANDNUTSFROMHISDIET!LL TENADULT%O%PATIENTSAVERAGEMONTHSRANGEnMONTHS IMPROVEDWITHOUR PRIMARYTREATMENTREGIMENOFESOPHAGEALDILATION%IGHTPATIENTSREPORTEDCOMPLETE RESOLUTION OF THEIR DYSPHAGIA EXEMPLIlED BY THE DECREASE OF THE GROUPS AVERAGE DYSPHAGIASCORESFROMTO)NADDITION NONEHADARECURRENTFOODIMPACTION !SREPORTEDBYOTHERS THEIMPROVEMENTINDYSPHAGIASYMPTOMSOCCURREDDESPITE

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Fig. 20.3 (a %NDOSCOPICIMAGEOFPATIENTATBASELINEWITHCLASSICRINGSwhite arrow) and longiTUDINALFURROWSyellow arrow $ISTALEOSINOPHILCOUNTSWAS(0&b !TMONTHSFOLLOW UP ONLYON00)ANDAFTERDILATIONTOMM THEENDOSCOPICFEATURESOF%O%HASRESOLVED DESPITE THEEOSINOPHILCOUNTSTILLBEINGABNORMAL(0&PROXIMALLYAND(0&DISTALLY

THE GENERAL ABSENCE OF CHANGES IN THE GROSS APPEARANCE OF THE ESOPHAGUS OR THE EOSINOPHILICINlLTRATIONONBIOPSIESOFTHEPROXIMALANDDISTALESOPHAGUS(OWEVER ONEPATIENTHADNORMALIZATIONOFTHEGROSSAPPEARANCEOFTHEESOPHAGUSONENDOSCOPY&IG20.3). /VERALL OUR REVIEW OF THE LITERATURE lNDS THAT A REMARKABLE   PATIENTSTREATEDBYESOPHAGEALDILATIONHADIMPROVEMENTINTHEIRDYSPHAGIASYMPTOMS

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FORUPTOTOYEARSWITHMINIMALCOMPLICATIONS4HREEOFTHECASESERIESCLEARLY SHOWED THAT CLINICAL RESOLUTION OF DYSPHAGIA SYMPTOMS WAS INDEPENDENT OF THE DEGREEOFSUBEPITHELIALEOSINOPHILINlLTRATION WHICHWASUNCHANGEDAFTERDILATION 4HISSUGGESTSTHATINADULT%O%PATIENTSSYMPTOMRESOLUTIONRATHERTHANEOSINOPHILIC INlLTRATIONMAYBEABETTERENDPOINTOFTREATMENT

Dilation Approach 4HEREARENORECOMMENDATIONSFROMOUR')SOCIETIESABOUTESOPHAGEALDILATIONIN PATIENTSWITH%O%4HEFOLLOWINGCOMMENTSAREBASEDONOURREVIEWOFTHISLITERAture and the senior author’s experience dilating over 50 EoE patients during the last YEARS!LLPATIENTSSHOULDBEFOREWARNEDTHATPAIN SOMETIMESPERSISTINGSEVERAL DAYS MAYBEAPROBLEMAFTERESOPHAGEALDILATION BUTTRUEPERFORATIONWITHTHENEED FORHOSPITALIZATIONISRARE4HEPAINRESPONDSWELLTOREASSURANCEANDMILDANALGESICS WITH INFREQUENT NEED FOR NARCOTICS 3INCE THE ESOPHAGEAL LUMEN CAN BE NARROWEDINMULTIPLESITESANDSOMETIMESDIFFUSELY 3AVARYOR-ALONEYBOUGIESARETHE DILATORSOFCHOICE$ILATIONSAREPERFORMEDAFTERCAREFULENDOSCOPYTOIDENTIFYTHE AREASOFMAXIMUMNARROWINGANDTOGENERALLYSIZETHEESOPHAGEALLUMENDIAMETER !TTHEINITIALENDOSCOPY MULTIPLEBIOPSIESARETAKENFROMTHEPROXIMALANDDISTAL ESOPHAGUSnTHISDOESNOTINCREASETHECHANCEOFCOMPLICATIONS4HEGUIDINGRULES ARETOSTARTWITHASMALLDIAMETERBOUGIE PROGRESSSLOWLYANDDILATETOnMM 4HESE ESOPHAGEAL DIAMETERS WILL ALLOW THE PATIENT TO EAT A MODIlED REGULAR DIET MMn&R ORAFULLREGULARMEALMMn&R ;37]. As the recent literature SUGGESTSANDOUREXPERIENCECONlRMS THEMORESEVERELYNARROWEDESOPHAGUSRESISTANCEWITHPASSAGEOFASTANDARDMMENDOSCOPE WILLREQUIREnDILATIONSESSIONS GENERALLYSEPARATEDBYSEVERALWEEKS/THERPATIENTSCANBEDILATEDTOTHEDESIRED LUMENINASINGLESESSIONIFTHEDEGREEOFRESISTANCEWITHPASSAGEOFTHEBOUGIEIS MINIMAL 3OME AUTHORS LIMIT THE PROGRESSION OF BOUGIE DIAMETER PER SESSION TO MMORLESS;32=3OMEMONITORTHEDILATIONSWITHREPEATINGENDOSCOPYTOLOOKFOR MUCOSALTEARS4HISISNOTOURAPPROACHSINCETHEREISNOEVIDENCETHATTHEDEGREEOF MUCOSALTEARCORRELATESWITHCHESTPAINORNEEDFORHOSPITALIZATION2ATHER OURSUBSEQUENTMANAGEMENTISGUIDEDBYTHEPOST DILATIONCLINICALSCENARIOMONITOREDBY TELEPHONECALLS IFNECESSARY0OST PROCEDURE'ASTROGRAFlNBARIUMESOPHAGRAMSARE RESERVEDFORTHERAREPATIENTWITHSEVEREPAINANDORFEVER

Safety and Potential Complications 4HEFEAROFESOPHAGEALPERFORATIONSEEMSTOBETHEAREAOFGREATESTCONCERN LIMITING THEUSEOFESOPHAGEALDILATIONBYCOMMUNITYGASTROENTEROLOGISTS4HISISINSTRIKING CONTRASTTOTHERELATIVECOMFORTLEVELTHATGASTROENTEROLOGISTSHAVEINDILATINGPEPTIC

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esophageal strictures. In patients with EoE, the esophageal wall has reduced elasticity FROMTHEEXTENSIVEDEPOSITIONOFCOLLAGEN ISFRAGILELIKEhCREPEPAPER vANDPRONETO DEEPMUCOSALTEARS;38]. 4HEMOSTCOMMONCOMPLICATIONOFESOPHAGEALDILATIONANDENDOSCOPYIN%O% ISMUCOSALTEARSASSOCIATEDWITHAFEWDAYSOFCHESTPAINORODYNOPHAGIA;28, 32, 34]. Cohen et al. conducted a retrospective review over a 5-year span at a tertiary CARECENTEROFENDOSCOPICCOMPLICATIONSAMONGADULTPATIENTSWITH%O%;39]. #OMPLICATIONSWEREDElNEDASMUCOSALLACERATIONSORRADIOGRAPHICEVIDENCEOF PERFORATION 4HE MEAN AGE AT PRESENTATION WAS  YEARS AND   OF THE PATIENTS WERE MEN #OMPLICATIONS OCCURRED IN   PATIENTS  MUCOSAL LACERATIONS PERFORATIONSWITHPNEUMOMEDIASTINUM ANDEMESIS INDUCEDRUPTURE3TRICTURESWEREREPORTEDINCOMPLICATEDCASESCOMPAREDWITHOF UNCOMPLICATEDCASES!MONGTHECOMPLICATEDCASESWITHSTRICTURES THROUGH THE SCOPEBALLOONDILATORSWEREUSEDINFOURCASES BOUGIENAGEDILATORINONECASEAND ANENDOSCOPEASADILATORINONECASE5NFORTUNATELY THEREPORTDIDNOTMENTION THETHERAPEUTICINTERVENTIONSIMPLEMENTEDAFTERTHESECOMPLICATIONSORTHEFINAL OUTCOME4HERISKOFCOMPLICATIONWASHIGHERINTHOSEWITHALONGERDURATIONOF SYMPTOMSYEARSCOMPLICATIONGROUPVSYEARSUNCOMPLICATEDGROUP AND MORE PRONOUNCED EOSINOPHILIC INlLTRATION  PATIENTS WITH A COMPLICATION SHOWEDORMOREEOSINOPHILS(0&COMPAREDTOPATIENTSWITHUNCOMPLIcated EoE). $ESPITETHENUMEROUSCASEREPORTSOF%O%PATIENTSTREATEDWITHESOPHAGEALDILATION THEREHAVEBEENONLYREPORTSOFESOPHAGEALPERFORATION&OURPERFORATIONS WERE RELATED TO PASSAGE OF THE ENDOSCOPE AND SIX WERE SPONTANEOUS PERFORATIONS "OERHAAVESSYNDROME ;41–46=#OHENETALREPORTEDTHEREMAININGTHREEPERFORATIONSINHISRETROSPECTIVEREVIEW BUTITISUNCLEARWHATINTERVENTIONORCLINICALSCENARIOPRECIPITATEDTHEM;39]. 3TRAUMANNETALREPORTEDARETROSPECTIVEREVIEWOFADOLESCENTSANDADULTS WITH %O% IN WHICH THREE PATIENTS EXPERIENCED AN ESOPHAGEAL PERFORATION ;40]. 4WOOFTHECASESWEREPROCEDURERELATEDINVOLVING%.4PHYSICIANSUSINGRIGID ESOPHAGOSCOPYTOREMOVEANIMPACTEDFOODBOLUS4HETHIRDCASEWASELICITEDBY RETCHING RESULTING IN A "OERHAAVES SYNDROME %ISENBACH REPORTED A CASE OF ESOPHAGEAL PERFORATION IN A  YEAR OLD GIRL WITH %O% AFTER DILATION 3HE WAS DILATED TO  MM AND POST DILATION ENDOSCOPY REVEALED MINOR BLEEDING AND MUCOSALLACERATIONS!#4SCANPOST PROCEDURESHOWEDAIRINTHEPARA ESOPHAGEAL SPACE &OUR WEEKS AFTER THE PROCEDURE THE AIR RESOLVED AND THE PATIENT REMAINEDCLINICALLYSTABLEWITHNOTHERAPEUTICINTERVENTION!DDITIONALLY +APLAN ETALPERFORMEDARETROSPECTIVEREVIEWREPORTINGANESOPHAGEALPERFORATIONINAN ADULT WITH %O% AFTER THE PASSAGE OF AN ENDOSCOPE 3PONTANEOUS PERFORATIONS UNRELATEDTOENDOSCOPYORESOPHAGEALDILATIONHAVEBEENREPORTEDIN%O%PATIENTS WITH SOME PATIENTS BEING TREATED CONSERVATIVELY AND OTHERS REQUIRING SURGERY ;43–46=4HEREHAVEBEENNODEATHSREPORTEDINTHELITERATUREFROMESOPHAGEAL PERFORATIONSSUFFEREDIN%O%PATIENTS

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Conclusion %SOPHAGEALDILATIONISASAFEANDEFlCACIOUSTREATMENTOFADULT%O%PATIENTSWITH SOLIDFOODDYSPHAGIAGIVINGMORELONG TERMRELIEFTHANOTHERAVAILABLETREATMENTS $ILATIONISESSENTIALTOSTRETCHTHElBROSISRESULTINGFROMESOPHAGEALREMODELING 7EBELIEVETHETREATMENTOF%O%INADULTSSHOULDBERE EVALUATEDANDESOPHAGEAL DILATION CONSIDERED lRST LINE THERAPY IN PATIENTS WITH SOLID FOOD DYSPHAGIA AND ESOPHAGEALSTENOSIS!NALGORITHMFOR%O%PATIENTSISOUTLINEDIN&IG20.4 with two TREATMENTPATHWAYSDEPENDINGONTHEAPPEARANCEOFTHEESOPHAGUSATENDOSCOPY 0ATIENTSWITHACTIVEINmAMMATIONANDDENSEEOSINOPHILICINlLTRATIONEVIDENTENDOSCOPICALLYBYFURROWS PLAQUES ANDMICROABCESSESAREMORELIKELYTOBENElTFROM ANTI INmAMMATORY TOPICAL OR SYSTEMIC OR DISEASE MODIFYING IMMUNOMODULATOR MEDICATIONS/NTHEOTHERHAND PATIENTSWITHESOPHAGEALREMODELINGANDlBROTIC CHANGESVISUALIZEDONENDOSCOPYBYSTRICTURES RINGS ORANARROWEDLUMENACHIEVE THE GREATEST CLINICAL IMPROVEMENT WITH ESOPHAGEAL DILATION BECAUSE IT DIRECTLY STRETCHESANDEXPANDSTHEESOPHAGEALLUMEN0AINMAYBEANEXPECTEDSIDEEFFECT BUTTHISSIDEEFFECTSEEMSTOBEOUTWEIGHEDINPATIENTSATISFACTIONBYTHEPROLONGED SYMPTOMIMPROVEMENTWITHESOPHAGEALDILATION

Fig. 20.4 0ROPOSEDALGORITHMFORTHETREATMENTOFPATIENTSWITH%O%BASEDONINITIALENDOSCOPIC APPEARANCE4HOSEWITHPREDOMINANTLYANINmAMMATORYPROCESSATENDOSCOPYCHARACTERIZEDBYTHE PRESENCEOFFURROWS PLAQUES EXUDATES ANDMICROABSCESSESSHOULDBETREATEDWITHANTI INmAMMATORY MEDICATIONSORIMMUNOMODULATORS/NTHEOTHERHAND PATIENTSWITHPREDOMINANTLYRINGS STRICTURES ORANARROWEDLUMENSHOULDBETREATEDlRST LINEWITHESOPHAGEALDILATIONANDA00)

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References &URUTA'4 ,IACOURAS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGYn 0ARlTT*2 'REGOR*# 3USKIN.' ETAL%OSINOPHILICESOPHAGITISINADULTSDISTINGUISHINGFEATURESFROMGASTROESOPHAGEALREmUXDISEASEASTUDYOFPATIENTS-OD0ATHOLn 2OTHENBERG-%%OSINOPHILICGASTROINTESTINALDISORDERS*!LLERGY#LIN)MMUNOL 11–28. 3PERGEL*- !NDREW4 "ROWN 7HITEORN4& ETAL4REATMENTOFEOSINOPHILICESOPHAGITISWITH SPECIlC FOOD ELIMINATION DIET DIRECTED BY A COMBINATION OF SKIN PRICK AND PATCH TESTS !NN !LLERGY!STHMA)MMUNOLn +AGALWALLA!& 3ENTONGO4! 2ITZ3 ETAL%FFECTSOFSIX FOODELIMINATIONDIETONCLINICALAND HISTOLOGICALOUTCOMESINEOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOLn +ELLY + ,AZENBY ! 2OWE 0 ET AL %OSINOPHILIC ESOPHAGITIS ATTRIBUTED TO GASTROENTEROLOGY REmUXIMPROVEMENTWITHAMINOACIDBASEDFORMULA'ASTROENTEROLOGYn -ARKOWITZ*% 3PERGEL*- 2UCHELLI% ETAL%LEMENTALDIETISANEFFECTIVEWAYTREATMENTFOR EOSINOPHILICESOPHAGITISINCHILDRENANDADOLESCENTS!M*'ASTROENTEROLn ,IACOURAS#! 3PERGEL*- 2UCHELLI% ETAL%OSINOPHILICESOPHAGITISA YEAREXPERIENCEIN CHILDREN#LIN'ASTROENTEROL(EPATOLn 'UPTA3 &ITZGERALD* $AVIS-4REATMENTOFALLERGICEOSINOPHILICESOPHAGITISWITHORALPREDNISONEANDSWALLOWEDmUTICASONEARANDOMIZEDPROSPECTIVESTUDYINCHILDREN'ASTROENTEROLOGY !  &AUBION 7 0ERRAULT * "URGART , ET AL 4REATMENT OF EOSINOPHILIC ESOPHAGITIS WITH INHALED CORTICOSTEROIDS*0EDIATR'ASTROENTEROL.UTRn ,ANGDON$%#ORRUGATEDRINGEDESOPHAGUS!M*'ASTROENTEROL 4EITELBAUM*% &OX6, 4WAROJ&* ETAL%OSINOPHILICESOPHAGITISINCHILDRENIMMUNOPATHOLOGICALANALYSISANDRESPONSETOmUTICASONEPROPIONATE'ASTROENTEROLOGYn .OEL2* 0UTNUM0% #OLLINS-( ETAL#LINICALANDIMMUNOPATHOLOGICEFFECTSOFSWALLOWED mUTICASONEFOREOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOLn 2EMEDIOS- #AMPBELL# *ONES$- ETAL%OSINOPHILICESOPHAGITISINADULTSCLINICAL ENDOSCOPIC HISTOLOGIClNDINGS ANDRESPONSETOTREATMENTWITHmUTICASONEPROPIONATE'ASTROINTEST %NDOSCn !RORA!3 9AMAZAKI+%OSINOPHILICESOPHAGITISASTHMAOFTHEESOPHAGUS#LIN'ASTROENTEROL (EPATOLn !CEVES33 "ASTIAN* .EWBURY2/ $OlL2/RALVISCOUSBUDESONIDEAPOTENTIALNEWTHERAPY FOREOSINOPHILICESOPHAGITISINCHILDREN!M*'ASTROENTEROLn 3CHAEFER%4 &ITZGERALD* -OLLESTON*0 ETAL#OMPARISONOFORALPREDNISONEANDTOPICALmUTICASONE IN THE TREATMENT OF EOSINOPHILIC ESOPHAGITIS A RANDOMIZED TRIAL IN CHILDREN #LIN 'ASTROENTEROL(EPATOLn +ONIKOFF-2 .OEL2* "LANCHARD# ETAL!RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED TRIAL OF mUTICASONE PROPIONATE FOR PEDIATRIC EOSINOPHILIC ESOPHAGITIS 'ASTROENTEROLOGY n -ISHRA! (OGAN30 "RANDT%" 2OTHENBERG-%!NETIOLOGICALROLEFORAEROALLERGENSAND EOSINOPHILSINEXPERIMENTALESOPHAGITIS*#LIN)NVEST -ISHRA! (OGAN30 "RANDT%" 2OTHENBERG-%), PROMOTESEOSINOPHILTRAFlCKINGTOTHE ESOPHAGUS*)MMUNOL -ISHRA! 2OTHENBERG-%)NTRATRACHEAL), INDUCESEOSINOPHILICESOPHAGITISBYAN),  EOTAXIN  AND34!4 DEPENDENTMECHANISM'ASTROENTEROLOGY 3PECHLER3* 'ENTA2 3OUZA2&4HOUGHTSONTHECOMPLEXRELATIONSHIPBETWEENGASTROESOPHAGEALREmUXDISEASEANDEOSINOPHILICESOPHAGITIS!M*'ASTROENTEROLn 4OBEY.! #ARSON*, !LKIEK2! ETAL$ILATEDINTERCELLULARSPACESAMORPHOLOGICALFEATURE OFACIDREmUX DAMAGEDHUMANESOPHAGEALEPITHELIUM'ASTROENTEROLOGYn

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Chapter 21

Steroid Therapy of EoE in Children Paola De Angelis and Luigi Dall’Oglio

Keywords #ORTICOSTEROIDSs0REDNISONEs%OSINOPHILICESOPHAGITIS

Introduction 4HECURRENTPRACTICEGUIDELINESFORTHEDIAGNOSISANDMANAGEMENTOF%O%AREBASED ONRETROSPECTIVESTUDIESANDEXPERTOPINION4HEPRIMARYGOALOFTREATMENTISACOMBINATIONOFSYMPTOMREDUCTIONANDRESOLUTIONOFHISTOLOGICINmAMMATIONWHEREVER POSSIBLETHISAIMISBESTACHIEVEDBYPROPERIDENTIlCATIONOFTHEUNDERLYINGCAUSE OFTHESYMPTOMS(OWEVER THEREREMAINQUESTIONSASTOTHEEXACTCAUSEOFTHISDISORDER7HILEAGROWINGBODYOFEVIDENCEHASESTABLISHEDTHATTHISDISEASEREPRESENTS ANIMMUNE MEDIATEDRESPONSEINVOLVINGSEVERALPRO INmAMMATORYMEDIATORSAND CHEMO ATTRACTANTSKNOWNTOREGULATEEOSINOPHILICACCUMULATIONINTHEESOPHAGUS SUCHAS),  ),  AND), ANDEOTAXIN   AND  TODATETHESPECIlCETIOLOGY REMAINSINDEBATE;1]. $EVELOPMENTOFDIAGNOSTICGUIDELINESBASEDONACOMBINATIONOFSYMPTOMSAS WELLASENDOSCOPICANDHISTOPATHOLOGICCRITERIAHASIMPROVEDTHEAWARENESSAMONG CLINICIANS FOR THE DIAGNOSIS OF %O% 4HE CLINICALLY CHALLENGING DISCRIMINATION OF %O%FROMGASTROESOPHAGEALREmUXDISEASE'%2$ HASBECOMEMORE APPARENT ANDHASEVOKEDTHENEEDFORMOREINDIVIDUALIZEDTHERAPYOPTIONS;2=%O%REMAINS AN EMERGING DISORDER WHOSE PATHOGENESIS INVOLVES FOOD ALLERGY AND 4(2 type IMMUNERESPONSETHERELATIONSHIPBETWEEN%O%AND'%2$REMAINSASUBJECT OFINVESTIGATION

0$E!NGELIS*) $IGESTIVE3URGERYAND%NDOSCOPY5NIT 0EDIATRIC(OSPITAL"AMBINO'ESU 0IAZZA3/NOFRIO  2OME )TALY E MAILPAOLADEANGELIS OPBGNET C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_21, © Springer Science+Business Media, LLC 2012

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)NFACT %O%AND'%2$MAYCOEXISTTHEESOPHAGUSOF%O%PATIENTSMAYHAVE ENHANCEDSENSITIVITYTOACID EVENINTHEABSENCEOFPATHOLOGICREmUX;=%O%COULD THEREFOREBECONSIDEREDONEOFTHECAUSESOFREFRACTORY'%2$;].

Dietary Treatment -ANYTHERAPIESAREAVAILABLEFOR%O%THEYADDRESSSYMPTOMSANDHISTOPATHOLOGY /NEOFTHEEFFECTIVETREATMENTAPPROACHESISDIETARYMANAGEMENT WHICHAIMSTO ELIMINATEEXPOSURETOFOODALLERGENS!PPROACHESTODIETARYMANAGEMENTINCLUDE THEUSEOFELEMENTALDIETS ELIMINATIONDIETS ANDTAILOREDELIMINATIONDIETS EACHOF WHICHPOSESPOTENTIALNUTRITIONRISKS;5].

Corticosteroids !S A COMPLETE UNDERSTANDING OF THE MECHANISMS UNDERLYING THE INmAMMATORY PROCESS IS YET TO BE DELINEATED STEROIDS STILL PLAY A SIGNIlCANT ROLE IN ENABLING PATIENTSWITHRECURRENTSYMPTOMSTOLEADAMORENORMALLIFE4HISPHARMACOLOGICAL TREATMENTREPRESENTSTHEOLDESTMEDICALTHERAPYFOR%O% STILLUSEDBOTHASACUTEAND MAINTENANCETHERAPY #ORTICOSTEROIDSACTAGAINSTEOSINOPHILS THROUGHINDUCTIONOFAPOPTOSIS DOWNREGULATIONOFCHEMOTACTICFACTORS ANDINHIBITIONOFPROINmAMMATORYMEDIATORS;]. 3YSTEMICCORTICOSTEROIDSAREAMAINSTAYOFTREATMENTFOREOSINOPHILICGASTROENTERITIS AND AS SUCH WERE AMONG THE lRST USED IN PEDIATRIC %O% LEADING TO WIDESPREAD RECOGNITIONOVERTHEPASTDECADE;6]. 2ISKFACTORSASSOCIATEDWITHLONG TERMUSEOFSYSTEMICSTEROIDSINCLUDEGROWTH ABNORMALITIES BONEABNORMALITIES MOODDISTURBANCE ADRENALAXISSUPPRESSION IN ADDITIONTOOTHERS4HEEFFECTIVEDOSAGEFORRELIEVINGCLINICO PATHOLOGICABNORMALITIES ARE SIMILAR TO THOSE USED IN INmAMMATORY BOWEL DISEASE n MGKGDIE OF PREDNISONE MAXIMUMMGDIE WITHASIMILARSCHEDULEFORDISCONTINUATION;]. 3YMPTOMATIC AND HISTOLOGIC REMISSION OF %O% HAS BEEN DOCUMENTED IN MORE THANOFCHILDRENTREATEDWITHSYSTEMICCORTICOSTEROIDSFORWEEKS ALTHOUGH SYMPTOMS AND ESOPHAGEAL EOSINOPHILIA COME BACK WITHIN  MONTHS OF STOPPING THERAPYINMOSTCASES;7, 8=4HEWELL KNOWNSIDEEFFECTSOFPROTRACTEDTREATMENT WITHSYSTEMICSTEROIDSHAVELIMITEDTHEIRUSEFULNESSFORLONG TERMTHERAPY LEADING TOTRIALSWITHTOPICALSTEROIDSSUCHASmUTICASONEPROPIONATE LESSFREQUENTLYASSOCIATED WITH ADRENAL SUPPRESSION AND SYSTEMIC ABSORPTION )N BOTH ADULTS AND CHILDREN SYMPTOMATIC IMPROVEMENT HAS BEEN DEMONSTRATED USING SWALLOWED mUTICASONE PROPIONATE WITHACONSEQUENTPOSITIVEHISTOLOGICRESPONSE%SOPHAGEALCANDIDIASIS ANDDRYMOUTHARETHEMOSTREPORTEDSIDEEFFECTSDURINGBRIEFTHERAPYRECURRENCEOF DISEASEAFTERTREATMENTDISCONTINUATIONISCOMMON ALTHOUGHTHEFEATURESTHATCONFER HIGHERRISKOFRELAPSEARENOTCLEAR;9].

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3CHAEFER ET AL IN  PERFORMED AN IMPORTANT COMPARISON BETWEEN ORAL AND TOPICALSTEROIDSINTHETREATMENTOFPEDIATRIC%O%INAPROSPECTIVERANDOMIZEDTRIAL PATIENTSWEREENROLLEDTORECEIVEORALPREDNISONECHILDREN ANDSWALLOWED mUTICASONECHILDREN FORWEEKS3YSTEMICADVERSEEFFECTSWEREPRESENTIN OF PATIENTS TREATED WITH PREDNISONE WHILE ESOPHAGEAL CANDIDIASIS WAS THE MOST COMMON ADVERSE EVENT  SEEN IN THOSE RECEIVING mUTICASONE 4HERE WAS A GREATERDEGREEOFHISTOLOGICIMPROVEMENTINPATIENTSTREATEDWITHPREDNISONE BUTNO SIGNIlCANTDIFFERENCEINTIMETOSYMPTOMATICRELAPSEWASFOUND HIGHLIGHTINGTHE NEEDFORMAINTENANCETREATMENTWITHEITHERTREATMENTAPPROACH;10]. 3YSTEMIC CORTICOSTEROIDS IN OUR CLINICAL EXPERIENCE ARE MOST APPROPRIATE IN URGENTSYMPTOMTREATMENTANDINEMERGENTCASES SUCHASSEVEREDYSPHAGIA DEHYDRATION WEIGHTLOSS ESOPHAGEALSTRICTURES ANDSMALLCALIBERESOPHAGUSATHIGHRISK OFPERFORATIONWEDONOTRECOMMENDTHEMFORLONG TERMUSE7HILETOPICALSTEROIDS AREALSOEFFECTIVEININDUCING%O%REMISSION THEIRUSEFORMAINTENANCETREATMENT HASNOTBEENWELLELUCIDATED;=&OLLOW UPDATAREGARDINGUSEOFSWALLOWEDSTEROIDSINCHILDRENARELACKINGA YEARFOLLOWUPOFTOPICALCORTICOSTEROIDSFOR%O% IN ADULTS WAS RECENTLY PUBLISHED BY (ELOU ET AL AND CONlRMED THE NECESSITY OF REPEATEDCYCLESOFTOPICALTREATMENT%O%ISACHRONICRELAPSINGCONDITIONRESEMBLINGBRONCHIALASTHMAITISOFINTERESTTHATTHEESOPHAGUSANDBRONCHIALTREEARE DERIVEDFROMTHESAMEEMBRYOLOGICALFOREGUT4HATTOPICAL AEROSOLIZEDSTEROIDSARE WELL TOLERATED AND APPEAR TO BE EFFECTIVE FOR TREATING BOTH CONDITIONS WITH RAPID ONSETOFRESPONSEANDLIMITEDSIDEEFFECTSMAYBEMORETHANCOINCIDENTAL;11]. 7HETHERTOPICALESOPHAGEALCORTICOSTEROIDSCANREVERSESTRICTURESORDECREASETHE NECESSITYORFREQUENCYOFESOPHAGEALDILATIONSREMAINSTOBEEVALUATED BUTINOUR EXPERIENCEONLYSYSTEMICSTEROIDTHERAPYHASBEENSHOWNSOFARTOBESUCCESSFULIN THIS ROLE )T IS NOT YET CLEAR WHETHER TOPICAL THERAPY HAS A RAPID ENOUGH ONSET TO PRECLUDETHENEEDFORDILATIONINSEVERECASES)NCASESWHERESYSTEMICSTEROIDSFAIL ORWHENCRITICALNARROWINGOFTHEESOPHAGUSISPRESENT DILATIONPLAYSANIMPORTANT ROLE)NANADULTSERIES AFTERFAILUREOFTOPICALCORTICOSTEROIDS 3HOEPFERETALDEMONSTRATED THAT DILATIONS LED TO PROMPT SYMPTOM RELIEF AND DID NOT LEAD TO SEVERE COMPLICATIONS APARTFROMTRANSIENTODYNOPHAGIA.EVERTHELESS ESOPHAGEALPERFORATION REMAINSACONCERNWHENDILATIONISPERFORMEDINPATIENTSWITH%O% ASTHELONG TERM EFlCACY AND SAFETY OF TOPICAL CORTICOSTEROIDS AND OF DILATION OF EOSINOPHILIC ESOPHAGITIS ASSOCIATEDSTRICTURESHAVENOTYETBEENTHOROUGHLYCLARIlED;12].

Conclusion )NSUMMARY MOSTPATIENTSWITH%O%CANBETREATEDSUCCESSFULLYWITHCORTICOSTEROIDS 3EVERALUNRESOLVEDQUESTIONSREMAIN HOWEVERHOWMANYCYCLESOFSTEROIDS ARE APPROPRIATEANDHOWLONGWILLTHEYBETOLERATEDWHATISTHEROLEOFTOPICAL STEROIDSTOGETHERWITHANTI REmUXDRUGS'%2$THERAPY INPATIENTSAFFECTEDBY%O% AND '%2$ hOVERLAPv %O%  HOW DO STEROIDS FIT IN WITH SEASONAL FLARES IN



0$E!NGELISAND,$ALL/GLIO

MILD MODERATE SYMPTOMS IN SEVERE HISTOLOGY WITH FEW CLINICAL FEATURES IN MAINTENANCETHERAPY2EGARDLESS CORTICOSTEROIDSREMAINONEOFTHEMOSTSTUDIED ANDDETAILEDTHERAPEUTICOPTIONSFOR%O% ANDWILLLIKELYCONTINUETOHAVEAROLE DESPITETHEONGOINGDISCOVERYOFOTHERTREATMENTS

References  -ISHRA ! -ECHANISM OF EOSINOPHILIC ESOPHAGITIS )MMUNOL !LLERGY #LIN .ORTH !M nVIII  3TRAUMANN! (RUZ07HATSNEWINTHEDIAGNOSISANDTHERAPYOFEOSINOPHILICESOPHAGITIS #URR/PIN'ASTROENTEROLn  &URUTA'4 ,IACOURAS#! #OLLINS-( 'UPTA3+ *USTINICH# 0UTNAM0% ETAL%OSINOPHILIC ESOPHAGITISINCHILDRENANDADULTSASYSTEMATICREVIEWANDCONSENSUSRECOMMENDATIONSFOR DIAGNOSISANDTREATMENT'ASTROENTEROLOGYn  ,IU ** 3ALTZMAN *2 2EFRACTORY GASTRO OESOPHAGEAL REmUX DISEASE DIAGNOSIS AND MANAGEMENT$RUGSn  3ANTANGELO#- -C#LOUD%.UTRITIONALMANAGEMENTOFCHILDRENWHOHAVEFOODALLERGIESAND EOSINOPHILICESOPHAGITIS)MMUNOL!LLERGY#LIN.ORTH!MnIXnX  9AN "- 3HAFFER %! 0RIMARY EOSINOPHILIC DISORDERS OF THE GASTROINTESTINAL TRACT 'UT n  ,IACOURAS#! 7ENNER7* "ROWN+ 2UCHELLI%0RIMARYEOSINOPHILICESOPHAGITISINCHILDREN SUCCESSFUL TREATMENT WITH ORAL CORTICOSTEROIDS * 0EDIATR 'ASTROENTEROL .UTR n  ,IACOURAS#! 3PERGEL*- 2UCHELLI% 6ERMA2 -ASCARENHAS- 3EMEAO% ETAL%OSINOPHILIC ESOPHAGITISA YEAREXPERIENCEINCHILDREN#LIN'ASTROENTEROL(EPATOLn  !CEVES33 &URUTA'4 3PECHLER3*)NTEGRATEDAPPROACHTOTREATMENTOFCHILDRENANDADULTS WITHEOSINOPHILICESOPHAGITIS'ASTROINTEST%NDOSC#LIN.!MnXI 3CHAEFER %4 &ITZGERALD *& -OLLESTON *0 #ROFlE *- 0FEFFERKORN -$ #ORKINS -2 ET AL #OMPARISON OF ORAL PREDNISONE AND TOPICAL mUTICASONE IN THE TREATMENT OF EOSINOPHILIC ESOPHAGITISARANDOMIZEDTRIALINCHILDREN#LIN'ASTROENTEROL(EPATOLn (ELOU %& 3IMONSON * !RORA !3  YR FOLLOW UP OF TOPICAL CORTICOSTEROID TREATMENT FOR EOSINOPHILICESOPHAGITISINADULTS!M*'ASTROENTEROLn 3CHOEPFER!- 'SCHOSSMANN* 3CHEURER5 3EIBOLD& 3TRAUMANN!%SOPHAGEALSTRICTURESIN ADULT EOSINOPHILIC ESOPHAGITIS DILATION IS AN EFFECTIVE AND SAFE ALTERNATIVE AFTER FAILURE OF TOPICALCORTICOSTEROIDS%NDOSCOPYn

Chapter 22

Medical Treatment for Pediatric Eosinophilic Esophagitis James P. Franciosi

Keywords %OSINOPHILIC ESOPHAGITIS s 4REATMENT s -EDICATION s #HILDREN s'ASTROESOPHAGEALREmUXDISEASE

Introduction 4REATMENTSFOREOSINOPHILICESOPHAGITIS%O% AREDIVIDEDINTOBROADCATEGORIESOF DIETARY RESTRICTIONS AND MEDICATIONS $IETARY ELIMINATION AND ELEMENTAL DIETS AS THERAPIESFOR%O%WILLBEDISCUSSEDSEPARATELY-EDICATIONFOR%O%GENERALLYFALLS INTOACIDSUPPRESSIONTHERAPY STEROIDMEDICATIONS ANDADDITIONALTHERAPIES 4HECURRENT#ONSENSUS'UIDELINESFOR%O%DElNETHISCONDITIONASPRESENT ONLYWITHTHEEXCLUSIONOFOTHERCONDITIONSSUCHASGASTROESOPHAGEALREmUXDISEASE (GERD) [1=%XCLUSIONOF'%2$ISACHIEVEDBYPERSISTENTCLINICOPATHOLOGIClNDINGSCONSISTENTWITH%O%DESPITENEGATIVEP(PROBETESTINGORWEEKSOFPROTON PUMP INHIBITOR 00) THERAPY IN THE DISTAL ESOPHAGUS 7ITH REGARD TO IMPEDANCE TESTING ARETROSPECTIVECASEnCONTROLSTUDYDEMONSTRATEDTHATCHILDRENWITH'%2$ HAD SIGNIlCANTLY HIGHER ACID REmUX EVENTS COMPARED TO CHILDREN WITH %O% AND PEDIATRIC%O%PATIENTSDIDNOTHAVEANINCREASEINACIDORNON ACIDREmUXCOMPARED to healthy children [2=(OWEVER USEOF00)THERAPYTOTREATESOPHAGEALEOSINOPHILIA HAS SHOWN VARYING DEGREES OF SYMPTOMATIC AND HISTOLOGIC SUCCESS IN PEDIATRIC patients [3n6=)NARETROSPECTIVECOHORTSTUDY $RANOVEETALDESCRIBEDTHATOF  PEDIATRICPATIENTSHISTOLOGICALLYRESPONDEDdEOSHPF ANDOF

*0&RANCIOSI*) $IVISIONOF'ASTROENTEROLOGY (EPATOLOGYAND.UTRITION #INCINNATI#HILDRENS(OSPITAL -EDICAL#ENTER "URNET!VENUE -, #INCINNATI /( 53! E MAIL*AMES&RANCIOSI CCHMCORG C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_22, © Springer Science+Business Media, LLC 2012

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HADIMPROVEDORRESOLVEDSYMPTOMSINRESPONSETO00)THERAPYMEANDOSEMG KGDAY RANGEn ;7=)NANOTHERPEDIATRICRETROSPECTIVECOHORTSTUDY 3AYEJ et al. [8=SHOWEDSIMILARRESULTSWITHMONTHSOFHIGHDOSE00)THERAPYMAXIMUM DOSING,ANSOPRAZOLEMG")$/MEPRAZOLEOR%SOMEPRAZOLEnMG")$ WITH  OF   SHOWING A HISTOLOGIC RESPONSE AND   REPORTED A RESOLUTIONOFSYMPTOMS;32=)NASMALLPROSPECTIVEADULT%O%COMPARATIVEEFFECTIVENESS TRIAL BETWEEN ESOMEPRAZOLE AND SWALLOWED &LUTICASONE 0ROPRIONATE ESOMEPRAZOLE AT  MG ONCE PER DAY WAS SUGGESTED TO ACHIEVE SYMPTOMATIC IMPROVEMENT IN   PARTIAL HISTOLOGIC RESOLUTION d EOSHPF IN   ANDCOMPLETEHISTOLOGICRESOLUTIONdEOSHPF IN (OWEVER NONEOFTHESEENDPOINTSACHIEVEDSTATISTICALSIGNIlCANCELIKELYDUETOASMALLSAMple size (a type II error) [9=)TISCLEARTHATBOTHADULTANDPEDIATRICWELL DESIGNED RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED CLINICAL TRIALS ARE NEEDED TO ASSESS THEEFlCACYOFHIGHDOSEACIDSUPPRESSIONTHERAPYTOTREATTHESYMPTOMSANDESOPHageal pathology associated with esophageal eosinophilia [10].

Swallowed Steroid Therapies 4OPICAL ESOPHAGEAL CORTICOSTEROID TREATMENT IS A CURRENT STANDARD OF CARE FOR PHARMACOLOGIC TREATMENT OF %O% 4HE ADVANTAGE OF USING TOPICAL STEROIDS AS MAINTENANCETHERAPYISTHATTHEIRSIDEEFFECTSARESIGNIlCANTLYLESSTHANSYSTEMIC STEROIDS&LUTICASONEPROPIONATECANBESPRAYEDINTOTHEPHARYNXANDSWALLOWED TO TOPICALLY COAT THE ESOPHAGUS AND REDUCE INmAMMATION 0ATIENTS DO NOT EAT DRINK ORRINSETHEIRMOUTHFORMINAFTERUSINGTHISMEDICATION7HENUSING TOPICAL SWALLOWED CORTICOSTEROIDS THE INITIAL DOSE VARIES FROM  TO  Pg, TWICE DAILY DEPENDING ON PATIENTS AGE DEGREE OF CLINICAL SYMPTOMS AND THE PREFERENCEOFTHEPRACTITIONER+ONIKOFFETAL;11=CONDUCTEDARANDOMIZED DOUBLE BLIND PLACEBO CONTROLLEDTRIALOFALOWDOSEOFSWALLOWEDmUTICASONEPg, PUFFS")$ INPEDIATRICPATIENTSWITHACTIVE%O%/FTHESE OFTHEmUTICASONE TREATEDPATIENTSACHIEVEDCOMPLETEHISTOLOGICREMISSIONCOMPAREDTO OFPATIENTSWHORECEIVEDPLACEBO2ESOLUTIONOFCLINICALSYMPTOMSALSOOCCURRED MORE FREQUENTLY WITH mUTICASONE COMPARED TO PLACEBO ! RECENT STUDY DEMONSTRATED SIMILAR CLINICAL AND HISTOLOGIC EFlCACY IN EXCESS OF  FOR BOTH ORAL PREDNISONE  MGKGDOSE ")$ MAX  MG ")$ AND HIGH DOSE SWALLOWED &LUTICASONEPROPRIONATEPUFFS1)$PGPUFFnYEARSOFAGE PGPUFF nYEARSOFAGE FOR%O%;12]. !N EQUALLY EFFECTIVE ALTERNATIVE SWALLOWED STEROID FORMULATION TO &LUTICASONE proprionate is swallowed Budesonide [13n17= "UDESONIDE IS ADMINISTERED IN A SLURRYFORMULATIONTHATISMADEUSING3PLENDA®lVEPACKETSPERPG TOIMPROVE TASTEANDCONSISTENCYFORTOPICALESOPHAGEALADMINISTRATION$OHILETAL;1] recently CONDUCTED A PEDIATRIC RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED TRIAL USING "UDESONIDE$OSINGOFTHE"UDESONIDEWASANDMGDIVIDED")$BASEDONTHE RESPECTIVE HEIGHT CLASSIlCATION OF  OR t FT TALL )N THIS STUDY ALL SUBJECTS WERE

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CONCOMITANTLY TREATED WITH 00) THERAPY FOR  MONTHS AND THERE WAS AN  HISTOLOGICRESPONSERATEINTHE"UDESONIDEGROUPCOMPAREDTONONEOFTHECONTROLS 3YMPTOMSCORESWEREALSOSIGNIlCANTLYIMPROVED &ROM THE CURRENT PEDIATRIC %O% LITERATURE IT IS CLEAR THAT THE MAJORITY OF %O% PATIENTSWILLRESPONDHISTOLOGICALLYANDSYMPTOMATICALLYTOSTEROIDADMINISTRATION (OWEVER INTERMITTENTDOSINGWILLLIKELYLEADTODISEASERELAPSE ANDTHEMAJORITYOF PATIENTSREQUIRECHRONICMAINTENANCETHERAPY;9, n]. Depending on the clinical SCENARIO THECLINICIANSHOULDDECIDEWHETHERTOSTARTWITHHIGHDOSEFORMULATIONS AND TITRATE DOWN OR TO BEGIN AT LOWER FORMULATIONS AND INCREASE IF NOT EFFECTIVE 2EGARDLESSOFTHESTRATEGY ENDOSCOPICASSESSMENTISNECESSARYTODETERMINEHISTOLOGICRESPONSERATETHATISBESTASSESSEDAFTERMONTHSOFTHERAPY;15]. !SCLINICALANDHISTOLOGICEFlCACYOFSWALLOWEDSTEROIDFORMULATIONSINPEDIATRIC %O%HASBEENDEMONSTRATED APPROPRIATECONSIDERATIONSHOULDBEGIVENTOTHESIDE EFFECTPROlLEOFMAINTENANCESWALLOWEDSTEROIDMEDICATIONTHERAPY3EVERALCONCERNSINCLUDE BUTARENOTLIMITEDTO ESOPHAGEALCANDIDIASISASWELLASOVERALLGROWTH ANDDEVELOPMENT4HERISKOFESOPHAGEALCANDIDIASISISAPPROXIMATELYn BUT ISUSUALLYEASILYTREATEDWITHANTIFUNGALMEDICATIONS;1=4YPICALLY &LUCONAZOLEIS USEDASAMGKGDAYMAXDOSE MG ONDAYFOLLOWEDBYMGKGDAYMAX DOSE MG TOCOMPLETEA DAYCOURSE2ECURRENTCANDIDIASISMAYBETREATED WITHPROPHYLAXISORALTERNATIVETHERAPIESFOR%O%MAYBENEEDED 7ITH REGARD TO THE IMPACT OF LONG TERM SWALLOWED STEROIDS USED TO TREAT %O% THEREISCURRENTLYNODIRECTLITERATURETOADDRESSTHISIMPORTANTQUESTION3TEROIDSARE KNOWN TO AFFECT BONE MINERALIZATION BY A DIRECT INHIBITORY ACTION ON OSTEOBLAST ACTIVITY REDUCTION OF INTESTINAL ABSORPTION OF CALCIUM STIMULATION OF PARATHYROID HORMONERELEASE ANDBYADVERSEEFFECTSONGROWTHHORMONEACTION;19=4HEMINIMUM DOSE ASSOCIATED WITH STEROID INDUCED BONE LOSS IS UNKNOWN REDUCED BONE DENSITYHASOCCURREDWITHDOSESASLOWASMGOFPREDNISONEPERDAY;19], while FRACTURERISKHASBEENSHOWNTOINCREASEWITHDAILYDOSESOFPREDNISONEEQUIVALENT TOnMG;20=(OWEVER NOTALLDISEASESMANAGEDWITHSTEROIDSAREASSOCIATED WITHCLINICALLYSIGNIlCANTBONEDISEASEANDGROWTHRETARDATION 'IVENTHATBOTHASTHMAAND%O%UTILIZEmUTICASONEORBUDESONIDECORTICOSTEROID MEDICATIONSFORMAINTENANCETHERAPY SOMESPECULATIONCANBEDRAWNFROMTHISLITERATURE)NTHATREGARD THEREISAGROWINGBODYOFEVIDENCETHATSUGGESTSTHECURRENT MANAGEMENT OF ASTHMA WITH INHALED CORTICOSTEROIDS HAVE LITTLE IF ANY SHORT TERM EFFECTS ON BONE HEALTH LINEAR GROWTH AND DEVELOPMENT ;21n23= 9ET IT WOULD BE PREMATURETOASSUMETHATTHESAMEWOULDBEFOUNDINPATIENTSWITH%O%MANAGED WITHmUTICASONEORBUDESONIDETHERAPIES-AJORDIFFERENCESEXISTBETWEENTHETREATMENTSFORASTHMAAND%O%7HEREASTHMATREATMENTSAREDESIGNEDFORINHALATIONAND ABSORPTIONVIATHEPULMONARYSYSTEM %O%TREATMENTWITHSWALLOWEDSTEROIDINTERACTSWITHTHEESOPHAGEALMUCOSALININGANDTHEREMAINDEROFTHE')TRACT!DDITIONALLY TREATMENTFOR%O%WITHSWALLOWEDSTEROIDSISTYPICALLYATMUCHHIGHERDAILYDOSES THAN ARE TYPICALLY USED FOR ASTHMA MAINTENANCE THERAPY &LUTICASONE PROPIONATE   OR   PG "UDESONIDE   OR  MG  )T SHOULD ALSO BE NOTED THAT BUDESONIDEINPARTICULARUNDERGOESEXTENSIVElRST PASSHEPATICMETABOLISM WHICH MAYLIMITSYSTEMICEFFECTSWHENABSORBEDENTERALLY4HEEFFECTSOFTHESEHIGHERDOSE



*0&RANCIOSI

TREATMENTSLOCALIZEDTOTHEESOPHAGEALMUCOSAONBONEHEALTH BONEDEVELOPMENT ANDGROWTHHASYETTOBEAPPROPRIATELYSTUDIED)TISALSOIMPORTANTTOMENTIONTHAT THECURRENTALTERNATIVETOSWALLOWEDSTEROIDTHERAPY DIETARYELIMINATION HASALSONOT BEENWELLSTUDIEDWITHREGARDTOLONG TERMNUTRITIONAL PSYCHOLOGICALANDDEVELOPMENTALEFFECTS;2].

Additional Therapies !S%O%HASSOMEFEATURESINCOMMONWITHALLERGICRHINITIS ASTHMA ANDINmAMMATORY BOWEL DISEASE IT IS REASONABLE TO QUESTION WHETHER SEVERAL THERAPIES UTILIZED FOR OTHERINmAMMATORYCONDITIONSMAYBESUCCESSFULIN%O%PATIENTS#ROMOLYNSODIUM ISAMASTCELLSTABILIZERANDANTI INmAMMATORYAGENTUTILIZEDFORALLERGICRHINITISAND ASTHMA)NASMALLCASESERIESOF%O%PATIENTS CROMOLYNSODIUMDIDNOTDEMONSTRATE ANY HISTOLOGIC OR CLINICAL IMPROVEMENT IN A SERIES OF  PATIENTS ;25]. !DDITIONAL CASE SERIES DATA FOR THE USE OF ,EUKOTRIENE RECEPTOR ANTAGONISTS WITH DOSESOFnMGDAYWEREPRESCRIBEDWITHREPORTSOFSYMPTOMATICBUTNOTHISTOLOGICIMPROVEMENT;25]. )NREFRACTORYANDSEVERE%O%CASES SOMECLINICIANSHAVEDRAWNFROMTHEEXPERIENCE IN INmAMMATORY BOWEL DISEASE AND SUGGESTED IMMUNOMODULATOR THERAPY /NE CASE SERIES OF ONLY THREE ADULT PATIENTS WITH STEROID DEPENDENT EOSINOPHILIC ESOPHAGITISWERESYMPTOMATICALLYANDHISTOLOGICALLYTREATEDWITH -ERCAPTOPURINE FORAPERIODOFnYEARSWITHRELAPSEUPONSUCCESSFULDISCONTINUATIONOFTHEMEDIcation [26=)NANATTEMPTTOUSEOTHERSUCCESSFULTHERAPIESININmAMMATORYBOWEL DISEASEFOR%O% AN!NTI 4.& ALPHAAGENTINmIXIMAB WASNOTABLETOINDUCEHISTOLOGICREMISSIONAFTERTWOINFUSIONSOFTHEMGKGDOSINGINACASESERIESOFTHREE adult patients [27=(OWEVER CAUTIONSHOULDBEEXERCISEDININTERPRETINGTHESEVERY SMALLCASESERIES ANDLARGERRANDOMIZEDCLINICALTRIALSAREWARRANTED /THERBIOLOGICTHERAPIESAREASOURCEOFCURRENTACTIVEINVESTIGATION"ASICSCIENCE AND MOLECULAR INVESTIGATIONS HAVE DETERMINED THAT ),  AND ),  CYTOKINES ARE IMPORTANTINTHEPATHOGENESISOF%O%;32n35=4HENATURALEXTENSIONOFTHISIMPORTANTMECHANISTICRESEARCHISTODETERMINEWHETHERAGENTSTHATBLOCKTHESECYTOKINES WILLBECLINICALLYEFFECTIVEINADDRESSINGTHESYMPTOMATICANDHISTOLOGICOUTCOMES IN%O%3TEINSTUDIEDTHEUSEOFANTI ), INFOURPATIENTSIDENTIlEDWITH%O%;28]. 4HESEPATIENTSHADLONG STANDINGDYSPHAGIAANDESOPHAGEALSTRICTURES!FTERRECEIVINGMONTHLYINTRAVENOUSINFUSIONSOFANTI ), FORTHREECONSECUTIVEMONTHS CLINICALSYMPTOMSANDREPEATUPPERENDOSCOPYWEREEVALUATED!NTI ), THERAPYWAS ASSOCIATEDWITHMARKEDDECREASESOFPERIPHERALBLOODANDESOPHAGEALEOSINOPHILIA ALONGWITHIMPROVEDCLINICALSYMPTOMSANDSIGNIlCANTRESOLUTIONOFDYSPHAGIA)N ASMALLADULTDOUBLEBLIND RANDOMIZEDCLINICALTRIAL SIXPATIENTSTOLERATEDMEPOLIZUMABINFUSIONSOFUPTO MG WITHREDUCTIONINEOSINOPHILIABUTNOTCOMPLETE REMISSION  PEAK EOSINOPHIL NUMBERHPF AND MINIMAL SYMPTOMATIC IMPROVEMENT;29=/THERBIOLOGICTHERAPIESINVARIOUSSTAGESOFDEVELOPMENTINCLUDEBIOLOGICTHERAPIESDIRECTEDTOWARD), ANDEOTAXIN;30n35].

