Eosinophilic gastroenteritis

Eosinophilic gastroenteritis also known as allergic or eosinophilic allergic gastroenteropathy, is a rare benign inflammatory gastrointestinal (GI) disease affecting both children and adults that is characterized by eosinophilic infiltration of the bowel wall, with the stomach and small intestine being the most commonly affected areas and rarely the colon ¹. Eosinophilic gastroenteritis may or may not be accompanied by higher counts of eosinophils in the peripheral blood. However, peripheral blood eosinophilia is present in about 70% of cases, with higher levels in patients with mucosa-predominant pattern and at greater risk of relapse ². Because the symptoms are very similar to other gastrointestinal disorders, eosinophilic gastroenteritis has been often underdiagnosed and thus considered a rare disorder. Till now only about 300 cases have been reported in the literature ³

Eosinophilic gastroenteritis prevalence in the US is estimated to range from 8.4 to 28 cases per 100,000 people ⁴ and it can occur at any age from infancy to the seventh decade, but it typically peaks between the third and fifth decade of life ⁵. In 1970, Klein et al ⁶ classified eosinophilic gastroenteritis according to the anatomical location of eosinophilic infiltration in the different layers of the intestinal wall into three subtypes: mucosal, muscular and serosal.

Mucosal eosinophilic gastroenteritis is the most common variety, seen in about 57% to 100% of cases ⁷ and presents with features of abdominal pain, nausea, vomiting, dyspepsia, diarrhea, malabsorption, or protein-losing enteropathy, which in turn may cause hypoalbuminemia, anemia, and weight loss. Additionally, the occurrence of lower-gastrointestinal bleeding may imply colonic involvement ⁸. Involvement of the muscular layer occurs in 30%–70% of all eosinophilic gastroenteritis cases, and may cause bowel-wall thickening and intestinal obstruction. Also, it can present as an obstructing cecal mass or intussusception. Patients with muscular eosinophilic gastroenteritis often have cramps and abdominal pain associated with nausea and vomiting ⁹. The serosal type is the least common, with an estimated prevalence of 4.5%–9% in Japan and 13% in the US ¹⁰ and causes peritoneal irritation that leads to eosinophilic ascites and abundant peripheral eosinophilia, peritonitis, and perforation in more severe cases ¹¹. Intestinal intussusceptions may occur in the serosal type too ¹². Furthermore, Chang et al ¹³ observed that the muscular and serosal types are associated with concomitant mucosal eosinophilic infiltration,8 suggesting centrifugal disease progression from the mucosa toward muscular and serosal layers.

What triggers such dense infiltration in eosinophilic gastroenteritis is not fully elucidated yet. It is possible that different pathogenetic mechanisms are involved, such as hypersensitivity to allergens. Some studies have reported that about 45%–63% of patients diagnosed with eosinophilic gastroenteritis had a history of allergies, such as asthma, rhinitis, drug or food allergies,and eczema ⁴, while others have found an association with other autoimmune conditions, such as ulcerative colitis ¹⁴, celiac disease ¹⁵ and systemic lupus erythematosus ¹⁶. However, the latter are quite questionable, because the definition of eosinophilic gastroenteritis requires the exclusion of secondary causes of gut eosinophilic inflammation (inflammatory bowel disease, autoimmune disease, and malignancies). Altogether, these data suggest that eosinophilic gastroenteritis may result from immuno-dysregulation in response to an allergic reaction. Furthermore, 64% of reported cases include a family history of atopic diseases, suggesting a possible hereditary component (genetic factors) as a risk factor ¹⁷. Finally, other environmental factors, such as parasitic infestation or drugs, have been suggested to act as predisposing factors too ¹⁸. In the allergic subtype of the disease, it is thought that food allergens cross the intestinal mucosa and trigger an inflammatory response, which includes mast-cell degranulation and recruitment of eosinophils ¹⁹.

