Eosinophilic gastroenteritis

Patients with EGE present with a combination of chronic, nonspecific GI symptoms, including abdominal pain, bloating, early satiety, abdominal cramping, diarrhea, nausea, and vomiting ^{1, 2, 9, 10, 18, 19}. EGE symptoms are often indistinguishable from those of functional GI disorders such as irritable bowel syndrome or functional dyspepsia, which can result in delayed diagnoses, misdiagnoses, and improper treatment ^20-22. Longer duration of GI symptoms has been correlated with probability of EGE²³.

The endoscopic features of the GI mucosa are varied and nonspecific in patients with EGE—many patients have no or mild endoscopic abnormalities, such as erythema ^{15, 18}, making it a challenge to detect ^{23, 24}. Collection of gastrointestinal biopsies and histologic analysis, with counting of eosinophils, is required for diagnosis of EGE ¹⁹. The variations in clinical presentation, subtle or nonexistent endoscopic abnormalities, involvement of several GI segments, requirement for collection of multiple biopsies, and patchiness of eosinophilic infiltration contribute to underdiagnosis of EGE^{14, 25}. Some but not all patients with EGE have increased serum levels of IgE, peripheral eosinophils, or α2-macroglobulin ^{12, 13, 18, 19, 26, 27}. The Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) aims to quantify endoscopic, molecular, and histologic findings in patients with EG ³.

Although EGIDs such as EG and EoD have been described as rare^{28, 29}, recent studies have shown that they are more common^{18, 23, 30}. EGE occurs in adults and children and affects both sexes ¹⁴. An analysis of data from 373 patients with diagnoses EGE in the Consortium of Eosinophilic Gastrointestinal Disease Researchers database (317 children and 56 adults) found that 38% had eosinophilic gastritis (EG), 33% had eosinophilic gastroenteritis (EGE), and 29% had eosinophilic colitis⁹. In a prospective study of 65 patients EGE, 10 patients (15%) had a diagnosis of EG, 25 patients (38%) had a diagnosis of EoD, and 30 patients (46%) had EG and EoD¹⁶.

Patients with EGE present with nonspecific symptoms and frequently receive many misdiagnoses, such as functional GI disorders (irritable bowel syndrome or functional dyspepsia); 44.3% of patients are diagnosed with another GI disorder before they receive a proper diagnosis of EG and/or EoD. The mean time from presentation with symptoms to diagnosis of EGE was 3.6 years. Factors that contribute to the long time until diagnosis include delayed referral to a gastroenterologist, delayed examination by upper endoscopy, and lack of biopsy collection and/or histopathologic evaluation. In patients who do undergo upper endoscopy, the diagnosis is missed in 38.2% of patients with EG and/or EoD ²².

EGE can be detected only by upper gastrointestinal endoscopy (also called esophagogastroduodenoscopy or EGD), collection of gastric and duodenal specimens, and histologic examination of the specimens for evidence of eosinophilia and exclusion of other disorders associated with eosinophilic infiltration ^{17, 31}. Eosinophils penetrate the mucosa to varying depths^{23, 26} and are often patchy or distributed in sheets. During endoscopy, the gastric and duodenal mucosa in patients with EGE often appears normal, or there are mild alterations, ^{32, 33}, but some patients have erythematous, friable, nodular, or ulcerative changes¹⁸. Mean mast cell and eosinophil counts do not correlate with endoscopic features of EGIDs⁸.

Although there are no consensus guidelines for diagnosis of EGE, different approaches have been published^{3, 17, 34-37} and interventional studies have used specific inclusion criteria. A mean count of 20 eosinophils/high-power field (eos/hpf) in gastric biopsies or 30 eos/hpf in duodenal biopsies identifies patients with EGIDs with high specificity⁸. Other studies have used the presence of ≥30 eos/hpf in ≥5 hpfs for diagnosis of EG and ≥30 eos/hpf in ≥3 hpfs for diagnosis of EoD^{15, 38, 39}. Collection and evaluation of at least 8 gastric and 4 duodenal biopsies increased detection of EG and/or EoD. Evaluation of multiple non-overlapping hpfs in each of the 8 gastric and 4 duodenal biopsies is required to capture 100% of EG/EoD cases in this study due to the patchy nature of tissue eosinophilia in this disease ¹⁵.

Duodenal biopsy section stained by H&E to show eosinophilia.

