Why Was the Consortium of Eosinophilic Gastrointestinal Disease Researchers Established?
There has been a surge of interest in the study of eosinophilic gastrointestinal disorders (EGIDs) in recent years, especially owing to the increasing recognition and prevalence of EGIDs and other allergic conditions. Furthermore, there are many unanswered questions regarding the diagnosis and management of EGIDs including the critical absence of any therapies approved by the US Food and Drug Administration.1 The unifying feature of EGIDs is eosinophil-predominant inflammation of the gastrointestinal tract. Under healthy conditions, eosinophils account for a small fraction of peripheral blood leukocytes and resident tissue cells, but accumulate in large numbers in the blood and/or tissues in patients with EGIDs.2 Diagnosing EGIDs can be a challenge for 3 primary reasons. First, pathologic involvement of EGIDs most likely extends beyond the gastrointestinal epithelium, but the depth of involvement is often difficult to ascertain owing to the limits of endoscopically obtained biopsies. Second, the diagnosis of eosinophilic gastritis (EG), eosinophilic gastroenteritis, and eosinophilic colitis (EC) may be confounded by resident eosinophils present in non-diseased gastrointestinal mucosa.3,4 Finally, increased numbers of mucosal/epithelial eosinophils are not pathognomonic for eosinophilic esophagitis (EoE), eosinophilic gastroenteritis, or EC, because mucosal eosinophilia also arises in a number of other conditions, including reflux esophagitis, parasitic infestations, rheumatologic conditions, and inflammatory bowel disease.5
Because these disorders are rare, collaboration is essential to advance the field and the Consortium of Gastrointestinal Eosinophilic Disease Researchers (CEGIR) was established and funded in 2014 by the National Institutes of Health (NIH) to address these disorders. The mission of CEGIR is to improve the lives of individuals with EGIDs through innovative research, clinical expertise, and education via collaborations among scientists, health care providers, patients, and professional organizations (Figure 1). This commentary highlights the work of CEGIR to date and how it is addressing various facets of EGIDs including clinical, social, financial, and medical burdens, diagnostic criteria, disease pathogenesis, and treatment regimens.
Figure 1.
Structure of the Consortium of Gastrointestinal Eosinophilic Disease Researchers. NCATS, National Center for Advancing Translational Science; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NIH, National Institutes of Health.
CEGIR Contributions
CEGIR, a multicenter clinical research program focused on EGIDs, was first formed as part of the Rare Diseases Clinical Research Network (RDCRN) (U54 AI117804) from the NIH through the Office of Rare Diseases Research, the National Center for Advancing Translational Science, and funded by collaborative efforts of the National Center for Advancing Translational Science, the National Institute of Allergy and Infectious Diseases, and the National Institute of Diabetes and Digestive and Kidney Diseases.6,7 To address the various facets of EGIDs, multiple components of CEGIR were created, each featuring multicenter collaborations, the accomplishments of which are highlighted herein.
Clinical Research Projects
With the aim to develop best outcome metrics for EGIDs and bring newer diagnostics and therapeutics to patients, CEGIR is conducting 2 large clinical research projects. The Outcome Measures for Eosinophilic Gastrointestinal Diseases across Ages (OMEGA) is an observational, prospective, multicenter study of the clinical, endoscopic, histologic, molecular, and patient-reported outcomes (PROs) in pediatric and adult patients with EGIDs, namely, EoE, EG, and EC, and is focused on defining the natural history of EGIDs (Figure 2). The underlying hypothesis is that there will be patient-reported and clinical outcome metrics in children and adults that will align with inflammation and molecular gene profiles. More than 739 patients have been enrolled with multiple clinical datapoints and >5000 biospecimens have been collected to date, providing a rich repository of data that would have been nearly impossible to achieve by any single center. The majority of patients have EoE, with smaller but substantial subsets of patients with EG and EC; a number of interesting observations have already emerged from the cohort. Although EoE is male predominant, EG and EC are less so. Three EoE endotypes (termed EoEe-1, -2, and -3) have been identified based on probing esophageal biopsies from pediatric and adult EoE subjects from CEGIR sites using the EoE Diagnostic Panel, a set of 95 informative transcripts.8 EoEe-1 is strongly associated with a normal-appearing esophagus and is characterized by relatively mild histologic, endoscopic, and molecular changes. EoEe-2 demonstrates an inflammatory and steroid-refractory phenotype that is characterized by the highest expression of cytokines and steroid-responding genes. EoEe-3 correlates with a narrow-caliber esophagus and showed the greatest degree of endoscopic and histologic severity and the lowest expression of epithelial differentiation genes. In addition, EoEe-3 is more aligned with adult-onset disease, whereas EoEe-2 is associated with pediatrics and an atopic response, and EoEe-1 may represent a more benign disease phenotype. These endotypes have the potential to allow for the personalization of EoE-specific therapy, as well as providing prognostic information in the future. As such, CEGIR is primed to answer longitudinal questions that enhance our understanding of EGIDs (Table 1).