New recent evidence suggests that mucosal eosinophilia is relatively common in patients with functional dyspepsia ²⁰, in both adults ²¹ and children ²². Du et al ²⁰ conducted a pilot study demonstrating that functional dyspepsia is directly correlated with increased infiltration of degranulated eosinophils, supporting early clinical evidence of a role of eosinophils in functional dyspepsia pathogenesis ²². Aro et al ²³ also found evidence of duodenal eosinophilia associated with dyspepsia among other factors that are commonly associated to eosinophilic gastroenteritis as well. A case series of patients with functional dyspepsia in whom eosinophilic gastroenteritis was established to be the correct diagnosis after further investigation was reported by Australian researchers ²⁴. Interestingly, patients with functional dyspepsia show low-grade gastrointestinal eosinophilia ²⁵. All these studies together suggest that functional dyspepsia may either be another eosinophil-mediated disease or a mild form of eosinophilic gastroenteritis, especially if we consider that drugs used for the treatment of eosinophilic gastroenteritis have also been found to be therapeutic in this population ²⁶.

Eosinophilic gastroenteritis can present with various gastrointestinal manifestations depending on the specific site and specific layer of the gastrointestinal tract involved. Majority of the cases involve stomach and proximal small bowel. The natural history of eosinophilic gastroenteritis has not been well documented. Eosinophilic gastroenteritis is a chronic, waxing and waning condition. Mild and sporadic symptoms can be managed with reassurance and observation, whereas disabling gastrointestinal (GI) symptom flare-ups can often be controlled with oral corticosteroids. When the disease manifests in infancy and specific food sensitization can be identified, the likelihood of disease remission by late childhood is high. Gastrointestinal obstruction is the most common complication. Fatal outcomes are rare.

The diagnostic criteria include demonstration of eosinophilic infiltration of bowel wall, lack of evidence of extra intestinal disease and exclusion of other causes of peripheral eosinophilia ²⁷.

Eosinophilic gastroenteritis causes

The cause of eosinophilic gastroenteritis remains unknown. Eosinophilic gastroenteritis is usually encountered in patients with a history of atopy or food allergies.

Patients with eosinophilic gastroenteritis have elevated IgE and eosinophilia of tissue and blood. An imbalance in the T-cell paradigm causing an increase in the production of IL-13, IL-4, and IL-5 and cytokines has been postulated as the cause of IgE synthesis and eosinophilia ²⁸.

In one study, immunohistochemistry detected IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 in the granule matrix of eosinophils, the release of which is thought to be involved in the perpetuation of intestinal eosinophil infiltration and inflammation.

Eosinophilic gastroenteritis symptoms

Patients with eosinophilic gastroenteritis may have various clinical presentations depending on the region of the gastrointestinal tract involved and the depth of the bowel wall involvement. The disease most often involves the stomach and the small bowel. A history of atopy and allergies is present in many of the cases ²⁹. Approximately 50% of patients have a history of atopy (eg, hay fever, asthma, food allergy). In children, a history of allergy is even more common.

Children and adolescents can present with growth retardation, failure to thrive, delayed puberty, or amenorrhea. Adults have abdominal pain, diarrhea, or dysphagia.

Patients with muscle layer involvement typically present with pyloric or intestinal obstruction. The eosinophilic involvement often is localized to the stomach but can involve the small bowel. Cramping and abdominal pain associated with nausea and vomiting occur frequently. Food allergy and past history of allergy are less common in these patients than in patients with mucosal layer disease.

Involvement of the serosal layer is the least common form of the disease. The entire GI wall usually is involved. These patients typically present with eosinophilic ascites. Serosal and visceral peritoneal inflammation leads to leakage of fluids.

Rarely, eosinophilic gastrointestinal disease may be associated with autoimmune connective tissue disease ³⁰.

• The mucosal form of eosinophilic gastroenteritis is characterized by vomiting, dyspepsia, abdominal pain, diarrhea, blood loss in the stools, iron deficiency anemia, malabsorption, protein-losing enteropathy, and failure to thrive.
• The muscularis form, characterized by infiltration of eosinophils predominantly in the muscularis layer, may present with gastrointestinal obstructive symptoms mimicking pyloric stenosis or gastric outlet syndrome.
• The serosal form, which is less common, presents with significant bloating, exudative ascites, and higher peripheral eosinophil counts.

Eosinophilic gastroenteritis complications

Some patients with eosinophilic gastroenteritis may present with bloody diarrhea, mimicking inflammatory bowel disease. Another complication includes intestinal perforation, which usually requires surgical repair ²⁸. Extraintestestinal presentations can also occur, such as eosinophilic hepatitis, cholecystopancreatitis with bile duct dilatation obstruction and jaundice.