 -EDICAL4REATMENTFOR0EDIATRIC%OSINOPHILIC%SOPHAGITIS

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Conclusion )N CONCLUSION MEDICAL THERAPIES FOR %O% CURRENTLY ARE LIMITED TO VARIOUS STEROID FORMULATIONS BUT WITH ACTIVE INVESTIGATIONS INTO IMMUNOMODULATOR AND BIOLOGIC THERAPIES&UTURETHERAPIESFORCHRONIC%O%WILLSEEKTOEFFECTIVELYINDUCESUSTAINED HISTOLOGICREMISSION POSITIVELYIMPACTPATIENTREPORTEDOUTCOMESOFSYMPTOMSAS WELLASQUALITYOFLIFE ANDOPTIMIZEGROWTHWITHMINIMALSIDEEFFECTSANDMEDICATIONTOXICITYPROlLES

References  &URUTA'4 ,IACOURAS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGYn  2OSEN2 &URUTA' &RITZ* ETAL2OLEOFACIDANDNONACIDREmUXINCHILDRENWITHEOSINOPHILIC ESOPHAGITISCOMPAREDWITHPATIENTSWITHGASTROESOPHAGEALREmUXANDCONTROLPATIENTS*0EDIATR 'ASTROENTEROL.UTRn  .GO 0 &URUTA '4 !NTONIOLI $! ET AL %OSINOPHILS IN THE ESOPHAGUS n PEPTIC OR ALLERGIC EOSINOPHILIC ESOPHAGITIS #ASE SERIES OF THREE PATIENTS WITH ESOPHAGEAL EOSINOPHILIA !M *'ASTROENTEROLn  !TTWOOD3% ,EWIS#* "RONDER#3 ETAL%OSINOPHILICOESOPHAGITISANOVELTREATMENTUSING -ONTELUKAST'UTn  -EYER '7 %OSINOPHILIC ESOPHAGITIS IN A FATHER AND A DAUGHTER 'ASTROINTEST %NDOSC   -ORROW *" 6ARGO ** 'OLDBLUM *2 ET AL 4HE RINGED ESOPHAGUS HISTOLOGICAL FEATURES OF '%2$!M*'ASTROENTEROLn  $RANOVE *% (ORN $3 $AVIS -! ET AL 0REDICTORS OF RESPONSE TO PROTON PUMP INHIBITOR THERAPYAMONGCHILDRENWITHSIGNIlCANTESOPHAGEALEOSINOPHILIA*0EDIATRn  3AYEJ7. 0ATEL2 "AKER2$ ETAL4REATMENTWITHHIGH DOSEPROTONPUMPINHIBITORSHELPS DISTINGUISHEOSINOPHILICESOPHAGITISFROMNONEOSINOPHILICESOPHAGITIS*0EDIATR'ASTROENTEROL .UTR n  0ETERSON+! 4HOMAS+, (ILDEN+ ETAL#OMPARISONOFESOMEPRAZOLETOAEROSOLIZED SWALLOWEDmUTICASONEFOREOSINOPHILICESOPHAGITIS$IG$IS3CIn $EBROSSE#7 &RANCIOSI*0 +ING%# ETAL,ONG TERMOUTCOMESINPEDIATRIC ONSETESOPHAGEAL EOSINOPHILIA*!LLERGY#LIN)MMUNOL n%PUB*UN +ONIKOFF-2 .OEL2* "LANCHARD# ETAL!RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED TRIAL OF mUTICASONE PROPIONATE FOR PEDIATRIC EOSINOPHILIC ESOPHAGITIS 'ASTROENTEROLOGY n 3CHAEFER %4 &ITZGERALD *& -OLLESTON *0 ET AL #OMPARISON OF ORAL PREDNISONE AND TOPICAL mUTICASONEINTHETREATMENTOFEOSINOPHILICESOPHAGITISARANDOMIZEDTRIALINCHILDREN#LIN 'ASTROENTEROL(EPATOLn 3TRAUMANN! #ONUS3 $EGEN, ETAL"UDESONIDEISEFFECTIVEINADOLESCENTANDADULTPATIENTS WITHACTIVEEOSINOPHILICESOPHAGITIS'ASTROENTEROLOGYn $OHIL2 .EWBURY2 &OX, ETAL/RALVISCOUSBUDESONIDEISEFFECTIVEINCHILDRENWITHEOSINOPHILICESOPHAGITISINARANDOMIZED PLACEBO CONTROLLEDTRIAL'ASTROENTEROLOGYn $E"ROSSE #7 #OLLINS -( "UCKMEIER "UTZ "+ ET AL )DENTIlCATION EPIDEMIOLOGY AND CHRONICITY OF PEDIATRIC ESOPHAGEAL EOSINOPHILIA n * !LLERGY #LIN )MMUNOL   n

306

*0&RANCIOSI

-APLES +- (ENDERSON 3# 'RAHAM - ET AL 4REATMENT OF EOSINOPHILIC ESOPHAGITIS WITH INHALED BUDESONIDE IN A  YEAR OLD BOY WITH CONCOMITANT PERSISTENT ASTHMA RESOLUTION OF ESOPHAGEALSUBMUCOSALlBROSISANDEOSINOPHILICINlLTRATION!NN!LLERGY!STHMA)MMUNOL n !CEVES33 "ASTIAN*& .EWBURY2/ ETAL/RALVISCOUSBUDESONIDEAPOTENTIALNEWTHERAPY FOREOSINOPHILICESOPHAGITISINCHILDREN!M*'ASTROENTEROLn !CEVES33 $OHIL2 .EWBURY2/ ETAL4OPICALVISCOUSBUDESONIDESUSPENSIONFORTREATMENT OFEOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOLnQUIZ ,UKERT "0 2AISZ ,' 'LUCOCORTICOID INDUCED OSTEOPOROSIS 2HEUM $IS #LIN .ORTH !M n 6AN3TAA40 ,EUFKENS(' !BENHAIM, ETAL5SEOFORALCORTICOSTEROIDSANDRISKOFFRACTURES *"ONE-INER2ESn "OOT!- DE*ONGSTE*# 6ERBERNE!! ETAL"ONEMINERALDENSITYANDBONEMETABOLISMOF PREPUBERTAL CHILDREN WITH ASTHMA AFTER LONG TERM TREATMENT WITH INHALED CORTICOSTEROIDS 0EDIATR0ULMONOLn 4ATTERSlELD!% 4OWN') *OHNELL/ ETAL"ONEMINERALDENSITYINSUBJECTSWITHMILDASTHMA RANDOMISEDTOTREATMENTWITHINHALEDCORTICOSTEROIDSORNON CORTICOSTEROIDTREATMENTFORTWO YEARS4HORAXn !LLEN$" "RONSKY%! ,A&ORCE#& ETAL'ROWTHINASTHMATICCHILDRENTREATEDWITHmUTICASONEPROPIONATE&LUTICASONE0ROPIONATE!STHMA3TUDY'ROUP*0EDIATRn  &RANCIOSI *0 (OMMEL +! $EBROSSE #7 ET AL 1UALITY OF LIFE IN PAEDIATRIC EOSINOPHILIC OESOPHAGITIS WHAT IS IMPORTANT TO PATIENTS #HILD #ARE (EALTH $EV  *UN  DOIJn ,IACOURAS#! 3PERGEL*- 2UCHELLI% ETAL%OSINOPHILICESOPHAGITISA YEAREXPERIENCEIN CHILDREN#LIN'ASTROENTEROL(EPATOLn .ETZER 0 'SCHOSSMANN *- 3TRAUMANN ! ET AL #ORTICOSTEROID DEPENDENT EOSINOPHILIC OESOPHAGITISAZATHIOPRINEAND MERCAPTOPURINECANINDUCE ANDMAINTAIN LONG TERM REMISSION%UR*'ASTROENTEROL(EPATOLn 3TRAUMANN! "USSMANN# #ONUS3 ETAL!NTI 4.& ALPHAINmIXIMAB THERAPYFORSEVERE ADULTEOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOLn 3TEIN -, #OLLINS -( 6ILLANUEVA *- ET AL !NTI ),  MEPOLIZUMAB THERAPY FOR EOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOLn 3TRAUMANN! #ONUS3 'RZONKA0 ETAL!NTI INTERLEUKIN ANTIBODYTREATMENTMEPOLIZUMAB INACTIVEEOSINOPHILICOESOPHAGITISARANDOMISED PLACEBO CONTROLLED DOUBLE BLINDTRIAL'UT n "HATTACHARYA " #ARLSTEN * 3ABO % ET AL )NCREASED EXPRESSION OF EOTAXIN  DISTINGUISHES BETWEENEOSINOPHILICESOPHAGITISANDGASTROESOPHAGEALREmUXDISEASE(UM0ATHOL n &UJIWARA( -ORITA! +OBAYASHI( ETAL)NlLTRATINGEOSINOPHILSANDEOTAXINTHEIRASSOCIATION WITH IDIOPATHIC EOSINOPHILIC ESOPHAGITIS !NN !LLERGY !STHMA )MMUNOL  n "LANCHARD# 7ANG. 3TRINGER+& ETAL%OTAXIN ANDAUNIQUELYCONSERVEDGENE EXPRESSION PROlLEINEOSINOPHILICESOPHAGITIS*#LIN)NVESTn -ISHRA! 2OTHENBERG-%)NTRATRACHEAL), INDUCESEOSINOPHILICESOPHAGITISBYAN),  EOTAXIN  AND34!4 DEPENDENTMECHANISM'ASTROENTEROLOGYn "LANCHARD# 3TUCKE%- "URWINKEL+ ETAL#OORDINATEINTERACTIONBETWEEN), ANDEPITHELIAL DIFFERENTIATION CLUSTER GENES IN EOSINOPHILIC ESOPHAGITIS * )MMUNOL  n  "LANCHARD # -INGLER -+ 6ICARIO - ET AL ),  INVOLVEMENT IN EOSINOPHILIC ESOPHAGITIS TRANSCRIPTOMEANALYSISANDREVERSIBILITYWITHGLUCOCORTICOIDS*!LLERGY#LIN)MMUNOL n

Chapter 23

Corticosteroid Treatment of Eosinophilic Esophagitis in Adults Karthik Ravi and Amindra S. Arora

Keywords %OSINOPHILIC ESOPHAGITIS s &LUTICASONE s "UDESONIDE s 0REDNISONE s4OPICALCORTICOSTEROIDSs3YSTEMICCORTICOSTEROIDS

Case Presentation ! YEAR OLD#AUCASIANGENTLEMANISREFERREDTOHISLOCALGASTROENTEROLOGISTFOR DYSPHAGIA4HEPATIENTREPORTSA YEARHISTORYOFINTERMITTENTSOLIDFOODDYSPHAGIA (ISPREVIOUSEVALUATIONS INCLUDINGENDOSCOPY HAVEBEENUNREMARKABLE$ESPITEA LACKOFHEARTBURNORREmUX THEPATIENTHASBEENONTWICEDAILYPROTONPUMPINHIBITOR THERAPYFORTHEPASTMONTHSWITHNOCHANGEINSYMPTOMS(ISHEALTHHASPREVIOUSLYBEENEXCELLENTASIDEFROMCHILDHOODASTHMA !N ESOPHAGRAM REVEALS NO STRUCTURAL ABNORMALITIES %NDOSCOPIC EVALUATION IS UNREMARKABLE WITH A NORMAL APPEARING ESOPHAGUS WITH NO ESOPHAGITIS NOTED -IDDLEANDDISTALESOPHAGEALBIOPSIESAREOBTAINEDWITHREVEALEOS(0&INTHE MIDANDEOS(0&INTHEDISTALESOPHAGUS 4HE PATIENT IS STARTED ON A TRIAL OF SWALLOWED mUTICASONE  PGPUFF  PUFFS TWICEDAILYFORWEEKS!TTHECOMPLETIONOFTHISMEDICATIONTRIAL HISSYMPTOMS HAVECOMPLETELYRESOLVEDANDTHEmUTICASONEISDISCONTINUED4HEPATIENTRETURNS MONTHSLATERWITHRECURRENTPROBLEMSWITHSOLIDFOODDYSPHAGIAANDANOTHERTRIAL OFSWALLOWEDmUTICASONEISINITIATEDWITHSUBSEQUENTRESOLUTIONOFSYMPTOMS

A.S. Arora (*) $EPARTMENTOF')( -AYO#LINIC &IRST3TREET37 2OCHESTER -. 53! E MAIL!RORAAMINDRA MAYOEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_23, © Springer Science+Business Media, LLC 2012

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Introduction Eosinophilic esophagitis (EoE) was first described by Landres et al. [1] and is charACTERIZEDBYEOSINOPHILSINTHESQUAMOUSEPITHELIUMORDEEPERLAYERSOFTHEESOPHAGUS4HEEXACTPATHOGENESISOF%O%REMAINSUNCLEAR LIMITINGTHEOPTIMIZATIONOF TREATMENT STRATEGIES FOR THE DISEASE %OSINOPHILS WHILE PRESENT AT LOW LEVELS THROUGHOUTTHEBODY INCLUDINGTHEGASTROINTESTINALTRACT AREABSENTFROMTHEESOPHagus in health. However, eosinophils are seen in conditions other than EoE, includINGGASTROESOPHAGEALREmUX COLLAGENVASCULARDISEASES #ROHNSDISEASE INFECTIONS and achalasia. %OSINOPHILS RELEASE INmAMMATORY MEDIATORS WHICH CAUSE MUCOSAL INJURY AND LEADTOACHRONICINmAMMATORYSTATE4HISINTURNLEADSTOSTRUCTURALANDFUNCTIONAL ABNORMALITIES IN THE ESOPHAGUS AND LIKELY THE CLINICAL MANIFESTATIONS OF %O% (OWEVER THE EXACT PATHOGENESIS OF THIS INmAMMATORY RESPONSE REMAINS POORLY UNDERSTOOD WITHMOSTINVESTIGATORSSUPPORTINGANALLERGEN RELATEDIMMUNERESPONSE #ONSEQUENTLY TREATMENT STRATEGIES HAVE FOCUSED ON THIS PATHWAY WITH STRATEGIES INCLUDINGELIMINATIONDIET LEUKOTRIENERECEPTORINHIBITORS ANDMONOCLONALANTIBODIESSHOWINGVARIABLESUCCESS4HISCHAPTERWILLFOCUSONTHEROLEOFCORTICOSTEROIDS INTHETREATMENTOF%O%INTHEADULTPOPULATION 4HEROLEOFCORTICOSTEROIDSINOTHEREOSINOPHILICINmAMMATORYCONDITIONSSUCH ASASTHMAISWELLDESCRIBED#ORTICOSTEROIDSAREBELIEVEDTOBEEFFECTIVEINTHETREATMENT OF EOSINOPHIL DERIVED INmAMMATION BY A VARIETY OF PROPOSED MECHANISMS [2, 3=#ONSEQUENTLY ITSUSEHASBEENEXTENDEDTOTHETREATMENTOF%O%

Systemic Corticosteroids ,IACOURASETALWERETHElRSTTODEMONSTRATETHATSYSTEMICCORTICOSTEROIDSWEREAN EFFECTIVE TREATMENT STRATEGY IN THE PEDIATRIC POPULATION )N THIS STUDY  CHILDREN WITHPRESUMEDEOSINOPHILICESOPHAGITISWERETREATEDWITHORALMETHYLPREDNISOLONE ATADOSEOFMGKGDAYDIVIDEDINTOTWICEDAILYDOSESFORATOTALOFWEEKS WITH CLINICALANDHISTOLOGICALIMPROVEMENTDEMONSTRATEDINALLBUTONEPATIENT;], with ALLPATIENTSTAPEREDOFFOFSTEROIDSAFTERWEEKS(OWEVER LONGTERMFOLLOWUPOF THESEPATIENTSATMONTHSFOUNDTHATOFTHEPATIENTSWHORESPONDEDTOSYSTEMIC CORTICOSTEROIDTHERAPY ONLYREMAINEDASYMPTOMATIC !SIMILARCLINICALEXPERIENCEHASBEENSEENINTHEADULTPOPULATION7HILEEFFECTIVE THERELAPSINGCOURSEOF%O%WITHDISCONTINUATIONOFSYSTEMICCORTICOSTEROIDS HASPROVENPROBLEMATIC4HISRELAPSINGCOURSEREQUIRESREPEATEDCOURSESOFSYSTEMIC CORTICOSTEROIDS INCREASINGTHERISKFORADVERSEEFFECTSSUCHASBONEABNORMALITIES MOODABNORMALITIES ANDADRENALSUPPRESSION4HESESIGNIlCANTADVERSEEFFECTSHAVE LIMITEDTHEUSEOFSYSTEMICCORTICOSTEROIDSFORACUTEEXACERBATIONSINSELECTPATIENT POPULATIONS)NTHE%OSINOPHILIC%SOPHAGITISCONSENSUSRECOMMENDATIONSTATEMENT SYSTEMICCORTICOSTEROIDSWERERESTRICTEDTOPATIENTSINWHOMURGENTSYMPTOM

 #ORTICOSTEROID4REATMENTOF%OSINOPHILIC%SOPHAGITISIN!DULTS

309

RELIEF WAS REQUIRED 4HIS PATIENT POPULATION WAS DElNED AS THOSE WITH SEVERE DYSPHAGIA DEHYDRATION SIGNIlCANTWEIGHTLOSS ORESOPHAGEALSTRICTURESASWELLOF THOSEWITHSMALLCALIBERESOPHAGUSDEEMEDTOBEHIGHRISKFORPERFORATIONWITHENDOscopic dilation [5=0REDNISONEISTYPICALLYTHEFORMULATIONUSED ATADOSEOFnMG KGDAYWITHAMAXIMUMOFMGDAY WITHSUBSEQUENTAPPROPRIATETAPERING

Topical Corticosteroids 4HE SIGNIlCANT SIDE EFFECT PROlLE AND LONG TERM COMPLICATIONS ASSOCIATED WITH SYSTEMIC CORTICOSTEROIDS SUGGESTED THE NEED FOR A MORE LOCALIZED ADMINISTRATION OF STEROIDS FOR THE TREATMENT OF %O% 4HIS VOID WAS lLLED BY THE USE OF TOPICAL corticosteroids. 7HILETHEINITIALSTUDIESOFTOPICALCORTICOSTEROIDSIN%O%WEREDONEINTHEPEDIATRICPOPULATION EFlCACYINTHEADULTPOPULATIONHASBEENDEMONSTRATED4ABLE23.1). &AUBIONANDCOLLEAGUESREPORTEDTHElRSTUSEOFTOPICALCORTICOSTEROIDS DESCRIBING THEUSEOFSWALLOWEDmUTICASONEORBECLOMETHASONEINFOURCHILDRENWITH%O% WITH CLINICALIMPROVEMENTSEENINALLCASES;6=3INCETHATTIME THEUSEOFTOPICALCORTICOSTEROIDSIN%O%HASBEENEXTENDEDTOTHEADULTPOPULATION !RORAETALREPORTEDTHECLINICALEXPERIENCEOFADULTPATIENTSWITH%O%AND SOLIDFOODDYSPHAGIAFORAMINIMUMOFYEARS;7]. All patients were treated with PUFFSOFmUTICASONEPGPUFF TWICEDAILYFORATOTALOFWEEKS!LLPATIENTS HADCOMPLETERESOLUTIONOFSOLIDFOODDYSPHAGIAATMONTHSAFTERCOMPLETIONOFTOPICAL CORTICOSTEROIDTHERAPY2EMEDIOSETALDESCRIBEDSIMILARRESULTSINPATIENTSTREATED WITH  PUFFS OF mUTICASONE  PGPUFF TWICE DAILY FOR A TOTAL OF  WEEKS ;8]. !LLPATIENTSHADSIGNIlCANTIMPROVEMENTOFSYMPTOMSATTHEENDOFTHE WEEK TREATMENTPERIOD WITHBEINGASYMPTOMATIC!DDITIONALLY DEMONSTRATEDHIStological response with significantly reduced eosinophil counts. 4OPICALCORTICOSTEROIDSHAVETRADITIONALLYBEENDELIVEREDINTHEFORMOFmUTICASONE!DMINISTRATIONISTYPICALLYGIVENVIAAMETERED DOSEINHALER-$) WITHOUT THEUSEOFTHESPACER4HEPATIENTISINSTRUCTEDTOINSERTTHE-$)INTOTHEIRMOUTHAND SPRAY WITH LIPS SEALED AROUND THE DEVICE 4HE POWDER IS TO BE SWALLOWED WITH PATIENTSABSTAININGFROMEATINGORDRINKINGFORAMINIMUMOFMIN$OSESRANGE FROMTO PGDAY TYPICALLYFORADURATIONOFnWEEKS !SWOULDBEEXPECTED ADVERSEEFFECTSWITHTOPICALCORTICOSTEROIDSAREMINIMAL COMPAREDTOTHOSEASSOCIATEDWITHUSEOFSYSTEMICCORTICOSTEROIDS)NTHECOMBINED EXPERIENCEOFPATIENTSFROMTHEABOVENOTEDSTUDIES ADVERSEEFFECTSWERENOTED INONLYPATIENTS4HESESIDEEFFECTSWERERELATIVELYMILDWITHASYMPTOMATICORAL CANDIDIASISIDENTIlEDDURINGENDOSCOPICEVALUATIONINTHREEANDSEVEREDRYMOUTHIN ONEPATIENT(OWEVER AMETA ANALYSISINASTHMATICPATIENTSSUGGESTEDTHATUSEOF INHALEDmUTICASONEATDOSESGREATERTHANPGDAYMAYBEASSOCIATEDWITHBONE loss [9=&URTHERMORE ATLEASTONECASEREPORTOF(36ESOPHAGITISHASBEENREPORTED INAPATIENTTREATEDWITHTOPICALCORTICOSTEROIDSFOR%O%;10].

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+2AVIAND!3!RORA

Table 23.1 #ORTICOSTEROIDTREATMENTINADULTSWITHEOSINOPHILICESOPHAGITIS .UMBER Study OFSUBJECTS Medication &OLLOWUP 2ESPONSETOTREATMENT nMONTHS Dysphagia resolution in all Arora 21 &LUTICASONE ATMONTHS$YSPHAGIA et al. [5] PUFFSPg recurrence in 3/21 at BID × 6 weeks nMONTHS MONTHS Dysphagia resolution in all 2EMEDIOS 19 &LUTICOSE and histological et al. [6] PUFFSPg IMPROVEMENTIN ")$¾WEEKS ATTREATMENTCOMPLETION2ECURRENT SYMPTOMSINOFAT MONTHFOLLOW UP "UDESONIDEMGTWICE .ONE (ISTOLOGICREMISSIONIN 3TRAUMANN 36 daily × 15 days 72.2% vs. 11.1% and et al. [10] CLINICIMPROVEMENTIN VSIN budesonide and placebo groups, respectively All 16 patients with at least .EUMANN 16 "UDESONIDEMGTWICE .ONE IMPROVEMENTIN daily × 1 week, then et al. [12] dysphagia, with 9 EITHERMGTWICE REPORTINGCOMPLETE daily (n = 5) or once resolution daily (n = 11) × 5 weeks

3IMILARTOTHOSETREATEDWITHSYSTEMICCORTICOSTEROIDS PATIENTSTREATEDWITHTOPICAL CORTICOSTEROIDS FREQUENTLY HAVE RECURRENT SYMPTOMS FOLLOWING DISCONTINUATION OF THERAPY /F THE  PATIENTS REPORTED BY !RORA ET AL  HAD RELAPSE OF DYSPHAGIA nMONTHSAFTERCOMPLETIONOFTHERAPY;5=3IMILARLY 2EMEDIOSETALREPORTED RECURRENTSYMPTOMSINPATIENTSATMONTHSFOLLOWINGCOMPLETIONOFTOPICALCORticosteroids [8=!RORAETALPROSPECTIVELYDESCRIBEDTHENATURALHISTORYOF%O%IN  PATIENTS TREATED WITH THE SAME mUTICASONE ;11= 4WENTY NINE PATIENTS REPORTED RECURRENT DYSPHAGIA OCCURRING AT A MEAN OF  MONTHS FOLLOWING COMPLETION OF TREATMENT 4WENTY TWO OF  PATIENTS REQUIRED REPEATED TREATMENT COURSES WITH SWALLOWEDmUTICASONEWITHOFTHESEREQUIRINGTWOORMOREREPEATEDTREATMENTS ANDREQUIRINGFOURORMOREREPEATEDTREATMENTSOVERAMEANFOLLOWUPOFYEARS (OWEVER THESEPATIENTSREQUIREDLESSFREQUENTESOPHAGEALDILATIONSFOLLOWINGTREATMENTWITHSWALLOWEDmUTICASONE 3IMILARLY ASTUDYPRESENTEDINABSTRACTFORMBY3TRAUMANNETALDEMONSTRATED TREATMENTEFlCACYOFBUDESONIDEINTHISPATIENTPOPULATION;12=4HIRTY SIXPATIENTS WITH %O% WERE TREATED WITH EITHER BUDESONIDE  MG TWICE DAILY VIA NEBULIZER OR PLACEBO4HEYREPORTEDHISTOLOGICREMISSIONINOFPATIENTSTREATEDWITHBUDESONIDECOMPAREDTOINTHEPLACEBOGROUP WITHAREDUCTIONINTISSUEEOSINOPHILIAFROMTOEOS(0&&URTHER SYMPTOMATICIMPROVEMENTWASNOTEDIN OFPATIENTSTREATEDWITHBUDESONIDEVSINTHEPLACEBOGROUP

 #ORTICOSTEROID4REATMENTOF%OSINOPHILIC%SOPHAGITISIN!DULTS

311

-ORE RECENTLY ORAL VISCOUS BUDESONIDE FORMULATIONS HAVE BEEN DEVELOPED SPECIlCALLYFORTHETREATMENTOF%O%4HEPRIMARYBENElTOFORALFORMULATIONSHAS BEEN THOUGHT TO BE THE RELATIVE EASE OF ADMINISTRATION AND THE POTENTIAL BENElCIAL EFFECTSONPATIENTCOMPLIANCE!CEVESANDCOLLEAGUESREPORTEDONTHEUSEOFORALVIScous budesonide in a pediatric population [13= 6ISCOUS BUDESONIDE WAS MADE BY MIXINGALIQUIDFORMULATIONOFBUDESONIDEWITHSUCRALOSE4WENTYCHILDRENWEREGIVEN nMGOFORALVISCOUSBUDESONIDEDAILYFORAPERIODOFnMONTHS WITHHISTOLOGIC RESPONSENOTEDINOFPATIENTSANDSYMPTOMATICIMPROVEMENTINALLPATIENTS 4HEUSEOFANORALGELCOMBININGBUDESONIDEANDTHEMUCOSALADHERENTRINCINOL HASALSOBEENREPORTEDUPONINTHEADULTPOPULATIONBY.EUMANNETAL;1=3IXTEEN PATIENTSWITH%O%WERETREATEDWITHMGOFBUDESONIDETWICEDAILYFORWEEKWITH THISORALGEL%LEVENPATIENTSREPORTEDSYMPTOMATICIMPROVEMENTANDTHEFREQUENCY was decreased to once daily, while the other five patients were continued on twice DAILYTHERAPY!LLPATIENTSCOMPLETEDA WEEKCOURSEOFTREATMENT!TTHECONCLUSIONOFTREATMENT ALLPATIENTSREPORTEDATLEASTAIMPROVEMENTINDYSPHAGIA WITHREPORTINGCOMPLETERESOLUTION

Proton Pump Inhibitors -ORERECENTLY EVIDENCEHASEMERGEDTOSUGGESTTHATPROTONPUMPINHIBITORS00)S AREANEFFECTIVETREATMENTOPTIONINPATIENTSWITHESOPHAGEALEOSINOPHILIA.GOETAL DESCRIBEDTHREEPATIENTSWITHCLINICALANDENDOSCOPICFEATURESOF%O%WITHGREATER THANEOS(0&!FTERMONTHSOFTREATMENTWITH00) ALLTHREEPATIENTSHADCLINIcal, endoscopic, and histologic response [15]. Desai et al. reported on patients preSENTING WITH FOOD BOLUS IMPACTION AND GREATER THAN  EOS(0& /F  PATIENTS TREATEDWITHnWEEKSOF00)THERAPY REPORTEDSYMPTOMATICIMPROVEMENTWHILE DIDNOT/FTHELATTERGROUP lVEOFSIXPATIENTSSUBSEQUENTLYTREATEDWITHTOPICAL CORTICOSTEROIDSREPORTEDSYMPTOMATICIMPROVEMENT;16='ASTROESOPHAGEALREmUXIS OFTENASSOCIATEDWITHEOSINOPHILICESOPHAGITIS7HILETHEABOVESTUDIESDEMONSTRATE THAT00)SMAYBEEFFECTIVEINTREATINGSYMPTOMSASSOCIATEDWITHSECONDARYREmUX 0ETERSON ET AL REPORTED A RANDOMIZED TRIAL OF  PATIENTS WITH %O% TREATED WITH OMEPRAZOLEMGDAILYVSmUTICASONEPg twice daily. He showed that there WASNOSIGNIlCANTDIFFERENCEINCLINICALORHISTOLOGICALRESPONSEINEITHERTREATMENT group [17=THUSHELPINGTOCONlRMTHEDISTINCTDIFFERENCEBETWEEN'%2$AND%O%

Conclusion #ORTICOSTEROIDS BOTHSYSTEMICANDTOPICALFORMULATIONS AREEFFECTIVETREATMENTSFOR %O%INTHEADULTPOPULATION4HEUSEOFSYSTEMICCORTICOSTEROIDSISLIMITEDBYSIGNIlCANT ADVERSE EFFECTS WITH CONTINUED USE AND SHOULD BE LIMITED TO ACUTE EMERGENT SYMPTOMS RELATED TO %O% 4OPICAL CORTICOSTEROIDS ARE ALSO AN EFFECTIVE TREATMENT

312

+2AVIAND!3!RORA

STRATEGY FOR %O% WITH LESS ASSOCIATED ADVERSE EFFECTS 3YMPTOMS OF %O% TEND TO RELAPSEFOLLOWINGDISCONTINUATIONOFCORTICOSTEROIDS ANDREPEATTREATMENTCOURSESARE TYPICALLYNECESSARY&UTUREDIRECTIONSINTHERAPYMAYINCLUDEFORMULATIONSSPECIlCALLYDEVELOPEDFOR%O%WITHSIMPLIlEDDELIVERYANDINCREASEDPATIENTCOMPLIANCE

References ,ANDRES24 +USTER'' 3TRUM7"%OSINOPHILICESOPHAGITISINAPATIENTWITHVIGOROUSACHALASIA 'ASTROENTEROLOGYn *EFFERY0+ 'ODFREY27 !DELROTH% ETAL%FFECTSOFTREATMENTONAIRWAYINmAMMATIONAND THICKENINGOFBASEMENTMEMBRANERETICULARCOLLAGENINASTHMAAQUANTITATIVELIGHTANDELECTRONMICROSCOPICSTUDY!M2EV2ESPIR$ISn $JUKANOVIC2 7ILSON*7 "RITTEN+- ETAL%FFECTSOFANINHALEDCORTICOSTEROIDSONAIRWAY INmAMMATIONANDSYMPTOMSINASTHMA!M2EV2ESPIR$ISn ,IACOURAS#! 7ENNER7* "ROWN+ 2UCHELLI%0RIMARYEOSINOPHILICESOPHAGITISINCHILDREN SUCCESSFUL TREATMENT WITH ORAL CORTICOSTEROIDS * 0EDIATR 'ASTROENTEROL .UTR n &URUTA&4 ,IACOURAS#! #OLLIS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGYn &AUBION*R7! 0ERRAULT* "URGART,* ETAL4REATMENTOFEOSINOPHILICESOPHAGITISWITHINHALED CORTICOSTEROIDS*0EDIATR'ASTROENTEROL.UTRn !RORA!3 0ERRAULT* 3MYRK4#4OPICALCORTICOSTEROIDTREATMENTOFDYSPHAGIADUETOEOSINOPHILICESOPHAGITISINADULTS-AYO#LIN0ROCn 2EMEDIOS- #AMPBELL# *ONES$- ETAL%OSINOPHILICESOPHAGITISINADULTSCLINICAL ENDOSCOPIC HISTOLOGIClNDINGS ANDRESPONSETOTREATMENTWITHmUTICASONEPROPIONATE'ASTROINTEST %NDOSCn ,IPWORTH"*3YSTEMICADVERSEEFFECTSOFINHALEDCORTICOSTEROIDTHERAPYASYSTEMATICREVIEW ANDMETA ANALYSIS!RCH)NTERN-EDn ,INDBERG'- 6AN%LDIK2 3ABOORIAN-(!CASEOFHERPRESESOPHAGITISAFTERmUTICASONE PROPIONATE FOR EOSINOPHILIC ESOPHAGITIS .AT #LIN 0RACT 'ASTROENTEROL (EPATOL  n (ELOU %& 3IMONSON * !RORA !3  9R FOLLOW UP OF TOPICAL CORTICOSTEROID TREATMENT FOR EOSINOPHILICESOPHAGITISINADULTS!M*'ASTROENTEROLn 3TRAUMANN! $EGEN, &ELDER3 ETAL"UDESONIDEASINDUCTIONTREATMENTFORACTIVEEOSINOPHILIC ESOPHAGTIS IN ADOLESCENTS AND ADULTS A RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED STUDY'ASTROENTEROLOGY!  !CEVES3 "ASTIAN*& .EWBURY2/ ETAL/RALVISCOUSBUDESONIDEAPOTENTIALNEWTHERAPYFOR EOSINOPHILICESOPHAGITISINCHILDREN!M*'ASTROENTEROLn .EUMANN$! !LEXANDER', &ARRUGIA' ETAL!NEWTHERAPYFOREOSINOPHILICESOPHAGITISIN ADULTS EFlCACY OF BUDESONIDE n RINCINOL GEL FOR  WEEKS IN PATIENTS WITH DYSPHAGIA !M *'ASTROENTEROL3 3 .GO0 'URUTA'4 !NTONIOLI$! ETAL%OSINOPHILSINTHEESOPHAGUS PEPTICORALLERGICEOSINOPILICESOPHAGITIS#ASESERIESOFTHREEPATIENTSWITHESOPHAGEALEOSINOPHILIA!M*'ASTROENTEROL n $ESAI4+ 3TECEVIC6 #HANG#( ETAL!SSOCIATIONOFEOSINOPHILICINmAMMATIONWITHESOPHAGEALFOODIMPACTIONINADULTS'ASTROINTEST%NDOSCn 0ETERSON+! 3AMUELSON7- 2YUJIN$4 ETAL4HEROLEOFGASTROESOPHAGEALREmUXINEXERCISETRIGGEREDASTHMAARANDOMIZEDCONTROLLEDTRIAL$IG$IS3CIn

Chapter 24

Dietary Treatment of Eosinophilic Esophagitis Amir F. Kagalwalla and Sally Ritz

Keywords %OSINOPHILICESOPHAGITISs&OODANTIGENSs%LEMENTALDIETs!NAPHYLACTIC food allergies

Introduction %OSINOPHILICESOPHAGITIS%O% ISANIMMUNE MEDIATEDCHRONICINmAMMATORYDISORDER THAT INMOSTCHILDRENANDMANYADULTS ISTRIGGEREDBYFOODANTIGENS)N +ELLY ETALlRSTDESCRIBED%O%INCHILDRENANDALSODEMONSTRATEDTHATCLINICALSYMPTOMS AND EOSINOPHILIC ESOPHAGEAL INmAMMATION WAS REVERSED WITH EXCLUSIVE AMINO ACID BASEDELEMENTALDIETANDEXCLUSIONOFALLFOODANTIGENS;1]. The authors also IDENTIlEDSPECIlCFOODANTIGENSINCLUDINGCOWSMILK SOY WHEAT EGG ANDPEANUTS ASPOTENTIALPROTEINSTHATINDUCEDTHEESOPHAGEALINmAMMATION4HESEINITIALIMPORTANTOBSERVATIONSFROMTHATlRSTPEDIATRICSTUDYFORMTHEBASISOFTHEDIFFERENTDIETARY approaches currently offered to treat EoE. 4HEGOALSOFTREATMENTIN%O% ASFORMOSTOTHERCHRONICDISORDERS INCLUDE  RESOLUTIONOFCLINICALSYMPTOMS  MAINTENANCEOFREMISSIONORPREVENTIONOF DISEASERELAPSE  PREVENTIONOFCOMPLICATIONSSUCHASlBROSISANDSTRICTURESBY MAINTAINING HISTOLOGICAL REMISSION  PREVENTION OF IATROGENIC TREATMENT RELATED ADVERSE REACTIONS SUCH AS NUTRITIONAL DElCIENCIES AS IN DIETARY TREATMENT AND  MAINTENANCEOFQUALITYOFLIFE1/,  ! GENOME WIDE MICROARRAY EXPRESSION STUDY OF ESOPHAGEAL TISSUE FROM %O% PATIENTSDEMONSTRATEDTHAT WITHINTHEUNIQUE%O%TRANSCRIPTSIGNATURE THEGENEFOR

!&+AGALWALLA*) $IVISIONOF'ASTROENTEROLOGY (EPATOLOGY AND.UTRITION .ORTHWESTERN5NIVERSITY &EINBERG3CHOOLOF-EDICINE #HILDRENS-EMORIAL(OSPITAL *OHN(3TROGER (OSPITALOF#OOK#OUNTY #HILDRENS0LAZA  #HICAGO ), 53! E MAIL!KAGALWA CHILDRENSMEMORIALORG C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_24, © Springer Science+Business Media, LLC 2012

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!&+AGALWALLAAND32ITZ

314

Table 24.1 /UTCOMEOFVARIOUSDIETARYAPPROACHESINEOSINOPHLICESOPHAGITIS

Author +ELLY;1]

.O 10

Allergy tests 304

Diet %LEMENTAL diet

/UTCOME #LINICALIMPROVEMENT 10/10 (100%) (ISTOLOGICIMPROVEMENT 9/10 (90%)

4EITELBAUM;9] 11

3042!34

Allergy test .OIMPROVEMENT BASED ELIMINATION

.OEL;10]

10

304

%LIMINATION diet

3PERGEL;6]

146

304AND!04 %LIMINATION diet

,AICOURAS;3]

172

.ORESPONSE Significant IMPROVEMENT 112 (77%) 0ARTIALIMPROVEMENT 19 (13%) 4REATMENTFAILURE 15 (10%)

%LEMENTALDIET Significant clinical and histologic IMPROVEMENT 160/164 (98%)

+AGALWALLA;4] 60

Allergy tests not utilized ELED 25 3&%$

3&%$

'ONSALVES;7]

18

3&%$

2ESIDUAL eosinophil count 0.5

1.1 ± 2.1

12.0 ± 3.2 36.3 ± 14.9 1.1 ± 0.6

3IGNIlCANTIMPROVEMENT 3.1 ± 3.2 3&%$ %LEMENTALDIET 3IGNIlCANTIMPROVEMENT 1.6 ± 2.1 %,%$ Significant clinical and histologic IMPROVEMENT 14/18 (78%)

EOTAXIN  WAS MOST HIGHLY INDUCED AND HIGH LEVELS OF EOTAXIN  CORRELATED WITH DISEASE SEVERITY ;2= )T IS SPECULATED THAT EOTAXIN  MAY BE INDUCED IN RESPONSE TO INNATESIGNALINGANDCOULDBETRIGGEREDBYINGESTEDSTIMULISUCHASFOODANTIGENSAND ITCOULDBEFURTHERSPECULATEDTHATPERHAPSTHISINDUCTIONCANBEREVERSEDBYELIMINATING THE EXTERNAL STIMULI IE FOOD ANTIGEN 4HE DIETARY APPROACH IS BASED ON THE HYPOTHESISTHATFOODANTIGENSTRIGGEREOSINOPHILICINmAMMATION ANDCLINICALALONG WITHHISTOLOGICALREMISSIONCANBEINDUCEDBYIDENTIFYINGANDEXCLUDINGTHECAUSATIVE FOODANTIGENS)TISBELIEVEDTHATELIMINATINGCAUSATIVEFOODANTIGENSTARGETSTHECAUSE ANDTHUSINDUCESLONG TERMREMISSION4HEREARENOPROSPECTIVECONTROLLEDDOUBLE BLIND STUDIES ASSESSING AND DEMONSTRATING THE EFlCACY OF THE DIFFERENT DIETARY APPROACHES4HECURRENTRECOMMENDATIONFORTREATMENTOF%O%WITHDIETAREBASEDON A NUMBER OF RETROSPECTIVE AND OBSERVATIONAL STUDIES ;3–7= 4HE AVAILABLE DIETARY APPROACHES INCLUDE  ELEMENTAL DIET WITH AN AMINO ACID BASED COMPLETE LIQUID FORMULATION ;1, 3–5=  DIRECTED ELIMINATION DIET BASED ON THE RESULTS OF ALLERGY

 $IETARY4REATMENTOF%OSINOPHILIC%SOPHAGITIS

315

TESTING;6= AND STANDARDORNONDIRECTEDELIMINATIONDIETWHEREANUMBEROFCOMMON FOODANTIGENSAREEXCLUDEDFROMTHEDIET;4=4HETYPEOFTREATMENTSELECTEDSHOULD BEINDIVIDUALIZEDANDTAILOREDTOTHENEEDSOFTHEPATIENTANDSHOULDDEPENDONTHE PRESENCEORLACKOFANAPHYLACTICFOODALLERGIES THEAGEOFTHECHILD ANDTHECOMFORT ANDACCEPTANCEOFTHEELIMINATIONDIETBYTHEFAMILY/UTCOMESOFALLTHEDIFFERENT SUCCESSFULASWELLASUNSUCCESSFUL DIETARYAPPROACHESARESUMMARIZEDIN4ABLE24.1.

Elemental Diet #RYSTALLINEAMINOACID BASEDEXCLUSIVE ELEMENTALDIETWASlRSTSUCCESSFULLYUSED TOTREATTENCHILDRENWITHGASTROESOPHAGEALREmUXDISEASE'%2$ LIKESYMPTOMS RESISTANTTOACIDSUPPRESSION;1=#LINICALANDHISTOLOGICALREMISSIONOCCURREDWITH INTRODUCTIONOFEXCLUSIVEAMINOACID BASEDFORMULAINLIEUOFREGULARDIET3UBSEQUENT controlled reintroduction of solid foods resulted in recurrence of gastrointestinal SYMPTOMSSPECIlCTOINDIVIDUALFOODS!CLEARLINKBETWEENFOODALLERGYANDESOPHAGEALINJURYWASESTABLISHEDINTHESEPATIENTS;1=3INCETHISSEMINALPUBLICATIONBY +ELLYETAL TWOSERIESOFANDCASESREPORTEDAREMISSIONRATEOFAND RESPECTIVELY IN CHILDREN TREATED WITH ELEMENTAL DIET .EOCATE .EOCATE %/ .EOCATE 3(3)NTERNATIONAL ,IVERPOOL 5+OR%LECARE 2OSS0EDIATRICS !BBOTT ,ABORATORIES !BBOTT 0ARK )LLINOIS ;3, 4= 4HIS TREATMENT OUTCOME WAS ACHIEVED WITHOUTANYREPORTEDCOMPLICATIONS4HELIKELIHOODOFACHIEVINGMUCOSALHEALING HASBEENSHOWNTOBEHIGHERWITHTHISMODALITYTHANOTHERDIETARYINTERVENTIONSOR WITHCORTICOSTEROIDS4HEADDEDADVANTAGESARETHEMUCHLOWERRESIDUALEOSINOPHIL COUNTSANDTHUSALMOSTCOMPLETEREMISSIONWITHELEMENTALDIET4HEDISADVANTAGE OF THISAPPROACHISTHEPOORTASTE PATIENTCOMPLIANCE ANDIMPAIRED1/,DUETO ELIMINATIONOFREGULARFOODS4HISLIMITSTHEABILITYTOINGESTITORALLYANDMANYOF THESE CHILDREN REQUIRE EITHER NASOGASTRIC OR GASTROSTOMY TUBES TO DELIVER ADEQUATE NUTRIENTS4HETUBEPLACEMENTISALSOASOURCEOFPATIENTDISCOMFORTANDPARENTAL DISTRESS,IMITINGACHILDTOANEXCLUSIVEELEMENTALDIETRESTRICTSTHECHILDSPARTICIPATIONINSOCIALACTIVITIES SINCEMANYCHILDHOODACTIVITIESINVOLVEFOOD WHICHCAN LEADTOIMPAIRED1/,%LEMENTALFORMULASAREEXPENSIVEANDNOTALWAYSCOVERED BYMOSTTRADITIONALINSURANCEPLANSTHEREBYPLACINGSIGNIlCANTlNANCIALANDSOCIAL BURDENONTHEFAMILIES4HEREMAYALSOBEADDITIONALCOSTSRELATEDTOTUBES PUMPS BAGS ANDOTHERSUPPLIES3EVERALSTATESARECOVERINGORWORKINGTOWARDPROVIDING COVERAGEFORTHEELEMENTALFORMULASFOR%O% BUTITCONTINUESTOBEASTRUGGLEFOR MOSTFAMILIESTOGETREIMBURSEMENTFORTHECOSTOFTHESEFORMULATIONS /NCEHISTOLOGICALREMISSIONISESTABLISHED ASDEMONSTRATEDWITHREPEATENDOSCOPY PERFORMEDnWEEKSAFTEREXCLUSIVEELEMENTALDIET FOODREINTRODUCTIONISINITIATED BEGINNINGWITHTHELEASTALLERGENICFOODSFROMVEGETABLEORFRUITGROUPSASINGLEFOOD ISINTRODUCEDEVERYnDAYS FOLLOWEDBYASINGLEFOODFROMWITHINTHEGRAIN MEAT ANDNUTGROUPSASOUTLINEDBY-ARKOWITZETAL;5=)NTHISALGORITHMTHEMOSTALLERGIC FOODGROUPWHICHINCLUDESFOODSSUCHASCOWSMILK SOY WHEAT EGG CHICKEN AND CORNARETHELASTFOODSREINTRODUCED3INGLEFOODSFROMASPECIlCFOODGROUPLABELED

316

!&+AGALWALLAAND32ITZ

Table 24.2 Dietary introduction approach to food reintroduction in eosinophilic esophagitis A B C D Legumes Vegetables (non-legume) Citrus fruits &ISHSHELLlSH ,IMABEANS CHICKPEAS Orange, grapefruit, #ARROTS SQUASHALL Corn WHITEBLACKREDBEANS LEMON LIME types), sweet potato, 0EAS white potato, string Grains Tropical fruits BEANS BROCCOLI /AT BARLEY RYE OTHERGRAINS 0EANUT Banana, kiwi, LETTUCE BEETS PINEAPPLE MANGO Wheat ASPARAGUS CAULImOWER Meat a PAPAYA GUAVA BRUSSELSPROUTS ,AMB CHICKEN TURKEY PORK Beef AVOCADO Fruit (non-citrus, Soy Melons nontropical) (ONEYDEW CANTAEgg Apple, pear, peaches, LOUPE WATERMELON PLUM APRICOT Milk nectarine, grape, Berries raisins 3TRAWBERRY BLUEBERRY RASPBERRY CHERRY Vegetables CRANBERRY 4OMATOES CELERY CUCUMBER ONION Grains garlic, any other 2ICE MILLET QUINOA VEGETABLES -ODIlEDWITHPERMISSIONFROM4ABLEPUBLISHEDBY3PERGELAND3HUKER'ASTROINTEST%NDOSC#LIN .!Mn a 0ROGRESSFROMWELLCOOKEDTORARER

FROM!TO$ASSHOWNIN4ABLE24.2AREREINTRODUCEDINTHEDIETEVERYnDAYS;8]. &OLLOWING SUCCESSFUL REINTRODUCTION OF ALL FOODS IN ONE FOOD GROUP ENDOSCOPIC ESOPHAGEALBIOPSIESAREPERFORMEDTODEMONSTRATECONTINUINGREMISSIONBEFOREINTRODUCINGTHENEXTSINGLEFOODFROMTHENEXTFOODGROUP(OWEVER IFTHEPATIENTISSYMPTOMATICFOLLOWINGINGESTIONOFANYGIVENFOOD THATFOODISEXCLUDEDFROMTHEDIETAND THEPATIENTPROCEEDSTOTHENEXTFOODINTHATGROUPONCETHESYMPTOMSHAVERESOLVED

Directed Elimination Diets Based on Results of Allergy Testing #HILDREN TREATED WITH ELIMINATION DIETS BASED ONLY ON RADIOALLERGOSORBENT TEST 2!34 ANDORSKINPRICKTEST304 RESULTSHAVEFAILEDTODEMONSTRATECLINICALAND HISTOLOGICALREMISSION;9, 10=)NAPROSPECTIVESTUDYINWHICHADULTSWERETREATED WITH STANDARD ELIMINATION DIET THE PREDICTIVE VALUE OF 304 FOR CAUSAL FOODS WAS ONLYINSUBJECTS;7=2!34TESTINGAND304ALONEORTOGETHERFAILTOCORRECTLY IDENTIFYFOODSCAUSINGESOPHAGEALINmAMMATIONINMOSTPATIENTS(OWEVER WHEN PATIENTSUNDERWENTBOTHSKINPRICKANDATOPICPATCHTESTING!04 ANDWERETREATED WITHANELIMINATIONDIETBASEDONTHERESULTSOFACOMBINATIONOF304AND!04TO COMMONFOODS DEMONSTRATEDSIGNIlCANTCLINICALANDHISTOLOGICALREMISSION ;6= 0ATIENTS IN THIS SERIES UNDERWENT TESTING TO COMMON FOODS INCLUDING MEATS

 $IETARY4REATMENTOF%OSINOPHILIC%SOPHAGITIS

317

CHICKEN TURKEY BEEF AND PORK VEGETABLES PEAS STRING BEANS SQUASH SWEET potatoes, potatoes, and carrots), fruits (apples, pears and peaches), and grains WHEAT RICE RYE OATS BARLEY ANDCORN 0ATIENTSWEREALSOTESTEDTOMILKPROTEIN SOY EGGS ANDPEANUTS-ILK SOY WHEAT CHICKEN ANDBEEFWERETHEFOODSMOST FREQUENTLY IDENTIlED BY BOTH !04 AND 304 /F THE  CHILDREN TREATED WITH AN ELIMINATIONDIETBASEDONTHERESULTSOFBOTH!04AND304  RESPONDED WITH BOTH CLINICAL AND HISTOLOGICAL IMPROVEMENT 7ITHIN THIS GROUP  SUBJECTS WEREALLERGICTOSPECIlCFOODSINCLUDINGMILK EGG SOY ANDBEEF0ATCHSKINTEST lacks standardization for food allergies and is currently a research tool awaiting RESULTSOFFURTHERSTUDIESTOVALIDATEIT;11].

Standard Elimination Diet 4HEADVANTAGEOFSTANDARDORNONDIRECTEDELIMINATIONDIET ASALSOINTHECASEOF ELEMENTALDIET ISTHATITDOESNOTREQUIREALLERGYTESTINGTODETERMINEFOODSFORELIMINATIONFROMTHEDIET)NARETROSPECTIVESTUDY SIX FOODELIMINATIONDIET3&%$ WAS UTILIZEDTOTREATACOHORTOFCHILDREN;4=#OWSMILKPROTEIN SOY WHEAT EGG PEANUTTREENUT lSH ANDSHELLlSHWERETHEONLYFOODSEXCLUDEDFROMTHEDIETWHILE ALLOTHERSOLIDFOODSWEREALLOWED4WENTY SIX CHILDRENEXPERIENCEDSIGNIlCANTCLINICALANDHISTOLOGICALIMPROVEMENTESOPHAGEALEOSINOPHILCOUNTd(0&  4HERE WAS COMPLETE MUCOSAL HEALING WITH n EOSINOPHIL(0& DOCUMENTED IN ESOPHAGEALBIOPSIESINOFTHESE CHILDREN#OMPLETEHISTOLOGICALREMISSIONINDUCEDBYELIMINATIONDIETISSHOWNIN&IG24.14HISTREATMENTAPPROACHHAS SINCEBEENVALIDATEDBYARECENTPROSPECTIVESTUDYINWHICHOFADULTSTREATED WITH3&%$DEMONSTRATEDHISTOLOGICALIMPROVEMENT;7=4HEPRIMARYADVANTAGEOF ELIMINATIONDIETOVEREXCLUSIVEELEMENTALDIETISTHATITALLOWSINTAKEOFAVARIETYOF TABLEFOODSINCLUDINGMEATS GRAINS FRUITS VEGETABLES ANDLEGUMESCOMPAREDTOA

Fig. 24.1 %SOPHAGEAL BIOPSIES a "EFORE TREATMENT DEMONSTRATING HIGH EOSINOPHIL COUNT (b AFTERTREATMENTWITHELIMINATIONDIET DEMONSTRATINGCOMPLETERESOLUTIONOFEOSINOPHILSAND INmAMMATION

318

!&+AGALWALLAAND32ITZ

SINGLENUTRIENTSOURCETAKENORALLYORVIAATUBE)NSITUATIONSWHEREALLERGYTESTING ISNOTEASILYACCESSIBLE ANDWHEREELEMENTALDIETISNOTACONSIDERATION THISAPPROACH ISTHEDIETARYTREATMENTOFCHOICE)NADDITION THISDIETISNOTASIGNIlCANTDRAINON THEFAMILIESBUDGET /NCE CLINICAL AND HISTOLOGICAL REMISSION WITH 3&%$ IS ACHIEVED SINGLE FOOD REINTRODUCTIONINTHEDIETISBEGUN0ATIENTSAREEVALUATEDAFTERnWEEKSOFNEW FOODREINTRODUCTIONBYENDOSCOPYWITHESOPHAGEALBIOPSY4HENEXTFOODISREINTRODUCEDAFTERTHEHISTOLOGYESTABLISHESREMISSION)NACOHORTOFCHILDRENWHOHAD ACHIEVEDCLINICALANDHISTOLOGICALREMISSIONWITH3&%$ COWSMILKWASTHEMOST COMMON FOOD TRIGGERING DISEASE RECURRENCE IN PATIENTS  FOLLOWED BY SOY  ANDWHEAT BASEDONDATAPRESENTEDBY3HAHETALDURINGANORALSESSION AT THE #HILDRENS $IGESTIVE (EALTH AND .UTRITION &OUNDATION #$(.& !NNUAL -EETINGIN3AN$IEGO #!ON.OVEMBER 

Food Substitutions and Cross-Contamination in Elimination Diets $IRECTED AND NONDIRECTED FOOD ELIMINATION DIETS REQUIRE MORE THAN THE PHYSICIAN JUSTDIRECTINGTHEPATIENTTOELIMINATETHEFOODS INQUESTION-ULTIPLECONCERNSARE RAISEDINCLUDINGTHEFACTTHATELIMINATINGMAJORFOODSSUCHASMILK SOY WHEAT AND EGGFROMTHEDIETOFAGROWINGCHILDMAYHAVEDELETERIOUSCONSEQUENCES4HEFOODS REMOVEDSHOULDBEADEQUATELYSUBSTITUTEDTOENSURETHEDIETISNUTRITIONALLYCOMPLETE4HISREQUIRESKNOWLEDGEANDUNDERSTANDINGOFTHENUTRIENTDElCIENCIESCAUSED BYELIMINATIONOFSPECIlCFOODASWELLASTHEAPPROPRIATESUBSTITUTIONFORTHATFOOD ASSHOWNIN4ABLE24.3. !NOTHERIMPORTANTASPECTOFELIMINATINGFOODSFROMTHEDIETINVOLVESFOODCROSS CONTAMINATION #ROSS CONTAMINATION CAN TRANSFORM A NATURALLY OCCURRING ANTIGEN FREEFOOD INTOANANTIGEN CONTAININGFOOD#ROSS CONTAMINATIONCANOCCURDURING PROCESSING PREPARING COOKING ORSERVINGFOOD-ANYPROCESSEDFOODSASWELLAS FAST FOODS MAYBE CROSS CONTAMINATED WITH ONE OR MORE FOODS SUCH AS MILK SOY WHEAT ORNUTS#ROSS CONTAMINATIONCANALSOOCCURDURINGTHEPROCESSOFFOODPREPARATION AT HOME AND CAN BE AVOIDED BY SIMPLE MEASURES SUCH AS USING DIFFERENT UTENSILSANDSTRICTHANDWASHINGBETWEENCOOKINGDIFFERENTFOODS4IPSFORAVOIDING CROSS CONTAMINATIONARESUMMARIZEDIN4ABLE24.4. )NDIVIDUALSONELIMINATIONDIETSMUSTREADFOODLABELSTOENSURETHATTHOSEPRODUCTSAREALLOWEDINTHEDIET&OODLABELSSHOULDBEREVIEWEDEACHTIMETHEPRODUCT ISCONSUMEDBECAUSEMANUFACTURINGORPROCESSINGMAYHAVECHANGED ANDAFOOD THATWASFORMERLYANTIGEN FREEMAYNOWCONTAINTHEEXCLUDEDANTIGEN4HE53&OOD AND $RUG !DMINISTRATION &OOD !LLERGEN ,ABELING AND #ONSUMER 0ROTECTION !CT &!,#! OFHASHELPEDCONSUMERSIDENTIFYFOODSTHATAREPOTENTIALALLERGENS ANDIFCROSS CONTAMINATIONISACONCERN4HISACTREQUIRESTHATALLFOODSMADEWITH ANYOFTHEEIGHTMOSTCOMMONFOODALLERGENSCOWMILK SOY EGG WHEAT PEANUT TREENUT lSH ANDSHELLlSH MUSTBECLEARLYLABELEDTOINDICATETHEPRESENCEOFTHESE INGREDIENTS;12].

 $IETARY4REATMENTOF%OSINOPHILIC%SOPHAGITIS Table 24.3 0OTENTIALNUTRITIONALDElCIENCIES &OOD .UTRIENTS Milk 0ROTEIN CALCIUM VITAMIN$ VITAMIN! " RIBOmAVIN PANTOTHENICACID POTASSIUM Egg 0ROTEIN VITAMIN" PANTOTHENICACID BIOTIN SELENIUM Soy 0ROTEIN IRON ZINC MAGNESIUM THIAMIN RIBOmAVIN PYRIDOXINE FOLATE Wheat )RON THIAMIN RIBOmAVIN NIACIN FOLICACID 0EANUTTREENUT 6ITAMIN% NIACIN MAGNESIUM MANGANESE CHROMIUM FOLICACID " COPPER ZINC SELENIUM PHOSPHORUS POTASSIUM &ISHSHELLlSH 6ITAMIN% " NIACIN PHOSPHORUS SELENIUM OMEGAFATTYACIDS

319

!LTERNATIVEFOODSOURCES -EATS LEGUMES WHOLEGRAINS nuts, fortified foods (with B VITAMINS CALCIUM VITAMIN$ -EAT CHICKEN LEGUMES whole grains Meats, allowed grains !LTERNATIVEGRAINSTHATAREFORTIlED ,EGUMES WHOLEGRAINS VEGETABLEOILS 7HOLEGRAINS MEATS SOYBEAN mAXSEED NUTS OILS

Table 24.4 4IPSTOAVOIDCROSS CONTAMINATION s s s s s s

&OLLOWPROPERHAND WASHINGPROCEDURES 0REPAREANTIGENFREEFOODSlRST THENCOVER #LEANSURFACESANDUTENSILSBEFOREAFTERPREPARINGANTIGEN FREEFOODS 3EPARATEANTIGEN FREEFROMANTIGEN CONTAININGFOODS 3EALORWRAPANTIGEN FREEFOODS 3EPARATECONDIMENTSTOAVOIDDOUBLEDIPPING ORUSESQUEEZEBOTTLESSPRAYS

Nutritional Assessment .UTRITIONAL ASSESSMENT OF CHILDREN WITH %O% BY A REGISTERED DIETITIAN PRIOR TO INITIATING THE ELIMINATION DIET IS WARRANTED 4HIS ASSESSMENT INVOLVES OBTAINING A DETAILEDNUTRITIONALHISTORYINCLUDINGDESCRIPTIONSOFFOODANDSUPPLEMENTSBEING CONSUMEDINCLUDINGBRANDNAMESOFFOODS PREPARATIONMETHODSANDEATINGENVIRONMENT TO IMPROVE COMPLIANCE OF PRESCRIBED NUTRITIONAL THERAPY !LTHOUGH NOT VERYCOMMON SOMECHILDRENMAYPRESENTWITHMALNUTRITION4HISISTYPICALLYSEEN INYOUNGERCHILDRENWHOSESYMPTOMSMAYINCLUDEVOMITINGANDFOODAVERSIONOR CHILDRENWITHMULTIPLE)G% MEDIATEDFOODALLERGIES4HEINITIALASSESSMENTMAYIDENTIFYPREEXISTINGNUTRITIONALDElCIENCIESWHICHCANBEADDRESSEDCONCURRENTLYWHEN PRESCRIBING AN ELIMINATION DIET #HILDREN WHO ARE ON ELIMINATION DIETS FOR A PROLONGEDPERIODWILLNEEDTOHAVETHEIRNUTRITIONALINTAKEMONITORED)NADDITIONTO ANTHROPOMETRIC MEASUREMENTS INCLUDING WEIGHT HEIGHT AND BODY MASS INDEX "-) SOMECHILDREN ESPECIALLYTHOSEWHOHAVEALARGENUMBEROFFOODSEXCLUDED WILL REQUIRE BIOCHEMICAL TESTS INCLUDING COMPLETE BLOOD COUNT PREALBUMIN IRON CALCIUM ANDVITAMIN$LEVELSTOMONITORFORDElCIENCIES;13, 14].

