Eosinophilic GI Disease

 Eosinophilic GI Disease (EGID) is a group of conditions that occur when there are elevated levels of eosinophils in segments of the GI tract, either the esophagus, stomach, small intestines or colon.  These conditions are called Eosinophilic Esophagitis (EoE), Eosinophilic Gastritis or Gastroenteritis (EoG), Eosinophilic Enteritis (EoN), and Eosinophilic Colitis (EC or EoC).  I have heard reference to Eosinophilic Duodenitis Eosinophilic Rectitis but I don't think either are official conditions.  The esophagus is the one part of the GI tract that doesn't normally have eosinophils, whereas the rest of the GI tract does.  This has led some to speculate that EoE is a different entity than the other EGIDs.  

EGIDs are diagnosed by biopsy.  Tissue samples are collected during endoscopy or colonoscopy, and then sent to a pathologist who looks at the samples under a microscope to identify the presence of eosinophils.  If the numbers are too high, a diagnosis is made.  Symptoms vary depending on the form of EGID a person has, and can be mild to severe.  In EoE, a common symptom, the one that often leads to diagnosis, are food impactions in the esophagus that require medical care to remove.  Symptoms of lower EGIDs tend to be vague such as cramping and pain, vomiting, nausea, diarrhea, food intolerances and a severely restricted diet, malnutrition, and bone pain (usually in the legs).  

Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis

Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study

Molecular analysis of duodenal eosinophilia

Elimination diets are often used by doctors to identify problem foods, as there are no tests to identify eosinophilic triggers.  Treatment often begins by having the patient avoid identified (or suspected) triggers.  If this doesn't adequately control symptoms, various medications can be used, including topical steroids such as Budesonide or Fluticasone (steroids that is swallowed), a PPI (Protono Pump Inhibitor), Singulair, or oral steroids to control flares.  A type of medication called biologics are starting to be used for some EGIDs, in particular Dupilumab (brand name Dupixent).  Eosinophils are the same cells that tend to be responsible for asthma so many of the same medications are used.  Some people describe EGIDs as "like asthma but in your GI tract".  If those treatments fail, it is not uncommon for people with EGIDs to require artificial nutrition such as elemental formula, a feeding tube, or even TPN (IV nutrition).  People with EoE can develop strictures in the esophagus, areas where the tissue has scarring which narrows the width of the esophagus.  This can be treated with dilations, a procedure in which the area is mechanically stretched.

Crafting a Therapeutic Pyramid for Eosinophilic Esophagitis in the Age of Biologics

The leading center for diagnosis and treatment of EGIDs, especially EoE, is Cincinnati Children's Hospital (they also work with adults with EGIDs) 

Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE

Food-specific IgG4 is associated with eosinophilic esophagitis

Common and disparate clinical presentations and mechanisms in different eosinophilic gastrointestinal diseases

Histopathology of Eosinophilic Gastrointestinal Diseases Beyond Eosinophilic Esophagitis
"EoG and eosinophilic duodenitis (EoD) are strongly associated with food allergen triggers and TH2 inflammation, whereas EoC shows minimal transcriptomic overlap with other EGIDs. The level of expression of certain genes associated with TH2 immune response is associated with certain histopathologic findings of EoG, EoD, and EoC. Current immune therapy for EoG depletes tissue eosinophilia with persistence of other histopathologic features of disease."

The Dual Lens of Endoscopy and Histology in the Diagnosis and Management of Eosinophilic Gastrointestinal Disorders—A Comprehensive Review
"Eosinophils, a specific type of leukocyte derived from CD34+ CD125+ stem cells in the bone marrow, are crucial in defending against pathogens, such as bacteria and parasites. Additionally, they play a pivotal role in modulating humoral immune IgA and cellular T-cell responses, and in maintaining tissue homeostasis.

In the context of EGIDs, the abnormal accumulation of eosinophils is primarily driven by interleukin-5 (IL-5), interleukin-4 (IL-4), and interleukin-13 (IL-13). These cytokines are primarily produced by type 2 helper lymphocytes (Th2) in response to exposure to aeroallergens and food allergens. The overproduction of interleukins is further amplified by dysregulated cells in the innate immune system, including Group 2 innate lymphoid cells (ILC2s) that mature directly in tissues like the GI tract or lungs, plasma cells, and mast cells.  Pathogenesis of Th2 inflammatory drive in Eosinophilic Gastrointestinal Disorders (EGIDs), especially EoE. Exposure to initial food antigens triggers lymphocyte-Th2 activation, resulting in the accumulation of eosinophils in the esophagus. Following stimulation with Eotaxin 3, eosinophil degranulation promotes acute damage to the esophageal epithelium, followed by subsequent chronic fibrotic remodeling of the esophagus, which is dependent on TGF-beta.