Eosinophilic gastroenteritis diagnosis

In 1990, Talley et al ⁵ suggested three criteria for the diagnosis of eosinophilic gastroenteritis, which are still used widely:

1. Presence of gastrointestinal symptoms,
2. Histological demonstration of eosinophilic infiltration into the gastrointestinal tract or presence of high eosinophil count in ascetic liquid (serosal disease),
3. And exclusion of other causes of tissue eosinophilia ³¹.

Interestingly, peripheral count is an insensitive marker for mucosal eosinophilia in functional gastrointestinal disorders ³².

History and clinical exams

Because there is no gold standard for eosinophilic gastroenteritis, a wide variety of diagnostic criteria are presented. After a detailed history of patients, including history of food or drug allergies, concomitant atopic diseases, and family history of allergies, and physical examination, thorough evaluation of the patient is necessary, starting with laboratory evaluation.

A complete blood count plays an important role in raising suspicion of eosinophilic gastroenteritis. Peripheral blood eosinophilia is present in about 70% of cases, with higher levels in patients with mucosa-predominant pattern and at greater risk of relapse ². The absolute eosinophil count is used to categorize the disease in mild (absolute eosinophil count, 600–1,500 eosinophils (eos)/μL), moderate (absolute eosinophil count, 1,500–5,000 eosinophils/μL), and severe (>5,000 eosinophils/μL). Iron-deficiency anemia may be evident and hypoalbuminemia present, especially in patients with mucosal involvement. Total serum IgE ≥100 IU/mL is reportedly present in about two-thirds of eosinophilic gastroenteritis cases ³³. Erythrocyte-sedimentation rate (ESR) has been reported elevated in a few cases ⁹.

To identify the inability to digest and adsorb proteins in the gastrointestinal tract, fecal protein loss is assessed by measuring the levels of α1-antitrypsin in a 24-hour feces collection. Normal α1-antitrypsin level is 0–54 mg/dL, and is highly increased in the feces of patients with eosinophilic gastroenteritis. Protein loss can also result in low levels of immunoglobulins, but serum IgE may stay elevated. Furthermore, stool examination should be performed to rule out parasitic infections (ie, Strongyloides, Ascaris, Ancylostoma, Anisakis, Capillaria, Toxicara, Trichiura, andTrichinella spp.) ³⁴. Mild–moderate steatorrhea is present in about 30% of patients, and can be detected by qualitative and quantitative stool tests. Finally, some reports of eosinophilic gastroenteritis cases have demonstrated the presence of exudative fluid with net eosinophilic predominance reaching about 90% of white blood cells in the peritoneal fluid ³⁵.

Endoscopic and imaging studies

The next step toward diagnosis requires either endoscopy or imaging studies.

The gross endoscopic appearance of eosinophilic gastroenteritis includes normal aspect, erythematous, nodular, friable, and often ulcerated mucosa ¹¹, pseudopolyps, and polyps ³⁶. Sometimes, diffuse inflammation with complete loss of villi, infiltration of the gastrointestinal wall, submucosal edema, and fibrosis may be present ³⁷. Although findings from endoscopic biopsies can play an important role in diagnosis ¹¹, endoscopy remains not sensitive or specific for diagnosis of the disease. Furthermore, the patchy distribution of eosinophilic infiltrates requires multiple biopsy specimens, at least five or six, from normal and abnormal mucosa to avoid the possibility of sampling error and missing a diagnosis ⁷. In patients with esophageal or colonic symptoms, additional biopsy specimens may be obtained from relevant sites to aid in the diagnosis. Endoscopic ultrasound is useful for the assessment of muscular and subserosal types, as it utilizes a fine aspiration needle that facilitates access to these tissue sites ³⁸. Patients with serosal involvement also present with ascites ¹¹.

Radiographic changes are aspecific, variable, and/or absent in about 40% of patients. It is possible to observe enlarged gastric folds with or without nodular filling defects. In extensive disease strictures, ulceration or polypoid lesions may be present, and valvulae conniventes may be thickened and flattened. In muscular eosinophilic gastroenteritis, localized involvement of the antrum and pylorus may occur, causing narrowing of the distal antrum and gastric retention. The small intestine may be dilated, with an increase in thickness of the mucosal folds, while in the colon prominent mucosal folds may be observed ⁹. Ultrasound and computed tomography (CT) may show ascites, thickened intestinal walls, and occasionally localized lymphadenopathy ³⁹. However, similar changes are also observed in Crohn’s disease, lymphoma, and granulomatous disease ⁴⁰. A “halo sign” and “araneid limb–like sign” can be observed on CT as secondary to bowel-wall layering, and both can help in differentiating between an inflammatory and neoplastic lesion ⁴¹. Radioisotope scan with technetium (99mTc) hexamethylpropyleneamineoxime–labeled white blood cells provides a useful tool in assessing the extent of the disease and monitoring therapeutic response, but has little diagnostic value, as this method does not differentiate eosinophilic gastroenteritis from other causes of intestinal inflammation ⁴².

