Abstract: The eosinophilic gastrointestinal diseases (EGIDs) are a group of chronic, immune-mediated gastrointestinal (GI) diseases characterized by GI symptoms and pathologic eosinophilic infiltration of specific areas within the GI tract in the absence of secondary causes of eosinophilia. The non–eosinophilic esophagitis EGIDs remain understudied and likely underdiagnosed, owing in part to the lack of clarity in the terminology previously used to describe these diseases. The newly established EGID nomenclature framework includes a first-tier description of the specific location of GI tract involvement and a second-tier description with more granular characterizations of disease involvement. EGIDs can involve any segment or layer of the GI tract, so patients can present with a wide array of common, nonspecific GI symptoms. Diagnosing EGIDs requires endoscopic evaluation and biopsies showing increased eosinophilic tissue infiltration in the correct clinical context after ruling out other causes of eosinophilia. Although the pathogenesis is not yet fully understood, EGIDs are likely allergic conditions triggered by food antigen exposure. Most patients are currently treated with corticosteroids, but investigations of other pharmacologic and dietary therapies are ongoing. This article highlights the recently updated EGID nomenclature and summarizes the current understanding of the diagnosis, pathogenesis, and treatment of EGIDs.
The eosinophilic gastrointestinal diseases (EGIDs) are a group of gastrointestinal (GI) diseases characterized by GI symptoms and pathologic eosinophilic infiltration of specific areas within the GI tract in the absence of secondary causes of eosinophilia.1 These conditions are considered to be chronic, immune-mediated disorders that may be linked to food allergen exposure.2-4 Although eosinophilic esophagitis (EoE) is the most common EGID, there is an increasing recognition of other EGIDs involving other areas of the GI tract.5,6 In 1937, Kaijser reported a case of eosinophilic gastritis (EoG), which is considered the first EGID described in the literature.7 Since the first report of EoE in 1978, the literature describing the pathophysiology, diagnosis, and management of EoE has grown significantly; however, other EGIDs have remained relatively understudied.8
Describing and naming specific EGIDs can be challenging because they can involve multiple areas and depths of the GI tract, and there is substantial variability in the terminology used. This has presented practical challenges and has limited advances in the collective understanding of these diseases. A recent effort by an international group of clinicians and researchers has arrived at a consensus on an updated framework for EGID nomenclature to help improve patient care and inform further research efforts.2 In addition to highlighting this updated nomenclature, this article will provide an overview of the current understanding of the diagnosis, pathogenesis, and treatment of EGIDs.
New Nomenclature
To understand and diagnose a group of diseases, clarity in terminology and nomenclature is of utmost importance. Previously, there was no consensus on how to refer to the non-EoE EGIDs. The catchall term eosinophilic gastroenteritis was frequently used, but this term has often been employed without delineating the involved part of the GI tract. Therefore, a more systematic method for naming these diseases to improve accuracy in clinical diagnosis and inform data collection was necessary. A group of 91 experts developed an international consensus for standardized EGID nomenclature, which was recently published.2
The result was a 2-tier framework applicable to both the clinical and research settings (Table).2 The first tier provides a basic description of the location involved for clinical practice, and the second tier provides more granular nomenclature for clinical specificity and research purposes. Another major change addressed the term eosinophilic gastroenteritis, which had previously described almost any non-EoE EGID. Now, the term EGID denotes this group of disorders. Specific diseases are now named by the involved areas of the GI tract using an Eo– prefix for the abbreviation. Specifically, when the stomach is involved, the term EoG is used. When the small bowel is involved, the term eosinophilic enteritis (EoN) is used with an option to further specify locations within the small bowel: eosinophilic duodenitis (EoD), eosinophilic jejunitis (EoJ), and eosinophilic ileitis (EoI). When the colon is involved, the term eosinophilic colitis (EoC) is used.
The contributing experts considered it important to identify a primary location of the EGID based on the area within the GI tract where symptoms, complications, endoscopic findings, and eosinophilic infiltration were predominant. There was also a need to describe involvement in multiple areas of the GI tract, but this remains challenging, as whether these diseases are distinct from one another or all part of the same spectrum is unclear. For instance, although there are some similarities to EoE, including an association with atopic diseases, there seems to be a unique gene expression in other EGIDs that is not consistent with that found in EoE.4,9 Therefore, no consensus was reached for how to describe overlapping esophageal involvement with other affected areas in the GI tract.2 For example, the group considered using the terms eosinophilic gastritis with esophageal involvement or eosinophilic gastritis and eosinophilic esophagitis, depending on whether gastric or esophageal symptoms predominated, respectively. Within the non-EoE EGIDs without esophageal involvement, clinicians and researchers should use granularity when possible. For example, disease involving both the stomach and colon should be termed eosinophilic gastritis and colitis, whereas disease in the duodenum and colon should be identified as eosinophilic duodenitis and colitis. To further classify EGIDs, more detailed characterization based on the layers of the GI wall involved or specific complications will be considered. Because the understanding of EGIDs continues to evolve, the terminology will likely be updated in the context of new data. This article will preferentially use the new terminology and abbreviations, but in cases of prior papers reporting on eosinophilic gastroenteritis and locations that are not specified (stomach and/or small bowel, or other location), the article will use the now historical term.