Figure 2.
Collection of biospecimens for the Consortium of Gastrointestinal Eosinophilic Disease Researchers. EC, eosinophilic colitis; ED, eosinophilic gastritis; EoE, eosinophilic esophagitis.
Table 1.
CEGIR: Contributions to the Field, and Lessons Learned
| Benefit | Comment |
|---|---|
| Funding | $1.25 million of annual funding is provided by the NIH |
| Collaborations | Enhanced collaboration among investigators and patient advocacy groups |
| Leverages other funding mechanisms | Cofunding provided by select institutions and PAGs |
| Unifies different stakeholders within the field | Brings together pediatric and adult gastroenterologists, allergists, pathologists, basic science investigators, NIH Institute Centers, and PAGs |
| Interaction with other consortia in network | Sharing of research platforms across sites |
| Data management and coordination | RDCRN provides this service as part of the participation The DMCC allows CEGIR to leverage a number of services not normally available to stand-alone grants |
| Support for trainees | Trainees benefit from participating in CEGIR clinical studies, can use CEGIR generated research resources and can participate in RDCRN wide training programs |
| Provides infrastructure upon which other studies are built | Registries provide resource for other studies |
| Partnership and Engagement of Expertise of NIH | The U54 grant mechanism is a cooperative agreement and benefits from interaction with NIH experts including Medical Officer, Project Scientist, Program Officers, DSMB, and others |
| Develops uniform processes and consensus opinions and approaches | Examples include central pathology review, standard operating manual for common procedures such as skin testing |
CEGIR, Consortium of Gastrointestinal Eosinophilic Disease Researchers; DMCC, Data Monitoring Coordinating Center; DSMB, Data Safety Monitoring Board; NIH, National Institutes of Health; PAG, patient advocacy groups; RDCRN, Rare Disease Clinical Research Network.
Furthermore, during OMEGA, subjects with EoE and their parents have been queried for baseline patient symptoms and quality of life (QOL) using the Pediatric Eosinophilic Esophagitis Symptom Score version 2, Pediatric QOL EoE module; biopsies were analyzed using the EoE histology scoring system (EoEHSS).9 This study found that parents of children with EoE accurately reflect their children’s disease symptoms and QOL and that self- and parent-reported symptoms correlate with proximal but not distal esophageal histology. These findings from CEGIR suggest that parent reports in young children can function as an adequate marker for PROs and that self-reported symptoms may reflect changes in tissue histology in the proximal esophagus. As such, new end points, novel PROs, and considerations for monitoring patients during clinical care and clinical trials are now being considered.9
Other findings emerging from OMEGA include:
Pediatric and adult EoE are molecularly, immunologically, and cellularly similar and as such can use similar treatments including diet, topical steroids, and emerging biological agents.
The endoscopic scoring system shows a strong correlation with esophageal eosinophil levels, and also epithelial hyperplasia.
Individuals affected by EGIDs have a constellation of complex unmet needs and perceived barriers across medical, health care, social, and emotional domains. For example, only 19% indicate that repeated endoscopies to monitor response to treatment was convenient; 67% of individuals lack appropriate levels of insurance coverage for elemental formula; and only 5% of respondents reported adequate awareness of EGIDs in schools.
The second clinical project, the Six Food versus One Food Eosinophilic Esophagitis Elimination Diet (SOFEED), is a randomized, interventional clinical trial of 6 food (SFED) versus 1 food (1FED [milk]) elimination diet as well as the effectiveness of changing therapy in the case of treatment failure (from 1FED to SFED or from SFED to swallowed topical fluticasone (880 μg twice daily) in adults with EoE. This trial was also designed to examine potential predictive markers of treatment response, including multiple forms of allergy testing (skin prick, specific IgE, IgG4, patch testing, and component resolved diagnostic testing), clinical phenotypes, and assessment of milk-specific T cells. Potential molecular markers will also be assessed in the esophageal transcriptome as well as blood and saliva. To date, 111 patients (accrual goal, 120 patients) have enrolled in this study, making it the single largest dietary interventional study in EoE. Lessons learned include how to successfully educate the study and clinical staff spread nationwide on a uniform dietary intervention trial and the generation of standardized and vetted dietary education materials that will be available for clinical use in the future. This study has the potential to change the way we treat EoE as it examines the response rate to a minimally restrictive (milk elimination alone) diet (1FED) and factors associated with responsiveness, compared with the standard SFED, topics which have been deemed to be important by the patient advocacy groups (PAGs) and the patient community.