Biopsy and histopathological analysis

Histopathological examination of gastric and duodenal biopsies has a crucial role in diagnosing eosinophilic gastroenteritis ⁴³. Despite many tools being able to aid in the obtainment of biopsies, the most accurate method is surgery, which provides a full-thickness specimen for comprehensive pathology and facilitates diagnosis of muscular and serosal eosinophilic gastroenteritis ⁴⁴. Biopsies from both normally and abnormally appearing mucosa should be taken, because even normal areas can harbor a diagnostic microscopic appearance ⁴³. Normal eosinophil count varies based on the anatomic site of the gastrointestinal tract. In the duodenum, it is set at <10 eosinophils per high-power field (HPF) in pediatric patients and <19 eosinophils per high-power field (HPF) in adults ²¹. Therefore, a microscopic examination that reveals >10 eosinophils per high-power field (HPF) in children and >20 eosinophils per high-power field (HPF) in adults has been set in most reports as the threshold for fulfilling the second diagnostic criterion for mucosal eosinophilic gastroenteritis ¹⁷. However, in the cecum the threshold must be set at higher values, as up to 40 eosinophils per high-power field has been suggested to be normal at this site ⁴⁵ and up to 16 in the colons of pediatric patients71 and up to 50 in adults ⁴⁶. Furthermore, when evaluating the number of eosinophils, environmental factors need to be considered: eosinophil counts are higher during peak allergy seasons ⁴⁷ and among populations living in southern regions of the US ⁴⁸.

It has been noted that the presence of intraepithelial eosinophils and eosinophils in Peyer’s patches ⁴⁹, as well as extracellular deposition of eosinophil major basic proteins ⁵⁰, favor the development of eosinophilic gastroenteritis. Particularly, the latter finding reflects the degree of degranulation in activated eosinophils, which is linked to greater structural damage ⁵¹. Observations of crypt hyperplasia, epithelial cell necrosis, villous atrophy, or abscesses are also common in eosinophilic gastroenteritis. Mast-cell infiltrates and hyperplastic mesenteric lymph nodes infiltrated with eosinophils may be present ⁵².

Interestingly, evidence exists suggesting that the degranulation observed on histology may be affected by the method of tissue procurement during biopsy ⁵³. Particularly, increased eosinophil degranulation is observed in tissue obtained by endoscopic forceps compared to a scalpel.

Eosinophilic gastroenteritis treatment

Several therapeutic options have been suggested for eosinophilic gastroenteritis management: dietary modifications, steroids, leukotriene inhibitors, mast-cell stabilizers, immunomodulators, and biological agents. All these treatment approaches have been described in small case series or single reports, and to our knowledge only a double-blind randomized, crossover trial has evaluated the efficacy of a leukotriene inhibitor, montelukast, in pediatric patients ⁵⁴. However, more randomized prospective clinical trials to describe the efficacies of different treatments or predictors of response to one or another option have not been reported in the literature yet, and thus are warranted so that the effectiveness of the various treatments can be more robustly established and provide guidance to clinicians.

Thus far, treatment for eosinophilic gastroenteritis has been empirical and based on the severity of the clinical manifestations, as well as on clinicians’ experience. Patients with mild disease can be treated symptomatically ⁴³, while more symptomatic patients and those with evidence of malabsorption need more aggressive therapy.

Eosinophilic gastroenteritis diet

The strong association of eosinophilic gastroenteritis with food allergies has prompted the introduction of many dietary strategies based on results from food-allergy tests. When a low number of food allergens are identified, patients should be maintained on a targeted elimination diet, while when more or no allergens are detected, the “empiric elimination diet” or elemental diet might be used, which consist of the elimination of a single food or a combination of them.The empirical elimination of the six most common food antigens from the diet (also called six-food elimination diet or 6-FED) and 7-FED (excluding red meats also) have been frequently assessed in recent years ⁵⁵.