Th2 cytokines, particularly IL-13, along with other inflammatory mediators such as Tumor Necrosis Factor Alpha (TNF-α) and other chemokines, play a direct role in the activation and degranulation of eosinophils. Eotaxin-3 serves as the primary chemokine involved in these processes and contributes significantly to eosinophilic chemotaxis and accumulation in GI tissues. The release of proteins from eosinophilic granules, including eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and major basic protein (MBP), leads to acute cytotoxic and oxidative damage to the tissue. This acute damage results in compromised barrier function through the downregulation of Desmoglein 1 (DSG1), Filaggrin (FGN), and the Epidermal Differentiation Complex (EDC).
The course of acute eosinophilic Th2 inflammation is typically self-sustained and progressive, often leading to chronic damage. This chronic state is often driven by T regulatory lymphocytes’ activation, accompanied by the recruitment of other cell types, including mast cells and basophils [26]. The persistent inflammatory insult can result in sub-mucosal fibrotic tissue deposition and muscular hypertrophy, primarily induced by Transforming Growth Factor beta (TGF-beta). 

A recent study on colonic biopsies conducted by Shoda et al. revealed that EoC is distinct from other EGIDs, with pathophysiological mechanisms that are not completely dependent on allergic inflammatory reactions [186]. The study identified 987 differentially expressed genes that were overexpressed in EoC tissues, thereby defining the “EoC transcriptome”.  Interestingly, the pathogenesis of EoC seems to have only a weak correlation with Th2-related allergic pathogenesis.  (A)dults typically experience chronic abdominal pain and watery diarrhea [25,179,180]. Additional symptoms can include nausea, vomiting, and weight loss. The presence of atopy history in EoC patients often complicates the clinical picture with conditions like asthma, food allergies, rhinitis, or eczema.

The depth of eosinophilic infiltration in the colonic wall allows for the identification of three disease patterns [147].

The mucosal involvement (type 1), defined as eosinophil infiltration of the mucosa, is the most common. This type often follows a continuous disease course (>6 months) without remission, with patients exhibiting symptoms such as bloody diarrhea, microcytic iron-deficiency anemia, and protein-losing enteropathy [5].

Transmural involvement (type 2) occurs when eosinophils infiltrate the muscular layer. It is associated with symptoms like abdominal spasms, pain, and a possible impact on intestinal motility. Complications such as intestinal obstructions, strictures, volvulus, and perforations may occur. The course of the disease in this form is typically recurrent [5].

The serosal subtype (type 3) is the rarest and occurs when eosinophilic infiltration reaches the serosa. This form can be associated with more severe symptoms, including eosinophilic ascites and intense abdominal pain [5].

Radiological signs include intestinal wall and mucosal fold thickening and submucosal edema [150,153]. Mucosal thickening, stenosis, and sub-mucosal edema form the basis of the “halo sign,” characteristic of EoC. The “arachnoid limb-like sign” may also be observed via radiological imaging [150]. In cases of transmural involvement, stenosis, particularly at the cecum, may be observed.

 

In approximately 70% of EoC cases, no alterations in the colonic mucosa are observed during endoscopic evaluation [183,187,188]. However, when abnormalities are present, they typically involve the colon segmentally, with only about 10% of patients presenting with pancolitis [14,25,183]. The endoscopic findings of EoC are often non-specific and do not correlate with the severity of symptoms [7].

 

Drug-induced colitis, triggered by antiplatelet drugs (clopidogrel, aspirin, and ticlopidine), Non-Steroidal Anti-Inflammatory Drug (NSAIDs) (especially ibuprofen), and estrogenic-progestogen agents is another cause of colonic hypereosinophilia [194,195].  Among connective tissue diseases, rheumatoid arthritis uniquely exhibits patterns of colonic eosinophilia [200]. 

 

In addition to hypereosinophilia, other microscopic characteristics that typify EoC histology include extensive degranulation, eosinophilic micro-abscesses, architectural distortion, fibrosis with mucosal atrophy, loss of mucin, and follicular lymphoid hyperplasia, often accompanied by lymphocytes and plasma cells [187,188].

 

According to the strongest evidence, a PEC with more than 50 eosinophils per HPF in the right colon, more than 35 eos/HPF in the transverse colon, or more than 25 eos/HPF in the left colon, along with a consistent clinical and symptomatic profile, indicates a diagnosis of EoC [14] 

 

adults typically receive steroid anti-inflammatory therapy, such as prednisone or budesonide, as the initial treatment [170,180]. If adults experience a relapse after discontinuing prednisone, indicating steroid-dependent disease, Budesonide Controlled Ileal Release (CIR) can be an effective maintenance therapy. Budesonide CIR has the advantage of primarily topical activity, minimizing the long-term adverse effects associated with steroids [202].

Immunomodulators like azathioprine and methotrexate also represent alternatives to maintenance therapy for EoC. Additionally, Montelukast, a leukotriene receptor antagonist, is beneficial in maintenance therapy due to its ability to block eosinophil homeostasis and prevent their infiltration into the intestinal wall [131]. Fecal microbiota transplantation has been suggested as a rescue strategy in EoC, though this evidence is limited to case reports [203]. Emerging therapies for EoC have mainly been tested in animal models. Studies evaluating the efficacy of anti-Siglec-F antibodies (targeting a sialic acid-binding immunoglobulin superfamily receptor) and anti-CCR3 (cysteine–cysteine chemokine receptor 3) antibodies have shown promising results [204,205]. Future therapeutic options are anticipated with the validation of biological drugs like dupilumab, reslizumab, and mepolizumab, which are currently undergoing testing.