Eosinophilic Esophagitis

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 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. Because PPI responsive esophageal eosinophilia has largely overlapping clinical, histological and molecular characteristics with PPI-resistent esophageal eosinophilia, but entities are referred to as EoE and usage of PPIs is now considered a treatment of EoE. 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 family members is <5% unless they are twins with the EoE patient. Several genes have been identified to contribute to EoE including CAPN14 and TSLP. A fundamental step in the development of EoE is loss of esophageal barrier function which is mediated by loss of anti-proteases such as SPINK7 and desmosomal proteins such as desmoglein-1 and dysregulated expression of the CAPN14 gene product (calpain-14).

The frequency of eosinophilic esophagitis has been estimated to be approximately 1 in 2,000 individuals. This condition has been reported in multiple continents including Europe, Australia, and America.

Symptoms of the following disorders are similar to those of eosinophilic esophagitis. Comparisons may be useful for a differential diagnosis:

Gastroesophageal reflux disease (GERD) is a digestive disorder characterized by reflux of the contents of the stomach or small intestines into the esophagus. Symptoms of gastroesophageal reflux may include a sensation of warmth or burning rising up to the neck area (heartburn or pyrosis), swallowing difficulties (dysphagia), and chest pain. This condition is a common problem and may be a symptom of other gastrointestinal disorders.

Ulcerative colitis is an inflammatory bowel disease (IBD) of unknown cause. It is characterized by chronic inflammation and ulceration of the lining of the major portion of the large intestine (colon). In most affected individuals, the lowest region of the large intestine, known as the rectum, is initially affected. As the disease progresses, some or the entire colon may become involved. Although associated symptoms and findings usually become apparent during adolescence or young adulthood, some individuals may experience an initial episode between 50 and 70 years of age. In other cases, symptoms may occur as early as the first year of life. (For more information about this condition, choose “ulcerative colitis” as your search term in the Rare Disease Database.)

Crohn’s disease is an inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or any portion of the gastrointestinal tract. The lower portion of the small intestine (ileum) and the rectum are most commonly affected by this disorder, but the esophagus can also be involved. Symptoms may include watery diarrhea, abdominal pain, fever, and weight loss. The exact cause of Crohn’s disease is unknown.

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.

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 divides patients into different subgroups, referred to as endotypes.

Treatment
Many children and adults with EoE show improvement with proton pump inhibitor therapy, as well diet modification 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.

In 2022, dupilumab (Dupixant) was approved by the U.S. Food and Drug Administration (FDA) to treat adults and children 12 years and older with EoE. This is the first FDA approved treatment for EoE.

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-13, and clinical studies with antibodies that block this cytokine as well as its receptor (IL-4Ra, which is also shared with IL-4) are in advanced stages. Additional research is being done on eosinophil growth factor (IL-5 using reslizumab or mepolizumab) as an off-label targeted treatment. Eosinophil depleting antibodies are also now available, including benralizumab (now approved for eosinophilic asthma) as well as AK002 (in development). These medications have not yet been FDA approved for EoE, but early clinical trials look very promising.

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 Network (RDCRN), supported by the National Institute of Health through the National Center for Advancing Translational Science (NCATS). CEGIR is funded by NCATS, the National Institute of Allergy and Infectious Disease (NIAID), the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), 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 pilot studies testing new hypotheses concerning EGID. A key mission of CEGIR is to train the next generation of physicians so they have expertise in EGID.

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: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

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/

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
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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.

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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

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