Pilot Studies
The goal of the pilot feasibility studies is to examine new ideas that have the potential to create and/or change paradigms concerning EGIDs. To date, 4 pilot studies have been funded and implemented. These studies address novel concepts, such as the potential use of losartan in EoE, advancing the understanding of the microbiome in EGIDs, elemental dietary management of EG, and transnasal endoscopy as a less-invasive means to monitor EoE. These projects are in various stages of completion and their outputs will impact the care of patients with EGID at multiple points, including pathogenesis, evaluation, and treatment.
Training and Career Development
The goal of the training and career development section of the CEGIR is to encourage and train younger investigators in the field of EGIDs and facilitate their networking and integration into the EGIDs research community, with the eventual goal of developing a cadre of independent investigators. To date, 8 scholars, from both adult and pediatric gastroenterology and allergy, both within the United States and internationally, including under-represented minorities and women, have become part of CEGIR. The scholars are pursuing a wide range of projects under direct mentorship of dedicated senior CEGIR members. These projects encompass clinical and translational research topics, including studies related to eosinophil biology, the role of mast cells in EGIDs, esophageal distensibility in EoE, and the demographics and clinical presentation of various subsets of patients with EGIDs. This training program has already been quite successful, leading to 23 peer-reviewed publications, additional grant funding of >$4.6 million, including an NIH-funded R01 independent investigator award, and, most important, retention of all scholars in EGIDs research. The training core has also developed 20 on-line educational videos by experts in EGIDs and patient advocacy group (PAG) leadership that are available to the medical community at large at www.rarediseasesnetwork.org/cms/cegir/Learn-More/Educational-Videos.
Pathology
With histopathology being central to the diagnosis of EGIDs, a pathology core was created and has been quite productive. The core uses whole slide imaging for central pathology review, mitigating the need for mailing thousands of slides to the central pathologists. Slides are transferred and stored using cloud technology. A novel histology scoring system (EoEHSS) has been defined based on scoring of 8 pathologic features, including eosinophil density/eosinophil inflammation, eosinophil abscesses, eosinophil surface layering, basal zone hyperplasia, dilated intercellular spaces surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis.10 EoEHSS has proven to be superior to the evaluation of eosinophil density alone in the diagnosis and monitoring of EoE, especially in determining the extent and degree of tissue damage. Multi-institutional collaborations occurring in CEGIR are building consensus recommendations for the histopathologic diagnosis of non-EoE EGIDs, because none currently exist, and to further develop a useful histologic scoring system for disease diagnosis, progression, and the clinical management of patients.11
Moving the Field Forward
An important strength of CEGIR is the development and use of common outcome metrics, which are central to the success of a multicenter effort and also important to improve the delivery of care for patients with EGID. Additionally, study monitoring and data management oversight by the NIH and the Data Monitoring Coordinating Center optimizes data collection and quality. Other roles of the CEGIR include addressing multiple unmet needs in the field. Currently, an EoE diagnosis requires invasive testing with esophagogastroduodenoscopy. CEGIR investigators are pioneering the use of less invasive transnasal endoscopic techniques, particularly in children. In addition, results of the longitudinal OMEGA study have already helped to defined various endotypes of EoE and alternate PROs for future use. Further OMEGA data will inform diagnostic algorithms for EG and EC, and improve the knowledge related to correlations between clinical outcome measures such as PRO instruments, histologic measures, and molecular features such as gene expression.10 Data from OMEGA will also yield an endoscopic severity measure for gastric findings in patients with EG, and promote consistency in evaluation and outcomes reporting. The SOFEED trial contributes to options for dietary therapy by comparing a less restrictive diet (dairy elimination only) to the more conventional 6-food elimination diet. The ELEMENT pilot study, which is treating patients with EG with elemental amino acid-based formula based on preliminary data by CEGIR investigators13 is the first prospective investigation of dietary therapy in EG.
Members of CEGIR have also partnered with PAGs to develop and disseminate instruments to formally assess EGID needs from a patient/caregiver perspective.12 Key areas identified included the burden of multiple endoscopies to monitor disease activity, the burden of high health care costs, lack of insurance coverage for elemental formula, poor awareness of EGIDs, difficulty getting accommodations in school, and significant stress owing to the condition, among many others. This partnership with PAGs and patient-based identification of areas of need allows CEGIR investigators to focus ongoing and future research endeavors on those issues most important to patients. In addition, a highly visible and widely accessed contact registry for patients with EGIDs was created under CEGIR and to date has >1450 subjects (www.rarediseasesnetwork.org/cms/cegir/Get-Involved/Contact-Registry). The CEGIR website has the second highest number of website visits among the 21 Rare Diseases Clinical Research Network consortia, averaging 835 visits per month.