Approach to Diagnosis
In contrast to EoE, the diagnostic criteria for non-EoE EGIDs remain less defined, as there are currently no published diagnostic guidelines, although these are in progress. The general approach to diagnosis requires the correct clinical presentation in the context of pathologic eosinophilic infiltration of the GI tract. However, diagnosis is challenging because other GI disorders are often considered first,10,11 and diagnosis is often prolonged, with 1 study reporting a mean delay of 3.6 years.12 Reasons may include the widely variable symptomatology, low suspicion among clinicians, inadequate number of biopsies during endoscopy, and underrecognition of eosinophils on pathologic evaluation, which also likely lead to underdiagnosis of these diseases.13
Prevalence in the United States has been estimated to be 6.3/100,000 for EoG, 8.4/100,000 for eosinophilic gastroenteritis (as reflected by the billing codes rather than the new nomenclature), and 3.3/100,000 for EoC6; similar values were reported in another study.14 However, a recent meta-analysis of the medical literature calculated the prevalence of non-EoE EGIDs to be 1.9%.15 In contrast to male predominance in EoE, there may be a slight female predominance in non-EoE EGIDs.6,16 Non-EoE EGIDs can also present at any age,17 and as many as 50% to 60% of those diagnosed may have at least 1 atopic condition.18,19 The natural history of these diseases remains unclear, given the paucity of long-term data on disease progression, but the diseases can be generally understood as chronic.17,20-22
The clinical presentation of EGIDs can vary widely. Symptoms include nausea, vomiting, abdominal pain, early satiety, diarrhea, bloating, and weight loss, among others. Some patients may present with bothersome nonspecific symptoms, whereas other patients can present with complications such as intestinal obstruction or protein-losing enteropathy.22 The presenting symptoms of EGIDs often vary by which parts of the GI tract and which layers of the GI tract lumen are involved in a particular patient, with the predominant symptoms often reflecting the predominant anatomic area of involvement.1,19 For example, patients with EoG may be more likely to present with nausea, vomiting, and abdominal pain, whereas patients with EoN or EoC may be more likely to present with diarrhea.9 Furthermore, in a study comparing patient-reported symptoms of EoE and non-EoE EGIDs, patients with non-EoE EGIDs reported more frequent symptoms than patients with EoE and were also more likely to report fatigue, isolation, and deep muscle or joint pain.23
Because non-EoE EGIDs can involve 1 or more layers of the luminal wall, patients can present with many different complications, including peripheral edema, ascites, iron deficiency anemia, GI bleeding, strictures, ulcers, perforation, and obstruction. The most common manifestation is involvement of the mucosal layer only,24 but diffuse involvement within the small bowel can lead to malabsorption, protein-losing enteropathy, and even failure to thrive.25,26 Involvement of the muscular layer can lead to wall thickening and dysmotility that can ultimately cause intestinal obstruction or even perforation. When the subserosa is affected, patients can develop ascites or pleural effusion, in which cases the ascitic or pleural fluid samples typically have markedly elevated eosinophils.24,25
A diagnosis of EGID should be considered when relatively common symptoms or complications manifest without another explanation. The initial laboratory evaluation, including complete blood count with differential, complete metabolic panel, ferritin, iron panel, and stool studies, is similar between EGID and other GI diseases.1 Peripheral eosinophilia, iron deficiency, or hypoalbuminemia should raise clinical suspicion of EGID.4,24-28 A recent study showed a higher diagnostic yield of biopsies in patients with mild peripheral eosinophilia and hypoalbuminemia.29 Additionally, imaging studies may show GI wall thickness or irregular narrowing of the small bowel, if there is involvement of the muscular layer of the bowel wall.30,31 Although initial research has suggested that less-invasive biomarker testing may have a role in diagnosing non-EoE EGIDs,32 such testing is not yet used clinically, and an endoscopy with biopsy is needed to complete the diagnostic evaluation.