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Potential Nutritional and Other Consequences of Elimination Diets )TISIMPORTANTTOBECAUTIOUSWHENRECOMMENDINGELIMINATIONDIETS SINCEEXCLUSION OFIMPORTANTFOODELEMENTSFROMAGROWINGCHILDSDIETCANHAVEDISASTROUSCONSEQUENCESINCLUDINGIMPAIREDGROWTH RICKETS ANDVITAMINDElCIENCIES;15, 16]. A recent REPORTDEMONSTRATEDSEVERALCASESOF+WASHIORKORCAUSEDBYPROTEINMALNUTRITIONOF TODDLERSSUSPECTEDOFHAVINGAMILKPROTEINALLERGYTHATWERESUBSEQUENTLYPUTONA DIETEXCLUDINGONLYMILKPROTEIN;17=&REQUENTLYITISNOTASPECIlCFOODPERSETHAT ISACAUSEOFNUTRITIONALDElCIENCYASISTHECONCURRENTEXCLUSIONOFALARGENUMBER OFPROCESSEDFOODSTHATMAYCONTAINTHATPARTICULARFOODANTIGENASACONTAMINANT %LIMINATION DIETS WITH EMPHASIS ON EXCLUDING MILK WHEAT SOY AND NUTS AMONG OTHERFOODSALSOCANBECHALLENGINGFORCHILDRENONAVEGETARIANDIET0ARTICIPATION OFAREGISTEREDDIETITIANISEXTREMELYIMPORTANTTOENSUREACALORICALLYADEQUATEDIET FORGROWTH TOPROVIDEEDUCATIONONAPPROPRIATEFOODSUBSTITUTIONS PREVENTCONTAMINATIONWITHEXCLUDEDFOODANTIGENSANDTOBEANONGOINGRESOURCEFORFAMILIESAS THEYLEARNTOADAPTTOTHEDIETMODIlCATION4IPSFORSUCCESSFULELIMINATIONDIETARE SHOWNIN4ABLE24.5. /THERISSUESRELATEDTOELIMINATIONDIETINCLUDEBEHAVIORALPROBLEMSINCLUDING REFUSALTOCOMPLYWITHTHEDIETSINCESOMEOFTHEYOUNGERCHILDRENINDAYCAREOR ELEMENTARYSCHOOLSETTINGSDONOTWANTTOAPPEARORSEEMDIFFERENTFROMTHEIRPEERS 4HIS INOURUNPUBLISHEDEXPERIENCE HASBEENACAUSEOFTREATMENTNONCOMPLIANCE $EPRESSION CHEATING LYING AND STEALING FOODS FROM OTHER CHILDREN ARE OTHER BEHAVIORALCONSEQUENCESOFDIETTHERAPYTHATHAVEBEENREPORTEDINCHILDRENONELIMINATIONDIETSFORCELIACDISEASEANDPRESUMEDFOODINDUCEDSEVEREECZEMA0ROPER PATIENTSELECTIONFORELIMINATIONDIETARYTHERAPYCANMINIMIZETHESECONSEQUENCES

Table 24.5 4IPSFORSUCCESSFULELIMINATIONDIET 0ROBLEM 0OTENTIALSOLUTION 5NFAMILIARFOODS )NVOLVECHILDINPREPARATION SERVEVARIETYOFSAFEFOODSUSINGDIFFERENT preparations, safe spices for different tastes Cooking &OODALLERGYANDANAPHYLAXISNETWORK&!!. COOKBOOKS NEWSLETTERS ONLINE COOKINGSHOWSCOOKINGMAGAZINES ADAPTIDEASTOSPECIALFOODS Eating out/ (AVEPLAN CALLAHEADTORESTAURANTS GOOFFPEAKTIMES TALKTOCHEFMANAGER socialization "RINGOWNFOODIFUNABLETOMEETNEEDS 4RAVELING "RINGOWNFOODSTAPLES IFPOSSIBLESTAYINHOTELWITHKITCHENETTE CALLHOTEL restaurants ahead regarding dietary restrictions (OLIDAYSBIRTHDAY 0LANGATHERINGSAROUNDNON MEALTIMES HAVENONFOODRELATEDACTIVITIES party i.e., “non-cake” cake Sneaking foods -AKESURECHILDUNDERSTANDSCONSEQUENCESnCHEATINGCANCAUSEHARMTO BODY,ET%O%TEAMKNOWSOCANPOSTPONEENDOSCOPY /THERCAREGIVERS 0ROVIDEAWRITTENEXPLANATIONOFWHAT%O%ISANDWHATTHEDIETIS0ROVIDE RELATIVES LISTOFACCEPTABLEANDUNACCEPTABLEFOODS#ONSIDERPROVIDINGSNACKS MEALSWHENOUTSIDEHOME

 $IETARY4REATMENTOF%OSINOPHILIC%SOPHAGITIS

321

Summary %LIMINATIONOFFOODPROTEINSTHATARETRIGGERINGESOPHAGEALINmAMMATIONOFTENLEADS TORESOLUTIONOFSYMPTOMSANDSUSTAINEDHEALINGOFTHEESOPHAGUS4HISTREATMENT APPROACH OF ELIMINATING THE CAUSE OF ESOPHAGEAL DAMAGE IS A LOGICAL CAUSE AND EFFECTWAYTOMANAGING%O%(OWEVER THEDIFFERENTDIETARYTREATMENTSCANBECHALLENGINGANDAREOFTENDIFlCULTTOIMPLEMENT%LEMENTALDIETWITHCOMPLETEELIMINATION OF ALL INTACT FOOD ANTIGENS OFFERS THE BEST OUTCOME RESULTS AS WELL AS MOST COMPLETE HEALING BUT SUBSEQUENT FOOD REINTRODUCTION IS LONG TEDIOUS AND OFTEN FRUSTRATING$IRECTEDANDSTANDARDORNONDIRECTEDDIETARYTREATMENTSARELESSEFFECTIVETHANELEMENTALDIETBOTHOPTIONSOFFERGOODOUTCOMESBUTDIRECTEDELIMINATION DIETHASTHEDRAWBACKTHATPATCHTESTINGREMAINSTOBEVALIDATEDANDISNOTUNIVERSALLYAVAILABLE7HENCONTEMPLATINGDIETARYOPTIONS ITISIMPORTANTTOREMEMBER THATONESIZEDOESNOTlTALLANDTHATDIETARYAPPROACHNEEDSTOBETAILOREDTOTHE NEEDSOFTHEINDIVIDUALPATIENT

References  +ELLY +* ,AZENBY !* 2OWE 0# 9ARDLEY *( 0ERMAN *! 3AMPSON (! %OSINOPHILIC ESOPHAGITIS ATTRIBUTED TO GASTROESOPHAGEAL REmUX IMPROVEMENT WITH AMINO ACID BASED FORMULA'ASTROENTEROLOGYn  "LANCHARD# 7ANG. 3TRINGER+& -ISHRA! &ULKERSON0# !BONIA*0 ETAL%OTAXIN AND A UNIQUELY CONSERVED GENE EXPRESSION PROlLE IN EOSINOPHILIC ESOPHAGITIS * #LIN )NVEST n  ,IACOURAS#! 3PERGEL*- 2UCHELLI% 6ERMA2 -ASCARENHAS- 3EMEAO% ETAL%OSINOPHILIC ESOPHAGITISA YEAREXPERIENCEINCHILDREN#LIN'ASTROENTEROL(EPATOLn  +AGALWALLA!& 3ENTENGO43 2ITZ3 (ESS4 .ELSON30 %MERICK+- ETAL%FFECTOFSIX FOOD ELIMINATION DIET ON CLINICAL AND HISTOLOGICAL OUTCOMES IN EOSINOPHILIC ESOPHAGITIS #LIN 'ASTROENTEROL(EPATOLn  -ARKOWITZ*% 3PERGEL*- 2UCHELLI% ,IACOURAS!%LEMENTALDIETISANEFFECTIVETREATMENT FOR EOSINOPHILIC ESOPHAGITIS IN CHILDREN AND ADOLESCENTS !M * 'ASTROENTEROL n  3PERGEL *- !NDREWS 4 "ROWN 7HITEHORN 4& "EAUSOLEIL *, ,IACOURAS #! 4REATMENT OF EOSINOPHILICESOPHAGITISWITHSPECIlCFOODELIMINATIONDIETDIRECTEDBYACOMBINATIONOFSKIN PRICKANDPATCHTESTS!NN!LLERGY!STHMA)MMUNOLn  'ONSALVES. 9ANG' $OERmER" 2ITZ3 $ITTO! (IRANO)!PROSPECTIVECLINICALTRIALOFSIX FOOD ELIMINATION DIET AND REINTRODUCTION OF CAUSATIVE AGENTS IN ADULTS WITH EOSINOPHILIC ESOPHAGITIS'ASTROENTEROLOGY  3PERGEL *- 3HUKER - .UTRITIONAL MANAGEMENT OF EOSINOPHILIC ESOPHAGITIS 'ASTROINTEST %NDOSC#LIN.!Mn  4IETELBAUM *% &OX 6, 4WAROG &* .URKO 3 !NTONIOLI $ 'LEICH ' ET AL %OSINOPHILIC ESOPHAGITISINCHILDRENIMMUNOPATHOLOGICALANALYSISANDRESPONSETOmUTICASONEPROPIONATE 'ASTROENTEROLOGYn .OEL2* 0UTNAM0% #OLLINS-( !SSAAD!( 'UAJARDO*2 *AMESON3# ETAL#LINICALAND IMMUNOPATHOLOGIC EFFECTS OF SWALLOWED mUTICASONE FOR EOSINOPHILIC ESOPHAGITIS #LIN 'ASTROENTEROL(EPATOLn

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!SSAAD!$ETECTIONOFCAUSATIVEFOODSBYSKINPRICKANDATOPYPATCHTESTSINPATIENTSWITH EOSINOPHILIC ESOPHAGITIS THINGS ARE NOT WHAT THEY SEEM !NN !LLERGY !STHMA )MMUNOL n  &OOD!LLERGEN,ABELINGAND#ONSUMER0ROTECTION!CTOF4ITLE))OF0UBLICLAWn 53#  3ALMAN3 #HRISTIE, "URKS7 -CCABE 3ELLERS"$IETARYINTAKESOFCHILDRENWITHFOODALLERGIES COMPARISON OF THE FOOD GUIDE PYRAMID AND THE RECOMMENDED DIETARY ALLOWANCES *!LLERGY#LIN)MMUNOL3 -ONFDI ! .UTRITIONAL MANAGEMENT OF PEDIATRIC FOOD HYPERSENSITIVITY 0EDIATRICS n #ARVALHO.& +ENNEY2$ #ARRINGTON0( (ALL$%3EVERENUTRITIONALDElCIENCIESINTODDLERS RESULTINGFROMHEALTHFOODMILKALTERNATIVES0EDIATRICSE .OIMARK, #OX(%.UTRITIONALPROBLEMSRELATEDTOFOODALLERGYINCHILDHOOD0EDIATR!LLERGY )MMUNOLn ,IU4 (OWARD2- -ANCINI!* 7ESTON7, 0ALLER!3 $ROLET"! ETAL+WASHIORKORINTHE 5NITED 3TATES FAD DIETS PERCEIVED AND TRUE MILK ALLERGY AND NUTRITIONAL IGNORANCE !RCH $ERMATOLn

Chapter 25

Nutritional Management of Eosinophilic Esophagitis in Pediatric Patients Mimi Girten, Elizabeth Goldberg, and Michele Shuker

Keywords %OSINOPHILIC ESOPHAGITIS s $IETARY THERAPY s %LIMINATION DIETS s 3KIN PRICKTESTINGs!TOPYPATCHTESTING

Introduction $IETARYTHERAPYISTHEPRIMARYMETHODOFTREATMENTOF%O%INTHEPEDIATRICPOPULATION 4HENUTRITIONALMANAGEMENTOFCHILDRENWITH%O%ISTHEREFOREANESSENTIALCOMPONENTOFCAREANDUNDERSCORESTHEIMPORTANTROLEPLAYEDBYTHEPEDIATRICNUTRITIONIST #URRENTLY THREENUTRITIONALORDIETARYAPPROACHESEXISTFOR%O% INCLUDINGGUIDED ELIMINATIONDIETS EMPIRICELIMINATIONDIETS ANDTOTALELEMENTALDIETS&OODSCANBE SELECTIVELYELIMINATEDFROMTHEDIETUSINGEITHERGUIDEDREMOVALBASEDONALLERGY TESTING OR ON EMPIRIC REMOVAL OF THE MOST COMMON FOODS KNOWN TO CAUSE %O% 'UIDEDFOODREMOVALUTILIZESTHECOMBINEDRESULTSOFBOTHSKINPRICKTESTING304 ANDATOPYPATCHTESTING!04 TODIRECTDIETARYTHERAPY;1]. !NALTERNATEMETHODISTHEEMPIRICREMOVALOFTHEMOSTCOMMONFOODALLERGENS MILK SOY WHEAT EGG lSH SHELLlSH PEANUTS TREENUTS ;2=/THERFOODSALSONOTED ASCOMMONCAUSESINCLUDECORN BEEF ANDCHICKEN;3="OTHTHEGUIDEDANDEMPIRIC METHODSOFFOODREMOVALHAVERESULTEDINSIMILARRATESOFIMPROVEMENT WITHNORMALIZATIONOFBIOPSIESOCCURRINGABOUTOFTHETIME;1, 2=4HETHIRDMETHODISTHE TOTALELEMENTALDIETTHATISTHEREPLACEMENTOFALLFOODSWITHANELEMENTALFORMULA 4HISCHAPTERWILLEXAMINETHESEAPPROACHESWITHEMPHASISONTHENUTRITIONALRISKS ANDADVANTAGESANDDISADVANTAGESOFEACHMETHOD!DISCUSSIONOFTHEROLEOFTHE REGISTEREDDIETITIANINMANAGINGTHEPEDIATRICPATIENTWITH%O%ASWELLASINFORMATION ONENTERALFEEDINGSANDPATIENTFAMILYEDUCATIONANDRESOURCESWILLALSOBEINCLUDED M. Shuker (*) $IVISIONOF!LLERGYAND)MMUNOLOGY 4HE#HILDRENS(OSPITALOF0HILADELPHIA -ARKET3TREET RD&LOOR 0HILADELPHIA 0! 53! E MAILSHUKER EMAILCHOPEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_25, © Springer Science+Business Media, LLC 2012

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Elimination Diet Overall Nutrition Assessment of the EoE Patient %ACHOFTHETHREEPROPOSEDMETHODSFORDIETARYTREATMENTOF%O%PRESENTSPOTENTIAL NUTRITIONALRISKS!THOROUGHNUTRITIONASSESSMENTWITHAREGISTEREDDIETITIAN2$ EXPERIENCEDINFOODALLERGYISTHEREFOREADVISABLEFORALLPATIENTSAFTERDIAGNOSIS 4HECHALLENGETOTHE2$ISNOTONLYEDUCATINGTHEPATIENTANDFAMILYASTOWHICH FOODSANDINGREDIENTSTOAVOID BUTHELPINGTHEMTOIDENTIFYAPPROPRIATESUBSTITUTIONSTOREPLACENUTRIENTSLOSTWHENMAJORALLERGENSAREREMOVED !DETAILEDNUTRITIONALASSESSMENTMUSTINCLUDE -EDICALHISTORYFAMILYHISTORY !NTHROPOMETRICDATAANDGROWTHTRENDS "IOCHEMICALDATA Clinical data $IETARYHISTORYINCLUDINGPSYCHOSOCIALASSESSMENTS !COMPLETEDIETHISTORYSHOULDBEOBTAINEDANDINCLUDEFOODPREFERENCES BRAND NAMESOFFOOD AMOUNTSCONSUMEDATMEALS EATINGBEHAVIORS NUMBEROFCAREGIVERS INVOLVEDINFOODSHOPPINGANDPREPARATION ANDMETHODSOFFOODPREPARATION!LLOF THESEFACTORSCANAFFECTADHERENCETOTHEPRESCRIBEDDIETANDACAREFULREVIEWCAN HELPIDENTIFYPOTENTIALBARRIERSTOSUCCESSFULNUTRITIONTHERAPY !SSESSMENTOFGROWTHISIMPORTANTFORALLCHILDREN4HEMAJORITYOFTHECHILDREN LIVINGINTHE5NITED3TATESHAVEADEQUATEINTAKESOFMOSTNUTRIENTS(OWEVER CHILDRENATRISKFORNUTRITIONALDElCIENCIESINCLUDETHOSEONMEDICALLYPRESCRIBEDDIETS SUCHASALLERGEN FREE GLUTEN FREE ORTUBEFEEDINGS;=3TANDARDMEASUREMENTSOF HEIGHT WEIGHT WEIGHT TO HEIGHTRATIOS ANDHEADCIRCUMFERENCEASPLOTTEDONTHE APPROPRIATE GROWTH CHARTS MAY NOT PROVIDE ENOUGH INFORMATION ABOUT A CHILDS GROWTH)THASBEENPROPOSEDTHATMONITORINGTHEGROWTHCHARTSFORACHANGEINTHE CHILDSGROWTHVELOCITYISANIMPORTANTASSESSMENTFORNUTRITIONALDElCIENCY4HISIS ESPECIALLYNECESSARYININFANTSANDYOUNGCHILDRENWHOPRESENTWITHFAILURETOTHRIVE #HRISTIEFOUNDTHATCHILDRENWITHMILKALLERGYORCHILDRENWITHTWOORMOREFOOD ALLERGIESWERESHORTER BASEDONHEIGHT FOR AGEPERCENTILESTHANTHOSEWITHONLYONE FOODALLERGY;5].

Estimating Nutritional Requirements %STIMATEDNUTRITIONALREQUIREMENTSAREDETERMINEDVIAESTABLISHEDMETHODSFORTHE PEDIATRIC POPULATION 2ECOMMENDED $IETARY !LLOWANCES 2$!S AND $IETARY 2EFERENCE)NTAKES$2)S ;6, 7=.UTRITIONALREQUIREMENTSFORCHILDRENWITH%O%ARE GENERALLY THE SAME AS FOR HEALTHY CHILDREN WITHOUT ALLERGIES !DDITIONAL CALORIES PROTEINANDORMICRONUTRIENTSMAYBEREQUIREDINCERTAINSITUATIONSFORCHILDRENWITH

 .UTRITIONAL-ANAGEMENTOF%OSINOPHILIC%SOPHAGITISIN0EDIATRIC0ATIENTS

325

AHISTORYOFPOORWEIGHTGAINANDORGROWTH ATOPICDERMATITIS OROTHERACCOMPANYING DIAGNOSESWHICHINCREASENUTRITIONALREQUIREMENTS #ARBOHYDRATES SHOULD PROVIDE n OF TOTAL CALORIES WITH AN EMPHASIS ONWHOLEGRAINS FRUITS ANDVEGETABLESFORMICRONUTRIENTSANDlBER#ONSUMPTIONOF WHOLEGRAINSANDFRESHFRUITSANDVEGETABLESSHOULDBEEMPHASIZEDNOTONLYFORTHE NUTRIENTVALUEBUTALSOTOPROVIDElBERTOTHEDIET7HEATISOFTENREMOVEDFROMTHE DIET OF CHILDREN WITH %O% WHICH NECESSITATES THE USE OF ALTERNATE GRAIN SOURCES (IGH QUALITYSOURCESOFPROTEINSHOULDMAKEUPFORnOFTHEDIET 0ROVISIONSMUSTBEMADETOSUPPLYADEQUATEESSENTIALAMINOACIDSBYENSURING SUFlCIENTINTAKEOFCOMPLETEPROTEINSANDORCOMPLIMENTARYPROTEINS;8=&ATSHOULD PROVIDETHEREMAININGnOFTOTALCALORIES!DEQUATEDIETARYFATHELPSTOENSURE APPROPRIATEENERGYINTAKE NORMALGROWTH ANDPREVENTIONOFESSENTIALFATTYACIDDElCIENCY!VARIETYOFDIETARYFATISENCOURAGEDSOTHATAPPROPRIATEAMOUNTSOFMONOUNSATURATED POLYUNSATURATED ANDSATURATEDFATSARECONSUMED .ORMALGROWTHIN INFANTSISDEPENDENTONADEQUATEAMOUNTSOF%SSENTIAL&ATTY!CIDS%&! 6EGETABLE OILS EXCEPTFORCOCONUTOIL AREMOSTLYUNSATURATEDFATS6EGETABLEOILSSUCHASSAFmOWER CANOLA CORN SOYBEAN ANDOLIVEOILSUPPLYMONOUNSATURATEDANDPOLYUNSATURATEDFATSAND%&!TOALLERGICINDIVIDUALS!NIMALPROTEINSPROVIDESATURATEDFATS 4HE 2$! AND $2) FOR VITAMINS MINERALS AND TRACE ELEMENTS CAN SERVE AS A GUIDELINEFORCHILDRENWITHFOODALLERGIES-ICRONUTRIENTINTAKEWILLVARYACCORDING TOTHESEVERITYOFDIETRESTRICTIONS3ALMANNOTEDTHATTHEINTAKEOFCHILDRENWITHFOOD ALLERGIESWASLOWINCALCIUM IRON VITAMIN$ VITAMIN% ANDZINC4HENEEDFOR SUPPLEMENTATION SHOULD BE CONTINUALLY ASSESSED WHEN DIET MODIlCATIONS CHANGE THROUGHOUTTREATMENT;9].

Nutritional Concerns with an Elimination Diet 4HE RISK OF DIETARY INADEQUACY WILL INCREASE WITH THE NUMBER AND TYPE OF FOODS REMOVEDFROMTHEDIET APOORNUTRITIONALSTATUSATTHETIMEOFDIAGNOSISANDTHEPRESENCE OF DYSFUNCTIONAL EATING BEHAVIORS SUCH AS FOOD REFUSAL SELECTIVE EATING OR texture aversion. %LIMINATION DIETS POSE SIGNIlCANT CHALLENGES TO PATIENTS AND FAMILIES 3OME FOODS ARE EASIER TO OMIT FROM THE DIET THAN OTHERS BUT THE REMOVAL OF EVEN ONE DIETARYSTAPLECANMAKEFORADIFlCULTADJUSTMENT4HEDIETOFTHEAVERAGECHILDIN OURPOPULATIONWOULDLIKELYNOTBESEVERELYALTEREDBYTHEREMOVALOFSOY PEANUT ANDSEAFOODASSUMINGTHEYWEREONANOPENDIETPREDIAGNOSIS -ILKANDWHEAT PROTEINSAREGENERALLYTHEMOSTDIFlCULTALLERGENSTOREMOVEASTHEYAREPRESENTIN THEDIETSOFSOMANYCHILDRENANDTHEIRREMOVALOFTENHASTHEGREATESTNUTRITIONAL IMPACT4ABLE25.1). &OREXAMPLE THOSEONADAIRY FREEDIETMAYNEEDTOREPLACECALCIUMANDPROTEIN &IBER SUPPLEMENTS MAY BE NEEDED IF GRAINS ARE REMOVED AND INTAKE OF FRUITS AND VEGETABLES IS SUBOPTIMAL 6ITAMIN AND MINERAL SUPPLEMENTS MAY BE NECESSARY !THOROUGHEVALUATIONOFTHESUPPLEMENTISESSENTIALWHENDETERMININGTHETYPETOBE

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M. Girten et al.

Table 25.1 .UTRIENTSINMAJORFOODALLERGENSANDAPPROPRIATESUBSTITUTES &OOD Nutrients 3UBSTITUTIONS -EATS LEGUMES WHOLEGRAINS NUTS Milk 0ROTEIN CALCIUM PHOSPHORUS FORTIlEDFOODS ANDBEVERAGES VITAMIN$ RIBOmAVIN PANTOTHENICACID EXENRICHEDSOYMILK FORTIlED VITAMIN" ORANGEJUICE 7HEAT )RON NIACIN RIBOmAVIN THIAMIN &ORTIlEDFOODS FRUITS VEGETABLES FOLATE lBER OTHERFORTIlEDGRAINSBARLEY OAT corn, rice, rye), alternative grains SUCHASBUCKWHEAT QUINOA SOY AMARANTH IFFORTIlED Egg 0ROTEIN CHOLINE VITAMIN! RIBOmAVIN -EATS LEGUMES WHOLEGRAINS DAIRY PANTOTHENICACID BIOTIN SELENIUM -EATS OTHERLEGUMES FORTIlEDBEVERAGES Soy 0ROTEIN THIAMIN RIBOmAVIN PYRIDOXINE FOLATE CALCIUM PHOSPHORUS MAGNESIUM IRON ZINC

GIVEN4HEhCOMPLETEvTYPEOFPEDIATRICMULTIVITAMINMINERALSUGGESTSTHATDIETCONTAINS A WIDE VARIETY OF BOTH VITAMINS AND MINERALS  IT DOES NOT SIGNIFY THAT IT CONTAINS OFTHERECOMMENDEDDIETARYALLOWANCEFOREACHNUTRIENT&OREXAMPLE GUMMY TYPEPRODUCTSTENDTOHAVEFEWERNUTRIENTSTHANTHECOMPLETECHEWABLETYPE;]. 7HENAFOODORFOODGROUPISELIMINATEDFROMTHEDIET CONSIDERATIONTOTYPESOF NUTRIENTSLOST WHETHEROTHERCOMPONENTSOFTHEDIETCANMAKEUPFORTHELOSTNUTRIENTS AND WHAT DIETARY ALTERATIONS ARE NEEDED TO REPLACE THE LOST NUTRIENTS MUST BE MADE! DAYDIETRECORDCANBEKEPTBYTHEFAMILYONCETHEPATIENTHASTRANSITIONED TOHISORHERRESTRICTEDDIET!NALYSISOFTHERECORDEDINTAKEISUSEFULINDETERMINING NUTRITIONALADEQUACYANDTHENEEDFORNUTRITIONALSUPPLEMENTATION3UPPLEMENTATION WITHANELEMENTALFORMULAMAYBENECESSARYATTHEOUTSETOFTREATMENTIFNUMEROUS DIET RESTRICTIONS ARE REQUIRED OR LATER IF INTAKE OF SOLID FOODS EVENTUALLY PROVES INADEQUATE !DDITIONALCALORIES WHENNEEDED CANBEPROVIDEDFROMAVARIETYOFSOURCES4HE MOSTEFlCIENTWAYTOADDCALORIESISWITHDIETARYFATVEGETABLEOILS WHICHISGENERALLY NOT RESTRICTED FOR MOST PATIENTS #OMMERCIAL MODULAR SUPPLEMENTS SUCH AS $UOCAL.UTRICIA 'AITHERSBURG -$ OR0OLYCOSE2OSS0RODUCTS$IVISION !BBOTT,ABORATORIES #OLUMBUS /( CANALSOBEUSEDFORMOSTPATIENTS

Milk Avoidance -ILKISALEADINGDIETARYSOURCEOFPROTEIN CALCIUM PHOSPHORUS VITAMIN$ RIBOmAVIN PANTOTHENICACIDANDVITAMIN"%NRICHEDSOYMILKCANSUBSTITUTEFORCOWS MILK ASITPROVIDESPROTEIN CALCIUM VITAMIN$ ANDRIBOmAVIN;8=)FSOYISALSO RESTRICTEDFROMTHEDIET ENRICHEDRICEMILKCANBEUSED2ICEMILKISNOTASIGNIlCANTSOURCEOFPROTEIN HOWEVER ANDTHEREMAINDEROFTHEDIETSHOULDBEREVIEWED

 .UTRITIONAL-ANAGEMENTOF%OSINOPHILIC%SOPHAGITISIN0EDIATRIC0ATIENTS

327

BYTHE2$TOENSURETHATPROTEINNEEDSCANBEMETBYSOLIDFOODS2ICEMILKISALSO LOWINFATANDOTHERSOURCESOFDIETARYFATSSUCHASVEGETABLEOILSMAYNEEDTOBE ADDEDTOTHEDIET;8=4HESAMECONCERNSHOLDTRUEFORBEVERAGESDERIVEDFROMOAT POTATO AND SOME HEMP BASED BEVERAGES BUT THESE PRODUCTS IF ACCEPTED CAN BE USEDASSIGNIlCANTSOURCEOFCALORIESINANOTHERWISEBALANCEDDIET5SEOFENRICHED PRODUCTSCANALSOHELPMEETCALCIUMREQUIREMENTS4ABLE25.2PROVIDESINFORMATION ONSOMECURRENTLYAVAILABLEDAIRYALTERNATIVESPRODUCTSSUCHAS5LTRACAREFOR+IDS -ETAGENICS )NC 3AN #LEMENTE #! AND -IMIC#REME .ON $AIRY #REAM 3UBSTITUTE-IMIC#REME !LBANY .9 CANBEUSEDTOPROVIDECALORIESORMISSING NUTRIENTSTOACHILDSDIET#AREFULANALYSISOFTHEDIETISREQUIREDONANONGOING BASIS4ABLE25.2).

Wheat Avoidance 7HEATANDENRICHEDWHEATPRODUCTSPROVIDEIRON NIACIN RIBOmAVIN THIAMIN FOLATE ANDlBER4HEREMOVALOFWHEATANDOTHERGRAINSCANSIGNIlCANTLYAFFECTTHEINTAKE OFDIETARYlBER0ATIENTSSHOULDBEENCOURAGEDTOINCREASEFRUITSANDVEGETABLES IF ALLOWEDINTHEDIET7HEATALTERNATIVESSUCHASAMARANTH ARROWROOT BARLEY BUCKWHEAT CORN OAT POTATO RICE SOYBEAN TAPIOCA AND QUINOA mOUR MAY BE USED IF PERMITTEDINTHEDIETANDTOLERATEDBYTHEPATIENT4HEREAREMANYWHEATANDGLUTEN FREE PRODUCTSAVAILABLETODAYANDFAMILIESSHOULDRECEIVEINFORMATIONONHOWTOOBTAIN THEMANDHOWTOINCORPORATEALTERNATIVEGRAINSINTORECIPES

Egg Avoidance %GGSPROVIDEPROTEIN CHOLINE VITAMIN! RIBOmAVIN PANTOTHENICACID BIOTIN AND SELENIUM-OSTOFTHESECANUSUALLYBEPROVIDEDBYOTHERFOODS DEPENDINGONWHAT REMAINSINTHEDIET"OTHEGGWHITESANDEGGYOLKSMUSTBEAVOIDED%GGSAREALSO AN IMPORTANT INGREDIENT IN BAKED GOODS PROVIDING LEAVENING AND STRUCTURE )NSTRUCTIONSONHOWTOREPLACEEGGSINBAKINGCANBEFOUNDAT4HE&OOD!LLERGYAND Anaphylaxis Network (HTTPWWWFOODALLERGYORG  #HOLESTEROL FREE EGG SUBSTITUTESSUCHAS%GG"EATERS#ON!GRA&OODS )NC /MAHA .% CONTAINEGGWHITES ANDARENOTAPPROPRIATEFORUSE%NERG '&OODSHTTPWWWENER GCOM) produces ANEGGREPLACERTHATISSAFEFORMANYRESTRICTEDDIETS

Soy Avoidance 3OYPROVIDESPROTEIN THIAMIN RIBOmAVIN PYRIDOXINE FOLATE CALCIUM PHOSPHORUS MAGNESIUM IRON ANDZINC)TSREMOVALMAYNOTPRESENTANUTRITIONALRISKUNLESSIT HASALREADYBEENUSEDASAREPLACEMENTFORDAIRYPRODUCTSOROTHERFOODSANDWASA

(EMPDREAMa ,IVINGHARVESTHEMPMILKd 0ACIlCFOODSHEMPMILK (contains rice)e

So delicious original COCONUTMILKF

0ACIlCFOODSORGANIC OATMILKe

(EMP BASED

#OCONUT BASED

/AT BASED 130

80

100 100 

120

Calories per 8 oz serving  100 100 

No

9ES 9ES

1 

No

9ES No No

3UITABLEASSOLE SOURCEOFNUTRITION No No No 9ES

!VAILABLEWITHADDED CALCIUMOTHERMICRONUTRIENTS 9ES 9ES 9ES 9ES

9ES 9ES 9ES

 2 

1

0ROTEINPER serving (g) 7  6 7

9ES

9ES 9ES

9ES

Additional mAVORSAVAILABLE 9ES 9ES 9ES No

.UT BASED

50 1 9ES No 9ES !LMONDDREAMa 0ACIlCFOODSHAZELNUT 110 2 9ES No 9ES MILKCONTAINSRICE e !VAILABILITYMAYVARYBASEDONGEOGRAPHICALAREA0LEASEREMEMBERTHATINGREDIENTSCANCHANGEATANYTIME#AREFULLYREADINGREDIENTLISTSANDPERIODICALLY CONTACTMANUFACTURERSTOENSURESAFETY a 4HE(AIN#ELESTIAL'ROUP )NC "OULDER #/ B 7HITEWAVE&OODS "ROOMlELD #/ c 0"-0RODUCTS 'ORDONSVILLE 6! d ,IVING(ARVEST&OODS )NC 0ORTLAND /2 e 0ACIlC&OODSOF/REGON 4UALATIN /2 F 4URTLE-OUNTAIN ,,# %UGENE /2

2ICEDREAMa

2ICEBASED

3OY BASED

0RODUCT 3OYDREAMa +IDZDREAMa Silk soy, vanillaB "RIGHTBEGINNINGSSOY pediatric drinkc

Table 25.2 $AIRY FREEBEVERAGES

328 M. Girten et al.

 .UTRITIONAL-ANAGEMENTOF%OSINOPHILIC%SOPHAGITISIN0EDIATRIC0ATIENTS

329

SIGNIlCANT PART OF THE DIET PRIOR TO DIAGNOSIS !S MENTIONED ABOVE FORTIlED RICE MILKSOROTHERGRAINANDORNUT BASEDBEVERAGESCANREPLACETHECALORIESANDSOME OFTHENUTRIENTSTHATSOYPRODUCTSPROVIDE3OYISASIGNIlCANTSOURCEOFPROTEIN AND CAREMUSTBETAKENTOENSURETHATPROTEINREQUIREMENTSCANBEMETBYTHEREMAINDER OFTHEDIET3OYOILANDSOYLECITHINARETYPICALLYNOTRESTRICTEDASTHEYCONTAINVERY LITTLEPROTEIN3TUDIESSHOWTHATMOSTSOYALLERGICINDIVIDUALSCANSAFELYCONSUME SOYOILANDSOYLECITHIN;10]. 4HEELIMINATIONOFSOY EGG PEANUT ANDSEAFOODFROMANALREADYOPENDIETDOES NOTUSUALLYPRESENTMAJORNUTRIENTLOSSES ASTHESEFOODSARENOTTYPICALLYEATENIN SIMILARAMOUNTSANDFREQUENCYASMILKANDORWHEAT)FTHEDIETISALREADYRESTRICTED HOWEVER THE REMOVAL OF THESE FOODS CAN RESULT IN SIGNIlCANT CHALLENGES TOWARD ENSURINGADEQUATEINTAKE-ICRONUTRIENTSUPPLEMENTATIONWILLLIKELYBENEEDEDAND ELEMENTALFORMULAORMODULARSUPPLEMENTATIONWITHVEGETABLEOILSOROTHERCOMMERCIALLYAVAILABLEPRODUCTSMAYBEREQUIREDTOPROVIDEOPTIMALINTAKEOFCALORIES PROTEIN ANDFAT

Nutritional Concerns with Elemental Diet 4HE SUCCESS OF ELEMENTAL DIETS IN TREATING %O% HAS BEEN DEMONSTRATED NUMEROUS TIMESANDTHEUSEOFAMINOACID BASEDFORMULASASTHESOLESOURCEOFNUTRITIONHAS BEENSHOWNTORESOLVEESOPHAGEALEOSINOPHILIAALMOSTALLOFTHETIME;2, 11n13]. !NELEMENTALDIETREQUIRESTHEREPLACEMENTOFALLSOLIDFOODSWITHANUTRITIONALLY COMPLETEELEMENTALFORMULA WHERETHEPROTEINSOURCEENTIRELYCOMPRISESSYNTHETIC AMINO ACIDS %LEMENTAL FORMULAS CONTAIN FREE ESSENTIAL AND NON ESSENTIAL AMINO ACIDS CORNSYRUPSOLIDS SAFmOWER COCONUT SOYOILS ANDMEDIUMCHAINTRIGLYCERIDES-#4 OIL4HEYARESUCROSE LACTOSE ANDMILK FREE3OMEOFTHEMORECOMMONLYUSEDFORMULASARE.EOCATE)NFANT .EOCATE*UNIOR %3PLASH.UTRICIA 'AITHERSBURG -$ %LECARE2OSS0RODUCTS$IVISION !BBOTT,ABORATORIES #OLUMBUS /( AND.UTRAMIGEN!!-EAD*OHNSON %VANSVILLE ).  .EOCATE.UTRA.UTRICIA ISANELEMENTALSEMISOLIDFOODTHATCANBEUSEDTOSUPPLEMENTELEMENTALFORMULA BUTISNOTINTENDEDFORUSEASASOLESOURCEOFNUTRITION (YDROLYZEDPROTEINORSEMI ELEMENTALFORMULASSUCHAS.UTRAMIGEN-EAD*OHNSON %VANSVILLE ).  OR 0EPTAMEN .ESTLE .UTRITION 'LENDALE #!  OR !LIMENTUM2OSS0RODUCTS$IVISION !BBOTT,ABORATORIES #OLUMBUS /( ARENOTACCEPTABLEFORUSEASTHEYCONTAINSMALLAMOUNTSOFMILKPROTEINS

Other Nutrients/Vitamins/Protein/Fat -ICRONUTRIENT SUPPLEMENTATION MAY BE REQUIRED ON AN ELEMENTAL DIET DEPENDING UPON THE VOLUME OF FORMULA CONSUMED -OST ADDITIONAL NEEDS CAN BE MET USING OVER THE COUNTERSUPPLEMENTS WHICHAREFREEOFMAJORALLERGENS+IRKMANHTTP WWWKIRKMANLABSCOM AND &REEDA HTTPWWWFREEDAVITAMINSCOM SELL MANY

330

M. Girten et al.

HYPOALLERGENIC PRODUCTS AS DO NUMEROUS OTHER COMPANIES 0RODUCT INGREDIENTS SHOULDBEREVIEWEDONAREGULARBASISTOENSURESAFETY )TISIMPORTANTTONOTETHATMOSTELEMENTALFORMULASDONOTCONTAINDIETARYlBER !N EXCEPTION TO THIS IS .EOCATE *UNIOR WITH 0REBIOTICS .UTRICIA .ORTH !MERICA 'AITHERSBURG -$  ! TEMPORARY LACK OF DIETARY lBER SHOULD NOT POSE LONG TERM HEALTHISSUES&IBERSUPPLEMENTSAREUSEFULFORTHOSECHILDRENWHODEVELOPORARE PRONETOCONSTIPATION ORFORTHOSEWHOREMAINDEPENDENTONELEMENTALFORMULAFOR LONGERPERIODSOFTIMEIFSOLIDFOODSCANNOTBEREINTRODUCED3UPPLEMENTSSHOULDBE FREEOFKNOWNALLERGENS'UAR GUM PSYLLIUM ANDINULIN BASEDSUPPLEMENTSCANBE USEDBYMOSTPATIENTS

Palatability /NEOFTHEMOSTFREQUENTLYENCOUNTEREDBARRIERSTOSUCCESSWITHANELEMENTALDIETIS THEACCEPTANCEOFTHEFORMULASBYPATIENTS4HEUSEOFAMINOACIDSASTHEMAINPROTEINSOURCERENDERSTHEFORMULASSIGNIlCANTLYLESSPALATABLETHANTHEIRINTACTPROTEIN COUNTERPARTS4HEmAVORSOFTHESEFORMULASHAVEIMPROVEDINRECENTYEARS ALTHOUGH THISREMAINS ASEXPECTED LARGELYAMATTEROFOPINION)TCANINDEEDBEOVERWHELMINGTOBEFACEDWITHTHEPROSPECTOFDRINKINGATLEASTALITEROFTHESEFORMULASPERDAY &LAVORED AND UNmAVORED FORMULAS ARE AVAILABLE AND DIFFERENT STRATEGIES CAN BE EMPLOYED TO ENHANCE PALATABILITY SUCH AS USING THE SUGAR BASED mAVOR PACKETS PROVIDED BY THE MANUFACTURER OR ADDING PROTEIN FREE mAVORINGS OF THE PATIENTS CHOICEALLERGEN FREECHOCOLATESTRAWBERRYSYRUP POWDEREDDRINKMIXES !NYmAVORINGS SHOULD BE DISCUSSED WITH THE ALLERGIST BEFORE USE TO ENSURE THEIR SAFETY ALTHOUGHTHEUSEOFSUGAR BASEDORARTIlCIALLYSWEETENEDPRODUCTSTHATDONOTCONTAINPROTEINARELIKELYTOPOSELITTLEALLERGENICRISK3UGAR BASEDCANDIES 'ATORADE ANDARTIlCIALLYmAVOREDWATERSMAYBEPERMITTEDFORSOMEPATIENTS )FAPATIENTISUNABLEORUNWILLINGTOCONSUMETHEREQUIREDVOLUMEOFELEMENTAL FORMULA ENTERALTUBEFEEDINGSMAYBENECESSARY4HISIS OFCOURSE ACONCEPTFOREIGN TO MOST PATIENTS AND FAMILIES BUT WITH PROPER TRAINING THE FEEDINGS CAN BE PROVIDEDSUCCESSFULLYINALMOSTALLCASES!NEXPERIENCED2EGISTERED$IETITIANCAN HELPINMANAGINGTUBEFEEDINGREGIMENS !RECENTREVIEWOFPATIENTSSEENINTHE#ENTERFOR0EDIATRIC%OSINOPHILIC$ISORDERS REVEALED THAT  OF THE POPULATION RECEIVED MORE THAN HALF OF THEIR NUTRITIONAL REQUIREMENTSFROMELEMENTALFORMULA/FTHESEPATIENTS TOOKTHEFORMULABY MOUTHANDVIAENTERALTUBEFEEDINGS

Enteral Tube Feedings 4HEREAREMANYCONTRIBUTINGREASONSWHYCHILDRENWITH%O%MAYREQUIREENTERAL TUBEFEEDINGS&OODREFUSAL DYSPHAGIA ANDREDUCEDVOLUMEORVARIETYOFINTAKE INCLUDINGTHEAVOIDANCEOFSOLIDSARECOMMONINCHILDRENWITH%O%;1=%LEMENTAL

 .UTRITIONAL-ANAGEMENTOF%OSINOPHILIC%SOPHAGITISIN0EDIATRIC0ATIENTS

331

FORMULASMAYBETHESOLESOURCEOFNUTRITIONORUSEDASASUPPLEMENTFORTHOSEONA SELECTIVE ELIMINATION DIET 5NFORTUNATELY ELEMENTAL FORMULAS HAVE AN UNPLEASANT TASTEANDMAYBEPOORLYACCEPTEDBYCHILDREN ALTHOUGHINFANTSUSUALLYDOBETTER 4ASTEFATIGUECANBECOMEANISSUEFORTHOSECHILDRENWHOAREWILLINGTOACCEPTFORMULA BY MOUTH ESPECIALLY WHEN THE USE OF FORMULA IS REQUIRED FOR AN EXTENDED PERIODOFTIME%NTERALTUBEFEEDINGSAREOFTENNECESSARYASITCANBEVERYDIFlCULT FORSOMECHILDRENTODRINKTHEVOLUMEOFELEMENTALFORMULANEEDEDTOMEETNUTRITIONALREQUIREMENTS %NTERAL FEEDING METHODS INCLUDE NASOGASTRIC .' AND GASTROSTOMY TUBE '4UBE FEEDINGS.ASOGASTRICTUBESARETYPICALLYUSEDFORSHORT TERMNUTRITIONSUPPORT7HILETHEREISNOSTANDARDIZEDDElNITIONOFhSHORT TERMvUSE IF.'TUBEFEEDS ARENEEDEDFORLONGERTHANnMONTHS THENGASTROSTOMYTUBEFEEDSSHOULDBECONSIDERED7HILEGROWTHANDDEVELOPMENTAREOFPRIMARYCONCERNANDMAYDICTATETHE NEEDFORENTERALFEEDING THEUSEOFTUBEFEEDINGSPRESENTSBOTHBENElTSANDRISKS )NFANTSANDCHILDRENLEARNHOWTOEATASWELLASHOWNOTTOEAT%O%ANDITSSYMPTOMSCANDERAILTHEDEVELOPMENTOFORALFEEDINGSKILLSANDALTERTHEFAMILYDYNAMICS ATMEALTIME)NINFANTS LEARNINGTOEATFOLLOWSAPREDICTABLEDEVELOPMENTALSEQUENCE 4HEACQUISITIONOFFEEDINGSKILLSCANBEINTERRUPTEDBYILLNESS PAIN ENVIRONMENTAL STRESSORS ANDTUBEFEEDS2EQUIREMENTSFORALIQUIDELEMENTALDIETORDELAYEDINTRODUCTIONOFSOLIDSANDTEXTURESMAYIMPACTFEEDINGSKILLDEVELOPMENT4HEUSEOF .'TUBEOR'TUBEFEEDINGMAYNEGATIVELYIMPACTFEEDINGSKILLDEVELOPMENTBY CONTRIBUTINGTOORALMOTORIMMATURITYSUCHASPOORJAWSTRENGTHORTONE ORORAL SENSORYDYSFUNCTION4HESEPROBLEMSMAYBEARESULTOFLACKOFEXPERIENCEORMAY BE SELF IMPOSED AS A RESULT OF SYMPTOMS OR TREATMENT /RAL SENSORY DYSFUNCTION MANIFESTSASFOODAVERSIONS GAGGINGWITHPARTICULARTASTESORTEXTURESORSPECIlC REFUSALSTOBRINGFOODITEMSTOTHEMOUTH;1=,ACKOFPLEASANTORALEXPERIENCES LEADSTOREDUCEDMOTIVATIONFOREATINGANDDELAYEDORALSKILLDEVELOPMENT)NOLDER CHILDRENWITH%O% THEFEAROFFOODSGETTINGhSTUCKvMAYCONTRIBUTETOALTEREDPATTERNSOFEATING )NTUBE FEDCHILDREN THEREISARISKOFALTEREDFEEDINGDEVELOPMENTANDCHANGES INMEALTIMEDYNAMICS(OWEVER THEUSEOFTUBEFEEDINGSCANSIGNIlCANTLYREDUCE PARENTAL ANXIETY OVER A CHILDS INADEQUATE ORAL INTAKE 4UBE FEEDINGS CAN REDUCE MEALTIMESTRESSANDLESSENTHETENSIONBETWEENTHECHILDANDTHEPRIMARYCAREGIVER THUS PAVING THE WAY FOR SUCCESSFUL FEEDING THERAPY IF SUCH THERAPY SHOULD BE necessary. !DVERSEEVENTSCANOCCURDURINGTHEADMINISTRATIONOFENTERALFEEDINGSIFPROPER CAREANDMONITORINGARELACKING0REVIOUSSTUDIESHAVESHOWNTHATBETWEENAND OFENTERALTUBEPLACEMENTSAREINCORRECT;15]. )NTHECASEOFNASOGASTRICTUBES THEREISAVERYREALRISKOFINCORRECTTUBEPLACEMENT WHICHISESPECIALLYSERIOUSIFTHE.'TUBEISPLACEDINTOTHECHILDSLUNGS )NADVERTENTPLACEMENTOFAN.'TUBEINTOTHEESOPHAGUSSIGNIlCANTLYINCREASESTHE RISKOFGASTROESOPHAGEALREmUXORASPIRATIONINTOTHELUNGS4HEREARESEVERALMETHODSFORMEASURINGTHEPLACEMENTLENGTHOFTHE.'TUBEASWELLASDIFFERENTTYPES AND SIZES OF .' TUBES 4HE NOSE TO EAR AND THEN MIDWAY BETWEEN XIPHOID AND UMBILICUSMEASUREMENTISTHOUGHTTOBETHEMOSTACCURATEMEANSOFMEASURING.'

332

M. Girten et al.

TUBELENGTH4HEDEVELOPMENTOFHEIGHT BASEDFORMULASTOPREDICTESOPHAGEALLENGTH APPEARPROMISINGBUTAREINNEEDOFMORERESEARCH;16=0OLYURETHANENASOGASTRIC TUBESAREOFTENUSEDINCHILDRENASTHESETUBESMAYREMAININPLACEFORUPTODAYS BEFORE NEEDING TO BE CHANGED 4HE hGOLD STANDARDv TEST FOR CONlRMING CORRECT PLACEMENTOFANASOGASTRICTUBEISBY8 RAY4HISISNOTFEASIBLEFORLONG TERMUSE OF.'TUBESORFORPATIENTSWHOUSE.'TUBESATHOME!STHEREISNOONENONRADIOLOGICMETHODTOCONlRMGASTRICPLACEMENTOFFEEDINGTUBES ACOMBINATIONOF SOMEOFTHESIMPLERANDMOREACCURATEMETHODSMAYBEUSEDANDWILLHELPDETERMINEWHENANABDOMINAL8 RAYMAYBENEEDEDTOCONlRMPLACEMENT!USCULTATION WHILEINJECTINGAIRINTOTHEFEEDINGTUBEISNOTARELIABLEMETHODFORCONlRMING.' TUBEPOSITIONASBOWELORCHESTSOUNDSMAYBEMISINTERPRETEDASCONlRMINGGASTRIC PLACEMENT;17=!SSESSMENTOFASPIRATEP(ANDCOLORARETHECURRENTLYPREFERRED METHODOFCONlRMING.'TUBEPLACEMENT !P(OFORBELOWISTHOUGHTTO INDICATEGASTRICPLACEMENT7HENGASTRICP(ISGREATERTHANOREQUALTO USINGP( TOPREDICTTUBELOCATIONISOFNOBENElTANDTHETUBEMUSTBEREMOVEDANDREPLACED OR A CONlRMATORY ABDOMINAL 8 RAY OBTAINED ;17]. Gastric aspirates are cloudy, GREEN TAN OFF WHITE BLOODY ORBROWN3MALLBOWELASPIRATESARETYPICALLYYELLOW ORBILECOLORED0LEURALmUIDISCLEARYELLOWANDWATERY/THERLESSFREQUENTCOMPLICATIONSASSOCIATEDWITH.'TUBEUSEINCLUDEPERFORATIONOFTHEESOPHAGUSORSTOMACH OBSTRUCTIONOFNASALBREATHING ANDPOSSIBLYINCREASEDINCIDENCEOFSINUSITISOR EARINFECTIONS;18]. 'ASTROSTOMYTUBESALLOWFORDIRECTACCESSINTOTHESTOMACHVIAANOPENINGCALLED ASTOMAANDAREUSEDFORLONG TERMNUTRITIONALSUPPORT4HEOBVIOUSBENElTTOHAVINGA'4UBEISTHEINCREASEDCERTAINTYTHATONEISFEEDINGINTOTHECHILDSSTOMACH 3OMECHILDRENVIEWTHEPLACEMENTOF.'TUBESASANINVASIVEPROCEDUREANDDISLIKETHEFACTTHATHAVINGAVISIBLE.'TUBEMAKESTHEMAPPEARDIFFERENTFROMOTHER CHILDREN!GASTROSTOMYTUBEREDUCESTHEIMPACTOFTHESEISSUES'ASTROSTOMYTUBE FEEDINGSARETOLERATEDWELLFORTHEMOSTPART(OWEVER THEYARENOTWITHOUTCOMPLICATIONS)NFECTIONS SKINIRRITATION ORBREAKDOWNFROMPOORlTTINGTUBESORLEAKAGE ANDTHEDEVELOPMENTOFPAINFULORBLEEDINGGRANULATIONTISSUEDOESOCCURWITHTHE USEOFGASTROSTOMYTUBES4HEREISNOEVIDENCETHATCHILDRENWITH%O%EXPERIENCE MORECOMPLICATIONSWITHGASTROSTOMYTUBEUSETHANDOOTHERCHILDREN!SFORANY CHILDWITHAGASTROSTOMYTUBE CAREFULATTENTIONTOCAREOFTHEPERISTOMALSKINAND PERIODICREMEASURINGFORPROPERlTOFTHETUBEWILLHELPTOREDUCEPROBLEMSCOMMONLYASSOCIATEDWITH'4UBEUSE

Financial Considerations %LEMENTALFORMULASAREQUITEEXPENSIVE4HEMONTHLYCOSTOFELEMENTALFORMULAFOR APATIENTNEEDING CALDAYCANEASILYEXCEED MONTH)NSURANCECOVERAGE FOR THESE FORMULAS VARIES AND INTERVENTION FROM THE CLINICAL TEAM IS ALMOST ALWAYS REQUIRED TO ASSIST WITH PREAUTHORIZATION LETTERS OF MEDICAL NECESSITY ETC #OVERAGEISNOTALWAYSPROVIDED DESPITEAGGRESSIVEEFFORTSOFTHEFAMILYANDDILIGENT

 .UTRITIONAL-ANAGEMENTOF%OSINOPHILIC%SOPHAGITISIN0EDIATRIC0ATIENTS

333

ADVOCACYOFHEALTH CAREPROVIDERS3OMESTATESHAVEPASSEDLEGISLATION MANDATING COVERAGEUNDERSPECIlCCONDITIONS!COMPLETEDISCUSSIONOFTHISISSUEISOUTSIDE THESCOPEOFTHISCHAPTER"UTITSHOULDBENOTEDTHATTREATMENTWITHANELEMENTALDIETn EVENSUPPLEMENTATIONOFSOLIDFOODWITHELEMENTALFORMULAnMAYBECOST PROHIBITIVE FORSOMEFAMILIES

Food Reintroduction !NIMPORTANTPARTOFNUTRITIONALMANAGEMENTOF%O%ISTHEREINTRODUCTIONOFFOODS BACKINTOTHEDIET/NCEANORMALBIOPSYHASBEENACHIEVED ONEITHERANELEMENTAL DIETORSELECTIVEELIMINATIONDIETWHEREMORETHANONEFOODWASREMOVED FOODS CANBEADDEDBACKINTOTHEPATIENTSDIET4ABLE25.3 shows the general protocol used ATTHE#HILDRENS(OSPITALOF0HILADELPHIAFORREINTRODUCTIONOFFOODSAFTERANELEMENTALDIET&OODSARECLASSIlEDINTOGENERALFAMILIESFROMGROUP!LEASTALLERGIC TOGROUP$MOSTALLERGIC  0ATIENTSSTARTWITHFOODSINCOLUMN!ANDMOVETOCOLUMN"ANDSOON/NENEW FOODISADDEDPERWEEK WITHAREPEATENDOSCOPYGENERALLYOCCURRINGnWEEKS AFTERTHELASTFOODISADDED4HISPROCESSISREPEATEDUNTILAPOSITIVEBIOPSYOCCURS 4HEFOODSTHATAPPEARTOCAUSEABNORMALBIOPSIESAREREMOVEDANDOTHERSARETRIED -OST FRUITS AND VEGETABLES ARE CONSIDERED LOW RISK FOODS FOR MOST PATIENTS WITH %O%4HEREFORE THEYARETYPICALLYTHElRSTTOBEREINTRODUCEDANDMOREOFTHEMARE ADDEDIN BETWEENENDOSCOPIES4HENUMBEROFFOODSADDEDBETWEENENDOSCOPIES DECREASESASTHEALLERGENICITYOFTHEFOODINCREASES(IGHER RISKFOODSSUCHASGRAINS

Table 25.3 &OODREINTRODUCTIONFOLLOWINGANELEMENTALDIET A B C “Allergic” fruit and Vegetables (non-legume) Tropical fruits vegetables Banana, kiwi, pineapple, #ARROTS SQUASH SWEET MANGO PAPAYA GUAVA Apple, potato, peas POTATO STRINGBEANS avocado BROCCOLI LETTUCE Grains Fruit (non-citrus, Melons 2ICE OAT BARLEY RYE nontropical) (ONEYDEW CANTALOUPE Meat a 0EAR PEACHES PLUM WATERMELON ,AMB CHICKEN apricot Berries turkey, pork Citrus fruits 3TRAWBERRY BLUEBERRY Fish/shellfish /RANGE GRAPEFRUIT RASPBERRY CHERRY Peanut and tree nuts LEMON LIME Legumes 0EANUT !LMOND ,IMABEANS CHICKPEAS walnut, hazelnut, WHITEBLACKREDBEANS BRAZILNUT 0ECAN a 0ROGRESSFROMWELLCOOKEDTORARER

D -OSTCOMMON FOODS Corn Chicken 7HEAT "EEF Soy Egg Milk



M. Girten et al.

MEATS EGGS SOYANDDAIRYOFTENREQUIREINDIVIDUALTRIALS ALTHOUGHSPECIlCMETHODS OFREINTRODUCTIONWILLVARYACCORDINGTOPATIENTHISTORYANDPREFERENCEANDCLINICAL EXPERIENCEOFTHE%O%TEAM;3].

Nutritional Needs and Evaluation .UTRITIONALRISKSSHOULDDECREASEASFOODSARESUCCESSFULLYREINTRODUCEDANDDIETARY VARIETYEXPANDS0ERIODICREASSESSMENTOFTHEDIETVIAA DAYFOODRECORDCANBE HELPFULINADJUSTINGMICRONUTRIENTSUPPLEMENTATION0ATIENTSWITHPREEXISTINGFEEDINGDIFlCULTIESFOODREFUSAL GAGGINGCHOKINGWITHFOODS TEXTUREAVERSION SHOULD HAVETHESEBEHAVIORSREASSESSEDTHROUGHOUTTHECOURSEOFTREATMENT)FIMPROVEMENT ISNOTOBSERVEDONCENORMALBIOPSIESAREACHIEVED AREFERRALTOAFEEDINGSPECIALIST WOULDBEINDICATEDTODETERMINETHENEEDFORBEHAVIORALTHERAPY

Patient Education !LLCAREGIVERSANDPATIENTSONCEMATUREENOUGH SHOULDBEEDUCATEDONTHENEED FORALLERGEN AVOIDANCETOENSURETHESELECTIONOFSAFEPRODUCTSANDFOODPREPARATION 4HE2$SHOULDEMPHASIZETOALLPATIENTSANDCAREGIVERSTHENEEDTOFOCUSONWHAT CHILDRENCANEATVSWHATTHEYCANNOT!LLOFTHEDIETARYTREATMENTSDISCUSSEDHERE WILLIMPACTTHEFAMILYSDAILYLIFE ANDTHISSHOULDBEACKNOWLEDGED&AMILIESSHOULD BEREFERREDTOAPPROPRIATERESOURCESFORADDITIONALINFORMATIONANDENCOURAGEDTO INVESTIGATE LOCAL SUPPORT GROUPS ANDOR ONLINE MESSAGE BOARDS 4HE !MERICAN 0ARTNERSHIPFOR%OSINOPHILIC$ISORDERSHTTPWWWAPFEDORG ISAVALUABLERESOURCE FOR MANY FAMILIES AND PROVIDES USEFUL INFORMATION WHICH THE FAMILIES OF NEWLY DIAGNOSEDPATIENTSMAYlNDESPECIALLYHELPFUL 2EFERRALS FOR PSYCHOLOGICAL COUNSELING SHOULD BE MADE IF PATIENTS EXPERIENCE ONGOINGSADNESSORANGERREGARDINGTHEIRTREATMENTPLAN

Label Reading ,ABEL READINGWILLBECOMEACRUCIALSKILLFORALLINVOLVEDINFOODSELECTIONANDPREPARATIONDURINGANELIMINATIONDIET,EGISLATIONHASBEENPASSEDTOASSISTPATIENTSAND FAMILIESWITHTHISTASK4HE&OOD!LLERGEN,ABELINGAND#ONSUMER0ROTECTION!CT OF&!,#0! WASIMPLEMENTEDIN*ANUARY ;19=!NOVERVIEWOFTHELAW FOLLOWSHEREANDCOMPLETEDETAILSCANBEFOUNDONTHE&OOD!LLERGYAND!NAPHYLAXIS .ETWORK WEBSITE AT HTTPWWWFOODALLERGYORG &!,#0! MANDATES THAT ANY FOODPRODUCTMANUFACTUREDFORSALEINTHE5NITES3TATESMUSTCONTAINONTHEPACKAGELABELACLEARLISTINGOFINGREDIENTSDERIVEDFROMCOMMONLYALLERGENICFOODS MILK EGG SOYBEAN WHEAT PEANUT TREE NUT lSH CRUSTACEAN SHELLlSH  4HE LAW

 .UTRITIONAL-ANAGEMENTOF%OSINOPHILIC%SOPHAGITISIN0EDIATRIC0ATIENTS

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APPLIES TO CONVENTIONAL FOOD PRODUCTS DIETARY SUPPLEMENTS INFANT FORMULAS AND MEDICALFOODSRAWAGRICULTURALCOMMODITIESARENOTAFFECTED-ANUFACTURERSMUST ALSOLISTTHESPECIlCTREENUT lSH ORCRUSTACEANSHELLlSHUSEDASANINGREDIENTMOLLUSKSARENOTCONSIDEREDMAJORFOODALLERGENSUNDER&!,#0! ;19]. -AJORFOODALLERGENSMUSTBELISTEDONTHEPRODUCTLABELINONEOFTHEFOLLOWING WAYS s )NTHEINGREDIENTLISThMILK EGG ORSOYv s 0ARENTHETICALLYFOLLOWINGTHEFOODPROTEINDERIVATIVEhCASEINMILK v s )MMEDIATELYBELOWTHEINGREDIENTLISTINAhCONTAINSvSTATEMENThCONTAINSMILKv;19] /NLYONEOFTHESEMETHODSISREQUIRED0ATIENTSANDFAMILIESSHOULDBETAUGHTTO AVOIDLOOKINGONLYFORhCONTAINSvSTATEMENTSANDCONTINUETOREADINGREDIENTLISTSAS NEEDED-AJORFOODALLERGENSMUSTALSOBEDECLAREDINSPICES mAVORINGS COLORINGS ORADDITIVES ORIFUSEDTOAIDINPROCESSING;19, 20]. These regulations apply only to INGREDIENTSDERIVEDFROMTHEEIGHTFOODSLISTEDABOVE)NDIVIDUALSWHONEEDTOAVOID INGREDIENTSNOTCOVEREDUNDER&!,#0!MUSTCONTACTTHEMANUFACTURERTOCONlRM PRODUCTSAFETY 3OME INGREDIENTS MAY BE DERIVED FROM AN ALLERGENIC SOURCE BUT CONTAIN SUCH INSIGNIlCANTAMOUNTSOFTHEALLERGENICPROTEINTHATTHEYAREUSUALLYWELLTOLERATED %XAMPLESOFTHISARELECITHINDERIVEDFROMSOY ANDKOSHERGELATINDERIVEDFROM lSH ;21, 22=(IGHLYRElNEDVEGETABLEOILSDERIVEDFROMMAJORFOODALLERGENSARE EXEMPTFROMLABELINGREQUIREMENTS ASTHEYCONTAINVERYLITTLEPROTEINANDARENOT THOUGHTTOPOSEARISKOFALLERGICREACTION;19n22]. )NGREDIENTSANDMANUFACTURINGPROCESSESCANCHANGEOVERTIME ANDLABELSSHOULD BEREVIEWEDEACHTIMEAFOODISPURCHASEDORCONSUMED EVENIFTHEFOODHASBEEN USEDSAFELYINTHEPAST&!!.HASAVAILABLEFORPURCHASEA'ROCERY-ANUFACTURERS $IRECTORY AND SMALL POCKET SIZED LAMINATED CARDS LISTING INGREDIENTS TO AVOID ON SPECIlCALLERGEN FREEDIETS;23].

Patient/Family Education %DUCATIONAL MATERIALS AND INSTRUCTIONS SHOULD BE THOROUGH UPDATED AND EASILY UNDERSTOOD !LLERGEN FREE SAMPLE MENUS CAN BE USED TO HELP PLAN MEALS AND SNACKS3OMEFAMILIESlNDITHELPFULFORALLFAMILYMEMBERSTOFOLLOWTHEPRESCRIBEDDIETRESTRICTIONS DEPENDINGONTHENUMBEROFFOODSREMOVED4HISSTRATEGY CAN ASSIST WITH DIETARY ADHERENCE IN SOME CASES PROVIDED EACH FAMILY MEMBERSNUTRITIONALREQUIREMENTSAREMET,ISTSOFALLERGEN FREEFOODSSHOULDBE PROVIDEDALONGWITHINFORMATIONONWHEREFOODSCANBEPURCHASED&OODALLERGY COOKBOOKSCANALSOBEUSEFUL0ATIENTSANDCAREGIVERSSHOULDBEENCOURAGEDTOTRY AVARIETYOFPRODUCTS ASABLE ANDINQUIREABOUTTHESAFETYOFUNFAMILIARINGREDIENTS4ABLE25.). 4HEFAMILYSHOULDALSORECEIVEGUIDANCEONHOWTOMANAGEDIETRESTRICTIONSWHEN EATINGOUTSIDETHEHOMEANDORONSPECIALOCCASIONS0ARENTSORCAREGIVERSSHOULDBE

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M. Girten et al. Table 25.4 2ESOURCESFOREOSINOPHILICDISORDERSFOODALLERGY American partnership for eosinophilic disorders HTTPWWWAPFEDORG CURED: Campaign urging research for eosinophilic disease HTTPWWWCUREDFOUNDATIONORG Food allergy and anaphylaxis network HTTPWWWFOODALLERGYORG Kids with food allergies HTTPWWWKIDSWITHFOODALLERGIESCOM American academy of allergy, asthma and immunology HTTPWWWAAAAIORG American dietetic association HTTPWWWEATRIGHTORG

ENCOURAGEDTOCONTACTTHEIRCHILDSSCHOOLTODISCUSSTHEDIETRESTRICTIONSWITHNOT ONLYTHETEACHERBUTTHESCHOOLNURSE FOODSERVICEPERSONNEL ANDSCHOOLADMINISTRATION IFNEEDED)TISUSUALLYBESTTOCONTACTRESTAURANTSAHEADOFTIMEANDVISITDURING NON BUSYHOURS#AREGIVERSSHOULDASKQUESTIONSABOUTINGREDIENTSANDFOODPREPARATIONORSTORAGE SOTHATTHERISKOFCROSS CONTAMINATIONCANBECONSIDERED 4HE&OOD!LLERGYAND!NAPHYLAXIS.ETWORK&!!. HASDEVELOPEDEXCELLENT EDUCATIONALMATERIALSFORUSEINSCHOOLS0ARENTSSHOULDBEENCOURAGEDTOFAMILIARIZETHEMSELVESANDTHEIRCHILDSSCHOOLWITHTHESEMATERIALS!DDITIONALRESOURCES FORFAMILIESARESHOWNIN4ABLE25..

