Eosinophilic Gastrointestinal Disorders consist of eosinophilic esophagitis, eosinophilic gastroenteritis, and eosinophilic colitis. Eosinophilic gastroenteritis is an inflammatory disorder that presents with variable degrees of infiltration of eosinophils within the gastrointestinal tract, first described by Kaijser in 19371.[rx][rx] The Klein classification has its basis in the degree of eosinophilic infiltration in different gastrointestinal layers, which include mucosal, muscle, and subserosal.[rx]
Eosinophilic Gastroenteritis (EGE) is a heterogeneous inflammatory bowel disorder, which commonly follows a chronic and relapsing course. Eosinophilic gastroenteritis (EGE) is a rare and benign inflammatory disorder that predominantly affects the stomach and the small intestine. The disease is divided into three subtypes (mucosal, muscular, and serosal) according to Klein’s classification, and its manifestations are protean, depending on the involved intestinal segments and layers. Hence, accurate diagnosis of EGE poses a significant challenge to clinicians, with evidence of the following three criteria required: Suspicious clinical symptoms, histologic evidence of eosinophilic infiltration in the bowel, and exclusion of other pathologies with similar findings.
Synonyms of Eosinophilic Gastroenteritis
- eosinophilic gastritis
- eosinophilic gastroenteropathy
- eosinophilic gastrointestinal disorders
The pathogenesis is not well understood; however, multiple studies have shown overproduction of T-helper-2 cytokines (e.g., interleukin-13) and chemokines (e.g., CCL26/eotaxin-3), eotaxin-1, interleukin-5, and interleukin-15 upregulates eosinophils. Once eosinophils get recruited in the intestinal epithelium, they become cytotoxic by producing factors major basic protein, an eosinophil-derived neurotoxin, eosinophilic cationic protein, and eosinophilic peroxidase.[rx][rx][rx][rx]
Other possible factors contributing to the pathophysiology include increased serum thymic stromal lymphopoietin (TSLP), interleukin-33 levels, and overactivation of TH17; however, it necessitates further study to define their exact roles.[rx][rx]
Causes of Eosinophilic Gastrointestinal Disorders
The exact cause of eosinophilic gastroenteritis is unknown. Some cases of this disease may be caused by a hypersensitivity to certain foods or other unknown allergens. Often, a family history of allergy is present. Atopy (asthma, hay fever or eczema) is present in a subset of patients. Food allergies are common.
Although the data is limited, research shows that food allergies, inflammatory conditions, infections, malignancy, and some medications like gold therapy, azathioprine, enalapril, carbamazepine, and antitumor necrosis factor can trigger the inflammatory process.[rx][rx]
Symptoms of Eosinophilic Gastrointestinal Disorders
The Eosinophilic Gastrointestinal Disorders symptoms are
EG typically presents with a combination of chronic nonspecific GI symptoms which include abdominal pain, diarrhea, occasional nausea and vomiting, weight loss and abdominal distension. Approximately 80% have symptoms for several years;[rx] a high degree of clinical suspicion is often required to establish the diagnosis, as the disease is extremely rare. It doesn’t come all of a sudden but takes about 3–4 years to develop depending upon the age of the patient. Occasionally, the disease may manifest itself as an acute abdomen or bowel obstruction.[rx][rx]
- Mucosal EG (25–100%) – is the most common variety,[rx][rx] which presents with features of malabsorption and protein-losing enteropathy. Failure to thrive and anemia may also be present. Lower gastrointestinal bleeding may imply colonic involvement.
- Muscular EG (13–70%) – present with obstruction of the gastric outlet or small intestine; sometimes as an obstructing caecal mass or intussusception.
- Subserosal EG (4.5% to 9% in Japan and 13% in the US) – [rx] presents with ascites which is usually exudative in nature, abundant peripheral eosinophilia and has favorable responses to corticosteroids.
Other documented features are cholangitis, pancreatitis,[rx] eosinophilic splenitis, acute appendicitis and giant refractory duodenal ulcer. Eosinophilic gastroenteritis may affect any part of the gastrointestinal tract from the esophagus to the rectum.
- Dysphagia (sometimes presenting as food impaction),
- Abdominal pain,
- Nausea, vomiting,
- Weight loss, and
- Bloating (ascites is possible).
- The particular symptoms present in each person depend upon the layer and the location of involvement. Most commonly, the stomach wall and the small bowel are involved.
- Mucosal involvement leads to protein-losing enteropathy and malabsorption. Muscle layer involvement causes abdominal pain, vomiting, dyspeptic symptoms and bowel obstruction.
- Subserosal involvement predominantly causes ascites with marked eosinophilia. Sometimes eosinophilic pleural effusion is present. Eosinophilic gastroenteritis is a chronic, waxing and waning condition.