Endoscopic evaluation is guided by the clinical picture, but upper endoscopy is most often performed. A multicenter study of 373 patients found that the most common endoscopic finding, observed in more than 60% of patients, was a normal appearance.33 However, many endoscopic findings have been reported in EGIDs, although they are almost all nonspecific. In EoG, these include erythema, ulceration, nodularity, friability, erosions, congestion, and pyloric stenosis. Patients with EoN have demonstrated villous dropout or flattening, erythema, congestion, ulceration, nodularity, friability, erosions, and stenosis. In patients with EoC, erythema, friability, congestion, and ulceration have been found.3,32-34
As a result, there have been ongoing efforts to develop an endoscopic grading system.35 Recently, the first endoscopic activity assessment system designed specifically for EoG, the Endoscopic Gastritis Endoscopic Reference System, was studied prospectively. The scores from this system strongly correlated with physician global assessment of endoscopic severity and were significantly correlated with histologic findings.36
Endoscopic examination is not only for visual assessment, but also to obtain biopsies to examine for eosinophilia and other histopathologic changes. However, there has been substantial variability in the number and location of biopsies as well as specimen handling,37,38 and there is not yet a consensus on a preferred approach.39,40 Because endoscopic appearance is often normal and eosinophilic involvement can be patchy, multiple biopsies should be taken from both normal and abnormal mucosa.33,34,41 A recent study determined that 8 total gastric biopsies with 4 biopsies of antrum and 4 biopsies of body, as well as 4 biopsies from the duodenum, were needed to maximize the diagnostic sensitivity for EGIDs,1,42 but this still needs to be confirmed. Because any layer of the GI wall can be infiltrated, full thickness biopsies may be required in circumstances in which EGID is strongly suspected but mucosal biopsies are normal.24,43,44
Interpreting biopsy results and the level of GI tract eosinophilia further complicates EGID diagnosis. Unlike in the esophagus, where eosinophils are not normally present,39,45 eosinophils are normal tissue resident cells in the GI tract distal to the esophagus. Normal values have been estimated as follows: stomach (5-10 eosinophils/high-power field [eos/hpf]), duodenum (10-25 eos/hpf), and terminal ileum and cecum (likely >50 eos/hpf), with a decreasing number in the distal colon.11,22,46 Thus, the specific thresholds required for documentation of pathologic eosinophilic infiltration continue to be debated.47,48 The thresholds will also differ depending on the specific area involved.9 Some proposed thresholds include at least 30 eos/hpf in the stomach,40 at least 50 eos/hpf in the duodenum, at least 100 eos/hpf in the ascending colon, at least 85 eos/hpf in the descending colon, and at least 65 eos/hpf in the sigmoid colon.49
The last and most critical step when considering a diagnosis of non-EoE EGIDs is to fully consider and rule out alternative etiologies of secondary peripheral eosinophilia. These include drug reactions, infections, adrenal disorders, malignancy, connective tissue diseases, vasculitis, Crohn’s disease, hypereosinophilic syndrome, graft-vs-host disease, and drug reactions, among others.22 Additional extensive testing may be required to investigate these conditions, depending on the clinical presentation.
To summarize the general approach to diagnosis, it is important to maintain a high index of suspicion in cases of symptoms persisting without another explanation, acknowledge that patients may not have typical laboratory findings, and thoroughly consider differential diagnoses.1 Making the diagnosis requires a careful endoscopic examination, taking a sufficient number of biopsies, and effectively communicating with the pathologist.40 Lastly and crucially, a finding of increased eosinophilic infiltration does not determine that the patient has a non-EoE EGID, as other causes of eosinophilia must be systematically considered and ruled out.