Summary %OSINOPHILICESOPHAGITISCANBESUCCESSFULLYMANAGEDWITHCAREFULDIETARYTHERAPY BUT DIET RESTRICTIONS PRESENT MANY CHALLENGES 4HE DEGREE OF FOOD RESTRICTION CAN RANGEFROMTHEELIMINATIONOFJUSTONEFOODGROUPTOTHEELIMINATIONOFALLFOODS FROMACHILDSDIET!NEXPERIENCEDREGISTEREDDIETITIANISACRUCIALMEMBEROFTHE MULTIDISCIPLINARY %O% TEAM &AMILIES MUST BE EDUCATED APPROPRIATELY TO ENHANCE SUCCESSWITHADHERENCETOSPECIlCDIETPLANS#HILDRENMUSTBEMONITOREDCLOSELYTO ENSURENUTRITIONALNEEDSAREMETANDADEQUATEGROWTHOCCURS 4HE IMPACT OF NUTRITIONAL THERAPY ON THE PATIENTS QUALITY OF LIFE SHOULD BE ASSESSEDONANONGOINGBASIS

References 3PERGEL *- !NDREWS 4 "ROWN 7HITEHORN 4& "EAUSOLEIL *, ,IACOURAS #! 4REATMENT OF EOSINOPHILICESOPHAGITISWITHSPECIlCFOODELIMINATIONDIETDIRECTEDBYACOMBINATIONOFSKIN PRICKANDPATCHTESTS!NN!LLERGY!STHMA)MMUNOL n +AGALWALLA!& 3ENTONGO4! 2ITZ3 ETAL%FFECTOFSIX FOODELIMINATIONDIETONCLINICALANDHISTOLOGICOUTCOMESINEOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOL n

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3PERGEL * 3HUKER - .UTRITIONAL MANAGEMENT OF EOSINOPHILIC ESOPHAGITIS 'ASTROINTESTINAL %NDOSC#LINT.!M n +IRBY- $ANNER%.UTRITIONALDElCIENCIESINCHILDRENONRESTRICTEDDIETS0EDIATR#LIN.!M n #HRISTIE, (INE2* 0ARKER*' "URKS7&OODALLERGIESINCHILDRENAFFECTNUTRIENTINTAKEAND GROWTH*!M$IET!SSOC n &OODAND.UTRITION"OARD)NSTITUTEOF-EDICINE$IETARYREFERENCEINTAKESnAPPLICATIONSIN DIETARYASSESSMENT!REPORTOFTHESUBCOMMITTEEONINTERPRETATIONANDUSESOFDIETARYREFERENCE INTAKES AND THE STANDING COMMITTEE ON THE SCIENTIlC EVALUATION OF DIETARY REFERENCE INTAKES7ASHINGTON $#.ATIONAL!CADEMY0RESS &OODAND.UTRITION"OARD.2#2ECOMMENDEDDIETARYALLOWANCESTHED7ASHINGTON $# .ATIONAL!CADEMY0RESS -OlDI 3 .UTRITIONAL MANAGEMENT OF PEDIATRIC FOOD HYPERSENSITIVITY 0EDIATRICS  0T n 3ALMAN 3 #HRISTIE , "URKS !7 -C#ABE 3ELLERS " $IETARY INTAKES OF CHILDREN WITH FOOD ALLERGIES COMPARISON OF THE FOOD GUIDE PYRAMID AND THE RECOMMENDED DIETARY ALLOWANCES THED*!LLERGY#LIN)MMUNOL3 #REVEL27 +ERKHOFF-! +ONING--!LLERGENICITYOFRElNEDVEGETABLEOILS&OOD#HEM 4OXICOL n +ELLY+ ,AZENBY! 2OWE0 9ARDLEY*( 0ERMAN* 3AMPSON( %OSINOPHILIC ESOPHAGITIS ATTRIBUTED TO GASTROESOPHAGEAL REmUX IMPROVEMENT WITH AN AMINO ACID BASED FORMULA 'ASTROENTEROLOGYn -ARKOWITZ*% 3PERGEL*- 2UCHELLI% ,IACOURAS#!%LEMENTALDIETISANEFFECTIVETREATMENTFOR EOSINOPHILICESOPHAGITISINCHILDRENANDADOLESCENTS!M*'ASTROENTEROL n ,IACOURAS#! 3PERGEL*- 2UCHELLI% ETAL%OSINOPHILICESOPHAGITISA YEAREXPERIENCEIN CHILDREN#LIN'ASTROENTEROL(EPATOL n (AAS!- -AUNE.##LINICALPRESENTATIONOFFEEDINGDYSFUNCTIONINCHILDRENWITHEOSINOPHILICGASTROINTESTINALDISEASE)MMUNOL!LLERGY#LIN.!M n %LLETT-,# #ROFlE*-" #OHEN-$ 0ERKINS3-'ASTRICTUBEPLACEMENTINYOUNGCHILDREN #LIN.URS2ES n "ECKSTRAND* %LLETT-,# -C$ANIEL!0REDICTINGINTERNALDISTANCETOTHESTOMACHFORPOSITIONINGNASOGASTRICANDOROGASTRICFEEDINGTUBESINCHILDREN*!DV.URS n -ETHENY .! -EERT +, -ONITORING FEEDING TUBE PLACEMENT .UTR #LIN 0RACT n -ETHENY.! -EERT+, #LOUSE2%#OMPLICATIONSRELATEDTOFEEDINGTUBEPLACEMENT#URR /PIN'ASTROENTEROLn 53&OODAND$RUG!DMINISTRATION&OOD!LLERGEN#ONSUMER0ROTECTION!CTOF HTTPWWWCFSANFDAGOV. Accessed 9 June 2010. 53&OODAND$RUG!DMINISTRATION1UESTIONSANDANSWERSREGARDINGFOODALLERGENSINCLUDING THEFOODALLERGENCONSUMERPROTECTIONACTOFTHED/CTHTTPWWWCFSANFDAGOV. Accessed 9 June 2010. (EmE3, 4AYLOR3,(OWMUCHFOODISTOOMUCH4HRESHOLDDOSESFORALLERGENICFOODS#URR !LLERGY!STHMA2EP n 4AYLOR3, (EmE3,&OODALLERGENLABELINGINTHE53!AND%UROPE#URR/PIN!LLERGY#LIN )MMUNOL n -UNOZ &URLONG!$AILYCOPINGSTRATEGIESFORPATIENTSANDTHEIRFAMILIES0EDIATRICS 0T n

Chapter 26

Oral Tolerance and Eosinophilic Esophagitis Pooja Varshney and A. Wesley Burks

Keywords %OSINOPHILIC ESOPHAGITIS s /RAL TOLERANCE s &OOD ALLERGY s2EGULATORY4CELLSs/RALIMMUNOTHERAPY

Introduction Eosinophilic esophagitis (EoE) is an increasingly recognized disease process charACTERIZEDBYSYMPTOMSOFVOMITING FOODREFUSAL ANDDYSPHAGIAASSOCIATEDWITH LOCALIZEDEOSINOPHILICINmAMMATIONOFTHEESOPHAGUS4HOUGHTHEPRECISELINKIS NOT COMPLETELY UNDERSTOOD %O% HAS BEEN SHOWN TO BE HIGHLY ASSOCIATED WITH ATOPIC DISEASE 3ENSITIZATION TO BOTH FOOD AND ENVIRONMENTAL ALLERGENS HAS BEEN seen in patients with EoE [1=3TUDIESHAVESHOWNTHATASIGNIlCANTPROPORTIONOF PATIENTSWITH%O%HAVEEVIDENCEOFALLERGICDISEASEBYHISTORYORSKINTESTING;2]. )N ONE SERIES OF  PATIENTS  HAD A HISTORY OF AN ALLERGIC DISORDER ASTHMA ALLERGICRHINITIS URTICARIA ATOPICDERMATITIS FOODALLERGY ORDRUGALLERGY ANDOR POSITIVE RADIOALLERGOSORBENT TESTING 2!34 OR SKIN PRICK TESTING ;3]. Another STUDYOFCHILDRENREVEALEDTHATOFSUBJECTSHADAPOSITIVERESULTTOFOODSON SKINOR2!34TESTING;4=)NPATIENTSWITHBIOPSY PROVEN%O% ELIMINATIONOFPOSITIVEFOODSIDENTIlEDBYBOTHSKINPRICKTESTINGANDPATCHTESTINGLEDTOCOMPLETE RESOLUTION OF THE CLINICAL SYMPTOMS IN  OF  PATIENTS SUGGESTING A POSSIBLE association [5]. 4HEMUCOSALACCUMULATIONOFEOSINOPHILSINTHEGASTROINTESTINALTRACTSUGGESTSA 4H MEDIATEDPROCESS;1=-URINESTUDIESHAVESHOWNIMPAIREDINDUCTIONOFESOPHAGEAL

A.W. Burks (*) $EPARTMENTOF0EDIATRICS $IVISIONOF!LLERGYAND)MMUNOLOGY $UKE5NIVERSITY-EDICAL#ENTER  $URHAM .# 53! E MAILWESLEYBURKS DUKEEDU C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_26, © Springer Science+Business Media, LLC 2012

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EOSINOPHILIAINRESPONSETOALLERGENINMICEWHOAREGENETICALLYDElCIENTINSIGNAL TRANSDUCERANDACTIVATOROFTRANSCRIPTION34!4 ),  ),  AND),  PROVIDINGEVIDENCETHATALLERGEN INDUCED%O%ISDEPENDENTONCLASSIC4HCYTOKINESIGNALing [6=,IKEOTHER4H DEPENDENTDISEASEPROCESSES EOSINOPHILICGASTROINTESTINAL DISEASESLIKELYREPRESENTTHEINTERPLAYOFEXTRINSICALLERGICTRIGGERSANDINTRINSIC4H CYTOKINESINGENETICALLYPREDISPOSEDINDIVIDUALS;1]. 4HEROLEOFFOODALLERGYIN%O%MAYBEEXPLAINEDBYABREAKDOWNINORALTOLERANCE OR A FAILURE IN THE INDUCTION OF TOLERANCE /RAL TOLERANCE IS THE PHYSIOLOGIC MECHANISM BY WHICH IMMUNE RESPONSES TO AN ANTIGEN ARE SUPPRESSED BY PRIOR ADMINISTRATIONOFTHEANTIGENBYTHEORALROUTE;7, 8=4HISNORMALPROCESSISCRUCIAL INALLOWINGAWIDEARRAYOFDIETARYPROTEINSACCESSTOTHEBODYWITHOUTACTIVATING HARMFULIMMUNERESPONSES /RAL TOLERANCE PRESUMABLY EVOLVED AS AN ANALOG OF SELF TOLERANCE TO PREVENT POTENTIALLY DANGEROUS HYPERSENSITIVITY REACTIONS TO HARMLESS FOOD PROTEINS AND COMMENSALGUTmORA4HELUMENOFTHEGASTROINTESTINALTRACT THELARGESTIMMUNOLOGICORGANINTHEBODY ISCONTINUALLYEXPOSEDTONUMEROUSDIETARYPROTEINS(ERE ANTIGEN PRESENTINGCELLSENCOUNTERFOODPROTEINSANDSUBSEQUENTLYACTIVATEREGULATORY4LYMPHOCYTESTHATRESIDEINTHELOOSECONNECTIVETISSUEBENEATHTHEGASTROINTESTINAL EPITHELIUM ;9= 4HESE CELLS THEN SUPPRESS CELLULAR AND HUMORAL IMMUNE RESPONSES TO THE PROTEIN )N NONALLERGIC HOSTS THE MAJORITY OF FOOD PROTEINS ARE ABSORBEDWITHOUTPROVOKINGINJURIOUSLOCALORSYSTEMICIMMUNERESPONSES;10]. 4HE PATHOLOGIC CELLULAR AND HUMORAL IMMUNE RESPONSES THAT CHARACTERIZE FOOD ALLERGYLIKELYRESULTFROMEITHERAFAILUREINESTABLISHINGTOLERANCEORABREAKDOWN IN EXISTING TOLERANCE ;9= )T IS POSSIBLE THAT SIMILAR MECHANISMS UNDERLIE THE PATHOGENESISOF%O%

Mucosal Immunology and Fundamentals of Oral Tolerance 4HESURFACEAREAOFTHEGASTROINTESTINALMUCOSAEXCEEDSTHATOFTHESKINBYSEVERAL FOLD;10=4HEGASTROINTESTINALMUCOSAISALSOMOREPERMEABLETOANTIGENSTHAN INTACTSKINAND THEREFORE REPRESENTSTHEMAJORSITEOFCONTACTWITHFOREIGNANTIGENICMATERIALS!PPROXIMATELYnGOFFOODPROTEINAREABSORBEDDAILYIN the gut [11=!NOTHERSOURCEOFNATURALANTIGENICSTIMULATIONISTHERESIDENTGUT MICROBIOTA WITHAPPROXIMATELY12MICROORGANISMSPERGRAMOFSTOOL;12=4HE GUTLODGESTHEMOSTABUNDANTLYMPHOIDTISSUEINTHEBODY WITH12LYMPHOID CELLS PER METER OF HUMAN SMALL INTESTINE THE POPULATION OF IMMUNOGLOBULIN SECRETINGCELLSINTHEGUTEXCEEDSTHETOTALNUMBERFOUNDINALLOTHERLYMPHOID organs [13]. &OREIGNANTIGENEXPOSUREINTHEGUTNORMALLYRESULTSINSEVERALMAJORIMMUNOLOGIC RESPONSES 4HE LOCAL PRODUCTION AND RELEASE OF NONINmAMMATORY SECRETORY )G! ANTIBODY IS THE INITIAL RESPONSE OCCURRING IN THE GASTROINTESTINAL MUCOSA !NTIGENS STIMULATE " LYMPHOCYTES IN THE ORGANIZED MUCOSAL LYMPHOID TISSUE 4HESE CELLS MIGRATE TO DISTANT MUCOSAL AND GLANDULAR SITES AND DIFFERENTIATE INTO

 /RAL4OLERANCEAND%OSINOPHILIC%SOPHAGITIS

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Fig. 26.1 )NDUCTION OF ORAL TOLERANCE a -ICE IMMUNIZED SUBCUTANEOUSLY AND THEN BOOSTED SUBCUTANEOUSLYWITHANANTIGENSHOWSTRONGINVITROCELL MEDIATEDANDANTIBODYRESPONSESTOTHE antigen. (b 7HENMICEARElRSTFEDTHEANTIGENORALLYANDTHENIMMUNIZEDSUBCUTANEOUSLY INVITRO IMMUNERESPONSESTOTHEANTIGENAREGREATLYREDUCEDc 4RANSFERRING4CELLSFROMMICETHATWERE FEDANTIGENTONAIVEMICERESULTSINREDUCEDINVITROIMMUNERESPONSESTOSUBSEQUENTSUBCUTANEOUS IMMUNIZATION 4HIS SHOWS THAT ORAL FEEDING OF AN ANTIGEN CAN INDUCE A 4 CELL MEDIATED ACTIVE INHIBITORYIMMUNERESPONSE!DAPTEDFROM#HEHADEAND-AYER/RALTOLERANCEANDITSRELATIONTO FOODHYPERSENSITIVITIES*!LLERGY#LIN)MMUNOL  WITHPERMISSION

ANTIGEN SPECIlCPOLYMERIC )G! PRODUCINGPLASMACELLS;14=/NSUBSEQUENTEXPOSURE POLYMERIC)G!CROSSLINKSLUMINALANTIGENSANDPREVENTSTHEIRINTERACTIONWITHGUT EPITHELIALCELLS0RIMINGOFTHESYSTEMICIMMUNESYSTEMMAYALSOOCCUR ACTIVATING HUMORALANDCELLULARIMMUNITYTOPROTECTAGAINSTTHEPATHOGENONFUTUREENCOUNters [10]. )NCONTRASTTOTHEACTIVATIONOFIMMUNOLOGICRESPONSESDESCRIBEDABOVE EXPOSURETODIETARYPROTEINSANDCOMMENSALBACTERIAINNONATOPICHOSTSGENERALLYLEADS TOASTATEOFSYSTEMICANDORLOCALIMMUNOLOGICTOLERANCE ALLOWINGTHESEEXOGENOUS antigens access to the body [10=)NTHEMID TWENTIETHCENTURY #HASEANDHISCOLLEAGUESESTABLISHEDTHATORALFEEDINGOFANANTIGENINDUCES4CELL MEDIATEDINHIBITION OF SUBSEQUENT IMMUNE RESPONSES ILLUSTRATING THE CONCEPT OF ORAL TOLERANCE &IG26.1) [7=(ECONTRASTEDTHEINDUCTIONOFORALTOLERANCEFROMTHEGENERATIONOF STRONGCELL MEDIATEDANDHUMORALRESPONSESTHATFOLLOWSSUBCUTANEOUSIMMUNIZATION

342

06ARSHNEYAND!7"URKS

AND BOOSTER ADMINISTRATION OF AN ANTIGEN !DDITIONAL EXPERIMENTS DEMONSTRATED THAT THE TRANSFER OF 4 CELLS FROM ANTIGEN FED hTOLERANTv MICE TO NAÉVE MICE ALSO RESULTEDINREDUCEDINVITROIMMUNERESPONSESTOSUBCUTANEOUSIMMUNIZATION %XPOSURETOFOODPROTEINSANDCOMMENSALGUTmORAEXERTSASTIMULATORYEFFECT ONTHEDEVELOPINGIMMUNESYSTEM;11=!DULTMICEGIVENABALANCEDDIETCONSISTINGOFAMINOACIDSBUTNOINTACTFOODPROTEINSHAVEPOORLYDEVELOPEDGUT ASSOCIATED LYMPHOID TISSUE RESEMBLING THAT OF SUCKLING MICE WITH LOW LEVELS OF SECRETORY )G!ANDFEWERINTRAEPITHELIALLYMPHOCYTES;15=4HEYALSOHAVEAPREDOMINANTLY 4H CYTOKINE PROlLE WITH HIGH CONCENTRATIONS OF INTERLEUKIN ),  AND ),  AND A LOW CONCENTRATION OF INTERFERON GAMMA )&. GAMMA  4HE PRESENCE OF MICROBESINTHEMURINEGUTALSOPLAYSANIMPORTANTROLEINDRIVINGTHEEXPANSION OF"AND4CELLSIN0EYERSPATCHESANDMESENTERICLYMPHNODES ILLUSTRATINGTHE IMPORTANCEOFCOMMENSALMICROBIOTAINTHEDEVELOPMENTOFTHEMUCOSALIMMUNE SYSTEM;16].

Antigen Processing in the Gastrointestinal Tract 4HEJOURNEYFORADIETARYPROTEININVOLVESMULTIPLESTEPSBEFORETOLERANCEORHYPERSENSITIVITYISESTABLISHED4HEDIGESTIONPROCESSITSELF FROMSALIVARYENZYMESTOGASTRIC ACID AND LUMINAL ENZYMES PROMOTES IMMUNOLOGIC TOLERANCE BY DEGRADING DIETARYPROTEINSANDDESTROYINGIMMUNOGENICEPITOPES;9=4HEDIGESTIONOFINTACT PROTEINSTOAMINOACIDCHAINSLESSTHANEIGHTAMINOACIDSLONGRENDERSTHEMNONREACTIVEWITHANTIGENRECOGNITIONSTRUCTURESANDTHEREBYIMMUNOLOGICALLYIGNORED;17]. $ISRUPTIONOFTHEENZYMATICDIGESTIONPROCESSHASBEENSHOWNTOIMPAIRTOLERANCEIN BOTHANIMALANDHUMANMODELS LEADINGTOFOODHYPERSENSITIVITY;18=0EPTICDIGESTS OFBOVINESERUMALBUMIN"3! ARETOLEROGENICWHENADMINISTEREDORALLYORDIRECTLY INJECTEDINTOTHEMOUSEILEUM;19=5NTREATED"3!ISIMMUNOGENICWHENADMINISTEREDTOMICEBYILEALINJECTION YETTOLEROGENICWHENADMINISTEREDORALLY LIKELYDUE TO DEGRADATION IN THE DIGESTIVE TRACT #LINICAL STUDIES HAVE ALSO DEMONSTRATED THE IMPORTANTROLEOFENZYMATICDIGESTIONINTHEINDUCTIONOFORALTOLERANCEINHUMANS 0HARMACOLOGICSUPPRESSIONOFGASTRICACIDSECRETIONBYANTIULCERMEDICATIONSHAS BEENASSOCIATEDWITHINCREASEDFOOD SPECIlC)G%PRODUCTIONIMPAIREDDIGESTIONOF FOODPROTEINSMAYRENDERTHEMPOTENTSENSITIZERS;20]. 0ROTEINSTHATARENOTDEGRADEDBYGASTROINTESTINALENZYMESENCOUNTERTHEINTESTINAL EPITHELIUMANDTHELYMPHOIDTISSUEBENEATHITINSEVERALWAYSSEE&IG26.2) [8]. $ENDRITICCELLSEXTENDPROCESSESBETWEENEPITHELIALCELLSTOSAMPLELUMINALANTIGENS -CELLSARESPECIALIZEDEPITHELIALCELLSOVERLYING0EYERSPATCHESTHATTAKEUPPARTICULATE ANTIGENSANDDELIVERTHEMTOSUBEPITHELIALDENDRITICCELLS WHICHINTURNPRESENTANTIGENSTO"CELLSIN0EYERSPATCHES3OLUBLEANTIGENS WHICHARENOTEFlCIENTLYTAKEN UP BY - CELLS CROSS THE EPITHELIUM BY TRANSCELLULAR OR PARACELLULAR ROUTES TO THE LAMINAPROPRIA WHERETHEYENCOUNTER4CELLSANDMACROPHAGES)NTESTINALEPITHELIAL CELLSACTASNONPROFESSIONALANTIGEN PRESENTINGCELLS ENDOCYTOSINGSOLUBLEANTIGENS ANDPRESENTINGTHEMTOPRIMED4CELLS

 /RAL4OLERANCEAND%OSINOPHILIC%SOPHAGITIS

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Fig. 26.2 3ITESOFANTIGENUPTAKEINTHEGUTa !NTIGENCANBESAMPLEDBYDENDRITICCELLSTHAT EXTENDPROCESSESINTOTHELUMENb -CELLSOVERLYING0EYERSPATCHESTAKEUPPARTICULATEANTIGENS ANDTHENDELIVERTHEMTODENDRITICCELLSINTHESUBEPITHELIALREGIONANDTHENTOUNDERLYING" CELL FOLLICLES WHERE)G!COMMITMENTOCCURSc 3OLUBLEANTIGENSCANCROSSTHEEPITHELIUMTHROUGH TRANSCELLULAR OR PARACELLULAR ROUTES TO THEN ENCOUNTER 4 CELLS OR MACROPHAGES IN THE LAMINA PROPRIA!DAPTEDFROM#HEHADEAND-AYER/RALTOLERANCEANDITSRELATIONTOFOODHYPERSENSITIVITIES *!LLERGY#LIN)MMUNOL  WITHPERMISSION

Mechanisms of Oral Tolerance /RALTOLERANCEISINDUCEDTHROUGHTWOPRIMARYEFFECTORMECHANISMSnACTIVESUPPRESSION BYREGULATORY44REG CELLSANDCLONALANERGYORDELETIONSEE&IG26.3 4HEDOSEOF THEANTIGENISAKEYFACTORDETERMININGWHICHWILLTAKEPLACE;21], although it is likely

344 Fig. 26.3 -ECHANISMSOF oral tolerance. (a) Generation OFANIMMUNERESPONSE REQUIRES4 CELLRECEPTOR LIGATIONWITHPEPTIDE -(# COMPLEXESINTHEPRESENCEOF APPROPRIATECOSTIMULATORY MOLECULES#$AND#$ and cytokines. (b (IGH DOSE TOLERANCEISINDUCEDBY4 CELL receptor cross linking in the ABSENCEOFCOSTIMULATIONOR INTHEPRESENCEOFINHIBITORY ligands (CD95 and CD95 ligand), leading to anergy ORDELETION RESPECTIVELY (c ,OWDOSESOFORALANTIGEN LEADTOTHEACTIVATIONOF REGULATORY#$#$4 CELLS WHICHSUPPRESSIMMUNE responses through soluble or CELLSURFACE ASSOCIATED CYTOKINES), AND4'& E). L,IGANDR receptor. !DAPTEDFROM#HEHADEAND Mayer. Oral tolerance ANDITSRELATIONTOFOOD HYPERSENSITIVITIES *!LLERGY#LIN)MMUNOL   WITHPERMISSION

06ARSHNEYAND!7"URKS

 /RAL4OLERANCEAND%OSINOPHILIC%SOPHAGITIS

345

Fig. 26.4 !LLERGICSENSITIZATIONVSORALTOLERANCE&OODANTIGENEXPOSUREINTHEGASTROINTESTINAL MUCOSAL IMMUNE SYSTEM CAN RESULT IN ORAL TOLERANCE INDUCTION OR ALLERGIC SENSITIZATION &OX0 FORKHEAD BOX 0 )&. INTERFERON ), INTERLEUKIN 4'& TRANSFORMING GROWTH FACTOR 4H 4 HELPER CELL4REG 4 REGULATORYCELL!DAPTEDFROM3CURLOCK "URKS AND*ONES/RALIMMUNOTHERAPYFOR FOODALLERGY#URR!LLERGY!STHMA2EP  WITHPERMISSION

THETWOPROCESSESARENOTMUTUALLYEXCLUSIVE,OWDOSESOFANTIGENINDUCE4REGCELLS THATPRODUCEIMMUNOREGULATORYCYTOKINESSUCHASTRANSFORMINGGROWTHFACTOR4'& BETAAND), ANDACTIVELYSUPPRESSREACTIVELYMPHOCYTES4REGCELLSWEREINITIALLY CHARACTERIZEDBYTHEIRSTABLESURFACEEXPRESSIONOFTHEHIGH AFlNITYCOMPONENTOFTHE IL-2 receptor, CD25 [22=-ORERECENTLY STUDIESHAVESHOWNTHATSUBSETSEXPRESSTHE TRANSCRIPTIONFACTORFORKHEADBOX0&/80 THEKEYREGULATORYGENEINTHEDEVELOPMENTOFNATURALLYOCCURRING#$4REGCELLSSEE&IG26.4) [23=4REGCELLSARE FUNCTIONALLYDISTINCTFROMEFFECTOR4CELLSBYTHEIRABILITYTOLIMIT4CELLPROLIFERATION ANDFUNCTION;24=#$#$4REGCELLSMIGRATETOLYMPHOIDORGANSANDSUPPRESS EFFECTORCELLSTHROUGHCELLnCELLINTERACTIONINVOLVINGSURFACE BOUND4'& BETA;25], ALTHOUGHTHEIRREGULATORYFUNCTIONCANALSOOCCURINDEPENDENTLYOF4'& BETA;26]. 4REGCELLSALSOMIGRATETOTARGETORGANS WHERETHEYEXERTTHEIRIMMUNOSUPPRESSIVE EFFECTSBYRELEASINGNONANTIGEN SPECIlCCYTOKINES;10]. $EFECTIVE4REGDEVELOPMENTHASBEENSHOWNTOPLAYAKEYROLEINTHEPATHOGENESISOFAUTOIMMUNEANDALLERGICDISEASE)MMUNEDYSREGULATION POLYENDOCRINOPATHY ENTEROPATHY 8 LINKED)0%8 SYNDROME WHICHISCAUSEDBYMUTATIONSINTHEGENE ENCODING &/80 IS CHARACTERIZED BY AUTOAGGRESSIVE LYMPHOCYTE CLONES DUE TO A FAILUREIN4REGDEVELOPMENT;27=!N)0%8VARIANTCHARACTERIZEDBYSEVEREALLERGIC ASWELLASAUTOIMMUNEMANIFESTATIONSHASBEENDESCRIBED;28=)NTHISCASE AMUTATIONINANONCODINGREGIONOFTHE&/80GENERESULTSINADISORDERCHARACTERIZEDBY SEVEREFOODALLERGY ATOPICDERMATITIS ELEVATEDSERUM)G% ANDEOSINOPHILIAINADDItion to enteropathy. Allergen-induced EoE pathogenesis is thought to be dependent ON ADAPTIVE 4 CELL IMMUNITY ;29= AND DEFECTS IN 4REG FUNCTION MAY UNDERLIE THE DEVELOPMENT OF %O% 2ECENT WORK HAS DEMONSTRATED AN IMBALANCE IN ESOPHAGEAL EFFECTORAND4REGCELLSINAMOUSEMODELOF%O% SUGGESTINGTHATTHISMAYBEACRUCIALFACTORINTHEPROMOTIONOFPATHOGENICIMMUNOLOGICALRESPONSESIN%O%;30]. 4REGCELLSMAYALSOBEIMPORTANTASAMARKEROFTOLERANCEINTHESETTINGOFRESOLVINGFOODALLERGY4HEAPPEARANCEOFCIRCULATING#$#$4CELLSHASBEENASSOCIATED WITH THE DEVELOPMENT OF TOLERANCE IN CHILDREN WITH A HISTORY OF NON )G% MEDICATED MILK ALLERGY ;11]. Milk-tolerant children also had decreased IN VITRO PROLIFERATIVE RESPONSES TO BOVINE BETA LACTOGLOBULIN IN PERIPHERAL BLOOD

346

06ARSHNEYAND!7"URKS

MONONUCLEARCELLSCOMPAREDWITHTHOSEWHOHADPERSISTENTALLERGY3IMILARLY THE UTILITYOF4REGQUANTIlCATIONISBEINGINVESTIGATEDASAPOTENTIALBIOMARKEROFTOLERANCEINSTUDIESOFORALIMMUNOTHERAPY/)4 FORFOODALLERGY)NTENSUBJECTSWHO RECEIVEDPEANUT/)4FORASLONGASMONTHS THENUMBEROF&OX04CELLSINCREASED APPROXIMATELY FOLDINPEANUT STIMULATEDCELLSATANDMONTHSANDDECREASED THEREAFTER RETURNINGTOBASELINELEVELSBYMONTHS;31]. 7HEREASLOWDOSESOFANTIGENFAVOR4REG DRIVENTOLERANCE HIGH DOSETOLERANCE IS MEDIATED BY LYMPHOCYTE ANERGY OR CLONAL DELETION !NERGY CAN BE INDUCED THROUGH BINDING OF A PEPTIDE ANTIGEN IN THE ABSENCE OF COSTIMULATORY SIGNALS PROVIDEDEITHERBYSOLUBLECYTOKINES),  ORBYINTERACTIONSBETWEENRECEPTORSON 4CELLS#$ ANDCOUNTERRECEPTORSONANTIGEN PRESENTINGCELLS#$AND#$ [32=(IGHDOSESOFANTIGENINDUCEDELETIONOFREACTIVE4CELLSBYMEANSOFAPOPTOSIS )N MICE TRANSGENIC FOR OVALBUMIN SPECIlC 4 CELL RECEPTOR GENES ORAL ANTIGEN ADMINISTRATIONLEDTODELETIONOFANTIGEN SPECIlC4CELLSIN0EYERSPATCHES;33]. 4HEDELETIONWASMEDIATEDBYAPOPTOSISOFTARGETCELLS)NTHEAFOREMENTIONEDSTUDY OFOPEN LABELPEANUT/)4 GENOME WIDEOLIGONUCLEOTIDEMICROARRAYANALYSESCOMPAREDTRANSCRIPTIONPATTERNSIN4CELLSOBTAINEDBEFOREANDMONTHSAFTER/)4TREATMENTANDREVEALEDDOWNREGULATIONOFGENESINSEVERALAPOPTOSISPATHWAYS ALTHOUGH ITISUNCLEARATTHISTIMEWHETHERTHEOBSERVEDCHANGESINCLUDEDALTEREDAPOPTOSISOF ANTIGEN SPECIlC 4 CELLS ;31= 4O HELP ISOLATE EFFECTS ON ANTIGEN SPECIlC 4 CELLS STUDIESUSING-(#CLASS))!RAHPEPTIDETETRAMERSARECURRENTLYUNDERWAY )T IS LIKELY THAT LOW AND HIGH DOSE TOLERANCE MECHANISMS ARE NOT MUTUALLY EXCLUSIVEANDACTUALLYOVERLAPINVIVO#YTOTOXIC4LYMPHOCYTE ASSOCIATEDANTIGEN #4,!  WAS lRST DESCRIBED IN A PATHWAY OF ANERGY INDUCTION AND HAS BEEN SHOWNTOPLAYACRUCIALROLEINTHEINDUCTIONOFHIGH DOSETOLERANCE;34=(OWEVER #4,!  BINDINGTO4CELLSALSOLEADSTOPRODUCTIONOF4'& BETA ANIMMUNOREGULATORYCYTOKINETHATMAYCOUNTERBALANCE#$ COSTIMULATIONOF4CELLACTIVATION [35=)NADDITION PHAGOCYTOSISOFAPOPTOTICCELLSBYMACROPHAGESRESULTSININDUCTIONOF4'& BETA FURTHERCONTRIBUTINGTOANIMMUNOSUPPRESSIVEMILIEUFAVORING tolerance [36].

Factors Influencing Development of Tolerance )NADDITIONTOANTIGENDOSE SEVERALOTHERFACTORSINmUENCETHEDEVELOPMENTOFTOLERANCE INCLUDINGANTIGENPROPERTIES ROUTEOFEXPOSURE AGEOFTHEHOST GENETICFACTORS AND GUTmORA&IG26.4 0ARTICULATEANTIGENSTENDTOBEMOREALLERGENICTHANSOLUBLE ANTIGENS ALTHOUGHMOSTFOODALLERGENSARESOLUBLEPROTEINS3OLUBILITYCANBEALTERED BYFOODPREPARATIONTECHNIQUESANDHEATTREATMENT&OREXAMPLE ROASTINGHASBEEN SHOWN TO PROGRESSIVELY DECREASE THE SOLUBILITY OF PEANUT PROTEINS RENDERING THE PROTEIN MORE IMMUNOGENIC AND INCREASING THE CAPACITY OF PEANUT SPECIlC )G% TO bind the protein when encountered in the gut [37=)NNATEIMMUNOSTIMULATORYPROPERTIES OFCERTAINDIETARYPROTEINSMAYALSOENHANCETHEIRALLERGENICITYANDRESULTINA4H RESPONSEINGENETICALLYSUSCEPTIBLEINDIVIDUALS&OREXAMPLE THEMAJORGLYCOPROTEIN

 /RAL4OLERANCEAND%OSINOPHILIC%SOPHAGITIS

347

PEANUTALLERGEN !RAH WASFOUNDTOINDUCEDENDRITICCELLSTHATPRIME4H SKEWED 4CELLRESPONSES;38]. 4HEROUTEOFALLERGENEXPOSUREALSOPLAYSANIMPORTANTROLEINTHEDEVELOPMENT OFALLERGYORORALTOLERANCE!SMENTIONEDPREVIOUSLY ORALADMINISTRATIONOFANANTIGEN FOLLOWED BY SUBCUTANEOUS IMMUNIZATION RESULTS IN GREATLY REDUCED IN VITRO IMMUNERESPONSESTOTHEANTIGEN ILLUSTRATINGTHECONCEPTOFORALTOLERANCE&IG26.1) [7=&OODANTIGENEXPOSUREBYOTHERROUTESMAYRESULTINSENSITIZATIONANDRESULTANT ALLERGY)NMURINEMODELS EPICUTANEOUSEXPOSURETOPEANUTPROTEININDUCESAPOTENT 4H IMMUNE RESPONSE WITH HIGH LEVELS OF )G% AND ),  PRODUCTION POTENTIALLY PREVENTINGTHEINDUCTIONOFORALTOLERANCE;39=4HISPRINCIPLEMAYALSOBERELEVANT TO THE PATHOGENESIS OF %O% AS EPICUTANEOUS ALLERGEN EXPOSURE IN MICE HAS BEEN SHOWNTOPRIMEFORMARKED4H DEPENDENTESOPHAGEALEOSINOPHILICINmAMMATION WITHSUBSEQUENTCHALLENGE;6=3IMILARLY EXPOSURETOANINHALEDRESPIRATORYALLERGENINMICEWASSHOWNTOPROMOTEEOSINOPHILICESOPHAGITIS SUGGESTINGCOMMON MECHANISMSREGULATINGEOSINOPHILICINmAMMATIONINTHERESPIRATORYTRACTANDESOPHagus [40= )N CONTRAST ORAL OR INTRAGASTRIC ALLERGEN ADMINISTRATION DID NOT ELICIT EOSINOPHILICINmAMMATIONINTHEESOPHAGUS !SWITHOTHERATOPICCONDITIONS HOSTFACTORSPLAYACENTRALROLEINTHEDETERMINATION OF FOOD ALLERGY OR ORAL TOLERANCE !N INDIVIDUALS GENETIC MAKE UP PLAYS AN IMPORTANTROLEINWHETHEREXPOSURETOAGIVENPROTEINRESULTSINSENSITIZATIONORTOLERANCE -URINE STUDIES HAVE DEMONSTRATED THE STRAIN DEPENDENCE OF ALLERGIC RESPONSES )N A MURINE STUDY OF PEANUT ALLERGEN GENE IMMUNIZATION MICE WERE IMMUNIZEDWITHPLASMID$.!ENCODING!RAH ONEOFTHEMAJORPEANUTALLERGENS [41=4HERESPONSETOSUBSEQUENTPEANUTPROTEININJECTIONWASSTRAIN DEPENDENTALL OFTHE#((E3NMICEBUTNONEOFTHE!+2*OR"!,"CMICEDEVELOPEDANAPHYLAXIS 3IMILARLY %O% HAS BEEN SHOWN TO HAVE A STRONG FAMILIAL ASSOCIATION ;2]. 4HESIBLINGRECURRENCERISKRATIOlSFOR%O%HASBEENESTIMATEDASAPPROXIMATELY with lSVALUEOFGREATERTHANINDICATINGINCREASEDRISKOFDEVELOPMENTOFTHEDISEASEAMONGSIBLINGSOFTHEPROBANDCOMPAREDWITHTHATOFTHEGENERALPOPULATION [42='ENOME WIDEEXPRESSIONANALYSESHAVEIDENTIlEDCCL26, the gene encoding THE EOSINOPHIL SPECIlC CHEMOATTRACTANT EOTAXIN  AS THE MOST HIGHLY INDUCED GENEIN%O%PATIENTSCOMPAREDWITHITSEXPRESSIONLEVELINHEALTHYINDIVIDUALS;43]. 4HEDISEASE ASSOCIATEDALLELEISONLYPRESENTINOF%O%CASES SUGGESTINGTHAT ADDITIONAL RISK VARIANTS EXIST ! RECENT GENOME WIDE ASSOCIATION STUDY IDENTIlED TSLP as an EoE susceptibility locus [44]. TSLPWASFOUNDTOBEOVEREXPRESSEDIN ESOPHAGEALBIOPSIESFROMINDIVIDUALSWITH%O% SIMILARTOlNDINGSINLESIONALATOPIC DERMATITIS SKIN AND THE ASTHMA AFFECTED LUNG ;45= 43,0 THYMIC STROMAL LYMPHOPOIETIN HAS BEEN IMPLICATED AS A KEY INITIATOR OF ALLERGIC SENSITIZATION ;46], WHICHMAYPROVETOBEASENTINELEVENTINTHEPATHOGENESISOF%O% 4HEHOSTSAGEISANOTHERFACTORINmUENCINGTHEDEVELOPMENTOFORALTOLERANCE )MMATURITYOFTHEIMMUNOLOGICANDGASTROINTESTINALSYSTEMSPREDISPOSESINFANTSTO IMPAIREDTOLERANCEANDRESULTANTFOODALLERGY;47=)NFANTSANDYOUNGCHILDRENHAVE ANIMMATUREGASTROINTESTINALMUCOSALSURFACE WITHINCREASEDINTESTINALPERMEABILITY DECREASED GASTRIC ACIDITY AND DECREASED PANCREATIC ENZYME PRODUCTION ;48]. In ADDITION SECRETORY)G!ISABSENTINNEWBORNS!SARESULT INTACTPROTEINSAREMORE

348

06ARSHNEYAND!7"URKS

LIKELYTOBESYSTEMICALLYABSORBEDANDMAYTHENSTIMULATETHEIMMUNESYSTEMAND result in IgE production [47= &URTHERMORE INFANTS IMMUNE SYSTEMS ARE SKEWED TOWARD4H SKEWEDALLERGEN SPECIlCRESPONSESATBIRTH;49=4HESERESPONSESARE RAPIDLYSUPPRESSEDDURINGTHElRSTYEAROFLIFEINNONATOPICCHILDRENBUTPERSISTIN atopic children. 4HE RESIDENT mORA OF THE GASTROINTESTINAL TRACT ALSO PLAYS A CENTRAL ROLE IN THE INDUCTION OF ORAL TOLERANCE 4HE MATURATION OF GUT ASSOCIATED LYMPHOID TISSUE DEPENDS ON THE PRESENCE OF COMMENSAL MICROORGANISMS ;16= !FTER ORAL ANTIGEN ADMINISTRATION MICE RAISED IN GERM FREE ENVIRONMENTS MAINTAINED 4H MEDIATED IMMUNE RESPONSES CHARACTERIZED BY PRODUCTION OF )G% )G' AND ),  ;50]. 2ECONSTITUTION OF THE GASTROINTESTINAL TRACT WITH Bifidobacterium infantis restored THEABILITYTOINDUCEORALTOLERANCE THOUGHONLYIFPERFORMEDINTHENEONATALPERIOD THUSDEMONSTRATINGTHESHAREDROLESOFINTESTINALmORAASWELLASAGEOFEXPOSUREIN THEDEVELOPMENTOFTOLERANCE

Conclusions /RALTOLERANCEISCRUCIALINALLOWINGAWIDEARRAYOFDIETARYPROTEINSACCESSTOTHE BODYWITHOUTACTIVATINGHARMFULIMMUNERESPONSES!BREAKDOWNINORALTOLERANCE MECHANISMSORAFAILURETOESTABLISHTOLERANCECANRESULTINFOODALLERGYANDMAY UNDERLIETHEPATHOGENESISOF%O%!LLERGYHASBEENIMPLICATEDINTHEETIOLOGYOF %O%BASEDONPATIENTCHARACTERISTICS EVIDENCEOFALLERGENSENSITIZATION ANDINVIVO ANDINVITROIMMUNOLOGIClNDINGS;51=(OWEVER THEPRECISEROLEOFFOOD CUTANEOUS ORAIRBORNEALLERGENSENSITIZATIONINTHEDEVELOPMENTOF%O%HASYETTOBEFULLY ELUCIDATED!LLERGYMAYBEASTIMULUSFORTHERECRUITMENTOFEOSINOPHILSTOTHEGASTROINTESTINALTRACTORMAYLEADTOTHEFAILUREOF4REGCELLSLEADINGTOADISRUPTIONIN low-dose oral tolerance [52=!BREAKDOWNINMECHANISMSOFHIGH DOSEORALTOLERANCE WHICHINCLUDELYMPHOCYTEANERGYORDELETION MAYALSOLEADTOTHEDEVELOPMENTOF%O%ASWELLASCLASSICFORMSOFFOODALLERGY&URTHERSTUDYTOCLARIFYTHEROLE OFORALTOLERANCEINTHEDEVELOPMENTOF%O%CANHELPIDENTIFYPOTENTIALPREVENTION strategies and therapeutic targets.

References "LANCHARD # 2OTHENBERG -% "ASIC PATHOGENESIS OF EOSINOPHILIC ESOPHAGITIS 'ASTROINTEST %NDOSC#LIN.!M nX .OEL 2* 0UTNAM 0% 2OTHENBERG -% %OSINOPHILIC ESOPHAGITIS . %NGL * -ED  n 6ITELLAS+-ETAL)DIOPATHICEOSINOPHILICESOPHAGITIS2ADIOLOGY n /RENSTEIN32ETAL4HESPECTRUMOFPEDIATRICEOSINOPHILICESOPHAGITISBEYONDINFANCYACLINICALSERIESOFCHILDREN!M*'ASTROENTEROL n 3PERGEL *- ET AL 4HE USE OF SKIN PRICK TESTS AND PATCH TESTS TO IDENTIFY CAUSATIVE FOODS IN EOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOL n

 /RAL4OLERANCEAND%OSINOPHILIC%SOPHAGITIS

349

!KEI(3ETAL%PICUTANEOUSANTIGENEXPOSUREPRIMESFOREXPERIMENTALEOSINOPHILICESOPHAGITIS INMICE'ASTROENTEROLOGY n #HASE-)NHIBITIONOFEXPERIMENTALDRUGALLERGYBYPRIORFEEDINGOFTHESENSITIZINGAGENT0ROC 3OC%XP"IOLn #HEHADE- -AYER,/RALTOLERANCEANDITSRELATIONTOFOODHYPERSENSITIVITIES*!LLERGY#LIN )MMUNOL nQUIZ "URKS!7 ,AUBACH3 *ONES3-/RALTOLERANCE FOODALLERGY ANDIMMUNOTHERAPYIMPLICATIONSFORFUTURETREATMENT*!LLERGY#LIN)MMUNOL n &ARIA!- 7EINER(,/RALTOLERANCE)MMUNOL2EVn +ARLSSON-2 2UGTVEIT* "RANDTZAEG0!LLERGEN RESPONSIVE#$#$REGULATORY4CELLS INCHILDRENWHOHAVEOUTGROWNCOWSMILKALLERGY*%XP-ED n -ACFARLANE'4 -ACFARLANE3(UMANCOLONICMICROBIOTAECOLOGY PHYSIOLOGYANDMETABOLIC POTENTIALOFINTESTINALBACTERIA3CAND*'ASTROENTEROL3UPPLn -ESTECKY * -C'HEE *2 )MMUNOGLOBULIN ! )G!  MOLECULAR AND CELLULAR INTERACTIONS INVOLVEDIN)G!BIOSYNTHESISANDIMMUNERESPONSE!DV)MMUNOLn +RAEHENBUHL*0 .EUTRA-24RANSEPITHELIALTRANSPORTANDMUCOSALDEFENCE))SECRETIONOF)G! 4RENDS#ELL"IOL n -ENEZES* $A3 ETAL3TIMULATIONBYFOODPROTEINSPLAYSACRITICALROLEINTHEMATURATIONOF THEIMMUNESYSTEM)NT)MMUNOL n (RNCIR4ETAL'UTMICROBIOTAANDLIPOPOLYSACCHARIDECONTENTOFTHEDIETINmUENCEDEVELOPMENTOFREGULATORY4CELLSSTUDIESINGERM FREEMICE"-#)MMUNOL !ALBERSE2#3TRUCTURALBIOLOGYOFALLERGENS*!LLERGY#LIN)MMUNOL n 5NTERSMAYR% *ENSEN *AROLIM%4HEROLEOFPROTEINDIGESTIBILITYANDANTACIDSONFOODALLERGY OUTCOMES*!LLERGY#LIN)MMUNOL nQUIZn -ICHAEL*4HEROLEOFDIGESTIVEENZYMESINORALLYINDUCEDIMMUNETOLERANCE)MMUNOL)NVEST n 5NTERSMAYR%ETAL!NTI ULCERDRUGSPROMOTE)G%FORMATIONTOWARDDIETARYANTIGENSINADULT PATIENTS&!3%"* n &RIEDMAN! 7EINER(,)NDUCTIONOFANERGYORACTIVESUPPRESSIONFOLLOWINGORALTOLERANCEIS DETERMINEDBYANTIGENDOSAGE0ROC.ATL!CAD3CI53! n 3AKAGUCHI3ETAL)MMUNOLOGICSELF TOLERANCEMAINTAINEDBYACTIVATED4CELLSEXPRESSING),  RECEPTORALPHA CHAINS#$ "REAKDOWNOFASINGLEMECHANISMOFSELF TOLERANCECAUSESVARIOUSAUTOIMMUNEDISEASES*)MMUNOL n (ORI3 .OMURA4 3AKAGUCHI3#ONTROLOFREGULATORY4CELLDEVELOPMENTBYTHETRANSCRIPTION FACTOR&OXP3CIENCE n !NA) *ANINE,# &IONA02EGULATORY4CELLSSUPPRESSSYSTEMICANDMUCOSALIMMUNEACTIVATIONTOCONTROLINTESTINALINmAMMATION)MMUNOL2EV n .AKAMURA + +ITANI ! 3TROBER 7 #ELL CONTACT DEPENDENT IMMUNOSUPPRESSION BY #$ #$ REGULATORY4CELLSISMEDIATEDBYCELLSURFACE BOUNDTRANSFORMINGGROWTHFACTORBETA *%XP-ED n 0ICCIRILLO#!ETAL#$ #$ REGULATORY4CELLSCANMEDIATESUPPRESSORFUNCTIONINTHE ABSENCE OF TRANSFORMING GROWTH FACTOR BETA PRODUCTION AND RESPONSIVENESS * %XP -ED  n /CHS ($ 'AMBINERI % 4ORGERSON 42 )0%8 &/80 AND REGULATORY 4 CELLS A MODEL FOR AUTOIMMUNITY)MMUNOL2ESn n 4ORGERSON42ETAL3EVEREFOODALLERGYASAVARIANTOF)0%8SYNDROMECAUSEDBYADELETIONIN ANONCODINGREGIONOFTHE&/80GENE'ASTROENTEROLOGY n -ISHRA!ETAL#RITICALROLEFORADAPTIVE4CELLIMMUNITYINEXPERIMENTALEOSINOPHILICESOPHAGITISINMICE*,EUKOC"IOL n :HU8ETAL!NIMBALANCEOFESOPHAGEALEFFECTORANDREGULATORY4CELLSUBSETSINEXPERIMENTAL EOSINOPHILICESOPHAGITISINMICE!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n *ONES3-ETAL#LINICALEFlCACYANDIMMUNEREGULATIONWITHPEANUTORALIMMUNOTHERAPY* !LLERGY#LIN)MMUNOL nEn !PPLEMAN,* "OUSSIOTIS6!4CELLANERGYANDCOSTIMULATION)MMUNOL2EVn

350

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#HEN 9 ET AL 0ERIPHERAL DELETION OF ANTIGEN REACTIVE 4 CELLS IN ORAL TOLERANCE .ATURE  n 3AMOILOVA %" ET AL #4,!  IS REQUIRED FOR THE INDUCTION OF HIGH DOSE ORAL TOLERANCE )NT )MMUNOL n #HEN 7 *IN 7 7AHL 3- %NGAGEMENT OF CYTOTOXIC 4 LYMPHOCYTE ASSOCIATED ANTIGEN  #4,!  INDUCESTRANSFORMINGGROWTHFACTORBETA4'& BETA PRODUCTIONBYMURINE#$ 4CELLS*%XP-ED n &REIRE DE ,IMA#'ETAL5PTAKEOFAPOPTOTICCELLSDRIVESTHEGROWTHOFAPATHOGENICTRYPANOSOMEINMACROPHAGES.ATURE n +OPPER2!ETAL0EANUTPROTEINALLERGENSTHEEFFECTOFROASTINGONSOLUBILITYANDALLERGENICITY )NT!RCH!LLERGY)MMUNOL n 3HREFmER 7' ET AL 4HE MAJOR GLYCOPROTEIN ALLERGEN FROM Arachis hypogaea, Ara h 1, is a LIGANDOFDENDRITICCELL SPECIlC)#!- GRABBINGNONINTEGRINANDACTSASA4HADJUVANTINVITRO *)MMUNOL n 3TRID*ETAL%PICUTANEOUSEXPOSURETOPEANUTPROTEINPREVENTSORALTOLERANCEANDENHANCES ALLERGICSENSITIZATION#LIN%XP!LLERGY n -ISHRA!ETAL!NETIOLOGICALROLEFORAEROALLERGENSANDEOSINOPHILSINEXPERIMENTALESOPHAGITIS*#LIN)NVEST n ,I8ETAL3TRAIN DEPENDENTINDUCTIONOFALLERGICSENSITIZATIONCAUSEDBYPEANUTALLERGEN$.! IMMUNIZATIONINMICE*)MMUNOL n "LANCHARD# 7ANG. 2OTHENBERG-%%OSINOPHILICESOPHAGITISPATHOGENESIS GENETICS AND THERAPY*!LLERGY#LIN)MMUNOL n "LANCHARD#ETAL%OTAXIN ANDAUNIQUELYCONSERVEDGENE EXPRESSIONPROlLEINEOSINOPHILIC ESOPHAGITIS*#LIN)NVEST n 2OTHENBERG-%ETAL#OMMONVARIANTSATQASSOCIATEWITHPEDIATRICEOSINOPHILICESOPHAGITIS .AT'ENET n /YOSHI -+ ET AL #ELLULAR AND MOLECULAR MECHANISMS IN ATOPIC DERMATITIS !DV )MMUNOL n ,IU9*43,0INEPITHELIALCELLANDDENDRITICCELLCROSSTALK!DV)MMUNOLn .OWAK 7EGRZYN ! 3AMPSON (! !DVERSE REACTIONS TO FOODS -ED #LIN .ORTH !M  n 3AMPSON(!&OODALLERGY0ARTIMMUNOPATHOGENESISANDCLINICALDISORDERS*!LLERGY#LIN )MMUNOL0T n 0RESCOTT3,ETAL$EVELOPMENTOFALLERGEN SPECIlC4 CELLMEMORYINATOPICANDNORMALCHILDREN,ANCET n 3UDO.ETAL4HEREQUIREMENTOFINTESTINALBACTERIALmORAFORTHEDEVELOPMENTOFAN)G%PRODUCTIONSYSTEMFULLYSUSCEPTIBLETOORALTOLERANCEINDUCTION*)MMUNOL n &URUTA'4ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTSASYSTEMATICREVIEWANDCONSENSUSRECOMMENDATIONSFORDIAGNOSISANDTREATMENT'ASTROENTEROLOGY n 3EIBOLD&&OOD INDUCEDIMMUNERESPONSESASORIGINOFBOWELDISEASE$IGESTION  n

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Chapter 27

Treatment of Eosinophilic Esophagitis with Biological Agents Kathryn A. Peterson, Molly O’Gorman, W. Daniel Jackson, and Gerald J. Gleich

Keywords %OSINOPHILICESOPHAGITISs$YSPHAGIAs#HESTPAINs)NFLAMMATION s3TEROIDADMINISTRATION

Introduction 4RADITIONALTHERAPIESFOREOSINOPHILICESOPHAGITISHAVEFOCUSEDONDIETARYMODIlCATIONS ANDORANTI INmAMMATORYTREATMENTS PRIMARILYSYSTEMICORTOPICALGLUCOCORTICOIDS (OWEVER BOTHSUCHAPPROACHESAREDIFlCULTTOMAINTAINFORBOTHPATIENTSANDCLINI CIANS%LEMENTALDIETS CONTAININGAMINOACIDSASAPROTEINSUBSTITUTEPLUSSIMPLE CARBOHYDRATESANDFATTYACIDS AREEFFECTIVEINUPTOOFCHILDREN;1–3= BUTDUE TOPOORPALATABILITYANDCOST THESEDIETSOFTENARENOTSUSTAINABLE!SIX FOODELIMI NATIONDIETISEFFECTIVEINUPTOOFCHILDRENANDOFADULTS; 4= BUTTHISDIETIS LIMITEDBYSIGNIlCANTNONCOMPLIANCE3UBSEQUENTLY CLINICIANSHAVEFOCUSEDONTHE USE OF MEDICATIONS ABLE TO SUPPRESS INmAMMATION FOR EOSINOPHILIC ESOPHAGITIS %O% 4HElRSTREPORTSOFTHEUSEOFORALGLUCOCORTICOIDS;5=ANDSWALLOWEDAERO SOLIZEDSTEROIDSFORTHETOPICALTREATMENTOF%O%;6=WEREPUBLISHEDIN4HE RESULTSOFTHElRSTRANDOMIZEDCONTROLLEDTRIALOFSWALLOWEDmUTICASONEINCHILDREN WITH%O%INWEREDISAPPOINTING WITHONLYOFCHILDRENACHIEVINGREMIS SION COMPAREDTOOFTHOSERECEIVINGPLACEBO;=4HEBIOPSIESFROMTHEDISTAL ESOPHAGUSAPPEAREDMORERESISTANTTOmUTICASONEADMINISTRATIONARGUINGTHATPER HAPSTHERESISTANCETOTHISTHERAPYWASRELATEDTOTHEROUTEOFADMINISTRATION

'*'LEICH*) $EPARTMENTOF$ERMATOLOGY 5NIVERSITYOF5TAH(OSPITAL .ORTH%AST 3ALT,AKE#ITY 54 53! E MAIL'ERALDGLEICH HSCUTAHEDU #!,IACOURASAND*%-ARKOWITZEDS Eosinophilic Esophagitis #LINICAL'ASTROENTEROLOGY $/)    ? Ú3PRINGER3CIENCE"USINESS-EDIA ,,#

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0RESENTLY THEEFlCACYOFSUSPENSIONANDVISCOUSFORMULATIONSOFSTEROIDSAREUNDER INVESTIGATIONFOR%O%3TRAUMANNRECENTLYREPORTEDSUCCESSTREATINGADOLESCENTS ANDADULTSWITH%O%USINGMGBUDESONIDEMGM, SUSPENSION;=4WOWEEKS OFTHERAPYWITHTHESUSPENSIONRESULTEDINADROPOFPEAKEOSINOPHILCOUNTSFROM TOEOSINOPHILSHIGHPOWERlELD(0& WITHPATIENTSACHIEVINGCOMPLETEHIS TOLOGICALREMISSION!PILOTTRIALOFORALVISCOUSBUDESONIDEDEMONSTRATEDRESPONSE EOSINOPHILS(0& INOFCHILDREN;=)NOTHERSTUDIESOFTHISISSUE CHILDREN RECEIVEDnMGDOSEDEPENDENTONHEIGHT ORALVISCOUSBUDESONIDEFORMONTHS WITHRESPONSEDElNEDASLESSTHANEOSINOPHILS(0& INOFCHILDREN; 10= !DDITIONALLY THECHILDRENEXPERIENCEDSUBSTANTIALSYMPTOMATICRELIEF (OWEVER ALTHOUGHTHESIDEEFFECTSSEENINTHERECENTTRIALSOFSWALLOWEDTOPICAL BUDESONIDESUSPENSIONSHAVEBEENMINIMALANDSYSTEMICABSORPTIONOFBUDESONIDE AND mUTICASONE FROM THE GASTROINTESTINAL TRACT ALSO IS MINIMAL ;11–13= CONCERNS REMAINOVERPOSSIBLECANDIDALESOPHAGITISANDADRENALSUPPRESSIONASSOCIATEDWITH PROLONGEDUSEOFSTEROIDS!DDITIONALLY ASUBSTANTIALNUMBEROFCHILDRENANDADULTS AREREFRACTORYTOSTEROIDADMINISTRATIONANDCONTINUETOSUFFERFROMONGOINGDYSPHAGIA ANDCHESTPAIN

Biological Agents Neutralization of IgE by Omalizumab %O%OFTENDEVELOPSINCONCERTWITHATOPYASSUGGESTEDBYTHEEFFECTIVENESSOFFOOD AVOIDANCEINCHILDREN&OODANDAEROALLERGENSENSITIVITIESAREFOUNDCOMMONLY AND ASTHMAISRELATIVELYPREVALENTINSUCHPATIENTS;14=)NDEED THEREISABUNDANTEVI DENCE IMPLICATING ACTIVATION OF MAST CELLS AND " CELLS WITHIN THE ESOPHAGUS 6ICARIO FOUNDEVIDENCEFORINSITUIMMUNOGLOBULINPRODUCTIONWITHINTHEESOPHAGUSITSELF;15= "CELLSANDMASTCELLSWITHBOUND)G%AREINCREASEDINTHEESOPHAGIOFPATIENTSWITH %O% REGARDLESS OF ATOPIC STATUS ;1 16= %VIDENCE OF LOCAL IMMUNOGLOBULIN CLASS SWITCHINGHASBEENDETECTEDVIALOCALIZATIONOFGERMLINETRANSCRIPTS ACTIVATION INDUCED CYTIDINEDEAMINASE )G%HEAVYCHAIN ANDMATURE)G%M2.!WITHINTHEESOPHAGEAL TISSUEOF%O%PATIENTS;1=!DDITIONALLY OF%O%PATIENTSHAVEELEVATEDSERUM )G%LEVELSANDATOPY;1= ANDTHEROBUST4(RESPONSEMAYACTIVATEMASTCELLSRESIDENT INTHEESOPHAGEALMUCOSA4HEREFORE ANTI )G%THERAPYMAYBLOCKTHEACTIVATIONOFSUCH CELLSANDREDUCEMEDIATORRELEASE INCLUDING4.& DANDPROTEASESRELEASE;1 20= /MALIZUMABISAHUMANIZEDRECOMBINANT DERIVED)G'ANTIBODYWHICHSELEC TIVELYBINDSTO)G%#URRENTLYOMALIZUMABISAPPROVEDFORPATIENTSWITHMODERATETO SEVERE ASTHMA ;21= /MALIZUMAB INHIBITS THE BINDING OF )G% TO ITS HIGH AFlNITY RECEPTOR &CH2EPSILON BYBINDINGTOTHEEPITOPEON)G%THATOVERLAPSWITH THE&CE2BINDINGSITE)NTURN )G%BINDINGTOMEDIATORCELLS SUCHASMASTCELLSAND BASOPHILS IS INHIBITED THEREBY PREVENTING RELEASE OF MEDIATORS FROM THESE CELLS ,ANGERHANSCELLSINTHEESOPHAGEALEPITHELIUMINEOSINOPHILICESOPHAGITISEXPRESS &CH2INABUNDANCE ANDTHEPRESENCEOF&CH2ISINCREASEDIN%O%PATIENTSABOVE