Diagnosis of Eosinophilic Gastrointestinal Disorders
The Diagnosis of Eosinophilic Gastrointestinal Disorders are
Normally eosinophils are present throughout the gastrointestinal tract except esophagus. A study in the pediatric population revealed that the established eosinophilic density per high power field per mm2 showed no eosinophils in all biopsies from normal mucosa esophagus (total number=33).[rx]
There is no established cutoff to make a diagnosis of eosinophilic gastroenteritis. However, the following are the proposed numbers based on reported literature[rx]:
Stomach: greater than or equal to 30 eosinophils per high-power field in 5 HPF
Duodenum: greater than or equal to 30 eosinophils
Ileum: more than 56 per HPF in the ileum
Right colon: more than 100 per HPF
Transverse and descending colon: more than 84 per HPF
Rectosigmoid colon: more than 64 per HPF
History and Physical
The presentation of eosinophilic gastroenteritis depends on the extent and depth of eosinophilic infiltration. Detailed history, along with physical examination, is essential, as differential diagnosis may be broad.
Clinical features of eosinophilic gastroenteritis
The mucosal variant can present with nausea, vomiting, abdominal pain, diarrhea, and weight loss. The muscular variant can present with intestinal obstruction and perforation. And finally, the subserosal variant is rare and can present with ascites and abdominal distention.[rx][rx]
Eosinophilic gastroenteritis is a rare condition that can present with a variety of signs and symptoms. It is a diagnosis of exclusion and calls for ruling out secondary causes of eosinophilia like intestinal tuberculosis, parasitosis, and malignant neoplasm.[rx][rx][rx]
Some of the common laboratory findings include eosinophilia, hypoalbuminemia, elevated IgE levels, iron deficiency anemia. Some cases reported positive antinuclear antibodies, Charcot Leyden crystals in the stool.[rx][rx][rx][rx] Both eosinophilia and eosinophilic infiltration on mucosal biopsy samples during endoscopy are guiding steps towards diagnosis.[rx] Gross endoscopic findings may vary from nonspecific to mucosal erythema and ulceration. In contrast, CT scan is valuable in detecting GI wall abnormalities, including irregular narrowing, gut wall thickening, and ascites. Of note, the ascitic fluid analysis will be significant for elevated eosinophilic counts.[rx][rx]
Treatment of Eosinophilic Gastrointestinal Disorders
Eosinophilic Gastrointestinal Disorders and its treatment in various steroid-sparing agents e.g. sodium cromoglycate (a stabilizer of mast cell membranes), ketotifen (an antihistamine), and montelukast (a selective, competitive leukotriene receptor antagonist) have been proposed, centering on an allergic hypothesis, with mixed results.[rx][rx] Oral budesonide (an oral steroid) can be useful in treatment, as well.
Management in Adults
Some studies recommend empiric elimination diet in people with malabsorption. However, empirical food-elimination in the diet warrants further studies for long-term outcome and efficacy in adult patients.[rx][rx][rx][rx]
Glucocorticoids are the mainstay treatment for eosinophilic gastroenteritis. The dose of steroids should be tapered quickly over two weeks. The goal of the tapering dose of steroids is to treat severe symptoms, not tissue eosinophilia, because fibrosis is comparatively less common than eosinophilic esophagitis.[rx][rx][rx]
Based on the case reports, other therapies include:
Leukotriene inhibitors (montelukast)
Mast cell stabilizers (oral cromolyn)
Interleukin- 5 inhibitors
Proton pump inhibitor and Helicobacter pylori eradication
Proton pump inhibitor (PPI) treatment has been shown to improve the extent of duodenal eosinophilic infiltration in a patient with EGE, and the mechanism has been hypothesized to involve blockade of IL-4 and IL-13 activity[rx]. H. pylori eradication has also been postulated as capable of inducing a cure of EGE disease[rx]. The antibiotic clarithromycin, which is commonly used to treat H. pylori-related ulcers, is also known to have immunomodulatory effect, whereby its actions cause inhibition of T cell proliferation and induction of eosinophil apoptosis; these mechanistic actions in the immune system have led to clarithromycin being applied as maintenance therapy for patients with steroid dependent EGE who are in remission[rx].