Pathogenesis
Although the pathogenesis of non-EoE EGIDs has not been investigated as thoroughly as that of EoE, understanding of the underlying mechanism is increasing rapidly, particularly for EoG. There are several lines of evidence for an allergic etiology. As noted earlier, there is a strong association with concomitant atopic conditions.19 Elevated serum immunoglobulin E levels have also been found in these patients,50 as have mast cells.51 Prior studies have shown improvement with dietary therapy,47,52 and a recent prospective dietary trial in adults found that an elemental formula diet led to clinicopathologic improvement in all patients.53 These and other data strongly suggest that antigen exposure triggers the condition,54,55 with an associated T helper 2–mediated upregulation of interleukin 5 (IL-5).4,56 EoG patients have also demonstrated a gastric transcriptome profile with a number of
T helper 2 signatures.4 Of note, emerging data may indicate that the pathogenesis of EoC may be different from other EGIDs and may not have the same allergic basis.49
Approach to Management
Treating non-EoE EGIDs remains challenging because there are no therapies that have been approved by the US Food and Drug Administration and almost all related data are from case reports, small case series, and retrospective studies.1,20,22 The first randomized trial of an experimental drug therapy was recently published57 and, as noted previously, the first prospective dietary trial was conducted.53 Despite the lack of effective treatment options, these patients should be followed closely to help manage symptoms and monitor for potential complications. Repeat endoscopy should also be performed to assess the endoscopic and histologic response following treatment, and to contextualize the symptom response.33
The most used class of medications are corticosteroids, but many other pharmacologic agents have been employed to treat non-EoE EGIDs. Clinicians often initially start treatment with systemic corticosteroids such as prednisone, but the results are variable9 and doses are not well studied or standardized.58,59 Most patients respond to corticosteroids initially, however.60 In order to avoid side effects, the dosage and duration are minimized, as systemic corticosteroids should not be used chronically. For the next step in treatment, some data show successful transition from prednisone to budesonide.61-64 Given the need to target release to different areas within the GI tract, enteric-coated budesonide must be directed to the relevant area of disease involvement. There are formulations of budesonide designed to release in the distal small bowel or colon, and these capsules can be swallowed intact when treating EoI or EoC. To treat EoG, the capsules must be opened and the granules crushed. When treating EoD or EoJ, the capsules can be opened and granules swallowed intact.1,64,65
Because long-term use of corticosteroids is not ideal, several other drug classes have been tried for treating non-EoE EGIDs.60 There have been reports of mast cell agents, including cromolyn and ketotifen, improving symptoms, but the results are conflicting.66,67 A case report discussed the leukotriene antagonist montelukast as an option.68 Proton pump inhibitors are used to treat gastric erosions and ulcerations, although data indicating whether this class of medications can reverse the underlying pathology are limited.1 A humanized anti–IL-5 antibody treatment reduced peripheral and tissue eosinophil counts, but failed to improve symptoms.69 An anti–immunoglobulin E monoclonal antibody was associated with an improvement in symptoms.16 A recent phase 2 randomized controlled trial of an anti–Siglec-8 antibody reduced GI eosinophils and symptoms when compared with placebo, but early data from the phase 3 study did not show a symptom benefit.57 There may also be a role for anti-integrin therapy, as some patients who had previously failed to respond to other immunotherapies seemed to improve with vedolizumab (Entyvio, Takeda).60,70 Proof-of concept data for an antibody against the IL-5 receptor have been released,71-73 and this agent is under further study.
Although the data on dietary therapy remain limited, some version of dietary intervention likely has a role in treatment when chosen for highly motivated patients. Historically, most of the available evidence on the dietary treatment of EGIDs has lacked objective evaluation of clinical changes and more often included limited assessment of histologic response.74 Elimination diets that aim to avoid foods that most commonly cause hypersensitivity, including the 6-food elimination diet, have been studied with mixed results.52,75 The elemental formula diet, which eliminates food allergens, may show more promise. Earlier data showed some response to amino acid–based formulas in EGID patients with protein-losing enteropathy.76 As noted previously, the first prospective trial of dietary therapy found that an elemental formula diet met its primary endpoint of histologic response (<30 eos/hpf) in all 15 patients who completed the trial.53 There was also improvement in the secondary endpoints, including symptomatic improvement, endoscopic severity scoring, and physician global assessment. Further investigation will help determine the specifics of dietary treatment plans in carefully selected patients, as well as the approach to reintroduction of foods from highly restrictive diets.
Conclusion
Although non-EoE EGIDs are rare diseases that can present with a wide array of symptoms, they likely remain underdiagnosed. Because of imprecise terminology used historically, an updated and more systematic nomenclature has been established that may clarify how these diseases are recognized, categorized, and researched. Additionally, efforts to establish diagnostic guidelines are ongoing. Because the diagnosis requires a high index of suspicion, clinicians should consider non-EoE EGIDs in the differential diagnosis when symptoms do not seem to fit with more common etiologies. On endoscopy examination, an adequate number of biopsies is required even in the context of a normal appearance, and communication with the pathologist may also be necessary for quantification of eosinophil counts and descriptions of associated findings. Finally, evaluating for and excluding other causes of eosinophilia are mandatory before confirming an EGID diagnosis. Although understanding of EGID pathogenesis has increased, it remains incomplete. As such, there is a lack of targeted treatment options, and clinicians continue to rely primarily on corticosteroids for treatment. New therapies are actively being investigated through clinical trials.