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THATOFCONTROLS ARGUINGTHATITPLAYSAROLEINTHEIMMUNERESPONSETOALLERGENSIN THEDISEASE;22= !TRIALEVALUATINGTHEEFlCACYOFOMALIZUMABASCOMPAREDTOPLACEBOIN%O%WAS RECENTLY COMPLETED 5NFORTUNATELY PRELIMINARY RESULTS DO NOT SHOW SIGNIlCANT IMPROVEMENTINSYMPTOMSOFDYSPHAGIAINPATIENTSENROLLED&ANG* 'LEICH'* 0ETERSON+/MALIZUMABINTHETREATMENTOFEOSINOPHILICESOPHAGITIS5NPUBLISHED  !DDITIONALLY OMALIZUMABDIDNOTREDUCETHENUMBEROFEOSINOPHILSWITHIN THEESOPHAGUSOFPATIENTSPEAKPROXIMALEOSINOPHILCOUNTSBEFOREANDAFTEROMALI ZUMAB THERAPY WERE  AND (0& RESPECTIVELY  4HESE PRELIMINARY RESULTS ARE SURPRISINGINVIEWOFTHEINFORMATIONDISCUSSEDABOVESUGGESTINGTHEIMPORTANCEOF )G% MEDIATEDFOODALLERGY ANDTHEYARGUETHATNON )G% MEDIATEDMECHANISMSMAY BEOFGREATERIMPORTANCEINTHEPATHOGENESISOF%O%THANHERETOFOREAPPRECIATED

Treatment of EoE with TNF-a (Alpha) Antagonists 4.& D ALPHA ANTAGONISTS HAVE BEEN UTILIZED IN THE TREATMENT OF GASTROINTESTINAL IMMUNEDISORDERSFORTHELASTYEARSTODOWNREGULATETHEINmAMMATORYPATHWAY ;23= ANDTHEIRUSEHASBENElTTEDPATIENTS ESPECIALLYTHOSEWITHINmAMMATORYBOWEL DISEASES SUCHASULCERATIVECOLITISAND#ROHNSDISEASE)N%O% 4.& D (alpha) is ELEVATEDINTHEESOPHAGEALTISSUEOFPATIENTSANDISHIGHLYEXPRESSEDBYTHEESOPHA GEALEPITHELIALCELLS;2 25=!DDITIONALLY EVIDENCEEXISTSTHATEOSINOPHILSTHEM SELVESPRODUCE4.& D;26= )NmIXIMAB IS A CHIMERIC HUMANnMOUSE )G' MONOCLONAL ANTIBODY AGAINST 4.& DALPHA ;2=3TRAUMANNETALTESTEDTHEEFlCACYOFINmIXAMABINTHREEMALE PATIENTSWITHSTEROID DEPENDENT%O%REFRACTORYTOALLOTHERTHERAPIES;25=!LLPRIOR THERAPIESWEREDISCONTINUEDWEEKSPRIORTOTHESCREENINGESOPHAGEALBIOPSIESAND EOSINOPHIL ASSESSMENT !FTER THE  WEEK RUN IN PERIOD PATIENTS WERE GIVEN TWO INFUSIONSOFINmIXAMABATANDWEEKS ANDBIOPSIESWEREOBTAINEDBEFOREAND WEEKSAFTERTHESECONDDOSE%OSINOPHILCOUNTSDIDNOTDIMINISHALTHOUGHPATIENTS TOLERATEDTHEINFUSIONSWELL4ISSUELEVELSOF4.& DDIDNOTCHANGESIGNIlCANTLY !MONGOTHERMARKERSOFINmAMMATION #$CELLSDECREASED BUTEOTAXIN EXPRES SIONANDTRYPTASE POSITIVECELLSDIDNOTCHANGE4HEAUTHORSCOMMENTTHATTHEVALUE OFTHESTUDYISLIMITEDBYITSDESIGNASANOPEN LABEL NONRANDOMIZEDPILOTSTUDY WITHASMALLNUMBEROFPATIENTS ANDTHEYEMPHASIZETHATFURTHERSTUDIESWITHALTER NATIVEDOSINGSCHEDULESARENEEDED

Treatment of EoE with Monoclonal Antibodies to IL-5 ), ISAPRIMARY4(CYTOKINEINVOLVEDINEOSINOPHILINCEPTION MATURATION AND RELEASE FROM THE BONE MARROW ;2 2= !DDITIONALLY IT IS INVOLVED DIRECTLY IN EOSINOPHILLONGEVITY ACTIVATION ANDSURVIVAL)THASBOTHSYSTEMICEFFECTSONEOSINOPHILS

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INCLUDINGTHETRAFlCKINGOFSUCHCELLS ASWELLASLOCALEFFECTSINTHEESOPHAGIOF %O% PATIENTS AS A CYTOKINE RELEASED DIRECTLY FROM EOSINOPHILS THEMSELVES ),  DIRECTLYINmUENCESEOSINOPHILRESPONSIVENESSTOLOCALCYTOKINESSUCHASEOTAXIN  ), HASBEENIMPLICATEDSTRONGLYASAPIVOTALCYTOKINEINVOLVEDINTHEDEVEL OPMENTANDPERPETUATIONOFESOPHAGEALEOSINOPHILIA;30=4RANSGENICMICETHAT OVEREXPRESS ),  DEVELOP %O% ;3 32= !NTIBODIES AGAINST ),  PREVENT THE DEVELOPMENT OF %O% IN THESE MICE AFTER THE INSTILLATION OF INTRANASAL ALLERGEN &URTHERMURINESTUDIESDEMONSTRATEDTHATTHE%O%TRANSCRIPTSINDUCEDBYINTRATRA CHEAL), WEREINHIBITEDINTHEABSENCEOF), ;33=9AMAZAKIETALDEMON STRATED THAT THE PERIPHERAL MONONUCLEAR CELLS OF %O% PATIENTS AS COMPARED TO CONTROLSDEVELOPINCREASEDLEVELSOF), WHENSTIMULATEDBYALLERGENS;34=),  M2.!LEVELSWEREINCREASEDINTHETISSUESOF%O%PATIENTSASCOMPAREDTONOR MALCONTROLS;35= )NITIAL HUMAN TRIALS INVESTIGATING ANTI ),  IN THE HYPEREOSINOPHILIC SYNDROME WEREPROMISING;36=ANDASUBSEQUENTPLACEBO CONTROLLEDMULTICENTERTRIALSHOWED THEEFlCACYOFANTI ), TREATMENT;3=3UBSEQUENTINVESTIGATIONSHAVEEXPLOREDTHE EFlCACYOFANTI ), IN%O%-EPOLIZUMABISAFULLYHUMANIZEDMONOCLONAL)G' ANTIBODYSPECIlCFORHUMAN), THATBLOCKSTHEABILITYOF), TOBINDTOTHEALPHA CHAIN OF THE ),  RECEPTOR ON THE EOSINOPHIL SURFACE ;3= -EPOLIZUMAB REDUCES PERIPHERALEOSINOPHILSBY)NASMALLPILOTTRIAL MEPOLIZUMABREDUCEDPERIPH ERALBLOODEOSINOPHILIAINFOURPATIENTSWITHHYPEREOSINOPHILICSYNDROME ANEFFECT THATWASSUSTAINEDFORWEEKSAFTERTHELASTDOSE;36=)NTHISTRIAL ONEPATIENTWITH ESOPHAGEALTISSUEEOSINOPHILIA PRESUMABLY%O% DEMONSTRATEDATENFOLDREDUCTION OF EOSINOPHILIC INlLTRATION SUGGESTING THAT MEPOLIZUMAB MAY BE EFFECTIVE IN THE TREATMENTOF%O% ! TEST OF THIS CONCEPT WAS CONDUCTED IN FOUR %O% PATIENTS MEAN ESOPHAGEAL EOSINOPHILIA OF n EOSINOPHILS(0& WITH THREE INFUSIONS OF MEPOLIZUMAB MGKGMAXIMUMMG INTRAVENOUSLYATMONTHLYINTERVALS;3=!SSESSMENT WITH ESOPHAGEAL BIOPSIES WAS PERFORMED  WEEKS AFTER THE LAST DOSE OF MEPOLI ZUMAB %OSINOPHIL COUNTS PER (0& DECREASED FROM     TO     RESPECTIVELY!LLDYSPHAGIASYMPTOMSIMPROVEDANDQUALITYOFLIFESCORESINCREASED INALLFOURPATIENTS 3UBSEQUENTLY 3TRAUMANN ET AL PERFORMED A DOUBLE BLIND PLACEBO CONTROLLED STUDYOFMEPOLIZUMABATADOSEOFMGKGINPATIENTS;2 40=)NTHISTRIAL TWO INTRAVENOUS INFUSIONS OF MEPOLIZUMAB OR PLACEBO WERE GIVEN AT WEEKS  AND  .ONEOFTHEPATIENTSACHIEVEDCOMPLETERESPONSEDElNEDASLESSTHANEOSINOPHILS (0& ANDCONTINUEDONTHEIRALLOCATEDMEDICATIONSMEPOLIZUMABAT MGOR PLACEBO FOR TWO ADDITIONAL INFUSIONS AT WEEKS  AND  WITH REPEAT ENDOSCOPIC ASSESSMENTSANDBIOPSIESATWEEK!LLRESPONDERSENTEREDINTOLONG TERMFOLLOW UPOFFALLMEDICATIONS ANDlNALASSESSMENTWASMADEATWEEKSWEEKSAFTER THE LAST INFUSION  -EPOLIZUMAB THERAPY RESULTED IN REDUCTION OF ESOPHAGEAL EOSINOPHILIAOFVSINTHEPLACEBOGROUP 4HEREWASNOCHANGEIN4CELL #$ ORMASTCELLSNUMBERSINTHEESOPHAGIOFSUBJECTS%OSINOPHIL DERIVEDNEU ROTOXIN%$. STAININGCELLSANDEXTRACELLULAR%$.WEREREDUCEDINTHEMEPOLI ZUMABARM!DDITIONALLY BYWEEK THEREWERESIGNIlCANTREDUCTIONSINREMODELING

 4REATMENTOF%OSINOPHILIC%SOPHAGITISWITH"IOLOGICAL!GENTS

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FACTORS4'&EBETA ANDTENASCIN C INTHEMEPOLIZUMABARMCOMPAREDTOPLACEBO .OCHANGESINEPITHELIAL4.& DOREOTAXIN LEVELSOCCURRED3YMPTOMSWEREPAR TIALLYIMPROVEDINTHEMEPOLIZUMABARM(OWEVER BYWEEK ALLPATIENTSINTHE MEPOLIZUMAB ARM REPORTED SIGNIlCANT WORSENING OF THEIR SYMPTOMS PRESENT AT ENROLLMENT 2ESLIZUMAB A SECOND HUMANIZED MONOCLONAL ANTIBODY TO ),  ;4 42= RECENTLYWASTESTEDFORITSEFlCACYINTHETREATMENTOF%O%INAPHASE)))))RAN DOMIZED DOUBLE BLIND PLACEBO CONTROLLEDMULTICENTERCLINICALTRIALOFPEDIATRIC PATIENTS3PERGEL*-ETAL2ESLIZUMABINCHILDRENANDADOLESCENTSWITHEOSINO PHILIC ESOPHAGITIS RESULTS OF A DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED STUDY5NPUBLISHED  !TOTALOFPATIENTSWEREENROLLEDWITHTHEFOLLOW INGCHARACTERISTICSMALE MEANAGEYEARS ANDEXPERIENCEDDYS PHAGIA PAINANDVOMITING%SOPHAGEALBIOPSIESSHOWEDEOSINOPHILS (0& AFTER TREATMENT WITH A PROTON PUMP INHIBITOR FOR  WEEKS 0ATIENTS WERE RANDOMIZED TO PLACEBO AND TREATMENT ARMS AND THE TREATMENT PATIENTS RECEIVED DOSESOF  ORMGKG2ESLIZUMABINFUSIONSWEREGIVENATWEEKS   AND !TTHEBEGINNINGOFTHESTUDY THEMEANEOSINOPHILCOUNTPERHIGHPOWERlELD FOR THE ENTIRE GROUP WAS  EOSINOPHILS AT THE END OF THE STUDY THE MEDIAN ESOPHAGEALEOSINOPHILCOUNTSPERHIGHPOWERlELDWEREFORPLACEBOAND  ANDFORTHERESLIZUMABDOSES  ANDMGKGp RESPECTIVELY!LL TREATMENT GROUPS INCLUDING PLACEBO REPORTED IMPROVEMENT IN THE PHYSICIANS %O%GLOBALASSESSMENTSCORE ANDTHEMAGNITUDEOFTHEIMPROVEMENTDIDNOTDIF FERBETWEENTHEPLACEBOANDTHERESLIZUMABGROUPS4HISSURPRISINGRESULTSHOWING NORELIEFINTHEPATIENTSSYMPTOMSCOULDBEINTERPRETEDASEVIDENCETHATTHEPRES ENCEORTHENUMBERSOFTHEEOSINOPHILSISNOTRELATEDTOTHEPATIENTSDISEASESEVER ITY ORALTERNATIVELY THATTHEGLOBALASSESSMENTSCOREMAYNOTBEACORRECTTOOLTO MEASURETHERESPONSETOTHETREATMENT

Future Directions !SUMMARYOFPRIORTESTSOFBIOLOGICALAGENTSIN%O%ISPRESENTEDIN4ABLE21 .EWAPPROACHESFORFUTURETREATMENTOF%O%INCLUDEFURTHERTRIALSWITHANTIBODIESTO ),  INTRODUCTIONOFEOTAXININHIBITORS ANDUSEOF), ANTAGONISTS4HETRIALSWITH RESLIZUMABCONTINUE;42= ALTHOUGHTHEINITIALRESULTSSEEABOVE APPEARCONFUSING %OTAXIN ISANOBVIOUSTARGET ANDANTAGONISTSAREINTHEWINGS;4 44=#ONCERNING ),  INTRATRACHEAL INSTILLATION OF ),  INDUCED ESOPHAGEAL EOSINOPHILIA IN A MURINEMODEL ANDTHERESULTINGEOSINOPHILIAWASNOTPRODUCEDINMICEDElCIENTIN ),  EOTAXIN  AND 34!4 SUGGESTING THAT THE ),  STIMULATED ESOPHAGEAL EOSINOPHILIA REQUIRES ALL OF THESE MOLECULES FOR ITS DEVELOPMENT )N THE HUMAN ESOPHAGUS ), INDUCESTHE%O%TRANSCRIPTOME;1= ANDCORTICOSTEROIDADMINIS TRATION BLUNTS THIS RESPONSE POSSIBLY IDENTIFYING A MECHANISM BY WHICH STEROIDS EFFECTABENElTIN%O%;4 46=#!4  AHUMANMONOCLONAL)G'ANTIBODYTO ),  NEUTRALIZES), INHUMANLUNGMASTCELLS;4=0HASE)STUDIESINASTHMA

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356 Table 27.1 "IOLOGICAGENTSUTILIZEDFOREOSINOPHILICESOPHAGITIS -ECHANISM -EDICATION OFACTION 4RIAL N $ESIGN 30 2ANDOMIZED /MALIZUMAB 2ECOMBINANT &ANGETAL DOUBLE BLIND 5NPUBLISHED ANTI )G% PLACEBO 2010) ANTIBODY CONTROLLED

)NmIXIMAB

#HIMERICLG' 3TRAUMANN ETAL;26] ANTI 4.& ANTIBODY

3TEINETAL;3] -EPOLIZUMAB (UMANIZED MONOCLONAL ANTI ),  ANTIBODY

3TRAUMANNETAL -EPOLIZUMAB (UMANIZED ;40] MONOCLONAL ANTI ),  ANTIBODY

2ESLIZUMAB

3 0ROSPECTIVEPILOT USEOFONLY TWOINFUSIONS

/UTCOME .OCHANGEINPEAK eosinophil COUNT.O DIFFERENCEIN SYMPTOMSAS COMPAREDTO PLACEBO /NEPATIENTWITH IMPROVEMENT

4 0ROSPECTIVEPILOT  -ARKED DECREASEIN TRIALWITHTHREE esophageal INFUSIONSOF eosinophilia MGKG  )MPROVED DYSPHAGIA QUALITYOFLIFE  $ECREASED 11 $OUBLEBLIND esophageal PLACEBO eosinophilia CONTROLLEDOF TWOINFUSIONS  $ECREASED OFMGKG LEVELSOF WEEKSAND esophageal THENWEEKS 4'&E AND TENASCIN

2EDUCTIONOF 226 2ANDOMIZED 3PERGEL (UMANIZED esophageal DOUBLEBLIND 5NPUBLISHED MONOCLONAL eosinophilia PLACEBOCONTROL 2011) !BTO),  FORALLDOSE DOSES  RANGES MGKG

HAVE SHOWN IT TO BE SAFE AND TOLERABLE TO PATIENTS ;4 4= -ICE PRETREATED WITH INTRAPERITONEAL #!4  DEMONSTRATED BLUNTED ),  INDUCED ESOPHAGEAL EOSINOPHILIAPRODUCTION ARGUINGFORAPOTENTIALTHERAPEUTICROLEIN%O%PATIENTS;50= #URRENT RESEARCH HAS FOCUSED ON THE EFlCACY OF ANTI ),  TREATMENT FOR %O% /THERPOSSIBLETARGETSFORFUTURESTUDYINCLUDE4(CELLSANDTHEIRCYTOKINEPRODUCTION !DDITIONALLY ANTIBODIESDIRECTEDTOWARDEOSINOPHILRECRUITMENTANDTHEIRINTERAC TIONSWITHINTHEESOPHAGEALLUMENMAYPROVIDESOMETHERAPEUTICBENElTTOPATIENTS 0ERHAPS DIRECTLY INHIBITING EOTAXIN  EXPRESSION IN THE ESOPHAGEAL EPITHELIUM MAY BETHEOPTIMALTARGET!LTERNATIVELY THEOPTIMALTREATMENTOF%O%MAYBEA COMBINATIONOFAGENTS SUCHANADMINISTRATIONOFANANTIBODYTO), ANDANOTHERTO EOTAXIN &URTHER DEVELOPMENT OF BIOLOGICAL AGENTS MAY NOT ONLY AID PATIENTS IN OVERCOMINGTHEIRESOPHAGEALDISEASE BUTTHESEAGENTSMAYSERVETOPROVIDEINSIGHTS INTOTHEPATHOGENESISANDPROGNOSISOF%O%ITSELF

 4REATMENTOF%OSINOPHILIC%SOPHAGITISWITH"IOLOGICAL!GENTS



References ,IACOURAS #! ET AL %OSINOPHILIC ESOPHAGITIS A  YEAR EXPERIENCE IN  CHILDREN #LIN 'ASTROENTEROL(EPATOL n 3PERGEL *- ET AL 4REATMENT OF EOSINOPHILIC ESOPHAGITIS WITH SPECIlC FOOD ELIMINATION DIET DIRECTED BY A COMBINATION OF SKIN PRICK AND PATCH TESTS !NN !LLERGY !STHMA )MMUNOL  n +AGALWALLA!&ETAL%FFECTOFSIX FOODELIMINATIONDIETONCLINICALANDHISTOLOGICOUTCOMESIN EOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOL n 'ONSALVES.ETAL!PROSPECTIVECLINICALTRIALOFSIXFOODELIMINATIONDIETORELEMENTALDIETIN THE TREATMENT OF ADULTS WITH EOSINOPHILIC ESOPHAGITIS 'ASTROENTOLOGY  3UPPL  !  ,IACOURAS#!ETAL0RIMARYEOSINOPHILICESOPHAGITISIN CHILDREN SUCCESSFUL TREATMENT WITH ORALCORTICOSTEROIDS*0EDIATR'ASTROENTEROL.UTR n &AUBION*R7!ETAL4REATMENTOFEOSINOPHILICESOPHAGITISWITHINHALEDCORTICOSTEROIDS *0EDIATR'ASTROENTEROL.UTR n +ONIKOFF-2ETAL!RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLEDTRIALOFmUTICASONEPROPI ONATEFORPEDIATRICEOSINOPHILICESOPHAGITIS'ASTROENTEROLOGY n 3TRAUMANN!ETAL"UDESONIDEISEFFECTIVEINADOLESCENTANDADULTPATIENTSWITHACTIVEEOSINO PHILICESOPHAGITIS'ASTROENTEROLOGY nE !CEVES33ETAL/RALVISCOUSBUDESONIDEAPOTENTIALNEWTHERAPYFOREOSINOPHILICESOPHAGITIS INCHILDREN!M*'ASTROENTEROL n $OHIL2ETAL/RALVISCOUSBUDESONIDEISEFFECTIVEINCHILDRENWITHEOSINOPHILICESOPHAGITISIN ARANDOMIZED PLACEBO CONTROLLEDTRIAL'ASTROENTEROLOGY n 3CHAEFER%4ETAL#OMPARISONOFORALPREDNISONEANDTOPICALmUTICASONEINTHETREATMENTOF EOSINOPHILIC ESOPHAGITIS A RANDOMIZED TRIAL IN CHILDREN #LIN 'ASTROENTEROL (EPATOL  n .OEL2*ETAL#LINICALANDIMMUNOPATHOLOGICEFFECTSOFSWALLOWEDmUTICASONEFOREOSINOPHILIC ESOPHAGITIS#LIN'ASTROENTEROL(EPATOL n 2EMEDIOS-ETAL%OSINOPHILICESOPHAGITISINADULTSCLINICAL ENDOSCOPIC HISTOLOGIClNDINGS ANDRESPONSETOTREATMENTWITHmUTICASONEPROPIONATE'ASTROINTEST%NDOSC n 2OY 'HANTA3 ,AROSA$& +ATZKA$!!TOPICCHARACTERISTICSOFADULTPATIENTSWITHEOSINO PHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOL n 6ICARIO-ETAL,OCAL"CELLSAND)G%PRODUCTIONINTHEOESOPHAGEALMUCOSAINEOSINOPHILIC OESOPHAGITIS'UT n !BONIA*0ETAL)NVOLVEMENTOFMASTCELLSINEOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOL  n "LANCHARD#ETAL), INVOLVEMENTINEOSINOPHILICESOPHAGITISTRANSCRIPTOMEANALYSISAND REVERSIBILITYWITHGLUCOCORTICOIDS*!LLERGY#LIN)MMUNOL n &URUTA'4ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTSASYSTEMATICREVIEWANDCON SENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGY   n 2OTHENBERG -% "IOLOGY AND TREATMENT OF EOSINOPHILIC ESOPHAGITIS 'ASTROENTEROLOGY  n (OLGATE3ETAL4HEANTI INmAMMATORYEFFECTSOFOMALIZUMABCONlRMTHECENTRALROLEOF)G% INALLERGICINmAMMATION*!LLERGY#LIN)MMUNOL n (ENDELES, 3ORKNESS#!!NTI IMMUNOGLOBULIN%THERAPYWITHOMALIZUMABFORASTHMA!NN 0HARMACOTHER n 9EN%(ETAL#OMPARATIVEANALYSISOF&CHEPSIV2)EXPRESSIONPATTERNSINPATIENTSWITHEOSINO PHILICANDREmUXESOPHAGITIS*0EDIATR'ASTROENTEROL.UTR n /USSALAH ! $ANESE 3 0EYRIN "IROULET , %FlCACY OF 4.& ANTAGONISTS BEYOND ONE YEAR IN ADULT AND PEDIATRIC INmAMMATORY BOWEL DISEASES A SYSTEMATIC REVIEW #URR $RUG 4ARGETS  n



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3TRAUMANN!ETAL)DIOPATHICEOSINOPHILICESOPHAGITISISASSOCIATEDWITHA4(  TYPEALLERGIC INmAMMATORYRESPONSE*!LLERGY#LIN)MMUNOL n 3TRAUMANN!ETAL!NTI 4.& DINmIXIMAB THERAPYFORSEVEREADULTEOSINOPHILICESOPHAGITIS *!LLERGY#LIN)MMUNOL n &INOTTO3ETAL4.& ALPHAPRODUCTIONBYEOSINOPHILSIN UPPER AIRWAYS INmAMMATION NASAL POLYPOSIS *)MMUNOL n .AM*,ETAL#URRENTEVIDENCEFORTHEMANAGEMENTOFRHEUMATOIDARTHRITISWITHBIOLOGICAL DISEASE MODIFYINGANTIRHEUMATICDRUGSASYSTEMATICLITERATUREREVIEWINFORMINGTHE%5,!2 RECOMMENDATIONSFORTHEMANAGEMENTOF2!!NN2HEUM$IS n -ATTHAEI+) &OSTER0 9OUNG)'4HEROLEOFINTERLEUKIN ),  INVIVOSTUDIESWITH),  DElCIENTMICE-EM)NST/SWALDO#RUZ3UPPLn 3ANDERSON#*4HEBIOLOGICALROLEOFINTERLEUKIN)NT*#ELL#LONING3UPPLn DISCUSSIONn 3TONE +$ 0RUSSIN # )MMUNOMODULATORY THERAPY OF EOSINOPHIL ASSOCIATED GASTROINTESTINAL DISEASES#LIN%XP!LLERGY n -ISHRA ! -ECHANISM OF EOSINOPHILIC ESOPHAGITIS )MMUNOL !LLERGY #LIN .ORTH !M  nVIII -ISHRA!ETAL!NETIOLOGICALROLEFORAEROALLERGENSANDEOSINOPHILSINEXPERIMENTALESOPHAGI TIS*#LIN)NVEST n -ISHRA! 2OTHENBERG-%)NTRATRACHEAL), INDUCESEOSINOPHILICESOPHAGITISBYAN),  EOTAXIN  AND34!4 DEPENDENTMECHANISM'ASTROENTEROLOGY n 9AMAZAKI + ET AL !LLERGEN SPECIlC IN VITRO CYTOKINE PRODUCTION IN ADULT PATIENTS WITH EOSINOPHILICESOPHAGITIS$IG$IS3CI n 4ANTIBHAEDHYANGKUL5ETAL)NCREASEDESOPHAGEALREGULATORY4CELLSANDEOSINOPHILCHARACTER ISTICSINCHILDRENWITHEOSINOPHILICESOPHAGITISANDGASTROESOPHAGEALREmUXDISEASE!NN#LIN ,AB3CI n 'ARRETT*+ETAL!NTI INTERLEUKIN MEPOLIZUMAB THERAPYFORHYPEREOSINOPHILICSYNDROMES *!LLERGY#LIN)MMUNOL n 2OTHENBERG -% ET AL 4REATMENT OF PATIENTS WITH THE HYPEREOSINOPHILIC SYNDROME WITH MEPOLIZUMAB.%NGL*-ED n 7ALSH '- -EPOLIZUMAB AND EOSINOPHIL MEDIATED DISEASE #URR -ED #HEM  n 3TEIN-,ETAL!NTI ), MEPOLIZUMAB THERAPYFOREOSINOPHILICESOPHAGITIS*!LLERGY#LIN )MMUNOL n 3TRAUMANN!ETAL!NTI INTERLEUKIN ANTIBODYTREATMENTMEPOLIZUMAB INACTIVEEOSINOPHILIC OESOPHAGITISARANDOMISED PLACEBO CONTROLLED DOUBLE BLINDTRIAL'UT n 2EICHERT*-!NTIBODY BASEDTHERAPEUTICSTOWATCHIN-!BS n 7ALSH '- 2ESLIZUMAB FOR PEDIATRIC EOSINOPHILIC ESOPHAGITIS )MMUNOTHERAPY  n *IN(ETAL%XPRESSIONANDCHARACTERIZATIONOFTHECHEMOKINERECEPTOR##2"FROMRHESUS MONKEY"IOCHEM0HARMACOL n :HANG,ETAL&UNCTIONALEXPRESSIONANDCHARACTERIZATIONOFMACAQUE#n#CHEMOKINERECEPTOR ##2 ANDGENERATIONOFPOTENTANTAGONISTICANTI MACAQUE##2MONOCLONALANTIBODIES *"IOL#HEM n :UO,ETAL), INDUCESESOPHAGEALREMODELINGANDGENEEXPRESSIONBYANEOSINOPHIL INDE PENDENT ), 2 INHIBITEDPATHWAY*)MMUNOL n .EILSEN#6 "RYCE0*)NTERLEUKIN DIRECTLYPROMOTESOESOPHAGUSPRODUCTIONOF##,AND ##,ANDTHEMIGRATIONOFEOSINOPHILS#LIN%XP!LLERGY n +AUR $ ET AL -AST CELLS EXPRESS ), 2 ALPHA  ),  PROMOTES HUMAN LUNG MAST CELL PROLIFERATIONAND&CEPSILON2)EXPRESSION!LLERGY n 3INGH $ ET AL ! PHASE  STUDY EVALUATING THE PHARMACOKINETICS SAFETY AND TOLERABILITY OF REPEATDOSINGWITHAHUMAN), ANTIBODY#!4  INSUBJECTSWITHASTHMA"-#0ULM -ED

 4REATMENTOF%OSINOPHILIC%SOPHAGITISWITH"IOLOGICAL!GENTS



/H #+ ET AL !N OPEN LABEL SINGLE DOSE BIOAVAILABILITY STUDY OF THE PHARMACOKINETICS OF #!4  AFTER SUBCUTANEOUS AND INTRAVENOUS ADMINISTRATION IN HEALTHY MALES "R * #LIN 0HARMACOL n "LANCHARD # ET AL )NHIBITION OF HUMAN INTERLEUKIN  INDUCED RESPIRATORY AND OESOPHAGEAL INmAMMATION BY ANTI HUMAN INTERLEUKIN  ANTIBODY #!4   #LIN %XP !LLERGY  n

sdfsdf

Chapter 28

Feeding Disorders and Eosinophilic Esophagitis Asim Maqbool and Colleen Lukens

Keywords %OSINOPHILIC ESOPHAGITIS s &EEDING DISORDERS s &EEDING BEHAVIORS s)NmAMMATION

Introduction &EEDINGDISORDERSFROMNONORGANICETIOLOGIESARECOMMONINCHILDREN!CCORDING TOTHE$IAGNOSTICAND3TATISTICAL-ANUALOF-ENTAL$ISORDERS$3- )6 42 THEY OCCURINOFCHILDRENUNDERYEARSOFAGE;1=4HEINCIDENCEISTHOUGHTTOBE GREATER IN CHILDREN WITH UNDERLYING MEDICAL CONDITIONS AS MULTIPLE ASPECTS OF A DISEASECANADVERSELYIMPACTTHEDEVELOPMENTOFNORMALFEEDINGSKILLSANDCONTRIB UTETOMALADAPTIVEFEEDINGBEHAVIORS%OSINOPHILICESOPHAGITIS%O% ISACHRONIC CONDITIONASSOCIATEDWITHINmAMMATIONINTHEESOPHAGUSASWELLASANATOMICALAND FUNCTIONALDIGESTIVESYSTEMIMPAIRMENTSWHICHPOSEAPARTICULARIMPEDIMENTTOTHE DEVELOPMENTOFNORMALFEEDINGBEHAVIORANDSKILLSINCHILDREN 4HE OBJECTIVES OF THIS CHAPTER ARE TO REVIEW THE MEDICAL ASPECTS OF %O% THAT IMPACTFEEDINGBEHAVIOR REVIEWTHECOMMONCLINICALANDBEHAVIORALPRESENTATIONS WITHWHICHTHESEPATIENTSMAYCOMETOACLINICIANSATTENTION ANDPROVIDEANOVER VIEWOFABEHAVIORALAPPROACHTOTHEMANAGEMENTOFMALADAPTIVEFEEDINGBEHAVIORS

!-AQBOOL* 0EDIATRIC'ASTROENTEROLOGY (EPATOLOGY AND.UTRITION 5NIVERSITYOF0ENNSYLVANIA 3CHOOLOF-EDICINE 4HE#HILDRENS(OSPITALOF0HILADELPHIA THAND#IVIC#ENTER"LVD 0HILADELPHIA 0! 53! E MAILMAQBOOL EMAILCHOPEDU #!,IACOURASAND*%-ARKOWITZEDS Eosinophilic Esophagitis #LINICAL'ASTROENTEROLOGY $/)    ? Ú3PRINGER3CIENCE"USINESS-EDIA ,,#

361



!-AQBOOLAND#,UKENS

Digestive Tract Factors %SOPHAGITISFROMANYCAUSECANBEASSOCIATEDWITHFEEDINGDIFlCULTYORRELUCTANT SWALLOWING4HEREAREMULTIPLECAUSESOFESOPHAGITISINADDITIONTO%O% INCLUDING GASTROESOPHAGEALREmUX'%2 CHEMICALINGESTIONEG PILLESOPHAGITIS INmAM MATIONASSOCIATEDWITHCAUSTICINGESTIONS INFECTIVEESOPHAGITISEG CANDIDALAND VIRAL RADIATIONESOPHAGITIS ANDGRAFTVSHOSTDISEASE3OMEOFTHESECONDITIONSCAN CO EXIST ANDTHERECANBEOVERLAPINTHESYMPTOMSOBSERVED SUCHASINTHECASEOF %O%AND'%2$%SOPHAGITISTYPICALLYIMPROVESFOLLOWINGTREATMENTOFTHEUNDERLY INGCONDITIONS HOWEVER ITCANHAVELASTINGEFFECTSONACHILDSEATINGBEHAVIOR %SOPHAGEAL MOTOR ACTIVITY HAS BEEN REPORTED TO BE IMPAIRED IN PATIENTS WITH ESOPHAGITIS PARTICULARLYINPATIENTSWITH%O%;=0EDIATRICPATIENTSWITH'%2nBOTH WITHANDWITHOUTHISTOLOGICALEVIDENCEOFESOPHAGITISnHAVEIMPAIREDESOPHAGEAL BODY MOTOR ABNORMALITY AS COMPARED TO PATIENTS WITHOUT EITHER CONDITION ;3= ! RECENT PEDIATRIC STUDY COMPARED HEALTHY PEDIATRIC SUBJECTS WITHOUT ESOPHAGITIS TO SUBJECTS WITH '%2 DISEASE '%2$ WHEN '%2 IS CONSIDERED PATHOLOGICAL WITH ADVERSEIMPACTONHEALTHANDBEHAVIOR ANDTOSUBJECTSWITH%O%UTILIZINGPHPROBE ANDESOPHAGEALMANOMETRY;=4HISSTUDYINDICATEDTHEOCCURRENCEOF'%2INBOTH THE'%2$AND%O%GROUPS WITHTHEMOST'%2NOTEDPREDICTABLYINTHEGROUPOF CHILDRENDIAGNOSEDWITH'%2$BYREmUXINDEX LONGESTDURATIONOFAREmUXEPISODE ANDTOTALNUMBEROFREmUXEPISODES &URTHERMORE ABNORMALPERISTALSISABNOR MALSWALLOWS ANDABNORMALSTATIONARYMOTILITYWERENOTEDINTHE%O%GROUPONLY 4HESElNDINGSUNDERLINEMOTILITYDISTURBANCESINTWOCONDITIONSTHATMAYCOEXIST %O%CANHAVEASIGNIlCANTSTRUCTURALIMPACTONTHEESOPHAGUS WITHESOPHAGEAL FURROWING RINGS ANDSTRICTURESCOMMONLYDESCRIBED4HESESTRUCTURALCHANGESMAY POSEANATOMICALIMPEDIMENTSTONORMALSWALLOWINGFUNCTION&OREXAMPLE MUL TIRINGEDESOPHAGUSMAYBEASSOCIATEDWITHANINTERMITTENTORMORECONSISTENTDYS PHAGIA AND HAS BEEN DESCRIBED AS BEING MORE COMMON IN YOUNG MALES 7HILE DYSPHAGIAHASBEENDEMONSTRATEDTOIMPROVEWITHDILATATION REPEATEDDILATATIONS AREOFTENNECESSARY;4= WHICHMAYINCREASETHERISKFORPERFORATION7HILETHICKEN INGANDFURROWINGAREMOSTCOMMONLYOBSERVEDINYOUNGERCHILDREN ESOPHAGEAL TRACHEALIZATIONANDSTRICTURINGARETHOUGHTTOBEMORECOMMONINOLDERCHILDREN ADOLESCENTS AND ADULTS )N ADDITION TO THESE lNDINGS EXISTING IN A CONTINUUM OF POSSIBLE PRESENTATIONS THEY MAY REPRESENT THE PROGRESSION OF UNTREATED DISEASE 4HEREFORE THE ONUS IS ON CARE PROVIDERS AND HEALTH PROFESSIONALS TO MAINTAIN AN INDEXOFSUSPICIONOFTHISDISORDERANDBECOGNIZANTOFITSTYPICALPRESENTATIONS TO ALLOWFOREARLYRECOGNITION ANDEARLY AGGRESSIVEMANAGEMENT

Clinical Presentations 4HEPRESENTINGSIGNSANDSYMPTOMSOF%O%MAYVARYWITHAGE WITHFAILURETOTHRIVE ANDFEEDINGDIFlCULTIESCOMMONININFANTS REmUXSYMPTOMSANDEMESISININFANTS ANDYOUNGCHILDREN ABDOMINALPAININPRE TEENS ANDDYSPHAGIAANDFOODIMPACTION

 &EEDING$ISORDERSAND%OSINOPHILIC%SOPHAGITIS Table 28.1 #OMMONPRESENTINGSYMPTOMSOF%O%INPEDIATRICSUBJECTS BYAGE 3YMPTOM !GE YEARSMEANÕ3$

363

n

&AILURETOTHRIVEORFEEDINGDIFlCULTIES Õ  'ASTROESOPHAGEALREmUXOREMESIS Õ  $YSPHAGIAORFOODIMPACTION Õ  -ODIlEDFROM3PERGELETAL*0EDIATR'ASTROENTEROL.UTRn5SEDWITHPERMISSION

INPRE TEENS ADOLESCENTS ANDADULTS;n=4ABLE1 $YSPHAGIAHASBEENREPORTED BYINDIVIDUALSOFALLAGES WITHDYSPHAGIAPLUSODYNOPHAGIAANDFOODIMPACTIONS WITHORWITHOUTSTRICTURESINOLDERCHILDRENANDADULTS; =!RETROSPECTIVESTUDY OFCHILDRENPRESENTINGTOAFEEDINGDISORDERSPROGRAMIDENTIlEDFOODREFUSAL ORAL AVERSIONS EMESIS FAILURETOGAINWEIGHT ANDECZEMAASTHEMOSTCOMMONSYMP TOMSSEENINCHILDRENWITHANESTABLISHEDDIAGNOSISOF%O%n ;1= /LDERCHILDRENANDADOLESCENTSWITH%O%CANBEMISDIAGNOSEDWITHEATINGDISOR DERS PARTICULARLYANOREXIANERVOSA!. 4HISISPOTENTIALLYCOUNTERPRODUCTIVETO MANAGEMENTOF%O% PARTICULARLYINTERMSOFFURTHERDEVELOPMENTOFFEEDINGDIFl CULTY 4HESE PATIENTS MAY NOT BE REFERRED FOR EVALUATION OF %O% UNTIL THEY HAVE DEMONSTRATEDLIMITEDPROGRESSWITHTREATMENTFOR!.!TTHATPOINTINTIME ONGOING EXPOSURETOPOTENTIALLYALLERGENICFOODSCANEXACERBATEDISEASEASWELLASCONTRIBUTE TOONGOINGFOODREFUSAL

Growth and Nutritional Concerns &AILURETOTHRIVEMAYBEACOMMONPRESENTINGDIAGNOSISFORCHILDRENWITH%O%AND FEEDINGDISORDERS;1=7ITHRESTRICTEDINTAKEPREDIAGNOSISANDASPARTOFTHEMAN AGEMENT APPROACH THESE CHILDREN MAY BE SUSCEPTIBLE TO BOTH MACRONUTRIENT AND MICRONUTRIENTDElCIENCIES4HESEVERITYOFTHESEDElCIENCIESISBASEDLARGELYONTHE DEGREEOFSELFIMPOSEDORMEDICALLYINDICATEDRESTRICTIONSONDIETARYREPERTOIREIN THEFOODSELECTIVEPATIENT 4HElRSTYEARSOFLIFEARENUTRITIONALLYIMPORTANTFROMANEUROCOGNITIVEPER SPECTIVE AND LINEAR GROWTH DURING THE lRST  YEARS OF LIFE PREDICTS ADULT STATURE ;11n13='IVENTHAT%O%ISMOSTOFTENDIAGNOSEDINCHILDRENLESSTHANYEARSOF AGE ANDOFTHAT THEMAJORITYUNDERYEARSOFAGE;6= THISCHRONICINmAMMATORY DISORDERTHATLIMITSORALINTAKECANHAVEASIGNIlCANTIMPACTONGROWTHANDNUTRI TIONALSTATUS#HRISTIEETALFOUNDTHATCHILDRENWITHCOWSMILKPROTEINALLERGYOR CHILDRENWITHTWOORMOREFOODALLERGIESWERESHORTERTHANCHILDRENWITHONLYONE ALLERGY BASEDONHEIGHT FOR AGEPERCENTILES;14=&URTHERMORE CHILDRENWHOHAD COWSMILKALLERGYORMULTIPLEFOODALLERGIESCONSUMEDLESSDIETARYCALCIUMTHAN CHILDRENWHODIDNOTHAVECOWSMILKALLERGYANDORHADONLYONEFOODALLERGY !NIMALPROTEINISARICHSOURCEOFBIOAVAILABLEIRONANDZINC ANDDIETSLIMITEDIN THESENUTRIENTSSECONDARYTOALLERGYCONCERNSMAYPLACECHILDRENATNUTRITIONALRISK FORDElCIENCYSTATES

!-AQBOOLAND#,UKENS

364

Table 28.2 4HEMOSTCOMMONFOODSIDENTIlEDTOBEASSOCIATED WITH%O%INPEDIATRICSUBJECTS &OOD /CCURRENCE -ILK  Egg 11 7HEAT  3OY  #ORN  "EEF  #HICKEN  0EANUT  Potato  2ICE  -ODIlED FROM 3PERGEL ET AL * 0EDIATR 'ASTROENTEROL .UTR  n5SEDWITHPERMISSION

4HETYPESANDNUMBERSOFFOODSTOWHICHPATIENTSMAYBEALLERGICINmUENCETHEIR CLINICALCOURSEANDMAYIMPACTFEEDINGBEHAVIOR4HEMOSTCOMMONFOODSTOWHICH PATIENTSWITHEOSINOPHILICESOPHAGITISMAYBEALLERGICARECOMMONPLACEANDNEARLY UBIQUITOUSINTHEDIET;6=4ABLE #OMPLETEFOODTOLERANCEFOLLOWINGAPERIODOF DIETARYELIMINATIONOCCURREDINONLYOF PEDIATRICPATIENTSINA YEAR RETROSPECTIVESTUDY4HIRTY THREESUBJECTS HADPARTIALRESOLUTIONOFTHEIRFOOD INTOLERANCEISSUES3UBJECTSWHOHADCOMPLETERESOLUTIONOFFOODALLERGIESWEREFOL LOWEDFORANAVERAGEOFYEARSANDTHEPATIENTSWITHPARTIALRESOLUTIONFORYEARS RESPECTIVELY4HEREFORE ITISSAFETOCONCLUDETHATIFMANAGEMENTOF%O%ISBASEDON RESTRICTIONOFFOODS TOWHICHPATIENTSMAYBEALLERGIC THISRESTRICTIONISLIKELYTOBE LONGTERMANDMAYLIMITTHEDIETARYREPERTOIRETHATPATIENTSAREADVISEDTOEAT

Behavioral Presentation !LTHOUGHTHEREEXISTSANINCREASINGLITERATUREDELINEATINGTHECLINICALPRESENTATION OF%O% THEREHASBEENLIMITEDSTUDYOFTHEBEHAVIORALMANIFESTATIONSOF%O% !  TASK FORCE COMPRISING PHYSICIANS PARTICIPATING IN THE &IRST )NTERNATIONAL 'ASTROINTESTINAL %OSINOPHIL 2ESEARCH 3YMPOSIUM &)'%23 PROPOSED CONSENSUS RECOMMENDATIONSBASEDONREVIEWOFTHEAVAILABLELITERATUREONTHENATUREANDTREAT MENTOF%O%;1=4HECOMMITTEEDESCRIBEDTHEPRESENCEOFBEHAVIORALSYMPTOMS INYOUNGCHILDRENWITH%O%INCLUDINGFOODREFUSALANDFAILURETOTHRIVEASWELLAS SYMPTOMS CONSISTENT WITH GASTROESOPHAGEAL REmUX DISEASE INCLUDING EMESIS AND ABDOMINAL PAIN WHILE IN OLDER CHILDREN DYSPHAGIA AND FOOD IMPACTION WERE OBSERVED(OWEVER THElNALCONSENSUSSTATEMENTINDICATEDTHATITREMAINSUNCLEAR WHETHER%O%ISCHARACTERIZEDBYASPECIlCBEHAVIORALPRESENTATION

 &EEDING$ISORDERSAND%OSINOPHILIC%SOPHAGITIS



!NECDOTALREPORTSSUGGESTTHEPRESENCEOFBEHAVIORALFEEDINGPROBLEMSCONSIS TENTWITHTHOSEIDENTIlEDBYTHE&)'%23TASKFORCE&OREXAMPLE (AASANDCOL LEAGUES DESCRIBED CHILDREN WITH %O% AS PRESENTING WITH COMPROMISED NUTRITIONAL STATUS FOOD REFUSAL CHRONIC DISCOMFORT ASSOCIATED WITH FOOD AND MEALTIMES AND DELAYEDFEEDINGSKILLS;16=4HEAUTHORSSUGGESTEDTHATCHILDRENWITH%O%MAYCON SUMEALIMITEDVARIETYANDVOLUMEOFFOOD DEMONSTRATEGAGGINGANDCOUGHINGDUR INGMEALS ANDDISPLAYLEARNEDFEEDINGPROBLEMS3PERGELETALLENDSUPPORTTOTHIS SUGGESTEDBEHAVIORALPRESENTATION NOTINGTHATTHEINITIALCOMPLAINTSOFPATIENTSLATER DIAGNOSED WITH %O% INCLUDED FEEDING DIFlCULTY GASTROESOPHAGEAL REmUX DISEASE VOMITING ABDOMINALPAIN DYSPHAGIA ANDFOODIMPACTION;6=0ENTIUK -ILLER AND +AULDOCUMENTEDTHEPRESENCEOFSPECIlCBEHAVIORALFEEDINGPROBLEMSINASUBSET OFCHILDRENWITH%O%;1=4HEAUTHORSEXAMINEDASAMPLEOFCHILDRENDIAGNOSED WITH%O%WHOWEREREFERREDTOANINTERDISCIPLINARYFEEDINGPROGRAMFOREVALUATION AND TREATMENT OF A FEEDING DISORDER 4HE CHILDREN DIAGNOSED WITH %O% PRESENTED WITHSYMPTOMSCOMMONLYASSOCIATEDWITHBEHAVIORALFEEDINGDISORDERSINCLUDING FOODREFUSAL ORALAVERSION VOMITING ANDFAILURETOGAINWEIGHT4HISDATASUGGESTS THATASUBSETOFCHILDRENWITH%O%MAYPRESENTWITHBEHAVIORALFEEDINGPROBLEMS BUT THE TRUE PREVALENCE OF BEHAVIORAL FEEDING PROBLEMS HAS NOT BEEN CLEARLY ESTABLISHED 4HEPRESENCEOFBEHAVIORALFEEDINGPROBLEMSINCHILDRENWITH%O%WOULDNOTBE SURPRISING GIVENTHATGASTROINTESTINALDISORDERSEG GASTROESOPHAGEALREmUX FOOD ALLERGYORINTOLERANCE CONSTIPATION AREFOUNDTOOCCURFREQUENTLYINCHILDRENPRE SENTINGWITHPEDIATRICFEEDINGDISORDERS&OREXAMPLE &IELD 'ARLAND AND7ILLIAMS FOUND THAT IN A SAMPLE OF CHILDREN REFERRED TO A FEEDING CLINIC FOR EVALUATION OF BEHAVIORAL FEEDING PROBLEMS  PRESENTED WITH GASTROESOPHAGEAL REmUX  WITHFOODALLERGYANDINTOLERANCE ANDWITHCONSTIPATION;1=3IMILARLY DATA COLLECTEDFROMANINTERDISCIPLINARYFEEDINGINTERVENTIONPROGRAMINDICATEDTHAT OFCHILDRENREFERREDFORINTERVENTIONWEREDIAGNOSEDWITHGASTROESOPHAGEALREmUX PRESENTEDWITHFOODALLERGY ANDPRESENTEDWITHESOPHAGITISORGASTRITIS ;1=4HEOCCURRENCEOFTHESEGASTROINTESTINALSYMPTOMSANDASSOCIATEDDISCOMFORT CAN INTERRUPT THE PROGRESSION OF TYPICAL FEEDING BEHAVIOR AT ANY STAGE OF FEEDING DEVELOPMENT LEADINGTOTHEONSETOFMALADAPTIVEMEALTIMEBEHAVIORS4ABLE3  -EALTIMEBEHAVIORPROBLEMSARECOMMONLYDEMONSTRATEDBYYOUNGCHILDREN ASPARTOFTHECOURSEOFTYPICALFEEDINGDEVELOPMENT;1 =(OWEVER THEMECH ANISMBYWHICHTHESEDIFlCULTIESDEVELOPINTOFEEDINGDISORDERSISCOMPLEXAND THEIRPROGRESSIONISINmUENCEDBYMULTIPLEFACTORS!MONGTHEMARETHEPHYSICAL COMPETENCE OF THE CHILD CAREGIVER COMPETENCY APPETITE ECOLOGICAL FACTORS PARENTnCHILD INTERACTIONS CHILD TEMPERAMENT AND MEDICAL CONDITIONS ;= 4HEREADERISREFERREDTOOTHERSOURCESFORANEXTENSIVEDISCUSSIONOFTHEIMPACTOF THESEINTERACTINGFACTORS4ABLE4 &ORTHEPURPOSESOFTHISCHAPTER THEDEVEL OPMENT OF BEHAVIORAL FEEDING PROBLEMS IN CHILDREN WITH %O% WILL BE DESCRIBED USINGTHETWO FACTORMODEL WHICHINCORPORATESRESPONDENTCLASSICAL ANDINSTRU MENTALOPERANT CONDITIONING;1= FOCUSINGONTHEIMPACTOFMEDICALCONDITIONS ONTYPICALFEEDINGDEVELOPMENT

&INGERFEEDINGANDREACHINGFORUTENSIL INTRODUCTIONOFSOLIDFOODINTRODUCTION OFCUP

#ANUSEUTENSILSSELF FEEDING

!PPETITEDECREASESFOODPREFERENCESINCREASE INCREASEDVARIABILITYINVOLUMEANDVARIETY

nMONTHS

nMONTHS

4YPICALEATINGBEHAVIOR; 34] $ISCOMFORTFROMHUNGERRESOLVEDBYFEEDING ONDEMANDDEPENDENTONBREASTMILKOR FORMULA )NTRODUCTIONOFCOMPLEMENTARYFOODS

nMONTHS

nMONTHS

!GE nMONTHS

Table 28.3 !DVERSEIMPACTOF%O%ONTYPICALFEEDINGDEVELOPMENT

#AREGIVERPLACESINCREASEDDEMANDS ATMEALTIMERELATEDTOMANAGEMENT OF%O%EG CONCERNFORWEIGHTLOSS FOODRESTRICTIONS

#HRONICDISCOMFORTLEADSTODECREASED INTERESTINFEEDINGEXPERIENCE

)NTRODUCTIONOFALLERGENICFOODSCANLEAD TOESOPHAGEALINmAMMATION ANDDISCOMFORT $ISCOMFORTASSOCIATEDWITHESOPHAGEAL INmAMMATIONBECOMESASSOCIATED WITHTABLEFOODCHEWABLEFOOD 4REATMENTMAYNECESSITATEDIETARY RESTRICTION

3YMPTOMSOF%O% &REQUENTVOMITINGOROTHERSYMPTOMS SIMILARTO'%2

#ANLIMITCHILDSEXPOSURETOAND EXPERIENCEWITHAWIDEVARIETYOF FOODSDURINGACRITICALPERIODIN FEEDINGDEVELOPMENTMAYLEADTO OVERLYSELECTIVEDIET #HILDMAYDEMONSTRATELIMITED ENGAGEMENTINFEEDINGPROCESS MAYEXPERIENCEDELAYED DEVELOPMENTOFSELF FEEDINGSKILLS #ONmICTSWITHINCREASEDAUTONOMY SEENATTHISAGEANDMAYLEADTO NEGATIVECAREGIVERnCHILD INTERACTIONSATMEALTIMES

2ESULTINGDISRUPTIONINFEEDING DEVELOPMENT #ANLEADTOWEIGHTLOSSNECESSITATING MOREFREQUENTFEEDINGOR SUPPLEMENTALNUTRITION $ISCOMFORTCANBECOMEASSOCIATED WITHFOODANDTHEFEEDING SITUATIONLEADINGTOFOODREFUSAL #ANLEADTODIFlCULTYADVANCINGFROM PUREEDFOODTOTABLEFOOD

366 !-AQBOOLAND#,UKENS

 &EEDING$ISORDERSAND%OSINOPHILIC%SOPHAGITIS



Table 28.4 2ESOURCESREGARDINGETIOLOGICALFACTORSRELATEDTOTHEDEVELOPMENTOFFEEDINGDISORDERS !UTHORS &ACTORSDISCUSSED &ISCHERAND3ILVERMAN;1] -EDICAL ANATOMICPHYSIOLOGIC DEVELOPMENTAL INTERRELATIONAL BEHAVIORAL $IET PHYSICALCOMPETENCE APPETITE ILLNESS INTERACTION CHILD +EDESDYAND"UDD;] CONSTITUTION CAREGIVERCOMPETENCE SYSTEMICFACTORS ,INSCHEIDETAL;1] 6ARIABILITYINAPPETITE SOCIALnEMOTIONALDEVELOPMENTOFCHILD CAREGIVERnCHILDINTERACTION MEDICALCONDITIONS ORALnMOTOR COMPETENCY ENVIRONMENTALEXPERIENCE

Conditioned Aversion -ANYINDIVIDUALSREPORTTHATTHEYHAVEEXPERIENCEDATLEASTONECONDITIONEDFOOD AVERSIONINTHEIRLIFETIME#ONDITIONEDFOODAVERSIONSARETYPICALLYSTRONG SUCHTHAT THEYAFFECTLATERFOODPREFERENCES ANDTHEYAREEASILYGENERALIZEDTOOTHERSIMILAR STIMULI;=!CONDITIONEDFOODAVERSIONISACQUIREDWHENANEGATIVEORAVERSIVE STIMULUSBECOMESASSOCIATEDWITHFOOD SUBSEQUENTLYLEADINGTOAVOIDANCEOFEITHER THATPARTICULARFOODORTHEFEEDINGEXPERIENCEENTIRELY)TISHYPOTHESIZEDTHATACHILD WHOEXPERIENCESDISCOMFORTWHILEEATINGORINANEATING RELATEDSITUATIONMAYCOME TOASSOCIATETHATDISCOMFORTWITHFEEDING RELATEDSTIMULI 'IVENTHEPURPORTEDPAINORDISCOMFORTEXPERIENCEDBYINDIVIDUALSWITH%O% IT ISSUSPECTEDTHATASIMILARCONDITIONINGEXPERIENCEOCCURS;6 1 16=)TISHYPOTH ESIZEDTHATHIGHLEVELSOFEOSINOPHILSLEADTOINmAMMATIONANDINmAMMATIONLEADS TO CLINICAL MANIFESTATIONS OF VOMITING AND SYMPTOMS OF GASTROESOPHAGEAL REmUX ;1=)FACHILDSDAILYFEEDINGEXPERIENCEBECOMESASSOCIATEDWITHVOMITINGORPAIN RELATEDTOINmAMMATIONINTHEGASTROINTESTINALSYSTEM FOODREFUSALANDOTHERDISRUP TIVEBEHAVIORSMAYDEVELOPASTHECHILDTRIESTOAVOIDTHEFEEDINGSITUATION !SWELL COMPONENTSOFTHEMEDICALTREATMENTOF%O%MAYLEADTOCONDITIONED AVERSION &OR EXAMPLE REPEATED ENDOSCOPIC PROCEDURES AS PART OF THE COURSE OF INTERVENTIONCANPRODUCEANXIETYASSOCIATEDWITHTHEFEEDINGSITUATION3IMILARLY CHALLENGESWITHSUSPECTEDALLERGENICFOODSMAYLEADTOPHYSIOLOGICREACTION FURTHER INmAMMATION ANDONGOINGDISCOMFORT!STHECHILDBEGINSTOASSOCIATEFOODANDTHE FEEDING SITUATION WITH SUCH DISCOMFORT FOOD REFUSAL BEHAVIORS MAY DEVELOP IN ATTEMPTSTOAVOIDTHEFEEDINGSITUATIONANDASSOCIATEDDISTRESS &INALLY THECOURSEOFTREATMENTFOR%O%MAYREQUIRESUPPLEMENTALNUTRITION EITHERORALLYORVIATUBEFEEDING3PERGELANDCOLLEAGUESREPORTEDTHATOFASAM PLEOFPATIENTSWITH%O%WHOREQUIREDSUPPLEMENTALNUTRITION NECESSITATED TUBEFEEDING;6=2ESUMPTIONOFORALFEEDINGFOLLOWINGPROLONGEDTUBEFEEDING ISOFTENADIFlCULTPROCESS;3=#HILDRENPRIMARILYDEPENDENTONTUBEFEEDINGS DUETOMEDICALCONDITIONSRECEIVEALARGEPORTIONOFTHEIRESTIMATEDCALORICNEEDS VIASUCHSUPPLEMENTATION4HISCALORICINTAKECANLEADTOADECREASEINAPPETI TIVEMOTIVATIONTOCONSUMEFOODORALLY!SWELL IFCHILDRENAREREPEATEDLYPRE SENTEDWITHFOODATTIMESWHENTHEYARENOTEXPERIENCINGHUNGER CONDITIONED AVERSIONCANOCCUR