However, the role of dietary therapy as an approach is controversial. A systematic review by Lucendo et al ⁵⁶ investigated the efficacy of dietary treatment in eosinophilic gastroenteritis and found significant improvement in most cases, with clinical remission in >75% of patients who undertook the elemental diet.

Interestingly, the efficacy of dietary restrictions has mainly been reported in the setting of mucosal eosinophilic gastroenteritis ⁵⁶, which is well known to be associated with food allergy, while efficacy in muscular and serosal diseases, less linked to food allergies ⁵, was has been only rarely reported. However, the findings reported in the review by Lucendo et al ⁵⁶ were not supported by histopathological exams, which makes the validity of the dietary approach questionable. Most importantly, the authors concluded that unequivocal use of dietary treatment cannot be supported, due to the lack of well-designed, high-quality studies ⁵⁶.

On the contrary, a retrospective study of Chen et al ¹¹ indicated that an elimination diet can lead to clinical and histological improvement; however, in this study the dietary therapy was used in combination with other pharmacological interventions. More recently, a retrospective study by Wong et al ⁷ reported that one in 18 patients with eosinophilic gastroenteritis tested positive for a food allergy and had clinical improvement with an elimination diet, and follow-up endoscopy showed resolution of eosinophilic infiltration. Conversely, Yamada et al ⁵⁷ showed that the elemental diet caused rapid improvement insymptoms, but duodenal eosinophilic infiltration persisted. However, Katz et al ⁵⁸ reported that an elimination diet might fail to prevent recurrence.

The most solid evidence of the efficacy of the dietary approach to treat eosinophilic gastroenteritis has been provided in pediatric patients (<3 years of age) ⁵⁹. However, no randomized studies exist to assess their efficacy accurately, but only single or small case series (up to 12 patients) have been reported, in which the conclusions are considered weak because histological assessment is rarely reported. Notably, a retrospective study by Ko et al ⁶⁰ trialed different dietary therapies (elemental diet, 7-FED, and empirical avoidance of one to three foods) in 30 children with eosinophilic gastroenteritis. Despite 82% of patients having a positive clinical response, histological assessment was not available for most of them, making it difficult to extrapolate these data to larger populations ⁶⁰.

Recently, trials have been conducted in adults to evaluate the effectiveness of dietary therapy in eosinophilic gastroenteritis treatment. In 2009, a prospective trial ⁶¹ was conducted in adults with histological diagnosis of eosinophilic gastroenteritis and treated for 6 weeks with the 6-FED or elemental diet. The results were encouraging, as clinical and histological remission was observed in both groups. However, the number of patients involved was small and the placebo-control group was missing, and theus further trials are needed. Finally, a prospective interventional study ⁶² is ongoing to evaluate the effect of a 6-week elemental diet in adult patients (18–65 years of age) with eosinophilic gastroenteritis, and complete histological remission (<30 eosinophils/HPF) and improvement are set as primary and secondary outcomes, respectively.

The overall data in the literature is insufficient to recommend empirical and total-elimination diets in routine management; however, an elemental diet may be considered initially as an adjunct treatment for severe cases. Additionally, from the literature it appears clear that the later eosinophilic gastroenteritis appears during childhood, the worse it responds to dietary modification ². Finally, patient tolerability and adherence to such strategies are difficult to track, especially when empirical elimination or elemental diets are used. Therefore, future randomized controlled studies are required, and must include assessment of histological remission to better characterize the phenotype of patients with eosinophilic gastroenteritis who respond to dietary therapy.

Corticosteroids

Corticosteroid therapy is the mainstay of eosinophilic gastroenteritis treatment in both adults and children. Corticosteroids suppress the gene transcription of IL3, IL4, IL5, GM-CSF, and various chemokines ⁶³. In many studies, it has been proven that corticosteroids decreased both the number of eosinophils and the effects of their toxic products ¹³. The appropriate duration of steroid therapy is unknown, and relapse often necessitates long-term treatment. Unfortunately, this may cause serious adverse effects in some patients, and there is also the risk that resistance to corticosteroids may develop, as it is already known to occur in asthma with patients maintaining eosinophilia despite high doses of steroids ⁶⁴. These patients will require alternative approaches.

Although evidence to date demonstrates that corticosteroids are the most effective therapy for eosinophilic gastroenteritis, no randomized controlled studies are available to guide treatment. Reasons for that may be attributed to the fact that the low prevalence of eosinophilic gastroenteritis can make difficult to enroll a big number of patients that can go to trial.