As with other eosinophil-mediated diseases, many patients who have non-EoE EGIDs face barriers across multiple domains.77 Patients have reported a number of medical, psychosocial, and financial barriers based on their clinical presentation and ensuing diagnostic journey. There is a need to further characterize the natural course of the disease over the long term.3 It is important to determine the optimal diagnostic approach, including the location of biopsies, number of biopsies, and threshold for pathologic eosinophilic counts.37 A more sophisticated understanding of pathogenesis is needed to help identify clinically meaningful outcomes and guide management strategies.9 This should include distinguishing pathologic differences depending on which area of the GI tract is predominantly involved.2 Lastly, there is a need for well-designed investigations of pharmacologic and dietary therapies.
Acknowledgement
This article was supported in part by NIH T32 DK007634.
Disclosures
Dr Dellon has received research funding from Adare/Ellodi, Allakos, Arena Pharmaceuticals, AstraZeneca, GlaxoSmithKline, Meritage Pharma, Miraca Life Sciences, Nutricia, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Revolo Biotherapeutics, and Shire/Takeda; has served as a consultant for Abbott Laboratories, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Allakos, Amgen, Arena Pharmaceuticals, AstraZeneca, Avir Pharma, Biorasi, Calypso Biotech, Celgene/Receptos/Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, GlaxoSmithKline, Gossamer Bio, Invea, Landos, Lucid Diagnostics, Morphic Therapeutic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts Clinical Trials/Alimentiv, Salix Pharmaceuticals, Sanofi, Shire/Takeda, and Target RWE; and has received educational grants from Allakos, Banner Pharmacaps, and Holoclara. Dr Redd has no relevant conflicts of interest to disclose.
References
1. Dellon ES. Eosinophilic gastrointestinal diseases beyond eosinophilic esophagitis. Am J Gastroenterol. 2022;117(5):697-700.
2. Dellon ES, Gonsalves N, Abonia JP, et al. International consensus recommendations for eosinophilic gastrointestinal disease nomenclature [published online February 16, 2022]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2022.02.017.
3. Gonsalves N. Eosinophilic gastrointestinal disorders. Clin Rev Allergy Immunol. 2019;57(2):272-285.
4. Caldwell JM, Collins MH, Stucke EM, et al. Histologic eosinophilic gastritis is a systemic disorder associated with blood and extragastric eosinophilia, TH2 immunity, and a unique gastric transcriptome. J Allergy Clin Immunol. 2014;134(5):1114-1124.
5. Dellon ES, Liacouras CA, Molina-Infante J, et al. Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE Conference. Gastroenterology. 2018;155(4):1022-1033.e10.
6. Jensen ET, Martin CF, Kappelman MD, Dellon ES. Prevalence of eosinophilic gastritis, gastroenteritis, and colitis: estimates from a national administrative database. J Pediatr Gastroenterol Nutr. 2016;62(1):36-42.
7. Kaijser R. Zur Kenntnis der allergischen Affektionen des Verdauungskanals vom Standpunkt des Chirurgen aus. Arch Klin Chir. 1937;188:36-64.
8. Bochner BS, Book W, Busse WW, et al. Workshop report from the National Institutes of Health Taskforce on the Research Needs of Eosinophil-Associated Diseases (TREAD). J Allergy Clin Immunol. 2012;130(3):587-596.
9. Steinbach EC, Hernandez M, Dellon ES. Eosinophilic esophagitis and the eosinophilic gastrointestinal diseases: approach to diagnosis and management. J Allergy Clin Immunol Pract. 2018;6(5):1483-1495.
10. Gupta SK, Falk GW, Aceves SS, et al; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Consortium of Eosinophilic Gastrointestinal Disease Researchers: advancing the field of eosinophilic GI disorders through collaboration. Gastroenterology. 2019;156(4):838-842.
11. Pesek RD, Rothenberg ME. Eosinophilic gastrointestinal disease below the belt. J Allergy Clin Immunol. 2020;145(1):87-89.e1.
12. Chehade M, Kamboj AP, Atkins D, Gehman LT. Diagnostic delay in patients with eosinophilic gastritis and/or duodenitis: a population-based study. J Allergy Clin Immunol Pract. 2021;9(5):2050-2059.e20.
13. Talley N, Kamboj A, Chey W, et al. 537 Endoscopy and systematic biopsy of patients with chronic gastrointestinal symptoms leads to high discovery rate of patients who meet histologic criteria for eosinophilic gastritis and/or eosinophilic duodenitis. Gastroenterology. 2021;160(6):S-110-S-111.
14. Mansoor E, Saleh MA, Cooper GS. Prevalence of eosinophilic gastroenteritis and colitis in a population-based study, from 2012 to 2017. Clin Gastroenterol Hepatol. 2017;15(11):1733-1741.