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Environmental Contingencies &OODREFUSALBEHAVIORATMEALTIMESOCCURSCOMMONLYINYOUNGCHILDREN; 1= )FCHALLENGINGBEHAVIORSAREMANAGEDEFFECTIVELY THEYWILLDECREASEINFREQUENCY ANDSEVERITY(OWEVER MEALTIMEBEHAVIORPROBLEMSMAYBEMAINTAINEDBYENVIRONMEN TALCONDITIONS ASWHATHAPPENSAFTERTHEBEHAVIORALTERSTHELIKELIHOODOFTHEBEHAV IOROCCURRINGINTHEFUTURE&ACTORSINTHEENVIRONMENTCANSERVETOINADVERTENTLY REINFORCE MALADAPTIVE EATING BEHAVIOR OR PUNISH APPROPRIATE EATING BEHAVIOR LEADINGTOTHEDEVELOPMENTOFASIGNIlCANTBEHAVIORALFEEDINGPROBLEM &OREXAMPLE THEREEXISTENVIRONMENTALSTIMULITHATREINFORCEFOODREFUSALBEHAVIOR )THASBEENDEMONSTRATEDTHATCAREGIVERSDRAWMOREATTENTIONTONON EATINGBEHAVIOR THANTOADAPTIVEEATINGBEHAVIORDURINGATYPICALMEALTIME;4=)TISTHISATTENTION THAT CAN INADVERTENTLY REINFORCE OR MAINTAIN THE PROBLEMATIC BEHAVIOR THEREBY INCREASINGTHEFREQUENCYWITHWHICHTHATBEHAVIOROCCURSATFUTUREMEALTIMES)FA CHILDWHOEXPERIENCESACONDITIONEDAVERSIONDEMONSTRATESFOODREFUSALBEHAVIOR ACAREGIVERMAYPROVIDEATTENTIONTOTHEFOODREFUSAL SUBSEQUENTLYREINFORCINGTHAT BEHAVIOR!SWELL ACAREGIVERMAYALLOWTHECHILDTOLEAVETHEFEEDINGSITUATION REINFORCINGTHEIRESCAPEFROMTHEMEALTIMESITUATION )N ADDITION THERE ARE ENVIRONMENTAL CONTINGENCIES THAT PUNISH ADAPTIVE EATING BEHAVIOR&OREXAMPLE IFCONSUMEDFOODLEADSTOTHEPRODUCTIONOFEOSINOPHILSAND SUBSEQUENTLY INmAMMATION IN THE GASTROINTESTINAL TRACT IT IS POSSIBLE THAT AN INDIVIDUALCANEXPERIENCEPAINWITHFURTHERCONSUMPTIONOFFOOD)TISHYPOTHESIZED THAT EATING BEHAVIOR CAN BE PUNISHED BY PAIN AND DISCOMFORT DECREASING THE LIKELIHOODTHATACHILDWILLCONTINUETOEAT !SDESCRIBEDPREVIOUSLYINTHISCHAPTER THEMANAGEMENTOF%O%OFTENINVOLVES ANELIMINATIONDIET,IMITINGACCESSTOFOODORRESTRICTIONOFFOODASOCCURSWITHAN ELIMINATION DIET CAN LEAD TO THE DEVELOPMENT OF FOOD REFUSAL AND SELECTIVITY &OR EXAMPLE IFACHILDREQUESTSFOODANDITISREPEATEDLYWITHDRAWNORREMOVED THE CHILDSEATINGORREQUESTINGBEHAVIORMAYBEEXTINGUISHEDVIANEGATIVEREINFORCE MENT3UCHENVIRONMENTALCONTINGENCIESDECREASETHEPROBABILITYTHATTHECHILDWILL REQUESTFOODAGAININTHEFUTURE

Management &EEDINGDISORDERSREQUIREANINTEGRATEDCOMPREHENSIVEAPPROACH SUCHASTHAT AFFORDED BY MULTIDISCIPLINARY FEEDING TEAMS &IG 1  -EDICAL NUTRITIONAL ANDBEHAVIORALASPECTSAREIMPORTANTINADDRESSINGANDMANAGINGFEEDINGDISOR DERSINTHISSETTING;=4HESEINTERVENTIONSAREINmUENCEDBYTHEMEDICALMAN AGEMENTOF%O%4HEYAREDEPENDENTUPONTHEREDUCTIONOFINmAMMATIONAND ARE AFFECTED BY THE NATURE AND EXTENT OF FOOD RESTRICTION AND TIME COURSE TO REINTRODUCTION

 &EEDING$ISORDERSAND%OSINOPHILIC%SOPHAGITIS



Fig. 28.1 !NINTEGRATEDAPPROACHTOFEEDINGDISORDERS

Medical 4HEMEDICALMANAGEMENTOFFEEDINGPROBLEMSASSOCIATEDWITH%O%PRIMARILY CONSISTSOFDIAGNOSISANDMANAGEMENTOF%O%ITSELF BYMEANSOFDIETARYRESTRIC TIONS MEDICATIONS OR BOTH 2EPEAT ENDOSCOPY FOLLOWING FOOD ELIMINATIONS OR REINTRODUCTIONISCOMMONPLACEINTHEONGOINGASSESSMENTANDMANAGEMENT OF%O%7HENTREATEDAGGRESSIVELYANDEARLY IMPROVEMENTANDEVENRESOLUTION OF FEEDING DISORDERS IS LIKELY ;1= !DDITIONAL INTERVENTIONS INCLUDING USE OF MEDICATIONSANDINTERVENTIONSFORESOPHAGEALSTRICTURESARECOVEREDELSEWHERE INTHISBOOK

Nutrition #HILDRENONRESTRICTIVEDIETSMAYBEATRISKFORMACRONUTRIENT CALORICANDMICRONUTRIENT DElCIENCIES ANDSUBSEQUENTLY CHILDRENWITH%O%MAYBEATRISKFORMALNUTRITION ;6=!LARGEPARTOFTHEMEDICALMANAGEMENTINPEDIATRIC%O%ISBASEDONRESTRICTION OF DIETARY PROTEINS 3PECIlCALLY THE THREE MOST COMMON DIETARY MANAGEMENT APPROACHESINCLUDEREMOVALOFFOODSBASEDONTESTING REMOVALOFTHEMOSTCOMMONLY RESPONSIBLEFOODS ORADOPTIONOFASEMI ELEMENTALORANELEMENTALDIET;=



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4HEADOPTIONOFTHEELEMENTALDIETMAYBEASHORT TERMORALONG TERMINTERVENTION !SMALLPERCENTAGEOFCHILDRENCOMPLETELYOUTGROWALLOFTHEIRFOODALLERGIESASSOCI ATED WITH %O% – IN THE  YEAR EXPERIENCE OF THE #HILDRENS (OSPITAL OF 0HILADELPHIA;6=(OWEVER RESOLUTIONOFTHESEALLERGIES WHENTHEYOCCUR CANTAKE SEVERALYEARS;6= 4HEREFORE HAVINGASOUNDNUTRITIONALMANAGEMENTPLANTOADDRESSNUTRITIONAND GROWTHCONCERNSISKEY4HEUSEOFASEMI ELEMENTALORANELEMENTALDIETASTHESOLE SOURCEOFNUTRITIONISNOTONLYEFFECTIVEINTHEMANAGEMENTOF%O% ITMAYBEREQUIRED ;n=)FVOLUNTARYORALINTAKEISINADEQUATETOMEETCALORICNEEDS SUPPLEMENTAL ENTERAL TUBE FEEDING MAY BE REQUIRED 4HE NUTRITIONAL REQUIREMENTS FOR NORMAL GROWTHANDDEVELOPMENTDIFFERBYAGEANDBYGENDER ANDATTENTIONTOMEETINGNUTRI TIONAL NEEDS ACCORDING TO THE $IETARY 2EFERENCE )NTAKES SHOULD BE A CORNERSTONE CONSIDERATIONINTHEMEDICALMANAGEMENTOFTHESEPATIENTS;3=%LEMENTALFORMULA DIETSMAYNOTMEETALLMICRONUTRIENTREQUIREMENTS ANDSUPPLEMENTALMICRONUTRIENT SUPPLEMENTATIONMAYBEINDICATED

Behavioral 4HERE IS SOME EVIDENCE THAT BEHAVIORAL SYMPTOMS ASSOCIATED WITH %O% IMPROVE SUBSEQUENT TO THE INITIATION OF MEDICAL INTERVENTION EG DIETARY MANIPULATION PHARMACOLOGICTHERAPY ;31=&OREXAMPLE INASAMPLEOFINFANTSANDTODDLERSDIAG NOSEDWITH%O%REFERREDTOACLINICFORTHETREATMENTOFPEDIATRICFEEDINGDISORDERS ALL CHILDREN DEMONSTRATED NORMAL ENDOSCOPIC APPEARANCE AS WELL AS LESS THAN  EOSINOPHILSPER(0&WITHINAnMONTHPERIODSUBSEQUENTTOMEDICALANDNUTRI TIONALINTERVENTIONFOR%O%;1=!SWELL OFTHESAMPLEDEMONSTRATEDIMPROVED ORALINTAKEANDSIGNIlCANTWEIGHTGAIN(OWEVER THESElNDINGSSUGGESTTHATTHEREIS ASMALLSUBSETOFCHILDRENFORWHOMDISRUPTIVEMEALTIMEBEHAVIORANDFOODREFUSAL BEHAVIORAREMAINTAINEDDESPITEADEQUATEMEDICALMANAGEMENT)TISTHISSUBSETOF CHILDRENWHOMAYHAVEDEVELOPEDASIGNIlCANTBEHAVIORALFEEDINGPROBLEMWARRANT INGINTERVENTION 4HEREAREMULTIPLEFACTORSTHATCONTRIBUTETOTHEMAINTENANCEOFFEEDINGPROBLEMS ONCEMEDICALMANAGEMENTHASBEENOPTIMIZED ANDTHESEFACTORSWARRANTDIFFERENT TYPESOFINTERVENTION7HENENVIRONMENTALCONDITIONSCONTRIBUTETOTHEMAINTENANCE OFFEEDINGDIFlCULTIES BEHAVIORALINTERVENTIONISWARRANTED"EHAVIORALINTERVENTION ENTAILSTHEIDENTIlCATIONANDMANIPULATIONOFANTECEDENTANDCONSEQUENTIALFACTORS WITHINTHEFEEDINGENVIRONMENTWITHGOALSOFALTERINGMEALTIMEBEHAVIOR "EHAVIORAL INTERVENTION HAS BEEN DOCUMENTED AS AN EMPIRICALLY VALIDATED TREATMENTFORTHEMANAGEMENTOFPEDIATRICFEEDINGPROBLEMS;3=$ESPITETHEDOCU MENTEDEFFECTIVENESSOFBEHAVIORALINTERVENTION SUCHTREATMENTISNOTRECOMMENDED UNTILMEDICALMANAGEMENTOF%O%HASBEENOPTIMIZEDINORDERTOPREVENTFURTHER AVERSIVECONDITIONING)NACHILDWITH%O% THISWOULDENTAILDELAYINGTHESTARTOF BEHAVIORAL INTERVENTION UNTIL DECREASED ESOPHAGEAL INmAMMATION IS OBSERVED AND THEGRADUALREINTRODUCTIONOFFOODSHASBEENRECOMMENDED

 &EEDING$ISORDERSAND%OSINOPHILIC%SOPHAGITIS



7ITHREGARDTOANTECEDENTMANIPULATION PRECURSORSTOTHEDISRUPTIVEMEALTIME BEHAVIOR CAN BE ALTERED TO OPTIMIZE THE MEALTIME SETTING &OR EXAMPLE ADEQUATE MANAGEMENTOFDISCOMFORTEG GASTROINTESTINALDIFlCULTY ISCRUCIALPRIORTOCON DUCTINGBEHAVIORALINTERVENTION!SWELL APPETITEMANIPULATIONISIMPERATIVE PAR TICULARLYIFSUPPLEMENTALNUTRITIONHASBEENINTRODUCEDORALLYORVIATUBEFEEDING -AINTAININGAREGULARMEALTIMEROUTINEANDSCHEDULEEG MEALSATTHETABLE APPRO PRIATE SEATING REGULAR MEALSNACK SCHEDULE LIMITED DISTRACTIONS AT MEALTIMES DESPITETUBEFEEDINGSANDSUPPLEMENTALNUTRITIONOPTIMIZESAPPETITEANDINCREASES THELIKELIHOODOFSUCCESSFULBEHAVIORALINTERVENTION;33= !S WELL CONTINGENCY MANAGEMENT IS AN IMPORTANT COMPONENT OF BEHAVIORAL INTERVENTION;1="YALTERINGENVIRONMENTALCONDITIONSMAINTAININGFEEDINGDIFl CULTY THEINTERVENTIONISTATTEMPTSTOCHANGETHELIKELIHOODOFAPARTICULARBEHAVIOR OCCURRINGATFUTUREMEALTIMES&OREXAMPLE POSITIVEANDNEGATIVEREINFORCEMENTARE UTILIZEDTOSTRENGTHENADAPTIVEMEALTIMEBEHAVIOR0ROVIDINGTOYSANDATTENTIONTOA CHILDAFTERTHEYENGAGEINBEHAVIORTHATSUPPORTSEATINGMAYINCREASETHEIRPOSITIVE EATINGBEHAVIOR!SWELL REMOVALOFACHILDFROMAPRESUMABLYAVERSIVEFEEDING SITUATIONAFTERTHEYHAVEDEMONSTRATEDAPPROPRIATEEATINGBEHAVIORISANEXAMPLEOF NEGATIVEREINFORCEMENT&INALLYMILDPUNISHMENTCANBEIMPLEMENTEDTODECREASE THEOCCURRENCEOFMALADAPTIVEMEALTIMEBEHAVIOR&OREXAMPLE AFTERACHILDENGAGES INDISRUPTIVEBEHAVIORORBEHAVIORINCOMPATIBLEWITHEATING ACAREGIVERMAYREMOVE ATTENTION AND OTHER POTENTIALLY REINFORCING STIMULI FROM THE FEEDING SITUATION BY TURNINGAWAYFROMTHECHILD

Implications for Future Study 4HE BEHAVIORAL PRESENTATION OF %O% HAS NOT YET BEEN CLEARLY DElNED (OWEVER GIVENPREVIOUSRESEARCHONTHEBEHAVIORALEXPRESSIONOFOTHERGASTROINTESTINALDISOR DERSITISLIKELYTHATASUBSETOFCHILDRENWITH%O%PRESENTWITHBEHAVIORALFEEDING DIFlCULTIES&URTHERRESEARCHISNECESSARYTOBETTERDEMARCATETHENATUREANDPREVA LENCEOFTHESEPROBLEMSINCHILDRENPRESENTINGSPECIlCALLYWITH%O% 4HEBEHAVIORALMANIFESTATIONOF%O%MAYBEIMPORTANTINDETERMININGTREATMENT ENDPOINTS ASITISCURRENTLYNOTCLEARIFCOMPLETERESOLUTIONOFEOSINOPHILIAISCRU CIALTOPREVENTFURTHERCOMPLICATIONSORIFREDUCTIONINSYMPTOMSEG DYSPHAGIA FOODIMPACTION VOMITING FOODREFUSAL ISANADEQUATEENDPOINTFORTREATMENT;1= &URTHERSTUDYOFTHEBEHAVIORALMANIFESTATIONSOF%O%ASWELLASCONTRIBUTINGRISK FACTORSCOULDALSOINFORMPREVENTIVEINTERVENTION&OREXAMPLE EARLYDIAGNOSISAND TREATMENTFROMBOTHAMEDICALANDBEHAVIORALSTANDPOINTISKEY ANDMAYPREVENTTHE ONSET OF MORE SEVERE BEHAVIORAL FEEDING PROBLEMS &AMILIES COULD BE EDUCATED REGARDINGAPPROPRIATEFEEDINGPRACTICESWHENDIETARYRESTRICTIONSAREIMPOSED WHEN TUBEFEEDINGISINITIATED ANDWHENFREQUENTENDOSCOPYISPRESCRIBED&INALLY ONGOING STUDYOFTHEEFFECTSOFAGEONSYMPTOMRESOLUTIONWILLBEBENElCIALINRECOMMEND INGAPPROPRIATEANDEFFECTIVEINTERVENTION



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Summary %OSINOPHILIC ESOPHAGITIS CAN ADVERSELY IMPACT FEEDING DEVELOPMENT $ISCOMFORT RELATEDTOESOPHAGEALINmAMMATIONANDVOMITINGCANEASILYBECOMEASSOCIATEDWITH FOODANDMEALTIMES LEADINGTOMALADAPTIVEEATINGBEHAVIOR)FTHISBEHAVIORPERSISTS FOLLOWING IMPROVEMENTS IN AND RESOLUTION OF THE CAUSATIVE FACTORS A SIGNIlCANT FEEDINGDISORDERCANDEVELOP%ARLYDIAGNOSISANDMANAGEMENTOFSYMPTOMSASSO CIATEDWITH%O%ISVITALINPREVENTINGTHEDEVELOPMENTOFMALADAPTIVEFEEDINGPAT TERNS %ARLY INTERVENTION IS IMPERATIVE TO CORRECT NUTRITIONAL AND BEHAVIORAL ABNORMALITIES BEFORE THEY CAN ADVERSELY IMPACT LONG TERM NUTRITIONAL AND BEHAV IORALMANIFESTATIONS-ULTIDISCIPLINARYFEEDINGTEAMSCANBEEXCELLENTANDIMPOR TANTRESOURCESINTHEINTEGRATIVEAPPROACHTOTHECAREOFPATIENTSWITH%O%

References  !MERICAN0SYCHIATRIC!SSOCIATION4ASK&ORCEON$3- )6$IAGNOSTICANDSTATISTICALMANUAL OFMENTALDISORDERS$3- )6 42THED7ASHINGTON $#!MERICAN0SYCHIATRIC!SSOCIATION   .URKO3 2OSEN2 &URUTA'4%SOPHAGEALDYSMOTILITYINCHILDRENWITHEOSINOPHILICESOPHAGITIS ASTUDYUSINGPROLONGEDESOPHAGEALMANOMETRY!M*'ASTROENTEROLn  #HITKARA$+ &ORTUNATO# .URKO3%SOPHAGEALMOTORACTIVITYINCHILDRENWITHGASTRO ESOPHAGEAL REmUXDISEASEANDESOPHAGITIS*0EDIATR'ASTROENTEROL.UTRn  ,EE'3 #RAIG0) &REIMAN*3 DE#ARLE$ #OOK)*)NTERMITTENTDYSPHAGIAFORSOLIDSASSOCI ATED WITH A MULTIRINGED ESOPHAGUS CLINICAL FEATURES AND RESPONSE TO DILATATION $YSPHAGIA n  +HAN3 /RENSTEIN32 $I,ORENZO# ETAL%OSINOPHILICESOPHAGITISSTRICTURES IMPACTIONS DYSPHAGIA$IG$IS3CIn  3PERGEL*- "ROWN 7HITEHORN4& "EAUSOLEIL*, ETAL9EARSOFEOSINOPHILICESOPHAGITIS CLINICALFEATURESANDPROGNOSIS*0EDIATR'ASTROENTEROL.UTRn  /RENSTEIN 32 3HALABY 4- $I ,ORENZO # ET AL 4HE SPECTRUM OF PEDIATRIC EOSINOPHILIC ESOPHAGITIS BEYOND INFANCY A CLINICAL SERIES OF  CHILDREN !M * 'ASTROENTEROL n  0RASAD '! 4ALLEY .* %OSINOPHILIC ESOPHAGITIS IN ADULTS 'ASTROENTEROL #LIN .ORTH !M nVnVI  $ESAI4+ 3TECEVIC6 #HANG#( 'OLDSTEIN.3 "ADIZADEGAN+ &URUTA'4!SSOCIATIONOF EOSINOPHILIC INmAMMATION WITH ESOPHAGEAL FOOD IMPACTION IN ADULTS 'ASTROINTEST %NDOSC n 0ENTIUK30 -ILLER#+ +AUL!%OSINOPHILICESOPHAGITISININFANTSANDTODDLERS$YSPHAGIA n 3CHROEDER$' -ARTORELL2 2IVERA*! 2UEL-4 (ABICHT*0!GEDIFFERENCESINTHEIMPACTOF NUTRITIONALSUPPLEMENTATIONONGROWTH*.UTR3n3 2UEL-4 2IVERA* (ABICHT*0 -ARTORELL2$IFFERENTIALRESPONSETOEARLYNUTRITIONSUPPLEMEN TATIONLONG TERMEFFECTSONHEIGHTATADOLESCENCE)NT*%PIDEMIOLn 0OLLITT% 'ORMAN+3 %NGLE0, 2IVERA*! -ARTORELL2.UTRITIONINEARLYLIFEANDTHEFULlLL MENTOFINTELLECTUALPOTENTIAL*.UTR3n3 #HRISTIE, (INE2* 0ARKER*' "URKS7&OODALLERGIESINCHILDRENAFFECTNUTRIENTINTAKEAND GROWTH*!M$IET!SSOCn

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&URUTA'4 ,IACOURAS#! #OLLINS-( ETAL%OSINOPHILICESOPHAGITISINCHILDRENANDADULTS A SYSTEMATIC REVIEW AND CONSENSUS RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT 'ASTROENTEROLOGYn (AAS!- -AUNE.##LINICALPRESENTATIONOFFEEDINGDYSFUNCTIONINCHILDRENWITHEOSINO PHILICGASTROINTESTINALDISEASE)MMUNOL!LLERGY#LIN.ORTH!MnIX &IELD$ 'ARLAND- 7ILLIAMS+#ORRELATESOFSPECIlCCHILDHOODFEEDINGPROBLEMS*0AEDIATR #HILD(EALTHn  ,AUD2" 'IROLAMI0! "OSCOE*( 'ULOTTA#34REATMENTOUTCOMESFORSEVEREFEEDINGPROBLEMS INCHILDRENWITHAUTISMSPECTRUMDISORDER"EHAV-ODIFn &ISCHER% 3ILVERMAN!"EHAVIORALCONCEPTUALIZATION ASSESSMENT ANDTREATMENTOFPEDIATRIC FEEDINGDISORDERS3EMIN3PEECH,ANGn +EDESDY*( "UDD+3#HILDHOODFEEDINGDISORDERSBIOBEHAVIORALASSESSMENTANDINTERVEN TION"ALTIMORE0AUL("ROOKES0UBLISHING#O ,INSCHEID 4 "UDD +3 2ASNAKE ,+ 0EDIATRIC FEEDING PROBLEMS )N 2OBERTS - EDITOR (ANDBOOKOFPEDIATRICPSYCHOLOGY.EW9ORK'UILFORDn ,OGUE !7 #ONDITIONED FOOD AVERSION LEARNING IN HUMANS !NN . 9 !CAD 3CI  n "YARS+# "URKLOW+! &ERGUSON+ /&LAHERTY4 3ANTORO+ +AUL!!MULTICOMPONENT BEHAVIORALPROGRAMFORORALAVERSIONINCHILDRENDEPENDENTONGASTROSTOMYFEEDINGS*0EDIATR 'ASTROENTEROL.UTRn 3TARK,* 0OWERS37 *ELALIAN% 2APE2. -ILLER$,-ODIFYINGPROBLEMATICMEALTIMEINTER ACTIONSOFCHILDRENWITHCYSTIClBROSISANDTHEIRPARENTSVIABEHAVIORALPARENTTRAINING*0EDIATR 0SYCHOLn !CEVES33 &URUTA'4 3PECHLER3*)NTEGRATEDAPPROACHTOTREATMENTOFCHILDRENANDADULTS WITHEOSINOPHILICESOPHAGITIS'ASTROINTEST%NDOSC#LIN.!MnXI +IRBY- $ANNER%.UTRITIONALDElCIENCIESINCHILDRENONRESTRICTEDDIETS0EDIATR#LIN.ORTH !Mn 3PERGEL *- 3HUKER - .UTRITIONAL MANAGEMENT OF EOSINOPHILIC ESOPHAGITIS 'ASTROINTEST %NDOSC#LIN.!MnXI -ARKOWITZ*% 3PERGEL*- 2UCHELLI% ,IACOURAS#!%LEMENTALDIETISANEFFECTIVETREAT MENTFOREOSINOPHILICESOPHAGITISINCHILDRENANDADOLESCENTS!M*'ASTROENTEROL n 3ANTANGELO#- -C#LOUD%.UTRITIONALMANAGEMENTOFCHILDRENWHOHAVEFOODALLERGIESAND EOSINOPHILICESOPHAGITIS)MMUNOL!LLERGY#LIN.ORTH!Mn)XnX /TTEN** (ELLWIG*0 -EYERS,$$2) DIETARYREFERENCEINTAKESTHEESSENTIALGUIDETONUTRIENT REQUIREMENTS7ASHINGTON $#.ATIONAL!CADEMIES0RESS ,IACOURAS#! 3PERGEL*- 2UCHELLI% ETAL%OSINOPHILICESOPHAGITISA YEAREXPERIENCEIN CHILDREN#LIN'ASTROENTEROL(EPATOLn +ERWIN-%%MPIRICALLYSUPPORTEDTREATMENTSINPEDIATRICPSYCHOLOGYSEVEREFEEDINGPROB LEMS*0EDIATR0SYCHOLnDISCUSSIONn ,INSCHEID 42 "EHAVIORAL TREATMENTS FOR PEDIATRIC FEEDING DISORDERS "EHAV -ODIF n 3CHROEDER#3 'ORDON".-ANAGINGCOMMONPROBLEMSEATINGPROBLEMS)N3CHROEDER#3 'ORDON ". EDITORS !SSESSMENT AND TREATMENT OF CHILDHOOD PROBLEMS A CLINICIANS GUIDE .EW9ORK'UILFORDPn

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Chapter 29

Psychological Perspectives on Pediatric Eosinophilic Esophagitis Mary Klinnert

Keywords Eosinophilic esophagitis s Psychosocial functions s Children s Adolescents s Chronic illness

Introduction Eosinophilic esophagitis (EoE) is a recently described disorder marked clinically by symptoms of upper gastrointestinal distress and by histological evidence of increased eosinophils in the esophagus [1]. Although EoE has been reported in individuals across the lifespan, the disease has been most comprehensively described in children and adolescents [2]. In addition to further clarifications of EoE symptom presentation, current studies are investigating the pathophysiology of the disease as well as the effectiveness and outcome of treatments [3, 4]. Attention has now turned to the impact of the disease on the quality of life and psychosocial functioning of children and their families [5–7]. Since investigation of psychological aspects of EoE is in its infancy, little systematic information is available at this time. Nevertheless, with some information from recent and current studies as well as from clinical experience, it is possible to pose key questions about the impact of the symptoms and the treatments specific to EoE on quality of life for children and adolescents. Further, a great deal of information is available regarding psychosocial effects of various chronic illnesses on children, and extrapolations from previous

M. Klinnert (*) Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO, USA Department of Psychiatry, School of Medicine, University of Colorado, Aurora, CO, USA e-mail: [email protected] C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6_29, © Springer Science+Business Media, LLC 2012

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studies are informative regarding likely effects on youth of all ages with EoE. This chapter reviews what is known about the impact of EoE on quality of life and psychosocial adjustment, discusses the bidirectional effects of pediatric chronic illness characteristics, psychosocial functioning, and quality of life, and examines the role of coping and adaptation in relation to psychosocial functioning and quality of life.

Demographics and Illness Characteristics of EoE in Children and Adolescents To fully consider the quality of life impact and psychosocial aspects of EoE, it is important to understand the demographics of the disease, co-morbid conditions, diagnostic criteria, symptom patterns, and current treatments. Reports from numerous studies have indicated that children diagnosed with EoE are predominantly male with an approximate 3:1 ratio, and they range in age from 6 months to 21 years of age, with an average age of about 9 years [1, 8]. A recent report on 620 patients identified in the past 14 years found that 68% of the children were less than 6 years of age and 36% were younger than 3 years [8]. Families of patients were more likely to be Caucasian, affluent, highly educated, and to reside in suburban areas. Increasingly, pediatric EoE is considered to be an allergic disease [9] and, like other allergic diseases, a chronic illness [3]. The majority of pediatric patients with EoE have co-morbid allergic disease such as eczema, allergic rhinitis, and asthma, as well as IgE-mediated food allergies [5]. Eosinophilic esophagitis may be seen as another manifestation of allergic disease in children, where the esophagus is the target organ responding to environmental antigens, in this case, food. Food allergies may be causative in more than 90% of patients, although IgE-mediated food allergies resulting in anaphylaxis have been documented for a smaller proportion of patients, ranging from 6 to 24% [9]. Although clinical symptoms of EoE are similar to those of gastroesophageal reflux disease (GERD), EoE is distinguished from GERD by the presence of eosinophils in the esophagus even after appropriate acid suppression. Endoscopy is thus required to document eosinophil levels. Recently established diagnostic criteria for EoE include the presence of 15 eosinophils per high power field, associated with characteristic clinical symptoms unresponsive to anti-reflux medication [1]. Presenting symptoms vary according to patient age [1, 2]. For infants and young children, typical presenting symptoms are reflux, gagging, choking, vomiting, and feeding aversion or refusal, resulting at times in failure to thrive [10, 11]. School-age children with EoE typically present with reflux, heartburn, regurgitation, vomiting, and abdominal pain. Dysphagia, or difficulty swallowing, and food impaction have been reported on occasion among school-age children [12], but become increasingly common in adolescence and are the primary presenting symptoms for adults.

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Clinicians have consistently reported that presenting symptoms for EoE are nonspecific and highly variable among patients of all ages, and that there is often little relationship between symptom reports and histological findings. Several studies have shown that the association between symptoms and eosinophil counts is minimal [13–15]. Among a small number of pediatric patients, symptom reports were unrelated to eosinophil counts derived from endoscopies and, while endoscopy results showed evidence of remission through decreased eosinophil counts, no correlated changes were seen for symptom decreases or quality of life improvements [15]. In a larger study, symptom questionnaire and endoscopy results were evaluated for pediatric patients aged 3–18 who either had an EoE diagnosis but were not yet receiving treatment, or who were receiving follow-up assessments after treatment [14]. Children with untreated EoE had a higher symptom score than treated subjects, and for these untreated patients there was a modest correlation between symptom scores and the number of eosinophils found on biopsy. However, for the total sample there was no correlation between peak eosinophil counts and symptom scores. Importantly, among treated patients, 10% with persistent high eosinophil counts (i.e., with active EoE) reported no symptoms, while for 85% of patients, symptoms persisted despite histological resolution. Some clarification of symptom patterns was provided in a study that used symptom scores to distinguish pediatric patients with EoE from a group with GERD and from control patients with and without allergies [13]. Symptom scores were higher for patients with EoE and GERD compared with the two control groups. Those with EoE and GERD complained of more nausea/vomiting, abdominal pain, heartburn/ regurgitation, and nocturnal awakening than control groups. EoE patients were distinguished from GERD patients only by reports of dysphagia and anorexia/early satiety. Total symptom scores were uncorrelated with histological and endoscopic findings. However, the individual symptoms that distinguished EoE from GERD patients, dysphagia and dysphagia plus anorexia, were significantly correlated with severity ratings of histological and endoscopic findings. Dysphagia, typically reported by older children and adolescents, may have a different symptom status in comparison with the nonspecific symptoms reported for younger children. The nonspecificity and high variability of EoE symptoms has many implications for the consideration of health-related quality of life and the relationship with psychosocial factors. For children and adolescents with EoE, the distinguishing diagnostic indicator is a high esophageal eosinophil count, while symptoms are highly variable. However, the psychological effects of EoE can be expected to be associated not with eosinophil counts, but with symptoms that are experienced or with treatments that are undergone. Given that children with EoE can have a wide variety of disease experiences, effects on quality of life or psychological adjustment can be expected to vary widely across individuals. Although decreases in symptoms may generally be associated with quality of life improvements, treatment may have clearer effects on some symptoms than on others, with associated improvements in quality of life or psychological adjustment more apparent for some children than for others. On the other hand, sometimes when symptoms fail to improve, psychological concerns may persist despite decreased eosinophil counts and histological disease

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remission. It may be important to provide behavioral treatment for certain nonspecific symptoms in their own right, albeit in parallel with the medical treatment. The complex interactions between symptoms and behavioral responses, such as those that occur with feeding disorders and persistent abdominal pain, impact quality of life and may lead to significant behavioral and emotional difficulties for children and adolescents with EoE. The primary treatments that have been demonstrated to be effective for treating pediatric EoE are consistent with data indicating that food allergies underlie symptoms. Investigators have demonstrated that optimal treatments involve removal or avoidance of the offending foods or topical application of anti-inflammatory medications [16]. Removal of exposure to food is accomplished through partial or complete elimination diets, which involve restricting a selected set of foods from the diet or removing all foods from the diet and providing nutrition with elemental formulas either by oral ingestion or through feeding tubes. The dietary restrictions that are central to treatment of EoE may well constitute the most powerful factor impacting quality of life and psychosocial adjustment among children and adolescents with this disease. With EoE, the treatment involving food restrictions at various levels is often a major cause of psychological distress. At times the distress due to the treatment far outweighs the distress related to symptoms, leading to a conundrum for patients and medical providers alike. With EoE, as with many other chronic illnesses, children often must continue to undergo treatments after symptoms have resolved in order to prevent further symptoms. For children in this situation, the disease experience primarily involves enduring treatments such as food restrictions, altered diets, and tube feeding for an indefinite period of time. In sum, emotional and behavioral responses to both symptoms and treatments for EoE have considerable potential for impacting quality of life and psychological adjustment for children and adolescents with this disease.

Impact of EoE on Quality of Life The impact of disease on children and adolescents’ health-related quality of life (HRQL) has been studied for a wide variety of illnesses that afflict pediatric patients. Studies of HRQL among children who have medical illnesses are concerned with the effects of the disease and associated medical treatments not only on the physical status, but also on the psychological and social aspects of children’s lives [17]. HRQL instruments assess disease impact on academics, social interactions, extracurricular activities, and emotional functioning, as well as on health status. Generic instruments have been developed for the assessment of HRQL for children with health conditions and illnesses (e.g., Child Health Questionnaire-CHQ [18] and PedsQL™ [19]). Disease-specific instruments have also been developed for assessments of HRQL for a variety of pediatric diseases such as asthma, food allergies, and gastroesophageal reflux disease (GERD) [20–22].

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In studies of HRQL, the primary focus is on the patient’s subjective perceptions of their illness and its impact on their life. Thus, children and adolescents’ self-report of their own experience provides the most valid HRQL information. Children of about age 8 years and older have been demonstrated as able to provide reliable reports of their subjective experience, although one self-report HRQL instrument has demonstrated reliability for children as young as 5 years of age [17, 19]. Proxy HRQL reports completed by parents, necessary for very young children, are often provided for older children and adolescents as well. However, there is evidence that quality of life ratings made by parents and physicians of chronically ill children may agree poorly with the children’s own ratings, particularly for scales assessing subjective attributes such as emotions and pain [23]. Parents may overestimate quality of life effects on their children. Mothers of children with peanut allergy reported a greater impact on quality of life for their child in comparison with ratings made by siblings, fathers, or the peanut allergic children themselves [24]. In making proxy QOL ratings related to the impact of their children’s asthma, parents’ ratings were largely determined by their own psychological status rather than by objective measures of asthma care experienced by the children [25]. Similarly, when caregivers rated quality of life for their young children with otitis media, ratings of the children’s quality of life was highly influenced by the caregivers’ personal quality of life and functional health status [26]. Thus, while caregiver reports of children’s HRQL are valuable and even necessary for young children, self-reports of the impact of the disease by children and adolescents with EoE on their quality of life are highly desirable. At the present time, several studies of HRQL for pediatric patients with EoE are underway, but results are as of yet unavailable. However, one published study presents an initial view of qualitative information about HRQL for children and adolescents with EoE. Flood and colleagues [12] used an interview methodology to explore quality of life concerns among caregivers and pediatric patients with self-reported diagnoses of EoE. One-on-one interviews were conducted with parents of younger patients, age 2–7 years, and with older patients, age 8–17 years, about the effects that EoE had on the patients’ everyday lives. Having EoE was reported to impact school attendance and school-related activities because of symptoms, and also academic performance because of difficulties with concentration. Both parents and older children reported that social interactions at school and outside of school were affected because of symptoms, as when feeling sick interfered with plans to play with friends, and also because dietary restrictions interfered with participating in activities such as school parties or eating with friends. Symptoms were reported to interfere with sports activities ranging from soccer to football. There was a significant emotional impact reported as a result of having EoE [12]. Children of all ages experienced feelings of frustration and anger about not being able to eat the same foods as other children. They talked about having worries about eating the wrong food or having symptoms. Older children talked about feeling sad, depressed, unhappy, and tired of being sick. Parents reported that when their young children were having symptoms, they were often irritable and moody. Children and adolescents were unhappy about feeling different from others. For children of all ages, having EoE was reported to have a significant impact on their families. Older

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children were concerned about stress for the family or about the need for parents to adapt the family’s eating patterns. Parents of younger children also talked about the effect of the EoE on family meals and restrictions on the family’s ability to go out to eat or to participate in social events. Some parents noted a negative impact on the siblings of the child with EoE. The concerns listed by the children and their parents illustrate how the symptoms of EoE and the treatments associated with it impact quality of life within all key domains of children’s lives: physical, emotional, social, and school functioning [12]. For example, children reported that symptoms such as “feeling sick” led to restrictions on social activities. Notably, many of the concerns reported in this qualitative study stemmed from the effects of treatment, which for this sample of youngsters with EoE constituted dietary restrictions. The well-articulated emotional responses that occurred in response to both symptoms and treatment ranged across major categories of negative emotion, including anger/frustration, anxiety/worry, sadness/depression, and for younger children, irritability and moodiness. While this initial qualitative study of QoL effects of EoE on children and adolescents was an important first step, future studies must attend carefully to the developmental status of the pediatric patients involved [7]. The changing impact of EoE across developmental stages of socioemotional development can hardly be overestimated. For each stage of development, pediatric patients have particular ways of communicating their symptom experiences and differing reactions to symptoms and to treatments. The disease impact occurs in social contexts that change with development and, perhaps most importantly, the contextual meaning of the disease experience for the child’s emotional and social development changes dramatically with age. For very young children, the social context in which EoE occurs is primarily confined to their immediate family, and for them the meaning of the disease is embedded in the quality of their interactions with their family members. For infants and toddlers, emotional responses to bodily sensations such as pain or nausea are expressed through behaviors such as food refusal, irritability and moodiness. Proxy reports of QOL for very young children are based on parents’ observations and interpretations of the children’s behavior. As noted above, parental reports of their young children’s quality of life are influenced by their own psychological status and stress level [26]. But it is not just the reports that are influenced by parental variables; young children’s behavior itself, while affected by multiple medical and developmental variables, is in part shaped by the parents’ caregiving behavior and the nature of the parent–child interactions, including their emotional communications regarding the burden and meaning of the disease. Thus, quality of life and reports of quality of life for young children cannot really be separated from their parents’ quality of life specific to the disease. Changes in disease status or treatment regimens, for better or worse, reflect the impact of the illness on both the child and the parent. Preschool age children may not yet be able to complete questionnaires, but they are capable of verbally communicating their symptom experience and their feelings about the treatments they undergo. Proxy reports by parents of preschoolers’ symptoms and quality of life, while still influenced by parents’ emotional status and

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stress levels, can be based on verbal complaints of tummy pain or feeling sick. Preschoolers’ emotional responses to their illness have to do not only with the physical discomfort they experience, but also with their observations of their own experience in relation to that of others. For example, preschoolers develop the ability to see that dietary restrictions apply to them and not to siblings or schoolmates. Nevertheless, their social context remains primarily centered within their family and they are amenable to parental influence such as being provided acceptable foods that are similar to those of their peers or being told that their food is “special.” While children at the school entry age of 5–7 years of age undergo enormous shifts in cognitive and emotional development, they continue to be influenced primarily by the guidelines and support provided by their families. An important developmental shift occurs when children are about 8 years of age, resulting in a qualitative change in their illness experience [20], and perhaps also in the factors affecting their quality of life. As noted, it is at this age that children are able to provide reliable reports of their physical and emotional state. Even while their family remains their primary social context, at this age children become increasingly peer-oriented. As they spend greater amounts of time away from home, dietary restrictions and limitations on social and academic activities can produce feelings of anger and frustration, as well as a heightened awareness of being different from others [12]. Thus, whereas they previously accepted their parents assurances and support, they no longer accept their disease status as being special, but instead begin to see their difference from peers in a negative light [20]. It is very important to assess quality of life for children in this age range independently from proxy reports made by their parents, as their views, attitudes, and feelings about their disease set the stage for their entry into adolescence. With adolescence, the social context involves even less parental supervision and more peer involvement, and is accompanied by the need to make independent decisions about handling social situations that involve eating. For teens, even more than in the younger years, disease-specific quality of life may be associated with overall psychological adjustment. Just as the quality of life of chronically ill children is significantly impacted by the physical and emotional demands of the disease, so too is the quality of life of parents and siblings. Effects on parents of their children’s chronic illness include time-consuming daily tasks, financial burdens, and effects on relationships within the family and social contacts outside the family [27]. Parents of chronically ill children aged 3–18 years from ten different types of pediatric chronic diseases had significantly lower health-related quality of life compared with parents of healthy school children. For the parents, the areas impacted included social activities, daily activities, vitality, and sleep. They reported fewer positive emotions and more depressive feelings than parents from the comparison group [28]. The areas of family life that are impacted by pediatric chronic illnesses are likely to be similar for families of children with EoE. Families of food-allergic children share with EoE several burdensome daily tasks, such as shopping for food the child is able to eat, adapting the family’s diet to the needs of the food-allergic child, and explaining the condition to relatives, friends, and

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school personnel [29]. They also share with EoE the worries regarding nutritional sufficiency of acceptable food and the long-term impact on their child’s growth and development [29]. Since the majority of children with EoE may be less than age 6 years [8], with symptoms often indistinguishable from GERD, the illness-related quality of life of caregivers of children with GERD are illustrative of parents’ day-to-day concerns. Parents have described how routine care-giving activities for their children required extra work and care, such as special feeding techniques involving small portions, frequent feedings, and preparation of special meals or formulas [22]. The parents also talked about emotional concerns specific to their children’s reflux and feeding problems, such as fearing that the child might choke on the their vomit when they put them to bed at night. Parents of children with food refusal and failure to thrive worried a great deal about their children’s condition and prognosis. This is consistent with other studies that have documented high levels of parenting stress among parents of children with feeding disorders [30], a common condition among young children with EoE. Available information is mixed about effects of children’s tube feeding on caregivers’ emotional functioning and quality of life. Although feeding tubes can initially bring relief to parents concerned about their children’s nutritional intake, one study showed that parents of children who had gastrostomy tubes had poorer quality of life in terms of social life, family life, sex life, and work [31]. However, another study showed no difference in rates of depression for caregivers of chronically ill children with a G-tube compared with those without [32]. Overall, available data indicate that both general concerns and burdens and EoEspecific issues have considerable impact on quality of life for the parents and siblings of children with EoE. However, like families of children with other diseases with comparable characteristics, families of children with EoE are likely to have varying emotional responses and coping strategies that result in a range of levels of adaptation.

Psychological Adjustment Among Children and Adolescents with Chronic Illness To our knowledge, no systematic research has been published regarding psychological adaptation among pediatric EoE patients. However, there is consistent evidence that children with a variety of chronic illnesses have increased levels of emotional and behavioral difficulties in comparison with healthy children [33–35]. Most often, these studies show that the average level of increased problems, although statistically significant, is small [35], which suggests that there is a subset of children with considerable difficulty adapting to their illness although the remainder may be managing effectively. It is likely that a similar pattern will be found for children with EoE, such that most of the children will be found to be coping adequately, but a subset will be found to have adjustment problems that are concerning [7].

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The physical symptoms experienced by chronically ill children, as well as the medical procedures and the treatments, can be thought of as a series of general and disease-specific stresses with which the child must find a way to cope. General stresses for chronically ill children include receiving a diagnosis for an illness that requires medical intervention, the possibility of long-term consequences on physical health, interference with developmentally normal experiences, feeling set apart from healthy children, and requirements for a variety and range of illness management strategies and behaviors. Other stresses associated with pediatric chronic illnesses are related to the unique characteristics of the disease and the treatments. Children have been shown to have more adjustment problems when their disease is visible, has an unpredictable course, is potentially fatal, or has a sensory or motor component [34]. In applying this to EoE, we might expect those children to have more difficulty adjusting to their disease who have visible symptoms such as vomiting at unpredictable times or food impactions in public settings. Children and adolescents who have food restrictions, who are on elimination diets, or who have gastrostomy tubes may experience these treatments as visible evidence that they are different from peers. Those with co-morbid, potentially anaphylactic food allergies may experience the anxiety that is associated with potentially life-threatening illness. While it is normal to have emotional responses to EoE-related stresses that include feelings of frustration, anxiety, or sadness, for some children these feelings are manageable, whereas for others the feelings can become overwhelming. The manner in which children and adolescents cope with chronic illnesses has an important influence on their quality of life and psychological adjustment. Coping responses involve problem-solving behaviors or cognitive strategies that aid in managing negative emotional responses, and when children and adolescents with chronic illness are having difficulty coping, they often report both poor quality of life and negative mood [36]. Certain cognitive coping strategies have been associated with better adjustment and quality of life and fewer feelings of anxiety, depression, and stress. For 8- to 17-year-old youth with food allergies, more negative attitudes toward food allergy predicted more anxious and depressive symptoms as well as social stress [37]. For adolescents with inflammatory bowel disease, a coping strategy marked by a depressive cognitions (e.g., often worrying about things in the past, not being able to think of anything else but the problem) was related to poorer quality of life, while an optimistic coping style was related to better quality of life [38]. For adolescents with cystic fibrosis, the coping strategy of social comparison was related to higher quality of life, whereas depressive coping was negatively related to quality of life [39]. Disease severity might be expected to predict poor psychological adjustment, but studies of pediatric chronic illness have been mixed as to whether increased disease severity is related to more psychological problems [35, 40]. In fact, the differing results appear to be due to the measurement of disease severity. Objective measures of illness severity, such as those based on physiological data or clinician ratings, have tended to be unrelated to psychological problems, while it has been the patient or parent’s perception of disease severity that has been correlated with psychological distress [39, 41]. Given that with EoE there is a minimal relationship between objective measures such as eosinophil counts and patients’ symptoms,

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psychological adjustment problems can be expected to be associated primarily with symptoms. Patients with frequent vomiting or food impactions might be more affected socially and emotionally than patients with periodic reflux or those with no clinical symptoms, regardless of esophageal eosinophil counts. Although EoE symptoms are generally nonspecific and variable, for pediatric patients with EoE and their families, several patterns of symptoms associated with characteristic child behaviors, family interactions, and psychological distress occur regularly. The age and developmental status of the patient is central to the nature of the adjustment difficulties that are encountered. Among infants and young children, the presenting symptoms of EoE are often feeding disorders, with organic and nonorganic factors intertwined [42], accompanied by a great deal of emotional distress on the part of all family members. A different set of medical, behavioral, and emotional issues are raised for children who require tube feeding. Abdominal pain, often persistent regardless of histological remission, is yet another medical/psychological complex that can be problematic among school-age children with EoE. And concerns about peer status, stigma, and depression are yet another complex of areas of psychological distress that occur for older children and adolescents with persistent EoE disease. For each symptom pattern, there are complex relationships between EoE histology and symptoms, the child’s emotional response to and coping with the disease, and interactions with the family and the family’s coping responses. The complex interrelationships between disease symptoms, patient and family emotional and behavioral responses, and child adjustment are illustrated in several of the symptom patterns that occur with EoE.

Feeding Disorders For infants and toddlers with EoE, the most common symptom presentation is food aversion or refusal, central components of feeding disorders among young children [1, 5, 10, 11]. Since more than a third of pediatric patients with EoE are less than 3 years of age [8], feeding disorders among patients with EoE are a common but significant problem. The nature of feeding dysfunction among children with eosinophilic gastrointestinal disease has been well described [43]. Feeding problems associated with eosinophilic gastrointestinal diseases include food refusal, gagging, coughing and vomiting, as well as delayed attainment of age-appropriate self-feeding skills and eating patterns [43]. These behaviors may lead to decreased variety and volume of oral intake, compromised nutritional status and may ultimately lead to failure to thrive [43]. The etiology of feeding problems among children with eosinophilic gastrointestinal diseases remains poorly understood. Although feeding disorders are known to occur in conjunction with a number of pediatric conditions, more than half of 700 young children with severe feeding problems had a gastrointestinal medical problem, and GERD was most frequently identified as the underlying medical condition [42]. Thus it is no surprise that feeding problems are common among children with EoE, since presenting symptoms for young children with EoE are the same as those for GERD. Among infants and toddlers with EoE who present with feeding problems,

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there appears to be an over-representation of neurodevelopmental disorders, with reports ranging from 12 to 67% of patients [10, 44]. This suggests that some children have oral motor or oral sensory deficits that have disrupted the normal process of learning to eat. For other children, the experience of pain with swallowing or reflux is believed to lead to a conditioned food aversion response. Thus, food aversion or intolerance is believed to stem from experiences of discomfort or pain with eating, leading to learned avoidance behavior in children too young to verbalize their pain. This causal pathway is supported by a study that showed that infants who have GERD during their first year of life were significantly more likely than healthy children to develop feeding problems within the following year [45], and it is likely that infants with EoE have a similar pattern. When children refuse food offered to them, parents often respond with altered feeding practices that reinforce ineffective eating behavior [43], setting in motion parent–child behavioral interaction patterns that can be extraordinarily resistant to change. Child behavioral patterns of food refusal are associated with significant stress for parents [30, 46, 47] and likely have a major impact on quality of life for siblings as well. Research is needed to address various aspects of feeding disorders among children with EoE. There is a need for a description of the frequency of oral motor and oral sensory deficits among these children, as well as the role of behavioral issues in this group of children. It would be helpful to understand developmental predictors and correlates of feeding disorders as they relate to the development of EoE in infants and young children. For example, while the prevalence of feeding dysfunction is high among young children with EoE, as it is with the infants with GERD, not all children with EoE symptoms, such as reflux and vomiting, develop feeding problems. The question is, why is it that some infants who experience these unpleasant symptoms do not develop food aversion, while others develop frustrating and persistent problems that can become life threatening? What are the infant medical and temperamental characteristics, the parent physical and behavioral factors, and the environmental variables that constitute risk factors for the development of this difficult behavior pattern? There is also a need to assess the effectiveness of current interventions for these problem behaviors, and to understand what child and parent characteristics are associated with successful interventions. Ultimately, it will be important to understand the relationship between the course of EoE and the long-term nutritional and behavioral outcomes for children with onset of EoE in their first years of life. Future research must address these issues surrounding feeding dysfunction in children with EoE, where biological, behavioral, and relationship systems all play a role.

Tube Feeding Another psychological adjustment necessary in children with EoE concerns tube feeding. Because allergic responses to food are the primary triggering factor for most pediatric patients with EoE, and removing foods from the diet is central to treatment, the provision of nutrition for these children can be extremely challenging. Treatment for some children involves placing nasogastric (NG) tubes for a limited

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period of time, in order to provide appropriate nutrition while allowing the esophagus to heal prior to re-introducing foods into the diet [48]. Some children continue to have high numbers of eosinophils in their esophagus and/or troublesome symptoms including the inability to ingest adequate nutrition and require gastrostomy tubes (G-tubes) [49]. The use of tube feeding in the treatment of EoE has clearly been associated with disease remission [48]. However, little information is available regarding the effect of either short- or long-term tube feeding on quality of life or behavioral and emotional functioning for children and adolescents with EoE, or on their families. The use of feeding tubes in the treatment of EoE has the potential to seriously impact children in a number of ways, and the effect of tube feeding for any length of time on children with normal neurodevelopmental functioning is unknown. Although G-tube feedings ensure adequate nutrition, they may impede the development of oral feeding skills by decreasing children’s hunger driven motivation to eat and by decreasing oral stimulation [50]. This may be a serious concern for infants and toddlers, who may miss oral stimulation and establishment of the connection between hunger and eating during critical periods for the development of eating behavior [43]. For older children with independent eating skills, eliminating the connection between hunger and eating may compound eating problems, making difficult the reinstatement of eating [50]. No information is available about how school-age children with NG or G-tubes feel about their bodies or about being different from others. Equally important for older children are the emotional effects of removing food from the diet and the resulting impact on social activities and peer relationships. Thus, research is needed to investigate multiple aspects of this common treatment, both concurrently with tube placement, but also over time, in order to discover the short- and long-term effects on eating behavior, quality of life, and psychological adjustment.

Abdominal Pain Abdominal pain, frequently a primary presenting symptom for EoE, represents another area in which medical and psychological factors are often inextricably intertwined. Although clinical symptoms of EoE are notoriously nonspecific, which is why the diagnosis depends on histological findings [14], some symptoms are more nonspecific than others. Dysphagia and anorexia/early satiety may be the most specific of reported symptoms, since they distinguished EoE patients from GERD patients [13], whereas abdominal pain may be the most nonspecific. In the study by Aceves, abdominal pain was present for both EoE and GERD patients, although it was among the symptoms distinguishing those two groups from normal controls [13]. In a group of 49 pediatric patients age 3–18 with diagnosed EoE, 69% reported experiencing abdominal pain; this was the most commonly reported symptom from this sample [14]. Among treated EoE patients who achieved histological remission, 88% continued to report symptoms. Given its frequency, abdominal pain is likely one of the symptoms that persisted after remission. Although explanations for the

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persistence of abdominal pain are being conceptualized and investigated [14], it seems that many patients with EoE who by objective measures have been successfully treated continue to have complaints of abdominal pain. The frequent persistence of abdominal pain in patients with EoE, regardless of treatment status or histological resolution, suggests that behavioral treatment specific to managing or alleviating the pain may be indicated. Assuming that pharmacological and nutritional interventions are already in place, behavioral treatment could follow the model of treatments for recurrent or functional abdominal pain, which have been shown to be moderately effective [51]. These cognitive behavioral treatments include cognitive coping, progressive muscle relaxation and/or diaphragmatic breathing, and contingency management training for parents. The cognitive aspect involves addressing the appraisal of pain as a serious threat with responses of fear and avoidance of activities, a style of coping that interferes with children’s ability to engage in developmentally appropriate activities [52]. Contingency management examines and addresses the manner in which parents, teachers, and health care providers respond to the child’s pain behavior. Protective and anxious responses can promote the child’s focus on the pain, increased anxiety, and withdrawal from school and other activities. In contrast, an active approach to pain management and maintenance of daily activities helps a child to stay fully functional and less anxious, and leads to better quality of life. Research is needed to investigate the relationship between abdominal pain and physiological aspects of EoE, such as eosinophil counts and levels of stomach acid. In addition, the reciprocal relationship between abdominal pain and psychological factors merits investigation. Family stress levels and child or adolescent psychological functioning in relation to abdominal pain, both prior to and following evaluation and treatment for EoE might be explored. In a study of youth ages 8–17 with abdominal pain but no known gastrointestinal or chronic illness, family stress and psychological functioning was assessed prior to diagnostic esophagogastroduodenoscopy [53]. For girls, depression predicted positive biopsy findings (including high levels of eosinophils for some children), while for boys, positive biopsies were predicted by family stress. These results are suggestive regarding relationships between stress, physiological processes, and symptoms. Also in need of investigation is the effectiveness of behavioral approaches for pain management with children with EoE who have persistent abdominal pain.

Social Stigma and Adherence As previously noted, children from about 8 years of age onward often struggle with feelings of self-consciousness and being different. For youngsters with EoE, these feelings may occur related to symptoms, as when a 12-year-old with dysphagia chokes on food in the school cafeteria. However, with EoE the dietary restrictions appear to be even more salient than the symptoms, as they impact all domains of children’s and teens’ lives [12]. The array of feelings related to being different from others has been

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commonly noted among older children and adolescents across a range of chronic illnesses. Adolescents with celiac disease vividly described how adherence to their prescribed diet complicated their social relationships by drawing attention to themselves and making visible their otherwise invisible medical condition [54]. For youth with EoE, dietary adherence might be compromised. as a result of difficult social interactions resulting from limited diets. Dealing with similar concerns, older children and adolescents with food allergy were concerned about the lack of understanding on the part of others and the social embarrassment they experienced when attempting to avoid certain foods; as a result they sometimes felt that “just chancing it would be okay.” [55] In a study of risk-taking behavior among adolescents with food allergy, a substantial number of the teens reported eating foods that “may contain” the foods to which they were allergic [56]. It seems likely that adolescents with EoE would have very similar experiences with their dietary restrictions as those reported by the adolescents with celiac disease and food allergies. If teens at risk for anaphylaxis take chances with possible exposure to foods, it seems very likely that the same behavior occurs for teens with EoE, where there is a less clear connection between ingesting restricted food and experiencing symptoms or developing increased eosinophils in the esophagus. Little is known about dietary adherence among children and adolescents with EoE. It is unclear how completely parents manage their children’s diets, and to what extent they do it independently of or in concert with diets of other family members. It is also unknown how well older children and adolescents comply with their dietary restrictions when they are on their own, or when they are at home in the family context. Drawing from research regarding adherence with other chronic illnesses, it is hypothesized that dietary adherence is predicted by understanding the illness, by the quality of parent–child relationships, and by the child’s psychological and social adjustment. Teens with food allergy who had better peer relationships and who had disclosed their illness to their friends took fewer risks with food [56]. Research is needed to determine how youngsters and their families manage and adhere with their dietary restrictions, about the burden involved, and also about factors that facilitate or impede adherence. Only by knowing to what extent families and children follow their diets will it be possible to evaluate the effectiveness of dietary restrictions in treating EoE. Further, only by systematically evaluating the perceived burden of dietary restrictions on children and families will it be possible to make treatment decisions that optimize effectiveness while minimizing burden.

Coping in Families of Children and Adolescents with EoE There are many demands on families of a child with EoE, from the onset of symptoms and requirements for medical appointments and diagnostic procedures, to the acceptance of a diagnosis and collaborative decision-making on a treatment plan. Not only are there medical issues to comprehend; parents also are responsible for integrating treatment plans into the family structure. They must determine how food restrictions will be accomplished and how special diets will be instituted, they must

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develop an understanding of the nutritional adequacy of recommended diets, and they may need to learn how to manage tube feeding. There are logistical issues of medical appointments, insurance concerns, and financial burdens. Besides these practical matters, parents have the task of helping the child with EoE to understand and cope with the illness and the related treatment plans and lifestyle changes that ensue. Further, they assume the responsibility of doing this in a developmentally appropriate, sensitive, and emotionally attuned manner. Finally, most parents attempt to stretch their attention and emotional and material resources to meet the needs of the other children in the family, and to create a family environment of mutual support and cohesiveness. No wonder that parents of children with EoE, like parents of other chronically ill children, often feel extremely stressed, and sometimes experience anxiety and depression. A large epidemiological study showed that mothers of chronically ill children reported more negative affect than those of healthy children, and mothers and fathers were 2–3 times more likely to seek mental health treatment [57]. Across different pediatric chronic disorders, mothers’ adjustment problems were found to be one standard deviation above the mean for the general population [58]. Although families can experience considerable stress and distress as they learn to cope with their children’s chronic illness, overall their responses to children’s illnesses vary along a continuum, with many families coping extraordinarily well while a subset of families experience considerable difficulty. In this way parents and family coping responses parallel those of the children, with the majority managing well. Recent research regarding families of children and adolescents with health problems has supported the overall competence of families in adapting to and managing their children’s illnesses [41], and emphasizes the importance of focusing on families’ competence and the adaptive processes they employ. As research is initiated regarding psychosocial aspects of EoE for children and adolescents, it is also important to investigate how the illness affects the child’s family. Consideration must be given to effects of the illness on parents and children’s quality of life, on their psychological adjustment, and their overall adaptation. While appreciating the burdens and demands of the disease and the impact of the disease on pediatric patients and their families, it is important to maintain focus on families’ competence. The overall goal is to understand the adaptive and coping processes, by developing an understanding of families’ experiences and how they deal with the demands they encounter. By gaining a thorough understanding of these complex processes, it will be possible to better support families as they learn to cope with and achieve optimal adaptation for the child with EoE and for the entire family.

Implications for Psychological Care of Children and Adolescents with EoE Clearly, there are many ways in which EoE impacts the quality of life and psychological adjustment of children and their families. For physicians and health care providers of these children and families, concerns about impact on quality of life

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have risen to the forefront, along with medical discoveries and treatment innovations. Attention by clinicians to both children and parents’ emotional responses and their coping effectiveness is critical if one is to have a child and family-centered approach to caring for EoE. The problems that children present in response to inquiries about their quality of life point to the issues that are particularly salient for them, and their attitude toward their illness provides a window into their coping strategies. Similarly, the questions that parents raise indicate which of the multiple facets of their child’s care is foremost among their concerns. Although attention by the clinician to the child and parents’ concerns is a crucial first step in facilitating families’ coping, a routine assessment by a psychosocial clinician that focuses on emotional concerns, quality of life issues, and coping strategies is an extremely helpful second step. The content of this quality of life assessment depends on each individual child’s developmental status as well as disease phase, whether it be in the stage of diagnostic testing, treatment planning and institution, or follow-up evaluation. Families may be dealing with symptom management, with implementation of food restrictions, or with introducing food back into the diet. Each family has unique concerns about how to manage these issues and tasks. The quality of life assessment necessarily includes brief interventions such as anticipating with families the stages and components of evaluation and treatment of EoE, educating them regarding illness demands and coping challenges experienced by other families, and clarifying the family’s specific questions, concerns, and coping style. Finally, the quality of life assessment allows a review of the patient and family’s emotional functioning and overall adaptation, with an opportunity to evaluate for risk factors of significant co-morbid psychological conditions such as depression and anxiety. The third level at which psychosocial issues can be addressed for pediatric patients with EoE and their families involves behavioral counseling or psychotherapy. The physician can make referrals based on clinical observations, or the need for treatment may become apparent during the quality of life assessment. Behavioral counseling may be required for patients having difficulties with EoEspecific issues such as self-image, peer relationships, or treatment adherence. Children with abdominal pain may benefit from pain management treatment. Anxiety and depression occur for a subset of children and adolescents with chronic illness, and these patients require treatment from mental health professionals. Children with asthma have been shown to benefit from group art therapy [59], and it is likely that children with EoE would benefit similarly from the opportunity to express their feelings about their disease and share their experiences with others who have similar problems. Parent counseling to address young children’s emotional, behavioral, or sleep regulation can be a useful adjunct to medical and feeding therapy. Finally, family therapy can be extremely helpful for parents and children struggling with the emotional burden of EoE, since family cohesion and open expression of feelings are associated with better child adjustment to chronic illness [60].