Many dietary strategies have been proposed for management of EGE based on results from food allergy tests. In general, when a limited number of food allergens is detected, patients should be maintained on a “targeted elimination diet” (TED). When many or no allergens are identified, the more aggressive “empiric elimination diet” or “elemental diet” can be used. Lucendo et al[rx] investigated dietary treatment efficacy in EGE through a systematic review and found significant improvement in most cases, especially in those who undertook the elemental diet, which induced clinical remission in > 75% of cases. However, the validity of such a high efficacy rate was questionable since no confirmation of histologic response was available for the majority of cases included in the review. On the other hand, the authors noted that dietary measures were predominantly considered in the setting of mucosal disease, which is well known to be associated with food allergy, while the efficacy in muscular and serosal types, which show weaker linkage to food allergy[rx], was only rarely reported. In addition, patients’ adherence and tolerability to such strategies remain an important drawback, especially when empiric elimination or elemental diets are used.
Thus, we suggest the TED for all EGE patients who show few food allergens upon testing. The overall data in the literature is insufficient to recommend empiric and total elimination diets in routine management; however, an elemental diet can be used initially as adjunct treatment for severe cases.
Prednisone remains the mainstay for induction of remission of EGE. While most of the case series reported have shown a response rate to prednisone (up to 90%)[rx,rx], the most recent reports showed remarkably lower values (only 50%). This steroid acts by inducing eosinophil apoptosis and inhibiting chemotaxis. The recommended initial dose of 0.5 to 1 mg/kg usually induces remission within a 2 wk period, with the most dramatic response occurring in patients with the serosal type[rx]. Thereafter, tapering dosage over a 6 to 8 wk period is recommended. Re-evaluation of the EGE diagnosis (and type) must be considered in cases of initial unresponsiveness[rx]. Steroid dependent disease reportedly accounts for about 20% of cases[rx] and, consequently, low doses of prednisone may be needed to maintain remission. Unfortunately, long-term steroid treatment predisposes some patients to serious side effects; in such cases, steroid-sparing agents can be of benefit.
Budesonide, a common steroid treatment of Crohn’s disease and ulcerative colitis, has a high affinity for steroid receptors and produces fewer side effects due to its lower systemic impact. It has also been demonstrated as effective for induction and maintenance of remission in the majority of reported cases [rx,rx,rx–rx]. The usual dose is 9 mg/d, which can be tapered to 6 mg/d for use as prolonged maintenance therapy. The better safety profile of budesonide, compared to other steroid drugs, is of particular benefit for the management of EGE cases over the long term, especially in the setting of steroid-dependent disease.
Azathioprine, a common immunosuppressive agent used in organ transplant and patients with autoimmune diseases, is an immunomodulator that induces apoptosis of T and B cells. The efficacy of this steroid-sparing agent has been demonstrated in patients with steroid-dependent and refractory EGE disease. The usual dose for EGE patients is similar to that used in patients with IBD (2-2.5 mg/kg)[rx,rx,rx]; lower doses may not be effective[rx].
Montelukast sodium, commonly used to treat asthma, is selective leukotriene (LTD4) inhibitor with demonstrated efficacy for various eosinophilic disorders, including EGE. The majority of reports in the literature concerning its use in EGE (Table [rx,rx,rx,rx,rx,rx–rx] have shown significant clinical response in patients, either when the drug is used alone or in combination with steroids for induction and maintenance of remission in steroid-dependent or refractory disease. The usual dose is 5-10 mg/d.
Oral cromolyn sodium
Oral cromolyn sodium is a mast cell stabilizer that blocks the release of immune mediators and the subsequent activation of eosinophils. While it has been shown to have significant efficacy in many of the reported cases of EGE, its effect was only modest in others, for unknown reasons [rx,rx,rx–rx]. The usual dose is 200 mg tid or qid.
Ketotifen is a 2nd-generation H1-antihistamine agent that also modulates the release of mast cell mediators. Melamed et al[rx] described 6 patients with EGE who responded clinically and histologically to ketotifen; however, Freeman et al[rx] reported a single case in which the drug failed to maintain disease remission. This agent has also been proposed as an adjunct to steroids and montelukast for treating refractory EGE[rx]. The usual dose is 1-2 mg twice daily.
Biologic agents have also been reported in some case studies of EGE. Mepolizumab (anti-IL5) was reported to have improved tissue and peripheral eosinophilia, but without relieving symptoms, in 4 patients with EGE[rx]; unfortunately, another report associated its use with rebound hypereosinophilia[rx]. Omalizumab (anti-IgE) was reported to similarly result in a significant histologic response[rx] but to be unlikely to efficiently treat EGE patients with a serum IgE level > 700 kIU/L[rx]. Infliximab (anti-TNF) was reported as highly effective for inducing remission in refractory EGE, but its use is limited by the development of resistance and secondary loss of response, both of which can be managed by switching to adalimumab[rx].
Surgery is indicated in cases of severe disease that are complicated by perforation, intussusception or intestinal occlusion. It has been reported that about 40% of EGE patients may need surgery during the course of their disease, and about half of those may experience persistent symptoms postoperatively[rx].