NORD gratefully acknowledges Marc E. Rothenberg, MD, PhD, Director of the Division of Allergy and Immunology, and The Cincinnati Center for Eosinophilic Disorders, Professor of Pediatrics, Dave and Denise Bunning Endowed Chair of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, for assistance in the preparation of this report.
Eosinophilic esophagitis (EoE) is a chronic disorder of the digestive system in which large numbers of a particular type of white blood cell called eosinophils are present in the esophagus. The esophagus is the tube that carries food from the mouth to the stomach. Eosinophils are an important part of the immune system and play a role in immune regulation and fighting certain infection, and their accumulation is a hallmark of allergic diseases. This condition is characterized by vomiting, stomach or chest pain, failure to thrive (particularly in children), difficulty swallowing, and food getting stuck in the throat.
The symptoms of eosinophilic esophagitis are variable, especially in people of different ages. Common symptoms include difficulty swallowing (dysphagia); food getting stuck in the throat (impaction); nausea; vomiting; poor growth; weight loss; stomach pain; poor appetite; and malnutrition. Because of an overlap of these symptoms with gastroesophageal reflux disease (GERD), many patients are initially thought to have GERD, but EoE patients do not typically respond to anti-GERD therapy and can be found not to have GERD upon diagnostic workup. Recently, it has been appreciated that some patients with pronounced esophageal eosinophilia can have complete responses to proton pump inhibitor (PPI) therapy, typically used for the treatment of GERD, but these patients with PPI responsive esophageal eosinophilia (PPI-REE) do not typically have GERD but rather a disease variant similar to EoE; the PPI appears to exert its effects by direct action rather than blockade of stomach acid alone. Individuals with eosinophilic esophagitis often have allergic diseases such as asthma or eczema.
Eosinophilic esophagitis is caused by the presence of a large number of eosinophils in the esophagus. The production and accumulation of eosinophils may be caused by many factors such as immune hypersensitivity responses to particular foods or environmental proteins (allergens) in some affected individuals. Some individuals with this condition have been found to have an unusually high expression of a particular gene called eotaxin-3. This gene codes for a protein that is important in controlling the accumulation of eosinophils. Eosinophilic esophagitis can run in families but the risk for additional families members is <5% unless they are twins with the EoE patient. Several genes have been identified to contribute to EoE including CAPN14 (at chromosome 2p23) and TSLP (at chromosome 5q22).
The frequency of eosinophilic esophagitis has been estimated to be approximately 1 in 1,000 children. This condition has been reported in multiple continents including Europe, Australia, and America.
The diagnosis of eosinophilic esophagitis is often delayed because of a lack of awareness of this condition. A small tube is inserted through the mouth into the esophagus (upper endoscopy) and small tissue samples are removed (biopsy) in order to count eosinophils, and look for tissue injury and thickening of tissue. If a diagnosis of EoE is made, allergy testing is usually then performed to determine if particular foods or environmental agents trigger esophageal symptoms or are contributing to other allergic problems.
Elevated expression of eotaxin-3 is part of a whole panel of dysregulated genes expressed by the esophagus of EoE patients, termed the “EoE transcriptome” which can now be used to diagnosis and test for EoE through a test called EoEgenius assay which is now commercially available via http://www.eogenius.com/.
Treatment
Many children and adults with EoE show improvement if the diet is modified so that allergenic food is removed, most commonly milk, egg, soy, wheat, nuts and fish. Some affected individuals require a liquid formula diet fed through a feeding tube. Steroid medications are often used to control inflammation if dietary changes alone are not sufficient. Additional endoscopies and biopsies are usually necessary to monitor the effectiveness of treatment.
Research is underway to develop medications to block the proteins produced as a result of the EoE transcriptome and the tissue inflammation. In addition, research is in progress concerning the role of Interleukin-5, an eosinophil growth factor, as drugs that block this protein reduce eosinophil levels and their activation and are now FDA approved for the treatment of eosinophilic asthma. The possibility of using anti-IL-5, and other anti-cytokine antibodies (such as anti-IL-13) in the form of humanized antibodies are promising strategies currently being tested. Companies involved in this research include GlaxoSmithKline, Teva Pharmaceuticals, Celgene, Regeneron and Shire.
A major advance in EoE is the formation of the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR), which is part of the Rare Diseases Clinical Research Center Network (RDCRN), supported by the National Institute of Health through the National Center for Advancing Translational Science (NCATS). CEGIR is directly funded by NCATS, as well as two other NIH institutes, the National Institute of Allergy and Infectious Disease (NIAID) and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), as well as funds from the American Partnership for Eosinophilic Disorders (APFED) and the Campaign Urging Research for Eosinophilic Disorders (CURED). CEGIR aims to improve the lives of individuals with eosinophilic gastrointestinal disease (EGID) through innovative research, clinical expertise and education via collaboration between scientists, health care providers, patients and professional organizations. CEGIR also carries out a series of pilot studies testing new hypotheses concerning EGID. A key mission of CEGIR is to train the next generation of physicians with expertise in EGID through its training program. Educational material and full description is available through the CEGIR website.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Davis BP, Rothenberg ME. Mechanisms of disease of eosinophilic esophagitis. Annu Rev Pathol. 2016 May 23; 11:365-93
Rothenberg ME. Humanized anti-IL-5 antibody therapy. Cell. 2016;165:509.