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Summary For pediatric patients with EoE, symptoms, the nonspecific and variable symptoms and treatment involving dietary restrictions often have a major impact on the quality of life of the children and adolescents and on that of their families. Psychological adjustment among children and adolescents with EoE may be impacted to a lesser degree, but a subset of children will likely develop concerning psychological difficulties that require treatment. Several patterns of symptoms and behavioral responses that are specific to EoE, including feeding dysfunction, tube feeding, and abdominal pain, can lead to considerable psychological difficulty, and older children and adolescents may be affected by problems often associated with chronic illness, including stigma, adherence challenges, and depression. Families of children with EoE experience a variety of burdens and challenges, and it is important to provide appropriate levels of intervention while supporting families’ competence.

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Chapter 30

Eosinophilic Esophagitis: Treatment Approach in Adults Ikuo Hirano

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&URTHERMORE HISTOLOGICRESOLUTIONOFINmAMMATIONONESOPHAGEALMUCOSALBIOPSIES COULDBEMISLEADING4HEINmAMMATORYPROCESSWITHINTHEESOPHAGUSISPATCHYAND LIMITED BIOPSY SAMPLING COULD INTRODUCE ERROR IN INTERPRETATION ;= &URTHERMORE STUDIESHAVEDEMONSTRATEDTHATESOPHAGEALEOSINOPHILIACANEXTENDTOINVOLVETHE SUBMUCOSAASWELLASMUSCULARISLAYERS REGIONSTHATARENOTROUTINELYSAMPLEDBY ESOPHAGEALMUCOSALBIOPSIES; 9= 4HE MAJORITY OF THE PUBLISHED THERAPEUTIC STUDIES TO DATE HAVE FOCUSED ON THERAPEUTICOUTCOMESOFSYMPTOMSANDESOPHAGEALEOSINOPHILIA7HENCOMPARING EXISTINGTREATMENTSTUDIES DIFFERENCESINPATIENTSELECTION DElNITIONOFTHERAPEUTIC RESPONSE ANDDURATIONOFTREATMENTAREIMPORTANTPARAMETERSTHATMAYEXPLAINHETEROGENEITYINRESULTS-ORERECENTLY INVESTIGATIONSHAVEINCLUDEDADDITIONALPARAMETERSOFHISTOLOGICTISSUEINJURYSUCHASSUBMUCOSALlBROSISASWELLASANATOMICAND PHYSIOLOGICCONSEQUENCESOF%O%DETERMINEDBYUSEOFHIGHFREQUENCYENDOLUMINAL ULTRASONOGRAPHYANDESOPHAGEALMURALCOMPLIANCE;5 9=$EVELOPMENTOFAN%O% ACTIVITYINDEXISUNDERWAYTHATCOMBINESCLINICALWITHENDOSCOPICANDHISTOLOGIC PARAMETERSANDWILLOFFERAVALIDATEDASSESSMENTOFPATIENTRESPONSETOTHERAPY

Evaluation Prior to Initiation of Therapy 4HEMANAGEMENTOF%O%INADULTSBEGINSWITHRECOGNITIONOFTHEDISEASE%O%IS CONSIDEREDINADULTSWITHDYSPHAGIAANDFOODIMPACTIONS REGARDLESSOFTHEPRESENCE ORABSENCEOFHEARTBURN%NDOSCOPICEVIDENCEOFESOPHAGEALSIGNSOF%O%INCLUDE RINGS LONGITUDINALFURROWS WHITEEXUDATES OREDEMA"IOPSIESSHOULDBEOBTAINED EVENWHENTHESEFEATURESAREABSENTSINCEUPTOOFADULTSMAYHAVEANORMAL APPEARANCETOTHEESOPHAGUSON%'$;=4HEPRACTICEOFEMPIRIC LARGECALIBER ESOPHAGEAL DILATION IN PATIENTS WITH UNEXPLAINED DYSPHAGIA SHOULD GENERALLY BE AVOIDEDGIVENREPORTEDCOMPLICATIONSOFDILATIONIN%O%)NSTEAD BIOPSIESOFTHE ESOPHAGUS FOR UNEXPLAINED DYSPHAGIA CAN IDENTIFY PATIENTS WITH %O% WHO WOULD BENElTFROMMEDICALORDIETARYTHERAPYANDACONSERVATIVEAPPROACHTOESOPHAGEAL DILATION/THERLESSCOMMONPRESENTATIONSOF%O%INADULTSINCLUDEATYPICALCHEST PAINORHEARTBURNTHATDOESNOTRESPONDTOEMPIRIC00)THERAPY)NSUCHCASES THE UTILITYANDCOST EFFECTIVENESSOFESOPHAGEALBIOPSIESTORULEOUT%O%ISUNCERTAIN 0ROSPECTIVESTUDIESHAVESHOWNTHATTHEDIAGNOSTICYIELDOFTHISAPPROACHISLOWIN THEABSENCEOFSYMPTOMSOFDYSPHAGIA/NTHEOTHERHAND SEVERALCASEREPORTSHAVE DESCRIBEDPATIENTSSUSPECTEDOFHAVINGREmUXREFRACTORYTOMEDICALORSURGICALFUNDOPLICATIONWHOWERESUBSEQUENTLYDIAGNOSEDWITH%O%; =)MPROVEMENTIN THEPATIENTSWASSUBSEQUENTLYACHIEVEDAFTERTREATMENTOF%O%;= )NPATIENTSWITHSUSPECTED%O% MULTIPLEMUCOSALBIOPSIESSHOULDBEOBTAINED SINCETHEINmAMMATORYCHANGESAREOFTENNOTUNIFORMBUTPATCHY"OTHAPEDIATRIC AND ADULT STUDY OF HISTOLOGIC VARIABILITY IN %O% DEMONSTRATED THAT THE YIELD FOR DETECTIONOFESOPHAGEALEOSINOPHILIADElNEDBYGREATERTHANEOSHPFWASMAXIMIZEDBYACQUISITIONOFSIXESOPHAGEALBIOPSIES; 3=4HENUMBEROFBIOPSIES



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NECESSARYINCREASESIFAHIGHERTHRESHOLDNUMBEROFEOSHPFISUSEDTODElNETHE DISEASE)NTERMSOFLOCATIONOFBIOPSIES THEPRACTICEOFOBTAININGSEPARATEBIOPSIES FROMTHEPROXIMALORMIDESOPHAGUSRATHERTHANDISTALESOPHAGUSISBASEDONTHE NOTIONTHATREmUXISASSOCIATEDWITHDISTALINmAMMATIONTHATMAYINCLUDEEOSINOPHILS4HEACCURACYOFTHISPROTOCOLISUNPROVEN3ELECTIVEBIOPSIESFROMONLYTHE PROXIMAL ESOPHAGUS MAY IMPROVE THE SPECIlCITY OF THE DIAGNOSIS OF %O% AT THE EXPENSE OF SENSITIVITY 4HERE IS ALSO VARIABILITY IN THE LOCATION OF BIOPSIES WITH SOMECENTERSOBTAININGPROXIMALANDOTHERSMIDESOPHAGEALBIOPSIES7HILETHE OPTIMAL LOCATION OF BIOPSIES REMAINS UNCERTAIN MULTIPLE BIOPSIES FROM DIFFERENT REGIONSOFTHEESOPHAGUSARERECOMMENDEDTOMAXIMIZEDETECTIONOFESOPHAGEAL EOSINOPHILIA /NCETHEPRESENCEOFINCREASEDESOPHAGEALEOSINOPHILIAHASBEENESTABLISHEDIN SYMPTOMATICPATIENTS SECONDARYCAUSESOFESOPHAGEALEOSINOPHILIANEEDTOBECONSIDERED -OST SECONDARY ETIOLOGIES INCLUDING INmAMMATORY BOWEL DISEASE DRUG HYPERSENSITIVITYREACTIONS ANDPARASITICDISEASESHOULDBEAPPARENTFROMAREVIEWOF THEPATIENTSPASTMEDICALHISTORY#ONCOMITANTEOSINOPHILICGASTROENTERITIS%O' IS AN ASSOCIATION THAT MAY NECESSITATE ADDITIONAL BIOPSIES OF THE GASTRIC AND SMALL BOWELMUCOSAATTHETIMEOFENDOSCOPY(OWEVER %O'ISUNCOMMONANDTHEMAJORITY OF %O' PATIENTS PRESENT WITH SYMPTOMS AS WELL AS ENDOSCOPICALLY EVIDENT MUCOSALFEATURESTHATWOULDPROMPTBIOPSYACQUISITION 'ASTROESOPHAGEAL REmUX DISEASE '%2$ HAS BECOME INCREASINGLY DIFlCULT TO DIFFERENTIATEFROM%O%;4=3TUDIESFROMTHEEIGHTIESEQUATEDESOPHAGEALEOSINOPHILIAWITHTHEDIAGNOSISOF'%2$)NTHEEARLYS REPORTSDESCRIBED%O%ASA ENTITYDISTINCTFROM'%2$BASEDEITHERONLACKOFRESPONSETOPROTONPUMPINHIBITOR 00) THERAPY OR ABSENCE OF DISTAL ESOPHAGEAL ACID EXPOSURE ON AMBULATORY P( TESTING/VERTHEPASTDECADE ITHASBECOMEEVIDENTTHAT%O%AND'%2$NOTONLY FREQUENTLYCOEXISTBUTMOREOVERTHATTREATMENTOFACIDREmUXISEFFECTIVEINASIGNIlCANTPROPORTIONOFPATIENTSWITHSYMPTOMS ENDOSCOPICFEATURES ANDHISTOPATHOLOGY THATARECONSISTENTWITH%O%!SYMPTOMPROlLEOFDYSPHAGIAANDFOODIMPACTION IN AN ATOPIC INDIVIDUAL COMBINED WITH CHARACTERISTIC FEATURES ON %'$ IS HIGHLY PREDICTIVE OF ESOPHAGEAL EOSINOPHILIA BUT DOES NOT PREDICT RESPONSIVENESS TO 00) THERAPY3EVERALPEDIATRICANDADULTSERIESDEMONSTRATEDNORMALIZATIONOFSYMPTOMS ANDTISSUEEOSINOPHILIAAFTER00)THERAPY;5–=/NTHEOTHERHAND THEPRESENCE OF'%2$DElNEDBYANABNORMALP(STUDYDOESNOTPRECLUDETHEPRESENCEOF%O% )NCREASEDACIDEXPOSUREEXISTSINPATIENTSWHOSEESOPHAGEALEOSINOPHILIAPERSISTSIN SPITEOF00)THERAPY; 9=7HETHERPATIENTSWITHSIGNIlCANTTISSUEEOSINOPHILIA RESPONSIVETO00)THERAPYSHOULDBEDIAGNOSEDWITH'%2$ORA00)RESPONSIVEFORM OF%O%ISUNCERTAIN'%2$MAYBEINVOLVEDINTHEPATHOGENESISOF%O%BYREDUCING TISSUEINTEGRITYTHATALLOWSEXPOSUREOFESOPHAGEALANTIGENPRESENTINGCELLSTODIETARY ALLERGENS&URTHERMORE ACIDEXPOSUREINCREASESEOSINOPHILVIABILITYANDTHERELEASE OF MEDIATORS INVOLVED IN EOSINOPHIL RECRUITMENT /WING TO THE EASE AND SAFETY PROlLEOF00)THERAPY ATRIALOF00)THERAPYISREASONABLEINPATIENTSWITHSUSPECTED %O%!VAILABLEDATA ALTHOUGHLIMITED DOESNOTSUPPORTTHEROUTINEUSEOFP(MONITORINGINTHEEVALUATIONOF%O%IFTHEINTENTISTHEIDENTIlCATIONOFPATIENTSWHOWILL BENElTFROM00)THERAPY

 %OSINOPHILIC%SOPHAGITIS4REATMENT!PPROACHIN!DULTS

399

Initial Therapy for EoE: Drugs, Diet, or Dilation? )F SYMPTOMS AND EOSINOPHILIA PERSIST DESPITE A TRIAL OF ACID SUPPRESSION PRIMARY TREATMENTOPTIONSFOR%O%AREDISCUSSEDWITHTHEPATIENT/VERTHEPASTYEARS ANUMBEROFMEDICAL DIETARY ANDENDOSCOPICAPPROACHESHAVEEMERGED4ABLE3) ;=-EDICALANDDIETARYTHERAPIESAREEFFECTIVEATREDUCINGSYMPTOMSASWELLAS TISSUEEOSINOPHILIA4HEDEGREETOWHICHTHESTRUCTURALALTERATIONSAREREVERSIBLEWITH MEDICAL OR DIETARY THERAPY IS UNCERTAIN &OR ADULTS TOPICAL STEROIDS ARE THE MOST COMMONLYUSEDTREATMENTGIVENTHEEASEOFADMINISTRATIONANDPUBLISHEDDATASUPPORTINGTHEIREFlCACYANDSAFETY3EVERALPROSPECTIVE UNCONTROLLEDSTUDIESANDlVE RANDOMIZED CONTROLLED TRIALS HAVE EVALUATED THE EFFECTIVENESS AND EFlCACY OF STEROIDS RESPECTIVELY;–=7ITHTHEEXCEPTIONOFONESTUDY THEADULTTRIALSWITH TOPICALSTEROIDSHAVECONSISTENTLYDEMONSTRATEDMARKED SIGNIlCANTCLINICALANDHISTOLOGICIMPROVEMENTAFTERTHERAPYADMINISTEREDFROMDAYSTOMONTHS(ISTOLOGIC RESPONSERATESDElNEDBYLESSTHANEOSHPFWEREACHIEVEDINRECENTSTUDIESINOVER OFPATIENTS%NDOSCOPICSIGNSOFRINGS FURROWS ANDSTRICTURESVISIBLYIMPROVE BUTMAYNOTCOMPLETELYRESOLVE;=&IG3 3IGNIlCANTVARIABILITYINTHEDEGREE OFRESPONSETOTOPICALSTEROIDSHASBEENOBSERVED)NTERESTINGLY INPEDIATRICSTUDIES ALLERGICINDIVIDUALSIDENTIlEDBYREACTIVITYONSKINTESTINGANDTALLERSUBJECTSDEMONSTRATEDLOWERRESPONSERATES; =4HEDATASUGGESTTHATTHEEFlCACYOFTOPICAL STEROIDS MAY BE AFFECTED BY THE DOSE OF STEROID AS WELL AS DEGREE OF UNDERLYING ATOPY4HEMODEOFADMINISTRATIONVIASWALLOWEDAEROSOLIZEDPARTICLESORVISCOUS LIQUIDPREPARATIONSMAYAFFECTTHEDELIVERYANDCONTACTTIMEOFTHESTEROIDWITHTHE ESOPHAGEAL MUCOSAL SURFACE "ASED ON PEDIATRIC DATA THE EFlCACY OF TOPICAL AND SYSTEMICSTEROIDSAPPEARSCOMPARABLE;5=!DHERENCECOMPLIANCEWITHPROLONGED THERAPYHASBEENACONCERNASTHESYMPTOMATICBENElTSARENOTIMMEDIATEANDTEND TOLASTFORPROLONGEDPERIODSAFTERCESSATION ,IMITATIONSOFTOPICALSTEROIDSINCLUDEDISEASERECURRENCEINFOLLOWINGCESSATION AND UNCERTAINTY REGARDING LONG TERM SAFETY ;= ! PROPORTION OF PATIENTS HAVE LIMITED RESPONSIVENESS TO TOPICAL STEROIDS PERHAPS OWING TO DRUG DELIVERY INTRINSICSTEROIDRESISTANCE ORANUNDERLYINGSTRONGALLERGICPREDISPOSITION7HETHER SUCHPATIENTSWOULDRESPONDTOHIGHERDOSESOFTOPICALSTEROIDS THERAPYDIRECTEDAT ALLERGICENVIRONMENTALTRIGGERS ORSYSTEMICSTEROIDSHASYETTOBEDETERMINED4HE PRIMARY SIDE EFFECT OF TOPICAL STEROIDS HAS BEEN OROPHARYNGEAL OR ESOPHAGEAL CANDIDIASIS ! PROSPECTIVE STUDY IN CHILDREN ADMINISTERED mUTICASONE AT DOSES OF n PG 1)$ FOUND ESOPHAGEAL CANDIDIASIS IN  OF PATIENTS ALTHOUGH THE PATIENTSDIDNOTREPORTSYMPTOMSATTRIBUTABLETOTHEINFECTION;5=0OTENTIALCONCERNS FORSTEROIDSIDEEFFECTSSUCHASADRENALINSUFlCIENCYOROSTEOPOROSISHAVENOTBEEN REPORTED0HARYNGEALIRRITATIONISMORECOMMONLYREPORTEDWITHAEROSOLIZEDSTEROID ANDMAYBERELATEDTOCONTACTIRRITATIONBYTHEPROPELLANT !VAILABLE DATA SUPPORT THE EFFECTIVENESS OF DIETARY THERAPY IN ADULTS WITH %O% ALTHOUGHTHEMAJORITYOFSTUDIESHAVEBEENFROMPEDIATRICCENTERS4HETHREEDIETARY APPROACHES USED IN CHILDREN INCLUDE  ELEMENTAL DIET  ALLERGY TESTING DIRECTED ELIMINATIONDIET AND EMPIRICELIMINATIONDIET;–3=!LTHOUGHPEDIATRICSERIES

Table 30.1 4REATMENTOPTIONSFOREOSINOPHILICESOPHAGITIS 4REATMENT !DVANTAGES $ISADVANTAGES Medications 4OPICALSTEROIDS &LUTICASONE %ASEOFADMINISTRATION %SOPHAGEAL#ANDIDIASIS "UDESONIDE #ONSISTENTEFFECTIVENESSIN 2ECURRENTDISEASEAFTERCESSATION UNCONTROLLEDSTUDIES (IGHDEGREEOFEFlCACYIN RANDOMIZEDCONTROLLEDTRIALS 3YSTEMIC (IGHDEGREEOFEFlCACYIN 4OXICITIESOFSYSTEMICSTEROID STEROIDS RANDOMIZED CONTROLLEDTRIALS %ASEOFADMINISTRATION 2ECURRENTDISEASEAFTERCESSATION !NTIHISTAMINES %ASEOFADMINISTRATION ,IMITEDDATATOSUPPORTEFFECTIVENESS 0ROTONPUMPINHIBITOR -ODERATEEFFECTIVENESS 5NCLEARWHETHERRESPONSEISSPECIlCFOR '%2$ORA00)REPONSIVEFORMOF%O% 3AFETYPROlLE ,EUKOTRIENE 3YMPTOMIMPROVEMENTIN (IGHDOSESMAYBENEEDEDFOREFFECT antagonist UNCONTROLLEDSTUDIES .OCHANGEINESOPHAGEALEOSINOPHILIA 3IDEEFFECTSOFNAUSEAANDMYALGIAS )MMUNOMODULATOR 3TEROIDSPARINGAGENT )MMUNOSUPPRESSION 3IDEEFFECTPROlLE ,IMITEDDATATHREEPATIENTS TOSUPPORT EFFECTIVENESS !NTI 4.&THERAPY 2ATIONALEBASEDONINCREASED .OCLINICALIMPROVEMENTINASMALL UNCONTROLLEDTRIAL 4ISSUEEXPRESSIONOF4.& ,IMITEDDATATOSUPPORTEFlCACY !NTI ), THERAPY 2ATIONALEBASEDONROLE OF), INSYSTEMIC EOSINOPHILICDISORDERS #ROMOLYNSODIUM 2ATIONALEBASEDONASTHMA ,IMITEDPEDIATRICDATADOESNOTSUPPORT MODEL EFFECTIVENESS Diet %LEMENTAL

$IRECTED ELIMINATION

%MPIRIC ELIMINATION

(IGHDEGREEOFEFFECTIVENESS

0OORPALATABILITY 2EQUIRESPROLONGEDPERIODOFFOOD REINTRODUCTION !VOIDANCEOFLONG TERMUSE .EEDFORREPEATED%'$ANDBIOPSIES OFMEDICATIONS TOIDENTIFYALLERGEN (IGHDEGREEOFEFFECTIVENESS 3KINPRICKTESTWITHPOORPREDICTIVEVALUE 4HEORETICALADVANTAGEOFMORE !TOPYPATCHTESTINGNOTSTANDARDIZEDOR SELECTIVEDIET WIDELYAVAILABLE !VOIDANCEOFLONG TERMUSEOF .EEDFORREPEATED%'$ANDBIOPSIESTO MEDICATIONS IDENTIFYALLERGEN (IGHDEGREEOFEFFECTIVENESS .EEDFORREPEATED%'$ANDBIOPSYTO IDENTIFYALLERGEN !VOIDANCEOFLONG TERMUSE (IGHDEGREEOFVIGILANCETOAVOID OFMEDICATIONS CONTAMINATION

Dilation (IGHDEGREEOFEFFECTIVENESS

0ROLONGEDSYMPTOMRESPONSE WITHOUTMEDICATIONS

2EPORTSOFESOPHAGEALLACERATIONCAUSING SIGNIlCANTPAINANDINFREQUENT HOSPITALIZATION )NFREQUENTREPORTSOFESOPHAGEAL PERFORATION

 %OSINOPHILIC%SOPHAGITIS4REATMENT!PPROACHIN!DULTS



Fig. 30.1 %NDOSCOPICFEATURESOFEOSINOPHILICESOPHAGITISBEFOREANDAFTERTOPICALSTEROIDADMINISTRATIONINTHREEADULTPATIENTSWITHEOSINOPHILICESOPHAGITIS0ATIENTHASESOPHAGEALRINGSAND FURROWS PATIENT  HAS LONGITUDINAL FURROWS AND EXUDATES AND PATIENT  HAS RINGS FURROWS AND EXUDATESupper panel !LLTHREEPATIENTSSHOWIMPROVEMENTINTHEENDOSCOPICSIGNSAFTERWEEKS OFTOPICALmUTICASONElower panel)

DESCRIBEHUNDREDSOF%O%PATIENTSTREATEDEFFECTIVELYWITHDIET NONEOFTHESERIESHAVE BEENRANDOMIZEDCONTROLLEDTRIALS)TISIMPORTANTTOEMPHASIZETHATTHEGOALOFDIETARY THERAPYISNOTONLYACHIEVINGSYMPTOMATICANDHISTOLOGICDISEASEREMISSIONBUTMOREOVERTHEIDENTIlCATIONOFSPECIlCFOODALLERGENS0ATIENTSVIEWTHEDIETARYAPPROACHAS ANONPHARMACOLOGICINTERVENTIONTHATSEEKSTOREMOVEENVIRONMENTALTRIGGERSTOTHEIR DISEASE 4HE DIETARY APPROACH REQUIRES A HIGHLY MOTIVATED PATIENT WILLING TO AVOID SEVERALCOMMONFOODSFORADElNEDPERIODOFTIMEWITHVIGILANCEREGARDINGDIETARY CONTAMINATION 4HE SUCCESS IS OPTIMIZED BY CLOSE SUPERVISION BY A DIETICIAN WITH EXPERIENCEINFOODALLERGY!RECENTLYCOMPLETEDPROSPECTIVESTUDYOFADULTSAT .ORTHWESTERNAPPLIEDTHEEMPIRICELIMINATIONOFCOMMONFOODALLERGENSWHEAT MILK PROTEIN SOY EGG NUTS ANDSEAFOOD FORWEEKSFOLLOWEDBYSYSTEMATICFOODREINTRODUCTION;3=(ISTOLOGICRESPONSERATESDElNEDBYLESSTHANEOSHPFWASACHIEVED IN3YMPTOMIMPROVEMENTINDYSPHAGIAOCCURREDINALMOSTEVERYPATIENTWITH DEMONSTRABLEIMPROVEMENTINENDOSCOPICABNORMALITIES&IG3 -ILKANDWHEAT WERE THE MOST COMMON FOOD TRIGGERS IDENTIlED "ASED ON THE RESPONSE TO FOOD REINTRODUCTIONTESTINGAMONGRESPONDERS SKINPRICKTESTINGFORFOODALLERGENSLEDTO BOTHFALSENEGATIVEANDFALSEPOSITIVERESULTSINTHEMAJORITYOFPATIENTS



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Fig. 30.2 %NDOSCOPICFEATURESOFEOSINOPHILICESOPHAGITISBEFOREANDAFTERSIX FOODELIMINATION DIET3&%$ INTWOADULTPATIENTSWITHEOSINOPHILICESOPHAGITIS0ATIENTHASESOPHAGEALEXUDATES ANDFURROWSWHILEPATIENTHASLONGITUDINALFURROWSANDEXUDATESleft panel "OTHPATIENTSSHOW IMPROVEMENTINTHEENDOSCOPICSIGNSAFTERWEEKSOFDIETARYELIMINATIONmiddle panel $URING REINTRODUCTION BOTHPATIENTSHADRECURRENTSYMPTOMS ENDOSCOPICSIGNS ANDESOPHAGEALEOSINOPHILIAFOLLOWINGREINTRODUCTIONOFWHEATright panel)

$ISADVANTAGES OF ELIMINATION DIET THERAPIES INCLUDE THE POTENTIAL IMPACT ON PATIENTQUALITYOFLIFEDURINGTHEINITIALELIMINATIONPHASEOFTHEDIETASWELLASLONG TERMSELECTIVEELIMINATIONOFSPECIlCFOODS 4HEREINTRODUCTIONPHASEGENERALLY INCORPORATES NOT ONLY SYMPTOM ASSESSMENT BUT ALSO PERIODIC ENDOSCOPIC SURVEILLANCEFORRECURRENTESOPHAGEALEOSINOPHILIA4HEPERFORMANCEOFMULTIPLE%'$WITH BIOPSIESISASSOCIATEDWITHBOTHTIMEANDEXPENSEFORPATIENTS4HEACCURACYOFFOLLOWING ONLY SYMPTOM RATHER THAN SYMPTOM AND HISTOLOGIC RECURRENCE UPON FOOD REINTRODUCTIONHASNOTBEENDETERMINED4WOFACTORSLIMITTHEUSEOFPURESYMPTOM DATA IN THE IDENTIlCATION OF FOOD TRIGGERS &IRST THE INmAMMATORY RESPONSE TO INGESTEDALLERGENSFOLLOWSADELAYEDRATHERTHANIMMEDIATEHYPERSENSITIVITYREACTION MAKINGITCHALLENGINGFORPATIENTSTOTEMPORALLYLINKFOODINGESTIONWITHRECURRENT SYMPTOMS 3ECOND TRACKING DYSPHAGIA AS A PRIMARY DETERMINANT OF RESPONSE IS PROBLEMATICASTHESYMPTOMSAREINTERMITTENT!NONINVASIVEBIOMARKEROFDISEASE ACTIVITY WOULD GREATLY IMPROVE THE ACCEPTANCE OF THE DIETARY THERAPY OF %O% -OREOVER ANALLERGYASSAYWHICHACCURATELYPREDICTSCAUSATIVEFOODALLERGENSWOULD CLEARLY BE IDEAL 4HE LONG TERM EFFECTIVENESS OF DIETARY ELIMINATION AND EVENTUAL ABILITYTOREINTRODUCEIDENTIlEDFOODTRIGGERSARETHESUBJECTOFONGOINGINVESTIGATIONS4HEROLEOFTREATMENTOFAEROALLERGIESASPRIMARYORADJUNCTIVETHERAPYIN%O% REMAINSSPECULATIVE %SOPHAGEALDILATIONWASONEOFTHElRSTTHERAPIESUSEDFORADULTPATIENTSWITH %O%%ARLYREPORTSOFCOMPLICATIONSRELATEDTOESOPHAGEALDILATIONIN%O%INCLUDED NOTONLYCHESTPAINBUTALSOPERFORATIONGENERATEDTREPIDATIONAMONGGASTROENTEROLOGISTS/FTHEADULTPATIENTSREPORTEDPRIORTOWHOUNDERWENTDILATION

 %OSINOPHILIC%SOPHAGITIS4REATMENT!PPROACHIN!DULTS



EXPERIENCEDANESOPHAGEALPERFORATIONANDWEREHOSPITALIZEDFORCHESTPAIN ;3=&URTHERCOMPOUNDINGTHISCONCERNWEREEARLYREPORTSOFESOPHAGEALTEARSAND PERFORATIONSFROMFOODIMPACTIONSANDDIAGNOSTICENDOSCOPIES SUGGESTINGAPARTICULARSUSCEPTIBILITYFORESOPHAGEALMURALFRAGILITYIN%O%;33=3UCHlNDINGSLEDTOA CONSENSUSSTATEMENTPUBLICATIONTHATRECOMMENDEDTHATMEDICALORDIETARYTHERAPY FOR%O%BEATTEMPTEDPRIORTOTHEPERFORMANCEOFESOPHAGEALDILATION;34= 4WORECENTRETROSPECTIVESTUDIESFROMADULTCENTERSREPORTEDCOMPLICATIONRATES FORSEQUELLAEOFPERFORATIONORPAINREQUIRINGHOSPITALIZATIONTHATWERECONSIDERABLY LOWERTHANTHATOFINITIALREPORTS; 35=.OPERFORATIONSWEREREPORTEDAMONG PATIENTSUNDERGOINGESOPHAGEALDILATION)NCORPORATINGTHISNEWDATA THEPERFORATION RATEFORDILATIONIS WITHCHESTPAININANDCHESTPAINREQUIRINGHOSPITALIZATIONIN!NIMPORTANTFACTORTHATMAYHAVEINmUENCEDTHEHIGHERCOMPLICATION RATESINEARLIERREPORTSHASTODOWITHDISEASEAWARENESS-ANYOFTHEINITIALREPORTS OFESOPHAGEALPERFORATIONOCCURREDINPATIENTSINWHOM%O%WASNOTINITIALLYRECOGNIZEDANDPRIORTOPUBLICATIONSDESCRIBINGTHEDANGERSOFESOPHAGEALDILATION!SSUCH THEGREATERSAFETYREPORTEDINTHESTUDIESBYMORERECENTSERIESMAYREmECTTHEADOPTION OF A MORE CONSERVATIVE APPROACH BY GASTROENTEROLOGISTS AWARE OF THE POTENTIAL HAZARDSOFDILATIONIN%O% )NSPITEOFTHEGREATERSAFETYMARGINREPORTEDINTHESERECENTSTUDIESOFESOPHAGEAL DILATION THEROLEOFDILATIONASAPRIMARYTHERAPYOF%O%ISSTILLCONTROVERSIALAND SHOULD BE INDIVIDUALIZED UNTIL MORE DATA IS AVAILABLE )N ADULTS %O% GENERALLY AFFECTSOTHERWISEHEALTHY YOUNGTOMIDDLE AGEDPATIENTSWHO IFGIVENTHEOPTION MIGHTPREFERPERIODICDILATIONTOREGULARUSEOFAMEDICATIONORANELIMINATIONDIET $ILATION CAN PROVIDE IMMEDIATE AND LONG LASTING RELIEF OF DYSPHAGIA IN PATIENTS WITHHIGH GRADEESOPHAGEALSTRICTURES;=/NTHEOTHERHAND MONOTHERAPYWITH DILATION DOES NOT IMPROVE THE UNDERLYING INmAMMATORY PROCESS /NE WOULD NOT RECOMMENDDILATIONWITHOUT00)THERAPYFORAPEPTICSTRICTURE SOSHOULD%O% ALSO AREVERSIBLECHRONICINmAMMATORYCONDITION BEANYDIFFERENT)FMEDICALORDIETARY THERAPYISSELECTEDASINITIALTHERAPY ITSEEMSREASONABLETODETERMINETHECLINICAL RESPONSE PRIOR TO DILATION 4HE RAPID AND POTENTIALLY LONG LASTING BENElTS OF DILATION SHOULD BE WEIGHED AGAINST THE SUBSTANTIAL CONSEQUENCES OF ESOPHAGEAL PERFORATION ALBEITRARE !TTHISTIME THEREISNOPROSPECTIVEDATATOGUIDETHEDECISIONFORSELECTINGTHE OPTIMAL INITIAL THERAPY FOR PATIENTS WITH EOSINOPHILIC ESOPHAGITIS 4HE AVAILABLE DATA SUPPORTS THE USE OF TOPICAL STEROIDS DIET OR DILATION AS EFFECTIVE MEANS OF MANAGING THE DYSPHAGIA THAT DOMINATES THE CLINICAL PRESENTATION IN ADULTS 4HE ONLYRANDOMIZED CONTROLLEDTRIALSPERFORMEDTODATEESTABLISHTHEEFlCACYOFTOPICAL STEROIDS!STEPWISEAPPROACHUSINGMONOTHERAPYISSUGGESTEDWHEREBYPATIENTSARE INITIALLYPLACEDONATRIALOF00)THERAPY&IG33 5NRESPONSIVEPATIENTSMEETING THECURRENTCONSENSUSSTATEMENTDElNITIONOFPRIMARY%O%AREOFFEREDTHERAPYWITH EITHERDIETORSTEROIDS WITHSELECTEDPATIENTSUNDERGOINGESOPHAGEALDILATION 0ATIENTSWHOAREUNRESPONSIVETOINITIALTHERAPYCANBESWITCHEDTOANALTERNATIVE THERAPY4HEROLEFORINITIALCOMBINATIONTHERAPY OTHERTHANDILATIONWITHTOPICAL STEROIDS HASNOTBEENEVALUATED



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Fig. 30.3 3UGGESTED MANAGEMENT ALGORITHM FOR EOSINOPHILIC ESOPHAGITIS IN ADULTS 0ATIENTS PRESENTINGWITHESOPHAGEALSYMPTOMS TYPICALLYDOMINATEDBYDYSPHAGIAANDFOODIMPACTION IN THESETTINGOFHISTORYOFATOPYARESUSPECTEDOFHAVINGEOSINOPHILICESOPHAGITIS(IGHLYSENSITIVE ENDOSCOPICSIGNSWITHESOPHAGEALEOSINOPHILIAARESUPPORTIVElNDINGSINPATIENTSHAVINGUNDERGONEUPPERENDOSCOPY!TREATMENTTRIALOFDOUBLE DOSEPROTONPUMPINHIBITIONISFOLLOWEDBYAN UPPERENDOSCOPYWITHESOPHAGEALBIOPSIES0ATIENTSWITHPERSISTENTSYMPTOMSCOMBINEDWITH HISTOLOGICEVIDENCEOFESOPHAGEALEOSINOPHILIAMEETTHECURRENTCONSENSUSSTATEMENTDElNITIONOF EOSINOPHILIC ESOPHAGITIS 0RIMARY THERAPY WITH EITHER TOPICAL STEROIDS OR DIETARY ELIMINATION IS DISCUSSED5SEOFESOPHAGEALDILATIONISCONSIDEREDINSELECTEDPATIENTS!FOLLOW UPENDOSCOPY WITH BIOPSY PROVIDES INFORMATION REGARDING THE ENDOSCOPIC AND PATHOLOGIC RESPONSE TO INITIAL THERAPYBUTMAYNOTBENECESSARYFORALLPATIENTS0ATIENTSWHODONOTRESPONDTOINITIALTHERAPYARE THENCANDIDATESFORSECONDARYTHERAPIES

Patients Refractory to Therapy 0ATIENTSDEMONSTRATINGLIMITEDRESPONSETOINITIALTHERAPYINCLUDETHOSEWITHPERSISTENT SYMPTOMS THOSE WITH PERSISTENT ESOPHAGEAL INmAMMATION AND THOSE WITH BOTH 7HEN BOTH SYMPTOMS AND INmAMMATION PERSIST THE INITIAL THERAPY NEEDS TO BE REEVALUATED0ATIENTSNOTRESPONDINGTOTOPICALSTEROIDSSHOULDBEQUESTIONEDASTO COMPLIANCEANDAPPROPRIATEMETHODOFADMINISTRATION$OSEESCALATIONWITHTOPICAL STEROIDS IS A CONSIDERATION AS HIGHER RESPONSE RATES WERE NOTED IN STUDIES USING FLUTICASONEAT PG")$COMPAREDWITHTHOSEUSING PG")$(OWEVER THIS COMPARISON IS MADE BETWEEN DIFFERENT STUDIES THAT ENROLLED DIFFERENT %O% POPULATIONS7HILESYSTEMICSTEROIDSWERESHOWNTOHAVESIMILAREFlCACYTOTOPICAL STEROIDSINAPEDIATRIC CONTROLLEDTRIAL THEHISTOLOGICIMPROVEMENTWASMORECOMPLETEWITHSYSTEMICSTEROIDSSUPPORTINGAPOTENTIALROLEFORSYSTEMICSTEROIDSINPATIENTS UNRESPONSIVE TO TOPICAL STEROIDS ;5= !NECDOTAL REPORTS HAVE NOTED PATIENTS WHO

 %OSINOPHILIC%SOPHAGITIS4REATMENT!PPROACHIN!DULTS



FAILEDTORESPONDTOSWALLOWEDmUTICASONEBYINHALERADMINISTRATIONWHORESPONDED TOLIQUIDBUDESONIDE$IETARYTHERAPYISANOPTIONFORPATIENTSUNRESPONSIVETOTOPICALSTEROIDSALTHOUGHTHEREISNODATAREGARDINGTHEEFFECTIVENESSOFTHISAPPROACH 5NCONTROLLED DATA POINT TO A GREATER RESPONSE TO ELEMENTAL COMPARED TO EMPIRIC ELIMINATIONDIETTHERAPY!LTERNATEMEDICALTHERAPIESINCLUDINGMONTELUKAST CROMOLYN SODIUM ORANTIHISTAMINESHAVESHOWNLIMITEDBENElTSINAFEW SMALLUNCONTROLLED STUDIES;3=#OMBINATIONTHERAPIESWITHSTEROIDSANDMONTELUKASTORSTEROIDSWITH ANTIHISTAMINESHAVENOTBEENREPORTED%SOPHAGEALDILATIONISAUSEFULADJUNCTIVE THERAPYTHATHASBEENUSEDINCOMBINATIONWITHMEDICALTHERAPY;=3AFETYCONCERNS THATSUPPORTACONSERVATIVEDILATIONSTRATEGYWEREDISCUSSEDINTHEPRECEDINGSECTION 0ATIENTSWITHRESOLUTIONOFEOSINOPHILIABUTCONTINUEDDYSPHAGIAMAYHAVEDEVELOPEDESOPHAGEALSTRICTURESAMENABLETOESOPHAGEALDILATION)TSHOULDBENOTEDTHAT THEREVERSALOFESOPHAGEALSUBMUCOSALlBROSISANDREMODELINGIN%O%MAYREQUIRE PROLONGED THERAPY OVER MONTHS WHEREAS THE TISSUE INmAMMATORY RESPONSE MAY REVERSE WITHIN DAYS OF TOPICAL CORTICOSTEROID ADMINISTRATION ! PROSPECTIVE ADULT STUDYDETECTEDSIGNIlCANTIMPROVEMENTINENDOSCOPICDETECTIONOFESOPHAGEALSTRICTURESFOLLOWINGMONTHSOFmUTICASONE;= .OVELBIOLOGICTHERAPIESHAVEEMERGEDFORTHETREATMENTOF%O%!NTI )G% ANTI ),  ANTI 4.&THERAPIESHAVEALLBEENREPORTEDINVERYSMALLSERIESASDISCUSSEDIN APRIORCHAPTER4HECONTROLLEDSTUDYOFANTI ), THERAPYINAGROUPOFADULTS WITH STEROID DEPENDENT OR UNRESPONSIVE DISEASE SHOWED SIGNIlCANT REDUCTIONS IN BOTHTISSUEANDPERIPHERALEOSINOPHILIABUTDIDNOTACHIEVEITSPRIMARYENDPOINTOF ACHIEVING  EOSHPF AND DID NOT DEMONSTRATE SIGNIlCANT SYMPTOM BENElT ;3= 4RIALS EXAMINING ANTI ),  ARE ONGOING AT THIS TIME !NALOGOUS TO THEIR USE IN INmAMMATORYBOWELDISEASE BIOLOGICTHERAPYOFFERSTHEPOTENTIALTHERAPYASDISEASE MODIFYINGAGENTS-OREDATAONTHEIRUSEASMONOTHERAPYORINCOMBINATIONWITH EXISTINGTHERAPIESARENEEDED

Treatment of Asymptomatic Patients &ROMTHE!MERICAN'ASTROENTEROLOGICAL!SSOCIATIONCONSENSUSSTATEMENT PATIENTS WITHSIGNIlCANTESOPHAGEALEOSINOPHILIAONESOPHAGEALBIOPSYBUTWITHOUTSYMPTOMSWOULDNOTMEETTHEDElNITIONOF%O%;34=(OWEVER ASNOTEDABOVE PATIENTS MAYHAVESIGNIlCANTESOPHAGEALSTRUCTURALALTERATIONSANDSTRICTURESBUTNOTREPORT DYSPHAGIADUETOCAREFULMASTICATION PROLONGEDMEALTIMES ANDORFOODAVOIDANCE 4HE SAME SITUATION IS ENCOUNTERED IN PATIENTS INITIALLY DIAGNOSED WITH %O% BUT ACHIEVINGSYMPTOMBUTNOTHISTOLOGICREMISSIONFOLLOWINGMEDICALORDIETARYTHERAPY #URRENTLY THEREISLITTLEINFORMATIONTOSUPPORTADDITIONALTREATMENTOFSUCHINDIVIDUALS !MOREPROACTIVEAPPROACHMIGHTBECONSIDEREDINPATIENTSWITHHIGHERDEGREESOF ESOPHAGEALSTENOSIS'IVENTHEUNCERTAINTIESREGARDINGTHENATURALHISTORYOF%O% IT SEEMSPRUDENTTOADVISECLINICALFOLLOW UPFORPATIENTSWITHESOPHAGEALEOSINOPHILIA EVENINTHEABSENCEOFSYMPTOMS



)(IRANO

Maintenance Therapy -AINTENANCE THERAPY IS AN IMPORTANT CONSIDERATION FOR %O% PATIENTS SINCE THE MAJORITYDEVELOPRECURRENTSYMPTOMSANDHISTOPATHOLOGYUPONCESSATIONOFTHERAPY WITHEITHERTOPICALORSYSTEMICSTEROIDS-AINTENANCETHERAPYISNOTDISCUSSEDAFTER ELIMINATIONDIETTHERAPYASITASSUMEDTHATPATIENTSCONTINUETOABSTAINFROMIDENTIlED TRIGGER FOODS !S THERE IS LIMITED DATA TO SUGGEST THAT %O% IS A PROGRESSIVE DISORDERTHATLEADSTOINCREASEDESOPHAGEALSTRUCTURINGOVERTIME LONG TERMTHERAPEUTICSTRATEGIESSHOULDBEINDIVIDUALIZED&ORPATIENTSWITHMILDANDINTERMITTENT DYSPHAGIAWITHOUTSIGNIlCANTSTRICTURESORFOODIMPACTION INTERMITTENTON DEMAND TOPICAL STEROIDS MAY BE APPROPRIATE ASSUMING THAT THE PATIENT IS RELIABLE AND HAS CLINICALFOLLOW UP&ORPATIENTSWITHSEVEREDYSPHAGIA REPEATEDFOODIMPACTIONAND HIGH GRADEESOPHAGEALSTRICTURESATPRESENTATIONANDWHORESPONDTOINITIALMEDICAL THERAPY MAINTENANCE THERAPY SEEMS REASONABLE ,OWERING THE DOSAGE OF TOPICAL STEROIDSBELOWTHATUSEDTOINDUCECLINICALREMISSIONISACONSIDERATIONBUTARECENT STUDYTHATATTEMPTEDTHISSTRATEGYNOTEDASIGNIlCANTREDUCTIONINTREATMENTEFlCACY -AINTENANCEWITHNONSTEROIDMEDICATIONSSUCHASANTIHISTAMINES IMMUNOMODULATORS ORLEUKOTRIENEANTAGONISTSHASBEENREPORTEDINVERYSMALLRETROSPECTIVECASESERIES &INALLY THEPROLONGEDRELIEFOFDYSPHAGIAREPORTEDAFTERESOPHAGEALDILATIONNEEDS TO BE CONSIDERED GIVEN THE INCONVENIENCE AND POTENTIAL SIDE EFFECTS OF LONG TERM MEDICALORDIETARYTHERAPY

References  3TRAUMANN! 3PICHTIN(0 'RIZE, "UCHER+! "EGLINGER# 3IMON(5.ATURALHISTORYOF PRIMARY EOSINOPHILIC ESOPHAGITIS A FOLLOW UP OF  ADULT PATIENTS FOR UP TO  YEARS 'ASTROENTEROLOGY n  3CHOEPFER!- 'ONSALVES. "USSMANN# ETAL%SOPHAGEALDILATIONINEOSINOPHILICESOPHAGITIS EFFECTIVENESS SAFETY AND IMPACT ON THE UNDERLYING INmAMMATION !M * 'ASTROENTEROL  n  4OTO% +ERN% -OY. +WASNY- 'ONSALVES. (IRANO)$URATIONOFDYSPHAGIAISASSOCIATED WITH INCREASED FREQUENCY OF DYSPHAGIA AND FOOD IMPACTION IN ADULTS WITH EOSINOPHILIC ESOPHAGITIS'ASTROENTEROLOGY 3   +ERN% 4AFT4 -OY. +WASNY- 'ONSALVES. +EEFER, ETAL0ATIENTREPORTEDOUTCOMESIN ADULTSWITHEOSINOPHILICESOPHAGITIS'ASTROENTEROLOGY 3   +WIATEK-! (IRANO) +AHRILAS0* 2OTHE* ,UGER$ 0ANDOLlNO*%-ECHANICALPROPERTIES OFTHEESOPHAGUSINEOSINOPHILICESOPHAGITIS'ASTROENTEROLOGYn  !CEVES33 .EWBURY2/ $OHIL2 "ASTIAN*& "ROIDE$(%SOPHAGEALREMODELINGINPEDIATRIC EOSINOPHILICESOPHAGITIS*!LLERGY#LIN)MMUNOL n  'ONSALVES. 0OLICARPIO .ICOLAS- :HANG1 2AO-3 (IRANO)(ISTOPATHOLOGICVARIABILITY AND ENDOSCOPIC CORRELATES IN ADULTS WITH EOSINOPHILIC ESOPHAGITIS 'ASTROINTEST %NDOSC  n  3TEVOFF# 2AO3 0ARSONS7 +AHRILAS0* (IRANO)%53 AND HISTOPATHOLOGIC CORRELATES IN EOSINOPHILICESOPHAGITIS'ASTROINTEST%NDOSC n  &OX6, .URKO3 4EITELBAUM*% "ADIZADEGAN+ &URUTA'4(IGH RESOLUTION%53INCHILDREN WITHEOSINOPHILIChALLERGICvESOPHAGITIS'ASTROINTEST%NDOSC n

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3GOUROS3. "ERGELE# -ANTIDES!%OSINOPHILICESOPHAGITISINADULTSWHATISTHECLINICAL SIGNIlCANCE%NDOSCOPY n +ELLY +* ,AZENBY !* 2OWE 0# 9ARDLEY *( 0ERMAN *! 3AMPSON (! %OSINOPHILIC ESOPHAGITISATTRIBUTEDTOGASTROESOPHAGEALREmUXIMPROVEMENTWITHANAMINOACID BASEDFORMULA'ASTROENTEROLOGY n $ELLON %3 &ARRELL 4- "OZYMSKI %- 3HAHEEN .* $IAGNOSIS OF EOSINOPHILIC ESOPHAGITIS AFTER FUNDOPLICATION FOR @REFRACTORY REmUX IMPLICATIONS FOR PREOPERATIVE EVALUATION $IS %SOPHAGUS n 3HAH! +AGALWALLA!& 'ONSALVES. -ELIN !LDANA( ,I"5 (IRANO)(ISTOPATHOLOGICVARIABILITYINCHILDRENWITHEOSINOPHILICESOPHAGITIS!M*'ASTROENTEROL n  3PECHLER3* 'ENTA2- 3OUZA2&4HOUGHTSONTHECOMPLEXRELATIONSHIPBETWEENGASTROESOPHAGEALREmUXDISEASEANDEOSINOPHILICESOPHAGITIS!M*'ASTROENTEROL n -OLINA )NFANTE* &ERRANDO ,AMANA, 'ALLARDO"0 ETAL3YSTEMICCLINICOPATHOLOGICFOLLOW UPONHIGHDOSEACIDSUPPRESSIONISMANDATORYTOAVOIDEOSINOPHILICESOPHAGITISOVERESTIMATIONINADULTS'ASTROENTEROLOGY 3 -ORROW*" 6ARGO** 'OLDBLUM*2 2ICHTER*%4HERINGEDESOPHAGUSHISTOLOGICALFEATURES OF'%2$!M*'ASTROENTEROL n $RANOVE*% (ORN$3 $AVIS-! +ERNEK+- 'UPTA3+0REDICTORSOFRESPONSETOPROTON PUMP INHIBITOR THERAPY AMONG CHILDREN WITH SIGNIlCANT ESOPHAGEAL EOSINOPHILIA * 0EDIATR  n .GO 0 &URUTA '4 !NTONIOLI $! &OX 6, %OSINOPHILS IN THE ESOPHAGUSnPEPTIC OR ALLERGIC EOSINOPHILIC ESOPHAGITIS #ASE SERIES OF THREE PATIENTS WITH ESOPHAGEAL EOSINOPHILIA !M * 'ASTROENTEROL n 3HAH! +AGALWALLA!& 'ONSALVES. -ELIN !LDANA( ,I"5 (IRANO)(ISTOPATHOLOGICVARIABILITYINCHILDRENWITHEOSINOPHILICESOPHAGITIS!M*'ASTROENTEROL n 'ARREAN # (IRANO ) %OSINOPHILIC ESOPHAGITIS PATHOPHYSIOLOGY AND OPTIMAL MANAGEMENT #URR'ASTROENTEROL2EP n $OHIL2 .EWBURY2 &OX, "ASTIAN* !CEVES3/RALVISCOUSBUDESONIDEISEFFECTIVEINCHILDRENWITHEOSINOPHILICESOPHAGITISINARANDOMIZED PLACEBO CONTROLLEDTRIAL'ASTROENTEROLOGY  n +ONIKOFF-2 .OEL2* "LANCHARD# ETAL!RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED TRIAL OF mUTICASONE PROPIONATE FOR PEDIATRIC EOSINOPHILIC ESOPHAGITIS 'ASTROENTEROLOGY  n 3TRAUMANN! #ONUS3 $EGEN, ETAL"UDESONIDEISEFFECTIVEINADOLESCENTANDADULTPATIENTS WITHACTIVEEOSINOPHILICESOPHAGITIS'ASTROENTEROLOGY n 0ETERSON+! 4HOMAS+, (ILDEN+ %MERSON,, 7ILLS*# &ANG*##OMPARISONOFESOMEPRAZOLE TO AEROSOLIZED SWALLOWED mUTICASONE FOR EOSINOPHILIC ESOPHAGITIS $IG $IS 3CI  n 3CHAEFER %4 &ITZGERALD *& -OLLESTON *0 ET AL #OMPARISON OF ORAL PREDNISONE AND TOPICAL mUTICASONEINTHETREATMENTOFEOSINOPHILICESOPHAGITISARANDOMIZEDTRIALINCHILDREN#LIN 'ASTROENTEROL(EPATOL n 2EMEDIOS- #AMPBELL# *ONES$- +ERLIN0%OSINOPHILICESOPHAGITISINADULTSCLINICAL ENDOSCOPIC HISTOLOGIC lNDINGS AND RESPONSE TO TREATMENT WITH mUTICASONE PROPIONATE 'ASTROINTEST%NDOSC n  ,UCENDO!* 0ASCUAL 4URRION*- .AVARRO- ETAL%NDOSCOPIC BIOPTIC ANDMANOMETRIClNDINGS IN EOSINOPHILIC ESOPHAGITIS BEFORE AND AFTER STEROID THERAPY A CASE SERIES %NDOSCOPY  n ,IACOURAS#! 3PERGEL*- 2UCHELLI% ETAL%OSINOPHILICESOPHAGITISA YEAREXPERIENCEIN CHILDREN#LIN'ASTROENTEROL(EPATOL n 3PERGEL *- !NDREWS 4 "ROWN 7HITEHORN 4& "EAUSOLEIL *, ,IACOURAS #! 4REATMENT OF EOSINOPHILICESOPHAGITISWITHSPECIlCFOODELIMINATIONDIETDIRECTEDBYACOMBINATIONOFSKIN PRICKANDPATCHTESTS!NN!LLERGY!STHMA)MMUNOL n  +AGALWALLA!& 3ENTONGO4! 2ITZ3 ETAL%FFECTOFSIX FOODELIMINATIONDIETONCLINICALAND HISTOLOGICOUTCOMESINEOSINOPHILICESOPHAGITIS#LIN'ASTROENTEROL(EPATOL n



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Chapter 31

Eosinophilic Esophagitis: Treatment Approach in Children Jonathan E. Markowitz and Chris A. Liacouras

Keywords %OSINOPHILIC ESOPHAGITIS s 'ASTROESOPHAGEAL REmUX s $YSPHAGIA s&OODINTOLERANCE

Introduction /VERTHEPASTYEARS EOSINOPHILICESOPHAGITIS%O% HASBECOMEONEOFTHEMOST DISCUSSEDDISEASESAMONGPEDIATRICGASTROENTEROLOGISTSANDALLERGISTSINTHE5NITED 3TATES!CCORDINGTOACONSENSUSSTATEMENTDRAFTEDBYAMULTIDISCIPLINARYWORKING GROUP %O% IS A CLINICOPATHOLOGICAL DISEASE CHARACTERIZED BY SYMPTOMS SUCH AS GASTROESOPHAGEALREmUX DYSPHAGIA ORFEEDINGINTOLERANCEALTHOUGHNOTLIMITEDTO THESE INTHEPRESENCEOFATLEASTEOSINOPHILSSEENPERMICROSCOPICHIGHPOWERED lELD IN AT LEAST ONE BIOPSY SPECIMEN TAKEN FROM THE ESOPHAGUS WITHOUT ANOTHER IDENTIlABLE ETIOLOGY ;= ,IKELY OWING TO A COMBINATION OF INCREASED AWARENESS AMONGPHYSICIANSANDANINCREASINGINCIDENCEAMONGTHEPOPULATION %O%ISNOW ONEOFTHEMOSTIMPORTANTCHRONICGASTROINTESTINALDISEASESTOAFFECTCHILDREN9ET DESPITE THE INCREASED ATTENTION PAID TO THIS PROBLEM THERE REMAINS CONSIDERABLE DEBATEASTOTHEOPTIMALWAYTODIAGNOSEANDTREATTHEDISORDER4HISCHAPTERWILL DISCUSSTHEVARIOUSPOTENTIALAPPROACHESTODIAGNOSINGANDTREATING%O%WITHREGARD TOTHELATESTINFORMATIONONTHESUBJECT

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409



*%-ARKOWITZAND#!,IACOURAS

Diagnosis !LTHOUGHITMAYSEEMSELF EVIDENT THESINGLEMOSTIMPORTANTASPECTINDEVISINGA TREATMENTSTRATEGYFOR%O%ISENSURINGTHATTHEDIAGNOSISISCORRECT)NMANYCIRCUM STANCES DIAGNOSING%O%INAPEDIATRICPATIENTISRELATIVELYSTRAIGHTFORWARD(OWEVER THEREEXISTSOMEIMPORTANT BUTSUBTLEGUIDELINESTOCONlRMINGTHEDIAGNOSISTHAT WHENNOTFOLLOWEDMAYLEAVETHEDIAGNOSISINDOUBT 4HEGOLDSTANDARDFORTHEDIAGNOSISOF%O%ISENDOSCOPYWITHBIOPSY7ITHOUT THEDEMONSTRATIONOFINCREASEDNUMBERSOFESOPHAGEALEOSINOPHILS THEDIAGNOSIS CANNOTBECONlRMED(OWEVER ASMENTIONEDPREVIOUSLY %O%ISACLINICOPATHOLOGIC DIAGNOSISTHEABSENCEOFAPPROPRIATECLINICALANDHISTOPATHOLOGIClNDINGSSHOULD IMMEDIATELYRAISECONCERNOVERALTERNATIVEDIAGNOSES)NTHEPEDIATRICPATIENT THE CLINICALlNDINGSTENDTOBEMOREVARIABLETHANTHOSECURRENTLYREPORTEDINADULTS 7HILEADULTPATIENTSWITH%O%MOSTCOMMONLYPRESENTWITHDYSPHAGIA ESOPHAGEAL NARROWING AND FOOD IMPACTION ;= CHILDREN WITH %O% MAY PRESENT WITH A WIDE ARRAYOFCOMPLAINTS;=4HEYOUNGESTPATIENTSWITH%O%MAYMANIFESTONLYNONSPE CIlCSYMPTOMSSUCHASIRRITABILITY FEEDINGREFUSAL ORREGURGITATION!STHEAGEAT PRESENTATION INCREASES SYMPTOMS TEND TO INCLUDE COMPLAINTS OF ABDOMINAL PAIN GASTROESOPHAGEALREmUX VOMITING ANDDYSPHAGIA&OODIMPACTIONISLESSCOMMON INCHILDRENTHANADULTS ANDWHENSEENISTYPICALLYPRESENTINTEENAGERS)TSHOULDBE NOTEDTHATALLOFTHESESYMPTOMSAREALSOCOMMONLYSEENINCHILDRENWITHUNCON TROLLEDACIDREmUX %ARLY STUDIES OF %O% TENDED TO DIFFERENTIATE GASTROESOPHAGEAL REmUX DISEASE '%2$ FROM%O%BYMEASURESSUCHASP( METRY;4=%ARLYDOGMAWASTHATTHE PRESENCEOFASIGNIlCANTAMOUNTOFREmUXONAP(STUDYWASINCONSISTENTWITHA DIAGNOSISOF%O%4ODAY THECO EXISTENCEOF%O%AND'%2$REMAINSAPOINTOF CONTENTIONAMONGEXPERTS(ISTORICALLY THEPRESENCEOFEOSINOPHILSINTHEESOPHA GUSWASFELTTOBEANINDICATOROF'%2$ ALTHOUGHTHEREPORTSTHATlRSTSUGGESTED THISASSOCIATIONUSUALLYDETAILEDRELATIVELYLOWEOSINOPHILICDENSITYINTHEESOPHAGUS COMPAREDTOTHETYPICAL%O%PATIENT;=,ATER RETROSPECTIVEANALYSISDEMONSTRATED THATDENSITYOFEOSINOPHILSINTHEESOPHAGUSPREDICTEDRESPONSETOACIDSUPPRESSION;]. 0ATIENTSWITHLOWLEVELSOFEOSINOPHILSINTHEESOPHAGUSWEREMOSTLIKELYTORESPOND ANDTHOSEWITHTHEHIGHESTLEVELSUNLIKELY0ATIENTSWITHMODERATEEOSINOPHILLEVELS TENDEDTORESPONDBUTRELAPSE (OWEVER CLINICALEXPERIENCEREVEALSTHATSEPARATIONOF%O%AND'%2$ISNOTSO CLEARCUT#ASEREPORTSHAVEDETAILEDPATIENTSWITHEXTREMELYHIGHDENSITYOFESOPHA GEAL EOSINOPHILS THAT HAVE HAD RESOLUTION OF SYMPTOMS AND EOSINOPHILIA ON ACID SUPPRESSIONALONE; =4ODAY SOMESUGGESTTHEREARETWOFORMSOF%O%nTHOSE PATIENTSWHORESPONDTOACIDSUPPRESSIONANDTHOSEWHOARENONRESPONSIVE4HIS DICHOTOMYISPROBLEMATICFROMADIAGNOSTICSTANDPOINTASITCOULDBEARGUEDTHAT %O%RESPONSIVETOACIDSUPPRESSIONWOULDBETTERBECHARACTERIZEDASEOSINOPHILIC '%2$ ORREmUXESOPHAGITISWITHAPREDOMINANCEOFEOSINOPHILS4HEIMPORTANCE OF THIS CHARACTERIZATION DERIVES FROM CHOOSING THE APPROPRIATE TREATMENT FOR THE DISORDER!ND ALTHOUGHONECANNOTNECESSARILYDElNEADISEASEBYITSRESPONSETO