15. Licari A, Votto M, Scudeller L, et al. Epidemiology of nonesophageal eosinophilic gastrointestinal diseases in symptomatic patients: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2020;8(6):1994-2003.e2.
16. Foroughi S, Foster B, Kim N, et al. Anti-IgE treatment of eosinophil-associated gastrointestinal disorders. J Allergy Clin Immunol. 2007;120(3):594-601.
17. Yamamoto M, Nagashima S, Yamada Y, et al. Comparison of nonesophageal eosinophilic gastrointestinal disorders with eosinophilic esophagitis: a nationwide survey. J Allergy Clin Immunol Pract. 2021;9(9):3339-3349.e8.
18. Yun MY, Cho YU, Park IS, et al. Eosinophilic gastroenteritis presenting as small bowel obstruction: a case report and review of the literature. World J Gastroenterol. 2007;13(11):1758-1760.
19. Pesek RD, Reed CC, Muir AB, et al; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Increasing rates of diagnosis, substantial co-occurrence, and variable treatment patterns of eosinophilic gastritis, gastroenteritis, and colitis based on 10-year data across a multicenter consortium. Am J Gastroenterol. 2019;114(6):984-994.
20. Egan M, Furuta GT. Eosinophilic gastrointestinal diseases beyond eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2018;121(2):162-167.
21. Pineton de Chambrun G, Gonzalez F, Canva JY, et al. Natural history of eosinophilic gastroenteritis. Clin Gastroenterol Hepatol. 2011;9(11):950-956.e1.
22. Walker MM, Potter M, Talley NJ. Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus. Lancet Gastroenterol Hepatol. 2018;3(4):271-280.
23. Jensen ET, Aceves SS, Bonis PA, et al; CEGIR Investigator group. High patient disease burden in a cross-sectional, multicenter contact registry study of eosinophilic gastrointestinal diseases. J Pediatr Gastroenterol Nutr. 2020;71(4):524-529.
24. Talley NJ, Shorter RG, Phillips SF, Zinsmeister AR. Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosa, muscle layer, and subserosal tissues. Gut. 1990;31(1):54-58.
25. Cello JP. Eosinophilic gastroenteritis—a complex disease entity. Am J Med. 1979;67(6):1097-1104.
26. Klein NC, Hargrove RL, Sleisenger MH, Jeffries GH. Eosinophilic gastroenteritis. Medicine (Baltimore). 1970;49(4):299-319.
27. Chang JY, Choung RS, Lee RM, et al. A shift in the clinical spectrum of eosinophilic gastroenteritis toward the mucosal disease type. Clin Gastroenterol Hepatol. 2010;8(8):669-675.
28. Katz AJ, Goldman H, Grand RJ. Gastric mucosal biopsy in eosinophilic (allergic) gastroenteritis. Gastroenterology. 1977;73(4 pt 1):705-709.
29. Brenner EJ, Greenberg SB, Chang NC, Corder SR, Cowherd EL, Dellon ES. Peripheral eosinophilia and hypoalbuminemia are associated with a higher biopsy diagnostic yield for eosinophilic gastroenteritis. Clin Res Hepatol Gastroenterol. 2021;45(5):101746.
30. MacCarty RL, Talley NJ. Barium studies in diffuse eosinophilic gastroenteritis. Gastrointest Radiol. 1990;15(3):183-187.
31. Ishihara S, Kinoshita Y, Schoepfer A. Eosinophilic esophagitis, eosinophilic gastroenteritis, and eosinophilic colitis: common mechanisms and differences between East and West. Inflamm Intest Dis. 2016;1(2):63-69.
32. Shoda T, Wen T, Caldwell JM, et al; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Molecular, endoscopic, histologic, and circulating biomarker-based diagnosis of eosinophilic gastritis: multi-site study. J Allergy Clin Immunol. 2020;145(1):255-269.
33. Pesek RD, Reed CC, Collins MH, et al; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Association between endoscopic and histologic findings in a multicenter retrospective cohort of patients with non-esophageal eosinophilic gastrointestinal disorders. Dig Dis Sci. 2020;65(7):2024-2035.
34. Ashitani K, Tsuzuki Y, Yamaoka M, et al. Endoscopic features and diagnostic procedures of eosinophilic gastroenteritis. Intern Med. 2019;58(15):2167-2171.
35. Hirano I, Collins M, King E, et al. 357 Prospective evaluation of a novel, endoscopic activity assessment system for eosinophilic gastritis. Gastroenterology. 2019;156(6 suppl 1):S-71-S-72.
36. Hirano I, Collins MH, King E, et al; CEGIR investigators. Prospective endoscopic activity assessment for eosinophilic gastritis in a multisite cohort. Am J Gastroenterol. 2022;117(3):413-423.