Prednisolone

Prednisolone acts by inducing eosinophil apoptosis and inhibiting chemotaxis. Prednisolone is the first-choice corticosteroid for induction of remission of eosinophilic gastroenteritis, and has been reported to be effective in >90% of cases ¹³. Prednisolone is orally administered at an initial dose of 30–40 mg/day for 6–8 weeks with various schemes of dose tapering ⁶⁵. It induces complete remission of symptoms within 2 or 3 weeks of treatment, reducing eosinophilic tissue infiltration, blood hypereosinophilia, and controlling ascitis ¹³. Notably, Zhang et al ⁶⁶ showed that the highest response rate to prednisolone was among patients with the serosal type. Because of the long-term side effects, prednisolone is suspended after remission has been achieved. However, relapses can occur, and require low maintenance doses (1–10 mg/day) of prednisolone for a longer time9,14 or substitution of prednisolone with budesonide ⁶⁷. In cases of initial unresponsiveness, either reevaluation of eosinophilic gastroenteritis diagnosis and type ⁶⁸ or switching to a different pharmacological agent (budesonide or steroid-sparing agents) must be considered. Additionally, long-term steroid treatments can predispose patients to adverse effects that may not be tolerated well, and in such cases steroid-sparing agents can be beneficial.

Budesonide

Budesonide is commonly used for Crohn’s disease and ulcerative colitis. It reduces inflammation and capillary permeability by binding to steroid receptors with high affinity ⁶⁹. The advantage of budesonide is that it can be administered as a topically active corticosteroid, thanks to slow-release enteric-coated capsules (budesonide CIR [controlled ileal release]) and has high (90%) first-pass metabolism, which together produce fewer side effects, due to its lower systemic impact. There has been only one case ⁷⁰ in which the patient could not be treated with budesonide CIR [controlled ileal release] because of gastric involvement, and thusthe patient was treated with regular budesonide oral tablets for 2 weeks and showed remission >2 years.

Many studies have demonstrated that budesonide is effective for induction and maintenance of remission ⁷¹, accompanied by histological improvement ininflammatory alterations ⁷². Reed et al ¹⁷ showed that treatment with budesonide, administered either as viscous slurry or enteral release, induced remission in 61% of patients. However, the results were not analyzed based on the specific formulation of budesonide, and thus we are most likely missing a piece of information about the real effectiveness of budesonide in those cases analyzed. The usual dose is 9 mg/day, and can be tapered to 6 mg/day for prolonged use, as well as for maintenance therapy. Collectively, the efficacy and better safety profile of budesonide compared to other corticosteroids are of particular benefit for the long-term management of certain eosinophilic gastroenteritis cases.

Leukotriene-receptor antagonists

Leukotriene-receptor antagonists are a class of drugs commonly used to treat asthma that prevent or reverse some of the pathological features associated with the inflammatory process mediated by leukotrienes C4, D4, and E4. It has demonstrated efficacy for various eosinophilic disorders, including eosinophilic gastroenteritis.

Montelukast sodium

Montelukast sodium is a potent and selective leukotriene D4 inhibitor at the cysteinyl leukotriene receptor CysLT1 ⁷³. The usual dose is 5–10 mg/day, shown to be effective either alone ⁷⁴ or in combination with a low dose of steroids ⁷¹ for induction and maintenance of remission in steroid-dependent or -refractory disease in both adults and children ³⁴. The majority of reports in the literature concerning its use in eosinophilic gastroenteritis have shown exciting results. Indeed, positive clinical and histological responses were achieved in a majority of patients within 2–4 weeks from the beginning of treatment ³⁵, with remission of at least 12 months ³⁴. Moreover, three case reports have displayed successful steroid tapering of steroid-dependent patients with eosinophilic gastroenteritis once montelukast sodium had begun ³³. Daikh et al ⁷⁵ commented on the reduction of eosinophilia with montelukast, but the absence of any symptomatic relief, in a patient with eosinophilic gastroenteritis. Tien et al ³³ observed that three patients treated with an leukotriene antagonist alone had a good outcome without relapse during follow-up. On the other hand, only two studies have shown a lack of montelukast efficacy in patients ⁷⁶. More randomized trials are required to assess the long-term benefits and side effects of leukotriene antagonists in eosinophilic gastroenteritis.