 %OSINOPHILIC%SOPHAGITIS4REATMENT!PPROACHIN#HILDREN



THERAPY THE EXCLUSION OF ANOTHER IDENTIlABLE CAUSE OF ESOPHAGEAL EOSINOPHILIA REMAINSANIMPORTANTASPECTINMAKINGTHEDIAGNOSIS!SSUCH IFACIDSUPPRESSION RESULTS IN IMPROVEMENT IN THE EOSINOPHILIA WITHOUT OTHER INTERVENTION ONE COULD ARGUETHECORRECTDIAGNOSISISTRULYACIDREmUXANDNOT%O%!SIDEFROMREmUX OTHER CAUSES OF ESOPHAGEAL EOSINOPHILIA INCLUDE HYPEREOSINOPHILIC SYNDROME EOSINO PHILICGASTROENTERITIS INmAMMATORYBOWELDISEASE ANDPARASITICINFECTION4HEPRES ENCEOFANYOFTHESEDIAGNOSESWOULDALSOEXCLUDE%O% 7ITHTHISPARTICULARCONmICTINMIND ITISOPTIMALTOTREATACHILDWITHSUSPECTED %O%WITHACIDSUPPRESSIONPRIORTOTHEDElNITIVEDIAGNOSTICTESTOFENDOSCOPYWITH ESOPHAGEALBIOPSY)TISPOTENTIALLYPROBLEMATICTHATTHEREISNODElNITIVEGUIDELINE FORTHETYPEOFACIDSUPPRESSION DOSE ORDURATIONTHATSHOULDBEEMPLOYEDPRIORTO ENDOSCOPY )NTUITIVELY AGGRESSIVE ACID SUPPRESSION WITH A PROTON PUMP INHIBITOR WOULDPROVIDETHEMOSTDElNITIVEEVIDENCEOFRESPONSEORLACKOFIT3EVERAL00)S ARE&$! APPROVEDFORCHILDRENAGEDANDABOVEWITHDOSINGGUIDELINESBASEDON WEIGHT ALLOWINGFORAREASONABLESTANDARDIZATIONOFDOSING3UBSEQUENTLY THEPRES ENCEOFAHIGHDENSITYOFESOPHAGEALEOSINOPHILSORMOREPERMICROSCOPICHIGH POWERED lELD AFTER A REASONABLE TREATMENT COURSE OF ACID SUPPRESSION COUPLED WITH ONGOING CLINICAL SYMPTOMS IS NECESSARY TO MAKE THE DIAGNOSIS OF %O% %NDOSCOPIC lNDINGS OF %O% SUCH AS MUCOSAL FURROWING RINGS OR WHITE PLAQUES INCREASETHESUSPICIONOF%O% BUTNONEOFTHESEAREENTIRELYSPECIlCTOTHEDISORDER ;= )N RARE CASES CIRCUMSTANCES EXIST WHERE ENDOSCOPY MAY NOT BE ABLE TO BE DELAYEDLONGENOUGHTOALLOWFORACOURSEOFACIDSUPPRESSION)NPARTICULAR PATIENTS WITHFOODIMPACTION SEVEREDYSPHAGIAORSIGNIlCANTWEIGHTLOSSANDANARROWED ESOPHAGUS MAY WARRANT EMERGENT OR URGENT ENDOSCOPY )N THOSE CIRCUMSTANCES WHILEAPRESUMPTIVEDIAGNOSISOF%O%CANBEMADE ADElNITIVEDIAGNOSISSHOULDBE RESERVEDUNTIL'%2$CANBEREASONABLYEXCLUDEDASAPOTENTIALETIOLOGY4HISCAN BEFACILITATEDWITHP( METRYANDORIMPEDANCEANALYSIS WHICHALLOWSFOREARLIER ASSESSMENTOFTHEPRESENCEOFACIDREmUXHOWEVER REmUXANDEOSINOPHILICESOPHAGI TISCANCO EXISTINSOMEPATIENTS,ONGITUDINALFOLLOW UPOFTHESEPATIENTSREMAINS THEBESTWAYTODETERMINETHEACTUALETIOLOGYOFTHEIRlNDINGS

Initial Management 4HE INITIAL MANAGEMENT OF THE PATIENT WITH %O% DEPENDS ON A NUMBER OF FACTORS INCLUDINGTHESEVERITYOFSYMPTOMS MEDICALRESOURCESAVAILABLETOTHEPATIENTAND PROVIDERS THEEXPERIENCEANDPREFERENCEOFTHETREATINGPHYSICIAN ANDTHEMOTIVATION ANDlNANCIALRESOURCESOFTHEPATIENTANDTHEIRFAMILY!MONGTHEMOSTCOMMONLY UTILIZED TREATMENTS ARE STEROIDS BOTH SYSTEMIC AND TOPICAL DIETARY ELIMINATION EMPIRICORDIRECTEDBASEDONALLERGYTESTING ANDELEMENTALDIET)NADDITION 00) THERAPY WHILENOTAPRIMARYTHERAPYFOR%O% ISOFTENUTILIZEDASACONCOMITANTTHERAPY BECAUSEOFSECONDARYREmUXSYMPTOMSDUETOANABNORMALLYFUNCTIONINGESOPHA GUS%ACHTREATMENTCHOICEHASPOTENTIALBENElTSANDCANBEJUSTIlEDBASEDONTHE AVAILABLEPUBLISHEDEXPERIENCE,IKEWISE EACHHASITSLIABILITIES



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Corticosteroids 3YSTEMICCORTICOSTEROIDSHAVEBEENPREVIOUSLYSHOWNTOBEEFFECTIVEINTREATINGSEVERAL ALLERGICDISORDERSASSOCIATEDWITHINCREASEDEOSINOPHILS INCLUDINGASTHMA ECZEMA ANDEOSINOPHILICGASTROENTERITIS;9n=)NPATIENTSWITH%O% SEVERALREPORTSHAVE DEMONSTRATEDARAPIDANDCOMPLETEIMPROVEMENTINSYMPTOMSANDHISTOLOGYWHENTHEY ARETREATEDWITHORALSTEROIDSSUCHASPREDNISONEANDMETHYLPREDNISOLONE; ]. 4HEADVANTAGESOFSYSTEMICSTEROIDSINCLUDEEASEOFADMINISTRATION RAPIDONSETOF RESPONSE ANDVERYHIGHRESPONSERATE(OWEVER THETOXICITIESRELATINGTOPROLONGED STEROIDUSEAREWELLDOCUMENTED ANDTHEHIGHRELAPSERATEOF%O%AFTERTHISTREATMENT ISDISCONTINUEDLIMITTHEUTILITYOFORALSTEROIDSASAMAINTENANCETHERAPY0RESENTLY SYSTEMICSTEROIDSSHOULDBERESERVEDFORISOLATEDCASESSUCHASPATIENTSWHOHAVE ESOPHAGEALSTRICTURESORSMALLCALIBERESOPHAGUSCAUSINGSIGNIlCANTDYSPHAGIA FOOD IMPACTION WEIGHTLOSS ORSEVERESWALLOWINGPROBLEMSTHATREQUIREARAPIDTREATMENT RESPONSEPRIORTOOTHERTREATMENTSBEINGINSTITUTED 4OPICALCORTICOSTEROIDSWERElRSTSUGGESTEDASAPOTENTIALTREATMENTFOR%O%A FEWYEARSAFTERSYSTEMICSTEROIDSWEREDEMONSTRATEDTOBEEFFECTIVE;=4HElRST TRIALSOFTOPICALSTEROIDSUTILIZEDAEROSOLIZEDFORMSOFSTEROIDSORIGINALLYDEVELOPED FORINHALATIONASATREATMENTFORASTHMA4HESEAEROSOLIZEDPREPARATIONSWERESWAL LOWEDRATHERTHANINHALED INANEFFORTTOCOATTHESURFACEOFTHEESOPHAGUSANDLIMIT THEIR SYSTEMIC EXPOSURE 5TILIZATION OF BUDESONIDE IN SOME PREPARATIONS FURTHER REDUCED THE LIKELIHOOD OF SYSTEMIC SIDE EFFECTS OWING TO RAPID lRST PASS HEPATIC METABOLISM; =4HEUSEOFTOPICALSTEROIDSPROVEDTOBESUCCESSFULINREDUCING SYMPTOMSASWELLASEOSINOPHILICINmAMMATION(OWEVER ASSEENWITHSYSTEMIC STEROIDTHERAPY THEEFFECTOFTOPICALSTEROIDSHASBEENSHOWNTOBELIMITEDASSYMP TOMS AND ESOPHAGEAL EOSINOPHILIA ALMOST ALWAYS RECUR WHEN THE MEDICATION IS WEANEDORDISCONTINUED!LTHOUGHSIGNIlCANTSIDEEFFECTSOFTOPICALSTEROIDSHAVE YETTOBEREPORTED ESOPHAGEALCANDIDIASISHASBEENSEENINAPROPORTIONOFPATIENTS WHORECEIVETHISTHERAPY;=)NADDITION SOMEHAVERAISEDCONCERNSABOUTGROWTH CHANGES IN THE HYPOTHALAMICnPITUITARYnADRENAL AXIS AND BONE DENSITY BUT THESE ABNORMALITIESHAVEYETTOBEDEMONSTRATED"ECAUSEOFTHECURRENTLYREPORTEDMINI MAL RISK OF SYSTEMIC SIDE EFFECTS MANY ADVOCATE ONGOING TREATMENT WITH TOPICAL STEROIDS WHILEOTHERSSUGGESTINTERMITTENTTREATMENT4ODATE THEREISNOMAINTE NANCEMETHODTHATHASBEENPROVENTOBEMOSTEFFECTIVE)TALSOREMAINSTOBESEEN WHETHER THIS THERAPEUTIC APPROACH REDUCES ESOPHAGEAL INmAMMATION ENOUGH TO PREVENTLONG TERMCOMPLICATIONSSUCHASlBROTICCHANGESINTHEESOPHAGUS !NALTERNATIVEAPPROACHTOAEROSOLIZEDTOPICALSTEROIDS BUDESONIDE SUCHASWOULD BE USED IN A NEBULIZER HAS BEEN MADE INTO A VISCOUS SOLUTION FOR INGESTION ;]. 6ISCOUSBUDESONIDEEXHIBITSANEFFECTSIMILARTOTHATSEENWITHTHESWALLOWEDAERO SOLIZEDSTEROID4HESIDEEFFECTSARESIMILARANDTHERISKOFSYSTEMICEFFECTSSHOULD ALSOBECOMPARABLE!RECENTTRIALOFTHISPREPARATIONINCHILDRENWITH%O%HASBEEN ONGOINGANDHASHADENCOURAGINGRESULTS;=!TTHISPOINT ITAPPEARSTHATEFFECTIVE NESSOFBOTHFORMSOFTOPICALSTEROIDTHERAPYARESIMILARANDTHATSELECTIONSHOULD DEPENDONADISCUSSIONBETWEENTHEPHYSICIAN THEPATIENT ANDHISORHERFAMILY

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Dietary Therapy &ROMTHETIMETHAT%O%WASlRSTRECOGNIZED ITWASSTRONGLYSUGGESTEDTHATITWASAN ALLERGICDISEASE4HEORIGINALCASESERIESTHATDEMONSTRATEDIMPROVEMENTINESOPHAGI TISONANELEMENTALDIETLAIDTHEGROUNDWORKFORUSINGRESTRICTIONOFFOODANTIGENSAS ATREATMENTFOR%O%;9=)NTHATSERIES PATIENTSNOTONLYRESPONDEDTOANELEMENTAL DIET BUTTHEYALSODEVELOPEDARECURRENCEOFSYMPTOMSWHENTHEYWERERE EXPOSED TOTHEOFFENDINGFOODS3UBSEQUENTSTUDIESHAVECONlRMEDTHATRESTRICTIONOFFOOD ANTIGENSCANRESULTINBOTHASIGNIlCANTSYMPTOMATICANDHISTOLOGICIMPROVEMENTOF %O%7HILETHEREISLITTLEDEBATEONTHESEPOINTS THEDIFlCULTYLIESINHOWBESTTO DETERMINEWHICHANDHOWMANYFOODANTIGENSARECAUSINGTHECLINICALSYMPTOMS ANDESOPHAGEALEOSINOPHILIA

Elemental Diet !MONGALLOFTHEMETHODSFORRESTRICTINGFOODSFROMTHEDIET THEADMINISTRATIONOF ANELEMENTALDIETUTILIZINGASTRICTAMINOACID BASEDFORMULAHASSHOWNTHEHIGHEST RESPONSERATEBOTHCLINICALLYANDHISTOLOGICALLY-ULTIPLEREPORTSHAVEDEMONSTRATED THATGREATERTHANOFPATIENTSRESPONDBOTHCLINICALLYANDHISTOLOGICALLYTOTHE INTRODUCTIONOFANELEMENTALDIET; 0=2EPORTSSUGGESTTHATSYMPTOMRESOLUTION MAYOCCURASQUICKLYASWITHINTHElRSTWEEKOFSTARTINGTHEDIET&OLLOWUPBIOP SIES  MONTH AFTER STARTING TREATMENT SHOW ESSENTIALLY COMPLETE RESOLUTION OF EOSINOPHILIAINMANYCASES/FTHECOMMONLYACCEPTEDTREATMENTSFOR%O% TREAT MENT WITH ELEMENTAL DIET CAN BE CONSIDERED THE MOST EFlCACIOUS (OWEVER THE EFFECTIVENESS OF THE DIET MEANING THE UTILITY IN REAL WORLD SITUATIONS RATHER THAN CONTROLLEDTRIALS MAYBELIMITEDBECAUSEOFSEVERALLOGISTICALISSUESASSOCIATEDWITH THISTREATMENT 4HEGREATESTLIMITATIONTOTHEUSEOFANELEMENTALDIETISPALATABILITY)NGENERAL THEMOREELEMENTALTHEPROTEINSOURCEINAFORMULA THEMOREUNPALATABLEITTENDSTO BE&URTHERADDINGTOTHEPOORTASTEISTHEPRESENCEOFAHIGHPROPORTIONOF-#4OIL ANDLACKOFSWEET TASTINGSUGARS7HENINTRODUCEDEARLYINLIFE CHILDRENCOMMONLY ADJUSTTOTHETASTEOFELEMENTALFORMULASHOWEVER THEINITIATIONOFTHESEFORMULASIN ACHILDORADOLESCENTWHOISALREADYUSEDTOAMORENORMALDIETISOFTENADIFlCULT PROPOSITION!TKCALOZ THEELEMENTALFORMULASDESIGNEDFORUSEINCHILDRENOVER YEAROFAGEREQUIRERELATIVELYLARGEVOLUMESOVERTHECOURSEOFADAYTOPROVIDE ADEQUATENUTRITION!MINIMUMOF,OFFORMULAISCOMMONLYADMINISTEREDINTHE SMALLESTOFCHILDREN WHILEOLDERCHILDRENANDADOLESCENTSMAYNEEDORMORELITERS OFFORMULAPERDAY)NMANYCASES CHILDRENAREUNABLETODRINKTHISVOLUMEOFFOR MULA NECESSITATING ENTERAL TUBE FEEDING VIA NASOGASTRIC TUBES OR A SURGICALLY OR ENDOSCOPICALLYPLACEDGASTROSTOMYTUBE !NOTHERPROBLEMISTHATTHECOSTOFELEMENTALFORMULASTENDSTOBEHIGHERTHAN INTACT PROTEIN FORMULAS OR HYDROLYZED PROTEIN FORMULAS 4HE COST TAKES ON MORE



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IMPORTANCEBECAUSEITISCOMMONFORMEDICALINSURERSTOEXCLUDEFORMULAFROMTHEIR BASICCOVERAGE THUS LEADINGTOSIGNIlCANTOUT OF POCKETEXPENDITUREFORTHEFAMILY %MOTIONALCOSTSALSOEXISTBECAUSEOFQUALITY OF LIFEISSUES5SINGASTRICTELEMENTAL DIETNOTONLYREMOVESINDIVIDUALSFROMTHESOCIALASPECTSOFEATINGBUTALSOIMPACTS THERESTOFTHEFAMILYWHOMAYBEASKEDTOALTERTHEIRDIETINSUPPORTOFTHEPATIENT )T IS IMPORTANT THAT THOSE WHO ATTEMPT TO USE AN ELEMENTAL DIET RECEIVE CLOSE OBSERVATIONTOENSURETHATTHEIRNUTRITIONALNEEDSAREBEINGMET4HISINCLUDESTOTAL CALORIESASWELLASMACRO ANDMICRONUTRIENTS.UTRITIONALDElCIENCIESHAVEBEEN RECOGNIZEDINCHILDRENONEXCLUSIVEELEMENTALDIETSFORPROLONGEDPERIODS;=)TIS ADVISABLETHATAPEDIATRICDIETITIANORNUTRITIONISTORAPHYSICIANWITHEXPERTISEIN NUTRITIONAL MANAGEMENT OVERSEE THE ADMINISTRATION OF ELEMENTAL DIET IN ORDER TO MINIMIZETHERISKSOFTHISFORMOFTREATMENT4HESEPATIENTSMAYALSONEEDTHESUP PORTOFSOCIALWORK CASEMANAGEMENT PSYCHOLOGY ANDFEEDINGSPECIALISTS

Dietary Restriction $ESPITE THE HIGH SUCCESS RATE OF ELEMENTAL DIETS IN PATIENTS WITH %O% THERE ARE NUMEROUSADVANTAGESTOBEINGABLETOEATANINTACTPROTEINDIET#HOOSINGWHICH FOODSTORESTRICTFROMTHEDIETCANBEDIFlCULT YETCHOOSINGCORRECTLYISVITALTOTHE SUCCESSOFTHISAPPROACH4HEDECISIONONHOWTORESTRICTTHEDIETALSODEPENDSON THERESOURCESAVAILABLETOTHEPATIENT4HETWOMOSTCOMMONAPPROACHESTODIETARY RESTRICTIONAREANEMPIRICDIETBASEDONTHEREMOVALOFTHEMOSTCOMMONPROBLEM ATICFOODANTIGENS ANDADIRECTEDDIETBASEDONTHERESULTSOFALLERGYTESTING  %MPIRICFOODELIMINATIONOFTHEMOSTCOMMONCAUSATIVEFOODSHASBEENSHOWN TOBEANEFFECTIVEAPPROACHINCHILDREN)N +AGALWALLACOMPAREDTHECLINICAL ANDHISTOLOGICALRESPONSEOFASIX FOODELIMINATIONDIET3&%$ THATRESTRICTEDCOWS MILK SOYPROTEIN PEANUT WHEAT EGG ANDSHELLlSHTOANOTHERCOHORTOF%O%PATIENTS WHO RECEIVED AN ELEMENTAL DIET ;= 3EVENTY FOUR PERCENT OF THE 3&%$ GROUP SHOWEDAHISTOLOGICRESPONSEAFTERAMINIMUMOFWEEKSOFTREATMENT WITHPEAK EOSINOPHILCOUNTDROPPINGFROMABOUTEOSINOPHILSPERHIGHPOWERlELDTO 7HILETHESERESULTSWEREFAVORABLE THOSEWHORECEIVEDANELEMENTALDIETOVERTHAT TIMEPERIODSHOWEDAMORECOMPLETEHISTOLOGICRESPONSE -EANWHILE DIRECTED DIETARY THERAPY HAS ALSO BEEN SHOWN TO BE SUCCESSFUL !S MENTIONEDINPREVIOUSCHAPTERS WHILETHEEXACTTYPEOFALLERGICRESPONSEINPATIENTS WITH%O%ISUNKNOWN ALLERGYTESTINGMAYSTILLBEBENElCIAL/FTENPATIENTSWITH%O% HAVE REACTIONS TO MULTIPLE FOODS 3PERGEL DEMONSTRATED THAT MANY PATIENTS WITH %O% MANIFEST EVIDENCE OF BOTH IMMEDIATE TYPE )G% MEDIATED AND DELAYED TYPE 4 CELL MEDIATED ALLERGY ;= 4RADITIONAL SKIN PRICK TESTING PROVIDES EVIDENCE OF )G% MEDIATED FOOD ALLERGY WHILE ATOPY PATCH TESTING MAY PROVIDE SUPPLEMENTAL DATAONDELAYED TYPEHYPERSENSITIVITYREACTIONSTOFOODS7HENUTILIZEDTOGETHER THE SENSITIVITYOFTHESEFORMSOFTESTINGTENDTOBEHIGH BUTTHESPECIlCITYISVARIABLE 4HESETESTSINCREASETHELIKELIHOODTHATSPECIlCDIETARYELIMINATIONWILLBESUCCESS FUL HOWEVER FALSEPOSITIVESANDFALSENEGATIVESFREQUENTLYOCCUR7HENUTILIZED THE ELIMINATION OF FOODS IDENTIlED BY TESTING IS USUALLY EMPLOYED FOR A MINIMUM OF

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n WEEKS FOLLOWED BY %'$ TO CONlRM A HISTOLOGIC RESPONSE 7HILE CLINICAL IMPROVEMENT MAY TAKE PLACE WITHIN THE lRST FEW WEEKS OF FOOD ELIMINATION IT REMAINS CRITICAL TO RE EVALUATE THE MUCOSAL RESPONSE WITH BIOPSY IN BOTH CLINICAL RESPONDERSANDNONRESPONDERS)TISNOTUNCOMMONFORSYMPTOMSTOWAXANDWANE EVEN WHEN INmAMMATORY ACTIVITY REMAINS CONSTANT &URTHER BECAUSE MANY SYMP TOMSOF%O%ARENOTSPECIlCTOTHISDISORDER ITISIMPORTANTTOCONlRMTHATONGOING SYMPTOMSARETRULYDUETOONGOINGEOSINOPHILICINmAMMATIONANDNOTANOTHERCAUSE SUCHASACIDREmUX !SWITHELEMENTALDIET ITISHIGHLYADVISABLETOHAVEADIETITIANAVAILABLETOTHE FAMILYTHATUNDERTAKESANYDIETARYTHERAPY WHETHERDIRECTEDBYALLERGYTESTINGOR EMPIRICTHERAPY*USTLIKETHEUSEOFELEMENTALFORMULAS RESTRICTIVEDIETSPUTPATIENTS ATRISKFORMACRO ANDMICRO NUTRIENTDElCIENCIES; =!DDITIONALLY THEUBIQUI TOUSNATUREOFCERTAINTYPESOFFOODANTIGENSSUCHASWHEAT SOY ANDCOWSMILK MAKECOMPLETEELIMINATIONEXTREMELYDIFlCULT!SKILLEDDIETITIANWHOHASEXPERI ENCECOUNSELINGPATIENTSANDTHEIRFAMILIESONRECOGNIZINGFOODANTIGENSININGREDI ENTLISTSCANGREATLYHELPTOPREVENTINADEQUATERESPONSEDUETOINADVERTENTEXPOSURE TOFOODS&URTHERSUPPORTFORPATIENTSCANBEPROVIDEDTHROUGHORGANIZATIONSSUCHAS THE&OOD!LLERGYAND!NAPHYLAXIS.ETWORK&!!. ANDTHE!MERICAN0ARTNERSHIP FOR%OSINOPHILIC$ISORDERS!0&%$ 

Suggested Approach to the Pediatric Patient with Eosinophilic Esophagitis $ESPITE THE GROWING EXPERIENCE WITH %O% OVER THE PAST  OR MORE YEARS THERE REMAINS DEBATE AS TO THE BEST APPROACH TO THE NEWLY DIAGNOSED PATIENT )N SOME CHRONIC DISORDERS SUCH AS INmAMMATORY BOWEL DISEASE THE TREATMENT APPROACH IS BASEDONAhPYRAMIDvWHEREINITIALTREATMENTISGIVENTOMOSTPATIENTSANDSUBSEQUENT TREATMENTS ARE GIVEN TO THOSE WITH PERSISTENT DISEASE ACTIVITY ;= )N THIS MODEL INITIALTREATMENTUSUALLYISCONSIDEREDTHESAFEST WHILEEACHSUBSEQUENTTREATMENT OFFERSTHEPROSPECTFORIMPROVEDEFFECTIVENESSBUTALSOMAYINCLUDEINCREASEDRISKOF SIDEEFFECTS)N%O% THEAPPROACHTOTREATMENTISMOREVARIED FOLLOWINGMOREOFA hHOPSCOTCHvGAMEWHERETHEREISNODElNITIVESTARTINGPOINTANDPATIENTSMAYhSKIPv OVER CERTAIN TREATMENTS IN LIEU OF OTHERS 4HE LACK OF A CONSISTENT AND SEQUENTIAL TREATMENTSTRATEGYSTEMSNOTONLYFROMALACKOFHEADTOHEADTRIALSOFTREATMENTSBUT ALSORELATESTODIFFERENCESINTHERESOURCESAVAILABLEINDIFFERENTAREASOFTHECOUNTRY 7ITHTHISINMIND WESUGGESTATREATMENTGUIDELINESIMILARTOTHATSUGGESTED IN&IG %'$WITHBIOPSYISTHEONLYSTANDARDWITHWHICHTHEDIAGNOSISOF%O%CANBE MADE7HEREVERPOSSIBLE %'$SHOULDBEDELAYEDUNTILANADEQUATETRIALOFACID SUPPRESSIONCANBEGIVEN!MINIMUMOFWEEKSOFTHERAPYWITHA00)GIVENAT HIGHDOSEISOPTIMAL)NCHILDREN MANYEXPERTSIN%O%SUGGESTUSINGTWICEDAILY DOSINGOFA00) ATADOSEUPTOMGKGDOSE TOAMAXIMALADULTDOSE/NGOING CLINICAL SYMPTOMS COUPLED WITH SIGNIlCANT ISOLATED ESOPHAGEAL EOSINOPHILIA OF GREATER THAN  OR MORE EOSINOPHILS PER MICROSCOPIC HIGH POWERED lELD ¾



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WITHOUTSIGNIlCANTEOSINOPHILIAINOTHERAREASOFTHE')TRACTISSUFlCIENTFORTHE DIAGNOSISOF%O%)NCIRCUMSTANCESWHERETHE%'$ISPERFORMEDPRIORTOANADE QUATETRIALOFACIDBLOCKADEABOVE ITWOULDBEADVISABLETOEVALUATEFORSIGNIlCANT ACIDREmUXASAPOTENTIALCAUSEOFTHEESOPHAGEALEOSINOPHILIA4HISCANBEACCOM PLISHEDBYP( METRYWITHORWITHOUTIMPEDANCEANALYSIS ORBYSUBSEQUENTTRIALOF ACIDBLOCKADEANDRE EVALUATIONOFTHEESOPHAGEALMUCOSA &OLLOWINGADIAGNOSISOF%O% EITHERDIETARYRESTRICTIONELIMINATIONORTHEUSEOF TOPICALSTEROIDSSHOULDBEINSTITUTED)NCERTAINCIRCUMSTANCES SUCHASASIGNIlCANT SMALLCALIBERESOPHAGUSORMULTIPLEFOODIMPACTIONSAMOREAGGRESSIVEINITIALTREAT MENTAPPROACH SUCHASSYSTEMICSTEROIDSORESOPHAGEALDILATATIONMAYBENEEDED /FTEN THETHERAPEUTICCHOICEISMADEDEPENDINGONTHERESOURCESOFTHEPHYSICIAN ANDAFTERADISCUSSIONWITHTHEPATIENTANDFAMILY7HENCONSIDERINGTHEUSEOFDIET RESTRICTIONELIMINATION INCASESWHEREALLERGYTESTINGDOESNOTREVEALANYPOTENTIAL FOODSFORREMOVAL ORWHERETHEDIETARYRESTRICTIONSPROVETOODIFlCULTFORTHEFAMILY TOMAINTAIN TOPICALSTEROIDTHERAPYSHOULDBECONSIDERED!LTERNATIVELY INPATIENTS WHOAREUNABLETOCOMPLYWITHUSINGTOPICALSTEROIDS DIETARYRESTRICTIONSSHOULDBE CONSIDERED$URINGANYTHERAPY AREPEAT%'$ISRECOMMENDEDMINIMUMnWEEKS LATER TODOCUMENTRESOLUTIONOFINmAMMATION!SMENTIONEDPREVIOUSLY CLOSEFOL LOW UPISREQUIREDREGARDLESSOFTREATMENTCHOICE7HENUSINGDIETARYRESTRICTIONS ONE MUST MAKE SURE THAT ADEQUATE NUTRITION IS SUPPLIED AND THAT GROWTH IS MAIN TAINED7HENUSINGSTEROIDS MEDICATIONSIDEEFFECTSANDGROWTHALSOREQUIREMONI TORING!FTERTHEINITIATIONOFTHERAPY WEADVISETHATACIDSUPPRESSIONBEMAINTAINED THROUGHOUTTHETREATMENTPROCESSUNTILAlNALCOURSEOFTHERAPYHASBEENCHOSEN 7ITHREGARDTOTOPICALSTEROIDTHERAPY INITIALDOSINGISUSUALLYTWICEDAILY4HE DURATIONOFTREATMENTWITHTOPICALSTEROIDSREMAINSUNCLEAR BUTITISWIDELYBELIEVED THATDISEASEALMOSTALWAYSRELAPSESUPONDISCONTINUATIONOFTREATMENT-OST%O% EXPERTSADVOCATEDECREASINGTHEDOSINGSCHEDULEONCESYMPTOMSARECONTROLLEDAND INmAMMATIONIMPROVES4OPICALSTEROIDTHERAPYSHOULDBEMAINTAINEDASLONGASIS NECESSARYTOMAINTAINASYMPTOMATICREMISSION3OMEWILLCHOOSETODISCONTINUE THERAPYPERIODICALLY WITHAPLANTORESTARTTREATMENTONCESYMPTOMSRE EMERGE !REPEAT%'$ISRECOMMENDEDAFTERMEDICATIONCHANGESMINIMUMnWEEKS TO DOCUMENTRESOLUTIONOFINmAMMATION0RESENTLY ITREMAINSUNCLEARWHATDEGREEOF EOSINOPHILIAPRESENTSARISKFORLONG TERMCOMPLICATIONSSUCHASESOPHAGEALlBROSIS ANDSTRICTUREFORMATIONBUTGENERALLYITISFELTTHATLOWERNUMBERSOFEOSINOPHILS AREBETTER 7ITHREGARDTODIETARYELIMINATION ONCEREMISSIONISACHIEVEDWITHDIETARYTHER APY FOODCHALLENGESWITHRESTRICTEDFOODSCANBESTARTED3YMPTOMRELAPSEFOLLOW ING INTRODUCTION OF A PREVIOUSLY RESTRICTED FOOD IS ADEQUATE TO DElNE FAILURE ON REINTRODUCTION BUTLACKOFSYMPTOMSDOESNOTENSURETHATDISEASEHASNOTRELAPSED !FTERTHEINTRODUCTIONOFONEORASMALLGROUPOFFOODS ANENDOSCOPYSHOULDBE PERFORMEDTOCONlRMTHATTHEREHASNOTBEENASUBCLINICALRELAPSE4HENUMBEROF FOODSTOBEINTRODUCEDBEFOREENDOSCOPYISAMATTEROFCHOICE%NDOSCOPYBETWEEN EACHFOODINTRODUCTIONISTHEMOSTDElNITIVEWAYTOEVALUATEEACHFOOD BUTISCOSTLY ANDRESULTSINCUMULATIVELYMORERISK ALBEITSMALL(OWEVER THEMOREFOODSINTRO DUCEDBETWEENEACHENDOSCOPYINTRODUCELESSCERTAINTYASTOWHICHFOODORFOODS

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ARERESPONSIBLEIFARELAPSEISFOUND!SAGUIDELINE ITISREASONABLETOINTRODUCEA FEW LOWER RISK FOODS AT A TIME BETWEEN ENDOSCOPY WHILE PERFORMING ENDOSCOPY BETWEENSINGLEFOODINTRODUCTIONSOFHIGHER RISKORFOODSTHATAREMOREOFASTAPLE OFTHETYPICALDIET SUCHASEGG MILK ANDWHEAT

Summary %OSINOPHILICESOPHAGITISPRESENTSCHALLENGESTOTHEPATIENT FAMILY ANDTREATINGPHY SICIAN7HILETHEREARESEVERALEFFECTIVETREATMENTSAVAILABLE EACHISACCOMPANIED BYPARTICULARDRAWBACKS)NCHOOSINGATREATMENT ONEMUSTCONSIDERTHESEVERITYOF SYMPTOMS THE RESOURCES AVAILABLE TO THE TREATMENT TEAM AND THE QUALITY OF LIFE IMPACTTHATTREATMENTWILLHAVEONTHEPATIENTANDTHEFAMILY)NTHEFUTURE HEAD TO HEAD EVALUATIONS OF THE TREATMENTS MAY PROVIDE BETTER INFORMATION AS TO THE BEST APPROACH&ORNOW ITISADVISABLEFORTHETREATINGPHYSICIANTOBEFAMILIARANDCOM FORTABLE WITH ALL OF THE AVAILABLE TREATMENTS AND TAILOR THERAPY TO THE INDIVIDUAL patient.

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Index

A Abdominal pain, 388–389 Acid suppression therapy, 19, 301–302 Adenotonsillar hypertrophy, 125 Adults. See also Eosinophilic esophagitis (EoE) allergy (see Allergy) asymptomatic patients, 407 corticosteroids clinical presentation, 307 proton pump inhibitors, 311 systemic corticosteroids, 308–309 topical corticosteroid, 309–311 dysphagia, 398 endoscopy, 400, 406 inflammatory process, 399 initial therapy dietary therapy, 401, 403–404 esophageal dilation, 404–405 evaluation prior to, 399–400 management algorithm, 405, 406 medical therapy, 401 patients refractory, 406–407 maintenance therapy, 408 natural history, 398 symptoms and signs, 397–398 therapeutic outcomes, 399 tissue injury, 398 Allergen. See Allergy Allergy. See also Eosinophilic esophagitis; Food allergy adults atopy patch testing, 262 demographics, 255 environmental allergens, 262–263 environmental specific IgE testing, 264

environmental SPT, 263–264 family history, 255 food allergens, 257–258 food skin prick testing, 259–260 food specific IgE testing, 261 pediatric patients, 254 treatment, 264–266 children aeroallergens and EoE, 244–247 allergen sensitization and eosinophilia, 248, 249 definition, 239–240 food allergy and EoE, 243–244 pathophysiology, 249–250 prevalence, 245, 247 eosinophilic proctocolitis, 224 esophagitis, 1 gastroenteritis, 227 Anaphylactic food allergy dietary treatment, 314–315 IgE mediated, 223–224 Angioedema, 222 Anorexia nervosa (AN), 365 Aspergillus fumigatus, 16, 87, 244 Asthma airway remodeling, 40–41 allergic rhinitis, 223 atopic and allergic features environmental allergens, 263 family history, 255 personal history, 257 SPT, 264 atopic disease, 16, 32, 221, 240 corticosteroids, 299 adults, 309 budesonide, 303–304

C.A. Liacouras and J.E. Markowitz (eds.), Eosinophilic Esophagitis, Clinical Gastroenterology, DOI 10.1007/978-1-60761-515-6, © Springer Science+Business Media, LLC 2012

419

420 Asthma (cont.) fluticasone proprionate, 302 topical steroids, 414 cromolyn sodium, 304 eosinophil activity, 47 experimental allergic model, 45, 48, 54 family history, 32–33 IL–5, 43–44 IL–4 and IL–13, 44 omalizumab, IgE neutralization, 354 oral tolerance, 341, 349 racial distribution, 15 subepithelial fibrosis, 40–41 tissue remodeling, 55–56, 84–85 TSLP, 102 Atopic dermatitis, 227 Atopic disease adults (see Allergy) children aeroallergens and EoE, 244–247 allergen sensitization and eosinophilia, 248, 249 definition, 239 family history, 241 food allergy and EoE, 243–244 incidence, 245, 247 pathophysiology, 249–250 prevalence, 16, 240–242 topical corticosteroids, 239 Atopic patch testing (APT), 230, 262, 325 blood sample analysis, 276–277 elimination diet, 316–317 immune response, 273 predictive value, 274–276 statistical evaluation, 274

B Barium esophagography ringed esophagus congenital esophageal stenosis, 152, 158 feline esophagus, 153, 160 fixed transverse folds, 152, 159 multiple distinctive, 151, 155 Schatzki ring, 151, 157 subtle, 151, 156 small-caliber esophagus caliber loss, 153, 161 distensibility loss, 153, 161 radiograph, 154 strictures chronic lye, 150, 153 distal thoracic esophagus, 149, 151

Index peptic, 150, 154 radiation, 150, 152 upper thoracic esophagus, 149, 150 technique, 148–149 Biological agents, 358 CAT–345, 357–358 IL–13, 357 monoclonal antibodies to IL–5 EoE development and perpetuation, 356 mepolizumab, 356–357 reslizumab, 357 omalizumab, IgE neutralization efficacy, 355 IgE binding, 354–355 mast and b cells, 354 TH2 cells and cytokine production, 358 TNF-D antagonists, 355 Boerhaave’s syndrome, 293 Budesonide adults, 310–311 esophageal remodeling inflammatory cells, 89 responders and non responders, 91–92 pediatric eosinophilic esophagitis, 302–303

C CAT–345, 357–358 CC chemokine receptor 3 (CCR3), 94 Celiac disease, 184, 226–227 Chest pain, steroid administration, 354 Contact dermatitis, 224 Corticosteroids adult clinical presentation, 307 proton pump inhibitors, 311 systemic corticosteroids, 308–309 topical corticosteroid, 309–311 children, 414 mechanism of action, 298 oral vs. topical steroids, 299 risk factors, 298 symptomatic and histologic remission, 298 systemic corticosteroids, 299, 308–309, 414 topical steroids (see Topical steroids) Cows milk allergy, 365 Crepe-paper esophagus, 171 Crystalline amino acid based elemental diet, 315 Cytotoxic T Lymphocyte-associated antigen (CTLA–4), 348

Index D Dermatitis herpetiformis, 224 Dextran sodium sulfate (DSS), 112 Dietary constituents, 19 Dietary protein enteropathy, 226 Dietary protein proctocolitis, 224 Dietary Reference Intakes (DRIs), 326, 327 Dietary restrictions, 380 children, 416–417 HRQL, 381 pediatric eosinophilic esophagitis, 418 preschoolers, 383 social stigma and dietary adherence, 389–390 Dietary treatment. See also Nutritional management adults, 401, 403–404 children, 298, 415 elemental diet crystalline amino acid based, 315 food reintroduction, 315–316 elimination diets behavioral problems, 320 directed elimination diets, 316–317 food substitutions and crosscontamination, 318–319 milk protein, 320 standard elimination diet, 317–318 food antigens, 314 genome-wide microarray expression study, 313–314 goals, 313 nutritional assessment, 319 outcomes, 314, 315 Dysphagia, 365 adults, 13, 33, 108, 398 children, 121, 123–124 endoscopy, 122 esophageal obstruction, 121 evaluation, 123–124 feeding disorder, 121 flbrosis, 86, 90 mepolizumab, 356 omalizumab, IgE neutralization, 355 pill-induced and viral esophagitis, 122 symptoms, 31, 33 TEF, 123 toddlers, 121

E Egg avoidance, 329 Elemental diet crystalline amino acid based, 315

421 food reintroduction, 315–316 pediatric EoE children, 415–416 dietary fiber, 332 elemental diet, 415–416 enteral tube feeding, 332–334 financial considerations, 334–335 formulations, 331 micronutrient supplementation, 331 palatability, 332 Elimination diet behavioral problems, 320 directed elimination diets atopic patch testing, 316–317 radioallergosorbent test, 316 skin prick test, 316–317 food substitutions and crosscontamination, 318–319 milk protein, 320 pediatric EoE egg avoidance, 329 food allergens and substitutes, 327, 328 milk avoidance, 328–330 nutritional assessment, 326 soy avoidance, 329, 331 wheat avoidance, 329 standard elimination diet, 317–318 Endoscopic ultrasound (EUS), 148 Endoscopy adults eosinophilic esophagitis, 406 eosinophilic gastroenteritis, 400 clinical findings, 165–166 concentric rings, 167–169 crepe-paper esophagus, 171 diagnostic utility, 173–174 diminished mucosal vascularity, 169–170 dysphagia, 165 endosonographic findings, 172–173 eosinophil counts, 379 esophageal biopsy, 413 food impaction, 165 food reintroduction allergenic foods, 315 elemental diet, 335 esophageal biopsy, 318 feeding problem, 371 symptom relapse, 418–419 linear furrowing, 167 normal esophagus, 166 pediatric EoE, anti-IL–5, 304 pseudodiverticulosis, 172, 173 Schatzki’s ring, 172 small caliber esophagus, 171

422 Endoscopy (cont.) strictures, 171 tube feeding, 373 white exudate, 169, 170 Endothelial leukocyte adhesion molecule–1 (ELAM), 51 Enteral tube feeding, 332–334 Environmental theory, 18–20 Eosinophil biology activation and function eosinophil-mediated tissue fibrosis, 40, 56–58 pathogenesis, 55 secretion and degranulation, 53–54 tissue remodeling and fibrosis, 40, 55–56 cationic proteins, 41–42 cytokines and growth factors biological process, 45 chemoattractants, 44 eosinophilopoietin, 43 eotaxins, 44 GM-CSF, 42, 43 IL–5, 43–44 IL–13, 44 RANTES, 44 TGF-E, 45 development and trafficking eosinophil extravasation, 50 eosinophilopoiesis, 47–48, 50 tissue inflammation, 50–53 transcriptional regulation, 48–49 effector cell, 39 eosinophil activity, 46–47 identification, 39 lipid mediators, 45–46 morphology and mediators, 41 multifunctional granulocyte, 40, 58 pro-inflammatory and tissue damage, 40 Eosinophil-derived neurotoxin (EDN), 47 Eosinophilic esophagitis (EoE). See also Barium esophagography; Eosinophilic gastrointestinal diseases; Esophageal dilation; Esophageal fibrosis and remodeling; Gastroesophageal reflux disease; Lymphocytes; Mast cell; Mucosal eosinophilia adults, 397 (see also Adults; Allergy) allergy testing, 131, 269–270 atopic disease, 32, 270 barium esophogram, 205, 206 complications, 132 distribution and diagnosis, 30–31 dysphagia, 130

Index endoscopy, 132 eosinophilic infiltration, 266 eotaxin–3, 131 epidemiology, 26, 129–130 esophageal eosinophilia, 26–27 food impaction, 130, 207 gender, 30 history, 25, 131–132 incidence and prevalence, 27–30 industrialized/westernized disease, 36 montelukast, 206 more-recognized disease, 35 newly-recognized disease, 34 nutritional habits, 37 pathogenesis, 25 pathophysiology, 253 positive family history, 32–33 seasonal/perennial disease, 35–36 sensitivity and specificity, 207 social status and education, 31–32 strictures, 204 symptoms, 33 upper endoscopy and/or esophageal biopsy, 29–30 allergy evaluation aeroallergens, 271–272 aeroallergen-specific IgE, 278 patient history, 272 SPT, 272–273 treatment, 278–279 APT blood sample analysis, 276–277 immune response, 273 predictive value, 274–276 statistical evaluation, 274 celiac disease, 184 characterization, 71 children (see also Atopic disease; Pediatric eosinophilic esophagitis) adenotonsillar hypertrophy, 125 airborne allergens and seasonal variation, 16–17 associated condition, 126 atopic disease, 16, 270 chronic disease, 126 comprehensive care, 127 corticosteroids, 414 crohn’s disease, 125 demographic descriptors, 20 diagnosis, 13, 412–413 dietary restriction, 416–417 dietary therapy, 415 dilation, 204 dysphagia (see Dysphagia)

Index elemental diet, 415–416 endoscopic assessment, 203 environmental theory, 18–20 eosinophilic inflammation, 120 epidemiology, 12 esophageal mucosal eosinophilia, 11–12 food antigens, 119 food impaction, 207 frequency metrics, 17–18 geographic distribution, 12 histologic esophagitis, 120 initial management, 413 pain, 124 racial distribution, 15 sex distribution, 13, 14 swallowing, 203 symptoms, 13, 15, 120–121 vomiting, 124–125 corticosteroids, 5 (see also Corticosteroids) cromolyn sodium, 6 definition, 181 degranulation, 180, 185 dendritic cells, 187–189 dietary treatment (see Dietary treatment) differential diagnosis, 181 DNA, 97 eating behaviour, 208–209 endoscopic features concentric rings, 167–169 crepe-paper esophagus, 171 diagnostic utility, 173–174 diminished mucosal vascularity, 169–170 dysphagia, 165 endoscopic findings, 165, 166 endoscopy, normal esophagus, 166 endosonographic findings, 172–173 food impaction, 165 linear furrowing, 167 pseudodiverticulosis, 172, 173 Schatzki’s ring, 172 small caliber esophagus, 171 strictures, 171 white exudate, 169, 170 eosinophilic gastroenteritis, 4–5 eosinophils, 184–186 epithelial reactivity, 185–187 esophageal biopsy endoscopic features, 165 histologic features, 177, 178 esophagitis history, 2 esophagus dysfunction, 196

423 muscular inflammation, 212 narrowing, 202 obstruction, 201 feeding disorders (see Feeding disorders) FIGERS, 6–7 food allergens, 270–271 food-specific IgE, 277 food-specific IgG, 277–278 vs. gastroesophageal reflux disease, 297–298 genetic regulation, 104 genetic risk variants eotaxin–3, 101 genetic heritability, 100 identification, 102, 103 susceptibility locus, 102 GERD, 183–184 history, 2–3 indeterminate esophagitis adolescent male, 181–183 patchy nature, 180, 181 inflammatory bowel disease, 177, 180, 184 lamina propria cell components, 193, 195 children and adult, 195 IL–5, 196 periostin, 196 TGFb (beta)–1 and phosphoSMAD2/3, 195–196 leiomyomatosis, 211–212 lymphocytes CD–8 positive suppressor cell, 193, 194 CD–3 positive T, 191, 192 esophageal mucosa, 191, 192 plasma cells, 193, 195 mast cells, 189–191 medical treatment, 209–210 mucosal eosinophils accumulation, 341–342 pediatric gastroenterologist, 6 perforation dilation, 209–210 endoscope passage, 211 spontaneous, 208 precautions, 212 psychological impacts, 209 radiographic diagnosis endoscopy, 147 esophageal dilation, 148, 162 esophageal intramural pseudodiverticula, 156, 161 esophageal perforation, 159 global examination, 147

424 Eosinophilic esophagitis (EoE). See also Barium esophagography; Eosinophilic gastrointestinal diseases; Esophageal dilation; Esophageal fibrosis and remodeling; Gastroesophageal reflux disease; Lymphocytes; Mast cell; Mucosal eosinophilia (cont.) granular esophagus, 156, 162 radiologic modalities, 157–158 surgical treatment, 210 TIGERS, 7 total IgE, 277 transcriptome EDC function, 99–100 eotaxin–3, 98–99 esophageal epithelium, 99 gene expression, 98 lysyl oxidase, 100 mast cell, 99 molecular profile, 98 periostin, 100 Eosinophilic gastroenteritis (EG), 108–109. See also Eosinophilic esophagitis Eosinophilic gastrointestinal diseases (EGIDs). See also Eosinophilic gastroenteritis allergic disease, 114 characterization, 107 phenotypic pattern, 115 Eosinophilopoiesis, 47–48, 50 Eosinophil peroxidase (EPX), 42, 47 Eosinophil progenitors (EoP), 41 Eotaxin airborne allergens and seasonal variation, 16 cytokines and growth factors, 44 eosinophilopoiesis and eosinophil extravasation, 50 eotaxin–3, 314 epithelium, 89 IL–13, 88 lipid mediators, 46 tissue inflammation, 51 transcriptional regulation, 48, 49 Epidermal differentiation complex (EDC), 93, 99 Epithelial mesenchymal transition (EMT), 45, 57 Esophageal biopsy, 2, 3, 18, 29–30 Esophageal dilation, 404–405 anti-eosinophilic treatment, 290 anti inflammatory medications, 284 clinical algorithm, 294 clinical resolution, 286, 287

Index complication, 292–293 dysphagia, 286 elemental diets, 284 endoscopy, 291 eosinophilic infiltration, 288 esophageal remodeling, 283 esophageal stenosis, 289 guiding rules, 292 pathophysiology, 284–285 polyvinyl filiform dilator, 289 proton pump inhibitor, 283 Esophageal fibrosis and remodeling asthma, 85 children, 86 clinical implications history, 91 symptoms and endoscopy, 90 clinical symptoms, 84 epithelial eosinophilia, 83, 84 hypereosinophilic syndrome, 84 metaplasia, 85 pediatric patients, 86 potential target eotaxin–3 and CCR3 blockade, 94 IL–13, 93–94 TGFE1(beta), 94 pro-fibrotic factors IL–5, 87–88 IL–13, 88 inflammatory cells, 88–89 TGFE1 (beta), 86–87 structural cells epithelium, 89 fibroblasts, 89–90 therapeutic interventions anti-IL5, 92–93 corticosteroids, 91–92 esophageal dilation, 93 vascular changes, 90 Esophageal gastro-duodenoscopies (EGD), 29

F Feeding disorders, 386–387 behavioral presentation conditioned food aversion, 369 environmental contingencies, 370 etiological factors, 369 future aspects, 373 gastrointestinal disorders, 367 typical feeding development, 367–368 clinical presentations, 364–365 digestive tract factors, 364

Index growth and nutritional concerns, 365–366 incidence, 363 management behavioral, 372–373 medical, 371 nutrition, 371–372 Feline esophagus, 153, 160 Filaggrins, 19 First International Gastrointestinal Eosinophilic Research Symposium (FIGERS), 6–7, 366, 367 Fluconazole, 303 Fluticasone adult, 309 pediatric EoE, 302 Food Allergen Labeling And Consumer Protection Act (FALCPA), 336–337 Food allergy adverse reactions, 219, 220 behavioral feeding problems, 367 definition, 219 diagnosis APT, 230 IgE antiboby measurement, 229 OFC, 230, 231 principles, 228, 229 PST, 228 test, 231–232 eosinophilic esophagitis, 233 epidemiology, 221–222 history, 233 IgE-mediated disorder, 222–224, 227 immunologic response, 219 management, 232–233 non IgE-mediated disorder celiac disease, 226–227 contact dermatitis and dermatitis herpetiformis, 224 dietary protein enteropathy, 226 dietary protein proctocolitis/allergic eosinophilic proctocolitis, 224 FPIES, 225–226 Heiner’s syndrome/ milk-induced pulmonary hemosiderosis, 224 oral tolerance, 342 pathophysiology, 220–221 social stigma and dietary adherence, 390 Food Allergy And Anaphylaxis Network (FAAN), 338 Food antigens, 314 Food protein-induced enterocolitis syndrome (FPIES), 225–226 Forkhead box (FOXP3), 347

425 G Gastroesophageal reflux disease (GERD) acid reflux, 136 adults, 398 antioxidant effect, 139 barium esophagography, 148 biopsy, 193, 195 clinical implications, 140–141 contribution/causes EoE, 138 definition, 135 dysphagia, 123 EoE and EGIDs clinical presentation, 112 feeding/eating dysfunction, 114 EoE coexistence, 137 EoE contribution/causes, 137–138 EoE pathogenesis, 141–142 vs. eosinophilic esophagitis, 412–413 epithelial injury/stimulation, 136–137 inflammatory cell effect, 139–140 intraepithelial eosinophils, 136 PPI, anti-inflammatory effect, 138, 139 PPI therapy, 301 pro-inflammatory cytokines, 140 TGFE1, 87 vascular changes, 90 vomiting, 125 Gastrointestinal anaphylaxis, 223 Gastrointestinal mucosal eosinophils colon eosinophilia, 110 enumeration, 109 esophageal eosinophilia, 110 stomach and small intestine eosinophilia, 110 Gnathostoma spinigerum, 18

H Health-related quality of life (HRQL), 380–381 Heiner’s syndrome, 224 Helicobacter pylori, 18, 140 High power field (HPF), 109 Hygiene hypothesis, 18 Hypereosinophilic syndrome (HES), 52

I Idiopathic eosinophilic esophagitis, 1 Immune dysregulation, polyendocrinopathy, enteropathy, x-linked (IPEX) syndrome, 347 Industrialized/westernized disease, 36

426 Inflammation, 363 feeding disorders conditioned food aversions, 369 environmental contingencies, 370 infliximab, 355 Inflammatory bowel disease, 417 Infliximab, 355 Intercellular cell adhesion molecule–1 (ICAM–1), 140

L Lamina propria cell components, 193, 195 children and adult, 195 corticosteroids, 91 EoE transcriptome, 99 epithelium, 89 fibroblasts, 90 IL–5, 87, 196 periostin, 196 TGFE1, 87 TGFE (beta)–1 and phospho-SMAD2/3, 195–196 Left posterior oblique (LPO), 148 Low density lipoproteins (LDLs), 139 Lower esophageal sphincter (LES), 284 Lymphocyte chemoattractant factor (LCF), 51 Lymphocytes allergic phenotype, 74–75 EOE esophagus, 73 induction of EOE, 73–74 normal esophagus, 72–73 role, 78 Lysyl oxidase-like 4 (LOXL4), 100

M Major basic protein (MBP), 284 Maladaptive mealtime behaviors, 367 Mast cell activation, 76 EoE esophagus, 75–76 pathogenesis, 76–78 role, 78 Mepolizumab, 356–357 Metered dose inhaler (MDI), 309 Milk avoidance, 328–330 Milk-induced pulmonary hemosiderosis. See Heiner’s syndrome Mucosal eosinophilia. See also Gastrointestinal mucosal eosinophils EoE and EGIDs differences, 112–113

Index similarities, 113–114 pathophysiological mechanism colon eosinophilia, 112 eosinophil migration, 110 esophageal eosinophilia, 111 stomach and small intestine eosinophilia, 112 therapeutic implications, 114 Muscularis mucosa, 72, 83 Muscularis propria, 83

N National Health Interview Survey (NHIS), 240 National medical association, 8 Negative predictive value (NPV), 274 North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), 7 Nutritional management. See also Dietary treatment elemental diets dietary fiber, 332 enteral tube feeding, 332–334 financial considerations, 334–335 formulations, 331 micronutrient supplementation, 331 palatability, 332 elimination diet egg avoidance, 329 food allergens and substitutes, 327, 328 milk avoidance, 328–330 nutritional assessment, 326 soy avoidance, 329, 331 wheat avoidance, 329 food reintroduction, 335–336 label reading, 336–337 nutritional requirements, 326–327 patient education, 336 patient/family education, 337–338

O Omalizumab, IgE neutralization efficacy, 355 IgE binding, 354–355 mast and b cells, 354 Oral food challenge (OFC), 230 Oral immunotherapy (OIT), 348 Oral tolerance antigen processing, GI tract, 344–345 factors influencing, 349 allergen exposure route, 349 antigen properties, 348–349

Index genetic factors, 349–350 gut flora, 350 host factors, 349 food proteins, 342 mechanism, 342, 345–348 mucosal immunology dietary proteins and commensal bacteria, 343 gastrointestinal mucosa, 342 gut microbiota, 342, 344 IgA antibody, 342–343 T cell mediated inhibition, 343–344

P Pediatric eosinophilic esophagitis. See also Eosinophilic esophagitis (EoE) anti-IL–5 therapy, 304 clinical manifestation, 377–378 coping in families, 390–391 cromolyn sodium, 304 demographics and illness characteristics allergic disease, 378 clinical symptoms, 378–380 treatment, 380 dietary treatment, 299, 418 (see also Dietary treatment) EGD with biopsy, 417–418 immunomodulator therapy, 304 inflammatory bowel disease, 417 leukotriene receptor antagonists, 304 nutritional management (see Nutritional management) proton pump inhibitor therapy, 301–302 psychological adjustment, chronic illness abdominal pain, 388–389 age and developmental status, 386 anxiety, 385 coping strategy, 385 disease severity, 385–386 feeding disorders, 386–387 social stigma and adherence, 389–390 stresses, 385 tube feeding, 387–388 psychological care, 391–392 quality of life academic activities, 383 assessment, 380 chronically ill children, 383–384 emotional impact, 381–382 illness-related quality of life of caregivers, 384 preschool age children, 382–383

427 psychological status and stress level, 382 qualitative information, 381 social activities, 382 subjective perceptions, 381 symptom relapse, 418–419 topical steroids, 418 advantages, 302 bone disease and growth retardation, 303 budesonide, 302–304 dose formulations, 303 esophageal candidiasis, 303 fluticasone proprionate, 302, 303 Peripheral blood mononuclear cells (PBMCs), 75 Phytohemagglutinin (PHA), 75 Picture archiving and communications system (PACS), 148 Piecemeal degranulation (PMD), 54 Platelet activating factor (PAF), 45, 136 Pollen-food allergy syndrome, 223 Positive predictive value (PPV), 274 Prednisone, 284, 286, 298, 299, 303 Prick skin test (PST), 228 Proton pump inhibitor (PPI) anti-inflammatory effect, 138, 139 antioxidant effect, 139 clinical implications, 140–141 EoE pathogenesis, 141–142 inflammatory cells effect, 139–140 pro-inflammatory cytokines, 140 therapy, 301–302 Proxy QOL, 381

Q Quality of life (QOL) academic activities, 383 assessment, 380 chronically ill children, 383–384 emotional impact, 381–382 illness-related quality of life of caregivers, 384 preschool age children, 382–383 psychological status and stress level, 382 qualitative information, 381 social activities, 382 subjective perceptions, 381

R Radioallergosorbent test (RAST), 228, 316 Reactive oxygen species (ROS), 42

428 Recommended Dietary Allowances (RDAs), 326, 327 Regulatory T cells Reslizumab, 357 Right anterior oblique (RAO), 148 Ringed esophagus congenital esophageal stenosis, 152, 158 feline esophagus, 153, 160 fixed transverse folds, 152, 159 multiple distinctive, 151, 155 Schatzki ring, 151, 157 subtle, 151, 156

S Schatzki ring, 151, 157, 172 Schistosoma mansoni, 54 Seasonal/perennial disease, 35–36 Several small proline-rich repeat (SPRR), 99 Single nucleotide polymorphism (SNP), 100 Six food elimination diet, 317–318 Skin prick testing (SPT), 316–317, 325 antigen sensitization, 272–273 environmental, 263–264 food, 259, 260 food-specific IgE antibodies, 220 Small-caliber esophagus, 171 caliber loss, 153, 161 distensibility loss, 153, 161 radiograph, 154 Solid food dysphagia, 309 Soy avoidance, 329, 3331 Specific granule deficiency (SGD), 49 Squamous epithelium, 83 Steroids therapy, 353–354. See also Corticosteroids Swallowed steroid therapies. See Topical steroids Systemic corticosteroids, 299, 308–309, 414

T The International Gastrointestinal Eosinophilic Researchers (TIGERS), 7 Thymic stromal lymphopoietin (TSLP), 101–102, 177

Index Tissue biopsy, 46 Tissue inflammation corticosteroids, 53 diurnal variation, 50–51 eosinophil interactions, 53 E-selectin, 51 factors, 52 hypersensitivity reaction, 50 sulfidopeptide leukotrienes, 51 Tissue inhibitor of metalloproteinases (TIMPs), 57 Tissue injury, adults, 398 TNF-D antagonists, 355 Topical steroids, 299 adult, 310 budesonide, 310–311 fluticasone, 309 vs. systemic corticosteroids, 309–310 pediatric eosinophilic esophagitis, 418 advantages, 302 bone disease and growth retardation, 303 budesonide, 302–304 dose formulations, 303 esophageal candidiasis, 303 fluticasone proprionate, 302, 303 Tracheo-esophageal fistula (TEF), 123 Tube feeding, 373, 387–388

U Urticaria, 222

V Vascular cell adhesion molecule–1 (VCAM–1) corticosteroids, 91–92 epithelial injury/stimulation, 136 inflammatory cells, 140 tissue inflammation, 51 vascular changes, 90

W Wheat avoidance, 329