Davis BP, Stucke EM, Khorki ME, Litosh VA, Rymer JK, Rochman M, Travers J, Kottyan LC, Rothenberg ME. Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment. JCI Insight 2016; 1:e86355.
Wen T, Dellon ES, Moawad FJ, Furuta GT, Aceves SS, Rothenberg ME. Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. J Allergy Clin Immunol. 2015;135:187-97.
Rothenberg ME. Molecular, genetic, and cellular bases for treating eosinophilic esophagitis. Gastroenterology. 2015;148:1143-57.
Molina-Infante J, Bredenoord AJ, Cheng E, Dellon ES, Furuta GT, Gupta SK, Hirano I, Katzka DA, Moawad FJ, Rothenberg ME, Schoepfer A, Spechler S, Wen T, Straumann A, Lucendo AJ. Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut. 2015; 65:524-31.
Kottyan LC, Davis BP, Sherrill JD Liu K, Rochman M, Kaufman K, Weirauch MT, Vaughn S, Lazaro S, Rupert AM, Kohram M, Stucke EM, Kemme KA, Magnusen A, He H, Dexheimer P, Chehade M, Wood RA, Pesek RD, Vickery BP, Fleischer DM, Lindbad R, Sampson HA, Mukkada VA, Putnam PE, Abonia JP, Martin LJ, Harley JB, Rothenberg ME. Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease. Nat Genet. 2014;46:895-900.
Alexander ES, Martin LJ, Collins MH, Kottyan LC, Sucharew HJ, He H, Mukkada VA, Succop PA, Pablo JP, Foote H, Eby MD, Grotjan TM, Greenler AJ, Dellon ES, Demain JG, Furuta GT, Gurian LE, Harley JB, Hopp RJ, Kagalwalla A, Kaul A, Nadeau KC, Noel RJ, Putnam PR, von Tiehl KF, Rothenberg ME. Twin and family studies reveal strong environmental and weaker genetic cues that explain high heritability of eosinophilic esophagitis. J Allergy Clin Immunol. 2014;134:1084-92.e1
Scheeren FA, Kuo AH, van Weele LJ, Cai S, Glykofridis I, Sikandar SS, Zabala M, Qian D, Lam JS, Johnston D, Volkmer JP, Sahoo D, van de Rijn M, Dirbas FM, Somlo G, Kalisky T, Rothenberg ME, Quake SR, Clarke MF. A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. Nat Cell Biol. 2014;16:1238-48
Henderson CJ, Abonia JP, King EC, Putnam PE, Collins MH, Franciosi JP, Rothenberg ME.Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2012;129:1570-8.
Bochner BS, Book W, Busse WW, Butterfield J, Furuta GT, Gleich GJ, Klion AD, Lee JJ, Lieferman KM, Minnicozzi M, Moqbel R, Rothenberg ME, Schwartz LB, Simon HU, Wechsler ME, Weller PF.Workshop report from the National Institutes of Health Taskforce on the Research Needs of Eosinophil-Associated Diseases (TREAD). J Allergy Clin Immunol. 2012:130:587-96.
Rothenberg ME, Aceves S, Bonis PA, Collins MH, Gonsalves N, Gupta SK, Hirano I, Liacouras CA, Putnam PE, Spergel JM, Straumann A, Wershil BK, Furuta GT. Working with the US Food and Drug Administration: progress and timelines in understanding and treating patients with eosinophilic esophagitis. J Allergy Clin Immunol. 2012;130:617-9.
Sherrill JD, Rothenberg ME.Genetic dissection of eosinophilic esophagitis provides insight into disease pathogenesis and treatment strategies. J Allergy Clin Immunol. 2011;128:23-32; quiz 33-4.
DeBrosse CW, Franciosi JP, King EC, Butz BK, Greenberg AB, Collins MH, Abonia JP, Assa’ad A, Putnam PE, Rothenberg ME. Long-term outcomes in pediatric-onset esophageal eosinophilia. J Allergy Clin Immunol. 2011;128:132-8.
Liacouris C, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: Updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128:3-20
Rothenberg ME. Biology and treatment of eosinophilic esophagitis. Gastroenterology. 2009;137:1238-1249.
Blanchard C, Wang N, Stringer, et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J Clin Invest. 2006;116:536-547.
Rothenberg ME. Eosinophilic gastroentestinal disorders (EGID). J Allergy Clin Immunol. 2004;113:11-28.
Noel RJ, Putman PE, Rothenberg ME. Eosinophilic esophagitis N Engl J Med. 2004;351:940-941.
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;125:1660-1669.
Cheung KM, Oliver MR, Cameron DJ, et al. Esophageal eosinophilia in children with dysphagia J Pediatr Gastroenterol Nutr. 2003;37:498-503.
Fox VL, Nurko S,Furuta GT. Eosinophilic esophagitis: it’s not just kid’s stuff. Gastrointest Endosc. Gastrointest Endosc. 2002;56(2):260-70.
Orenstein SR, et al. The spectrum of pediatric eosinophilic esophagitis beyond infancy: a clinical series of 30 children. Am J. Gsstroenterol. 2000;95:1422-1430.
Walsh SV, et al. Allergic esophagitis in children: a clinicopathologicl entity Am J Surg Pathol. 1999;23:390-396.
Kelly KJ, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with amino acid-based formula. Gastroenterology. 1995;109:1503-1512.
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