37. Dellon ES, Collins MH, Bonis PA, et al. Substantial variability in biopsy practice patterns among gastroenterologists for suspected eosinophilic gastrointestinal disorders. Clin Gastroenterol Hepatol. 2016;14(12):1842-1844.
38. Sperry SL, Shaheen NJ, Dellon ES. Toward uniformity in the diagnosis of eosinophilic esophagitis (EoE): the effect of guidelines on variability of diagnostic criteria for EoE. Am J Gastroenterol. 2011;106(5):824-832.
39. Hurrell JM, Genta RM, Melton SD. Histopathologic diagnosis of eosinophilic conditions in the gastrointestinal tract. Adv Anat Pathol. 2011;18(5):335-348.
40. Collins MH. Histopathologic features of eosinophilic esophagitis and eosinophilic gastrointestinal diseases. Gastroenterol Clin North Am. 2014;43(2):257-268.
41. Hui CK, Hui NK. A prospective study on the prevalence, extent of disease and outcome of eosinophilic gastroenteritis in patients presenting with lower abdominal symptoms. Gut Liver. 2018;12(3):288-296.
42. Dellon ES, Gonsalves N, Rothenberg ME, et al. Determination of biopsy yield that optimally detects eosinophilic gastritis and/or duodenitis in a randomized trial of lirentelimab. Clin Gastroenterol Hepatol. 2022;20(3):535-545.e15.
43. Zhang L, Duan L, Ding S, et al. Eosinophilic gastroenteritis: clinical manifestations and morphological characteristics, a retrospective study of 42 patients. Scand J Gastroenterol. 2011;46(9):1074-1080.
44. Lee M, Hodges WG, Huggins TL, Lee EL. Eosinophilic gastroenteritis. South Med J. 1996;89(2):189-194.
45. 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):210-218.
46. Silva J, Canão P, Espinheira MC, Trindade E, Carneiro F, Dias JA. Eosinophils in the gastrointestinal tract: how much is normal? Virchows Arch. 2018;473(3):313-320.
47. Ko HM, Morotti RA, Yershov O, Chehade M. Eosinophilic gastritis in children: clinicopathological correlation, disease course, and response to therapy. Am J Gastroenterol. 2014;109(8):1277-1285.
48. Reed C, Woosley JT, Dellon ES. Clinical characteristics, treatment outcomes, and resource utilization in children and adults with eosinophilic gastroenteritis. Dig Liver Dis. 2015;47(3):197-201.
49. Shoda T, Collins MH, Rochman M, et al; Consortium of Eosinophilic Gastrointestinal Diseases Researchers (CEGIR). Evaluating eosinophilic colitis as a unique disease using colonic molecular profiles: a multi-site study. Gastroenterology. 2022;162(6):1635-1649.
50. Caldwell JH, Tennenbaum JI, Bronstein HA. Serum IgE in eosinophilic gastroenteritis. Response to intestinal challenge in two cases. N Engl J Med. 1975;292(26):1388-1390.
51. Reed CC, Genta RM, Youngblood BA, Wechsler JB, Dellon ES. Mast cell and eosinophil counts in gastric and duodenal biopsy specimens from patients with and without eosinophilic gastroenteritis. Clin Gastroenterol Hepatol. 2021;19(10):2102-2111.
52. Gonsalves N, Doerfler B, Yang G, Hirano I. S1861 A prospective clinical trial of six food elimination diet or elemental diet in the treatment of adults with eosinophilic gastroenteritis. Gastroenterology. 2009;136(5 suppl 1):A-280.
53. Gonsalves N, Doerfler B, Zalewski A, et al. 229 – Results from the Element study: prospective study of elemental diet in eosinophilic gastroenteritis nutrition trial. Gastroenterology. 2020;158(6):S-43.
54. Hogan SP, Mishra A, Brandt EB, Foster PS, Rothenberg ME. A critical role for eotaxin in experimental oral antigen-induced eosinophilic gastrointestinal allergy. Proc Natl Acad Sci USA. 2000;97(12):6681-6686.
55. Desreumaux P, Bloget F, Seguy D, et al. Interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 in eosinophilic gastroenteritis. Gastroenterology. 1996;110(3):768-774.
56. Prussin C, Lee J, Foster B. Eosinophilic gastrointestinal disease and peanut allergy are alternatively associated with IL-5+ and IL-5(-) T(H)2 responses. J Allergy Clin Immunol. 2009;124(6):1326-1332.e6.