The increased numbers of mast cells and eosinophils in gastric and duodenal tissues from patients with EGIDs supports the concept that these cell types are involved in pathogenesis⁸. Decreased tissue eosinophilia associates with reduced symptoms, as well as endoscopic and histologic findings, indicating that eosinophils contribute to symptoms and that disease activity is reversible^{16, 33}.

Under normal physiological conditions, eosinophils and mast cells are present throughout the gastrointestinal tract distal to the squamous esophagus⁴⁰. Eosinophils help maintain immune homeostasis in gut-associated tissues⁴¹.

It is not clear how the eosinophils and mast cells become activated or how increased numbers infiltrate the GI mucosa, but food allergies and intestinal dysbiosis have been implicated^{6, 36}. Food allergens are believed to cross the intestinal mucosa and induce inflammatory responses that include mast cell degranulation and recruitment of eosinophils.The damage to the gastrointestinal tract wall is caused by eosinophilic infiltration and degranulation.

Hypersensitivity is believed be involved in pathogenesis because many patients have a history of seasonal allergies, food sensitivities, asthma, or eczema ^{12, 18, 31}. Eosinophils could contribute to the development of EGIDs via allergic response to food or environmental allergens through mediators such as eotaxin-3, interleukin 5 (IL5), IL13, transforming growth factor beta (TGFB), and periostin) ⁴². Mast cells release mediators that attract eosinophils and have other inflammatory effects. Studies have shown activated eosinophils and mast cells to mediate sensitization to foods via the cytokines IL5 and IL13⁴³.

A significant increase in the number of eosinophils (eosinophilia, see figure), along with levels of eotaxin-3, IL5, and IL13, were observed in duodenal and colon tissues from patients with EGE compared with controls^{44, 45}. Serum and colon tissues from infants with EGE had significant increases in levels of TSLP and IL33 compared with controls.

Progression of EGE varies—some patients have a single episode without relapse, whereas others have relapsing-remitting or chronic disease^{6, 12} EGE resolves in approximate 30%–40% of EGE cases, 37% have been reported to have multiple flares separated by periods of remission (recurring disease), and 21% have chronic disease ^{13, 18}.

Treatment options for this disorder include dietary and pharmacological approaches ¹. Approximately 80% of patients with EGE receive treatment with corticosteroids^{10, 36}. Symptoms have been reported to improve or resolve with steroid treatment in 60%–80% of patients ^{10, 18, 36}. However, steroid therapy may be inappropriate for long-term use—as many as 85% of patients have been reported to relapse when steroids are discontinued ^{1, 26}. No therapies have been approved by the Food and Drug Administration for treatment of EGIDs.

Other potential therapies include mast-cell stabilizers, leukotriene antagonists, antihistamines, immunomodulators, and biologic agents ^{31, 46}. Relapsing or refractory disease might respond to steroid-sparing immunosuppressive or biologic agents⁶. Agents that block immune signaling via IL4 receptor (https://clinicaltrials.gov/ct2/show/NCT03678545), the IL5 receptor (https://clinicaltrials.gov/ct2/show/NCT03473977 and https://clinicaltrials.gov/ct2/show/NCT04543409), and the sphingosine 1-phosphate receptor (https://clinicaltrials.gov/ct2/show/NCT04682639) are in clinical trials for patients with EGIDs.

Lirentelimab (AK002), a monoclonal antibody against Siglec-8 that reduces eosinophils and inhibits mast cells ^{47, 48}, has shown promise in clinical trials⁴⁹. In a phase 2 clinical trial of patients with EG and/or EoD, lirentelimab reduced gastrointestinal eosinophils by 95%, compared with 10% in the placebo group; significantly more patients in the lirentelimab group had a treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) than in the placebo group ^{16, 38}. Studies are underway to evaluate the effects of this drug in larger populations of patients with EG, EoD (phase 3, https://clinicaltrials.gov/ct2/show/NCT04322604) and/or EoE (phase 2/3, https://clinicaltrials.gov/ct2/show/NCT04322708).

• Eosinophilic esophagitis (EoE)
• Coeliac disease
• Protein losing enteropathy from intolerance to cow's milk protein

• Eosinophil
• Mast Cell
• Gastroenteritis
• Irritable Bowel Syndrome (IBS)
• Functional Dyspepsia

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