Ultimately, at the heart of this collaboration is the underlying mission of CEGIR to use the research gained from these studies to improve the lives of our patients with EGIDs and promote Clinical Trial Readiness through multiple avenues including defining endpoints, such as PRO, QOL, endoscopic scoring systems, and EoEHSS. By partnering with dedicated researchers, the NIH, and PAGs, CEGIR is optimally positioned to accomplish these important aims and get us closer to the finish line.
Acknowledgments
CEGIR (U54 AI117804) is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. CEGIR is also supported by patient advocacy groups including APFED CURED and EFC.
Conflicts of interest
The authors have made the following disclosures: Dr Aceves reports grants from the National Institutes of Health (NIH), and oral viscous budesonide, a UCSD patented licensed to Shire Pharma, and is a consultant for Regeneron. Dr Chehade received research funding from the NIH, PCORI and Nutricia, consulting fees from Shire and Allakos, and clinical trial funding from Regeneron and Shire. Dr Collins reports grants from the NIH, during the conduct of the study; grants from Shire and grants from Regeneron, outside the submitted work. She is also Chair of the Medical Advisory Panel of the American Partnership for Eosinophilic Disorders (APFED) and an Executive Committee member of The International Group of Eosinophil Researchers (TIGERS). Dr Dellon reports grants and personal fees from Adare, Banner, Celgene/Receptos, GSK, Regeneron, and Shire; personal fees from Alivio, Allakos, AstraZeneca, Enumeral, and Robarts Clinical Trials; grants from Meritage, Miraca, Nutricia, and Holoclara. Dr Falk reports grants and personal fees from Shire, ADARE, and Regeneron; personal fees from Banner Bioscience; and grants from Allakos and Celgene, outside the submitted work. Dr Furuta reports other from EnteroTrack, Shire, and UpToDate, outside the submitted work. Dr Gonsalves has royalties from UpToDate. Dr Gupta reports personal fees from Adare, Allakos, Abbott, Receptos, and QOL; and grants from Shire, outside the submitted work. Dr Hirano reports grants and consultant fees from Adare, Shire, Regeneron, and Receptos. Dr Mukkada reports grants from the NIH; grants and personal fees from Shire Pharmaceutical, outside the submitted work. Dr Peterson has nothing to disclose. Dr Rothenberg reports grants from the NIH, US-Israel Binational Grant, and PCORI; ch; equity in Immune Pharmaceuiticals, PulmOne, and Spoon Guru; and personal fees from Glaxo Smith Kline, Merck, Allakos, AstraZeneca, Genetech, Celgene, and Regeneron; in addition, Dr Rothenberg receives royalties from UpToDate and reslizumab (Teva Pharmaceuticals). Dr Spergel reports grants and personal fees from DBV Technologies, grants from End Allergy Together, Food Allergy Research Education and Aimmune Therapeutics; personal fees from UpToDate, Regeneron, and personal fees from Shire, outside the submitted work. Dr. Yang has nothing to disclose. All other authors have nothing to disclose.
Other members of CEGIR Principal Investigators Group are J. Pablo Abonia, Cincinnati; Peter Bonis, Boston, John Leung, Boston; David Katzka, Rochester, MA; Paul Menard-Katcher, Denver.
Contributor Information
SANDEEP K. GUPTA, Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Illinois College of Medicine, and Children’s Hospital of Illinois, Peoria, Illinois
GARY W. FALK, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
SEEMA S. ACEVES, Division of Allergy Immunology, University of California-San Diego, San Diego, California
MIRNA CHEHADE, Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York, New York.
MARGARET H. COLLINS, Division of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
EVAN S. DELLON, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
NIRMALA GONSALVES, Division of Gastroenterology & Hepatology, Northwestern University, Chicago, Illinois.
IKUO HIRANO, Division of Gastroenterology & Hepatology, Northwestern University Chicago, Illinois.
VINCENT A. MUKKUDA, Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical, Cincinnati, Ohio
KATHRYN A. PETERSON, Division of Gastroenterology, University of Utah School of Medicine, Salt Lake City, Utah
JONATHAN SPERGEL, Division of Allergy and Immunology, University of Pennsylvania Perelman School of Medicine/Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
GUANG-YU YANG, Department of Pathology and Laboratory Medicine, Northwestern University, Chicago, Illinois.
GLENN T. FURUTA, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children’s Hospital Colorado and Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
MARC E. ROTHENBERG, Division of Allergy and Immunology, Department of Pediatrics, University of Cincinnati College of Medicine/Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
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