57. Dellon ES, Peterson KA, Murray JA, et al. Anti-Siglec-8 antibody for eosinophilic gastritis and duodenitis. N Engl J Med. 2020;383(17):1624-1634.
58. Lee CM, Changchien CS, Chen PC, et al. Eosinophilic gastroenteritis: 10 years experience. Am J Gastroenterol. 1993;88(1):70-74.
59. Chen MJ, Chu CH, Lin SC, Shih SC, Wang TE. Eosinophilic gastroenteritis: clinical experience with 15 patients. World J Gastroenterol. 2003;9(12):2813-2816.
60. Grandinetti T, Biedermann L, Bussmann C, Straumann A, Hruz P. Eosinophilic gastroenteritis: clinical manifestation, natural course, and evaluation of treatment with corticosteroids and vedolizumab. Dig Dis Sci. 2019;64(8):2231-2241.
61. Tan AC, Kruimel JW, Naber TH. Eosinophilic gastroenteritis treated with non-enteric-coated budesonide tablets. Eur J Gastroenterol Hepatol. 2001;13(4):425-427.
62. Siewert E, Lammert F, Koppitz P, Schmidt T, Matern S. Eosinophilic gastroenteritis with severe protein-losing enteropathy: successful treatment with budesonide. Dig Liver Dis. 2006;38(1):55-59.
63. Elsing C, Placke J, Gross-Weege W. Budesonide for the treatment of obstructive eosinophilic jejunitis. Z Gastroenterol. 2007;45(2):187-189.
64. Kubo K, Kimura N, Mabe K, Matsuda S, Tsuda M, Kato M. Eosinophilic gastroenteritis-associated duodenal ulcer successfully treated with crushed budesonide. Intern Med. 2020;59(18):2249-2254.
65. Kennedy K, Muir AB, Grossman A, et al. Modified oral enteric-coated budesonide regimens to treat pediatric eosinophilic gastroenteritis, a single center experience. J Allergy Clin Immunol Pract. 2019;7(6):2059-2061.
66. Van Dellen RG, Lewis JC. Oral administration of cromolyn in a patient with protein-losing enteropathy, food allergy, and eosinophilic gastroenteritis. Mayo Clin Proc. 1994;69(5):441-444.
67. Melamed I, Feanny SJ, Sherman PM, Roifman CM. Benefit of ketotifen in patients with eosinophilic gastroenteritis. Am J Med. 1991;90(3):310-314.
68. Quack I, Sellin L, Buchner NJ, Theegarten D, Rump LC, Henning BF. Eosinophilic gastroenteritis in a young girl—long term remission under montelukast. BMC Gastroenterol. 2005;5:24.
69. Prussin C, James S, Huber M, Klion A, Metcalfe D. 827 Pilot study of anti-
IL-5 in eosinophilic gastroenteritis. J Allergy Clin Immunol. 2003;111(2):S275.
70. Kim HP, Reed CC, Herfarth HH, Dellon ES. Vedolizumab treatment may reduce steroid burden and improve histology in patients with eosinophilic gastroenteritis. Clin Gastroenterol Hepatol. 2018;16(12):1992-1994.
71. Kuang FL, Legrand F, Makiya M, et al. Benralizumab for PDGFRA-negative hypereosinophilic syndrome. N Engl J Med. 2019;380(14):1336-1346.
72. Kuang FL, De Melo MS, Makiya M, et al. Benralizumab completely depletes gastrointestinal tissue eosinophils and improves symptoms in eosinophilic gastrointestinal disease. J Allergy Clin Immunol Pract. 2022;10(6):1598-1605.e2.
73. ClinicalTrials.gov. Benralizumab for Eosinophilic Gastritis (BEGS): a randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy of benralizumab (anti-IL5RA) in subjects with eosinophilic gastritis. https://clinicaltrials.gov/ct2/show/NCT03473977. Identifier: NCT03473977.
74. Arias A, González-Cervera J, Tenias JM, Lucendo AJ. Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis. Gastroenterology. 2014;146(7):1639-1648.
75. Gonsalves N, Yang GY, Doerfler B, Ritz S, Ditto AM, Hirano I. Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology. 2012;142(7):1451-1459.e1.
76. Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Sampson HA, Sicherer SH. Allergic eosinophilic gastroenteritis with protein-losing enteropathy: intestinal pathology, clinical course, and long-term follow-up. J Pediatr Gastroenterol Nutr. 2006;42(5):516-521.
77. Hiremath G, Kodroff E, Strobel MJ, et al. Individuals affected by eosinophilic gastrointestinal disorders have complex unmet needs and frequently experience unique barriers to care. Clin Res Hepatol Gastroenterol. 2018;42(5):483-493.