Mast-cell stabilizers

Mast-cell stabilizers block mast-cell degranulation, stabilizing the cells and thereby preventing the release of histamine and related mediators, which are hypothesized to be involved in the pathogenesis of eosinophilic gastroenteritis.

Sodium cromoglycate or cromolyn

Oral sodium cromoglycate or cromolyn blocks the release of such mediators as histamine, leukotrienes, and others from mast cells that attract inflammatory cells, including eosinophils. The dose used has been different among different reports, ranging from 100 mg to 300 mg three or four times daily and the duration of treatment may vary from 10 weeks to over a year ³⁴. These differences can be imputable to the severity of the disease at the moment of diagnosis. Studies on sodium cromoglycate efficacy are controversial, as it has been found effective in many cases, with complete clinical and histological remission ⁷⁷, but not in others ⁷⁸. Considering that in these studies, both responsive and unresponsive patients to sodium cromoglycate had similar features in terms of the intestinal layer (~90% vs muscular eosinophilic gastroenteritis) and site involved (~64% stomach and duodenum), we can hypothesize that the underlying pathogenic mechanism of eosinophilic gastroenteritis in unresponsive patients does not involve mast-cell degranulation. However, altogether the results provide evidence of sodium cromoglycate efficacy in the treatment of eosinophilic gastroenteritis and suggest its employment as an alternative to the steroids commonly used.

Antihistamines

Ketotifen

Ketotifen is a first-generation H1 antihistamine ⁷⁹ and mast-cell stabilizer ⁸⁰, as it also modulates the release of mast-cell mediators. It is used at a dose of 1–2 mg twice dailybid. Thus far, there have been few studies on the use of ketotifen, and with contrasting results. Melamed et al ⁸¹ described six patients with eosinophilic gastroenteritis who responded clinically and histologically to ketotifen. The same result was achieved in the single case report described by Bolukbas et al ⁸². On the other hand, Freeman et al ⁸³ reported a single case in which the drug provided only symptomatic benefits, with prompt clinical relapse when the treatment was interrupted. Furthermore, despite the use of ketotifen, endoscopic abnormalities persisted and appeared to progress. This agent has also been proposed as an adjunct to steroids and montelukast for treating refractory eosinophilic gastroenteritis in pediatric patients ³³. In that study, one patient had a good prognosis, while another did not improve in any symptoms. Finally, it is hard to make conclusions about the use of ketotifen in eosinophilic gastroenteritis, as it has never been used as monotherapy.

Overall, given the natural history of eosinophilic gastroenteritis, it is not clear if the remissions described in individual case reports were due to medications or spontaneous remission. Studies to date do not support use of leukotriene-receptor antagonists, cromolyn, proton-pump inhibitors (PPIs), or ketotifen as monotherapy for eosinophilic gastroenteritis. However, if patients have comorbid conditions for which they are indicated, evidence demonstrates they are unlikely to be harmful.

Surgical care

Surgical treatment is avoided as far as possible; however, it is necessary in cases of severe eosinophilic gastroenteritis that are complicated by perforation, intussusception, or intestinal occlusion or when performing a full-thickness intestinal biopsy to establish the diagnosis. It has been reported that about 40% of eosinophilic gastroenteritis patients may need surgery during the course of their disease, and about half of those may experience recurrence, even after surgical excision ⁸⁴.

Eosinophilic gastroenteritis prognosis

The natural history of eosinophilic gastroenteritis has not been well documented. Although eosinophilic gastroenteritis is reported to wax and wane, no changes in survival rate have been observed, whereas growth alterations were seen in children and adolescents ⁸⁵. However, when eosinophilic gastroenteritis manifests in infancy and specific food sensitization can be identified, the likelihood of disease remission by late childhood is high.

Mild and sporadic symptoms can be managed with reassurance and observation, whereas oral corticosteroids can control disabling gastrointestinal symptom flare-ups and reduce blood and tissue eosinophil levels, but in certain cases they can reappear if the treatment is stopped. Dietary management and steroid-sparing agents are necessary to lower the collateral effects of steroid use and maintain an adequate quality of life. Altogether, follow-up studies in small case series and retrospective studies have demonstrated that eosinophilic gastroenteritis has a good prognosis and is not associated with malignancy.

There are very few published studies on the natural progression of eosinophilic gastroenteritis. In a retrospective study of 43 patients over a mean duration of 13 years, De Chambrun et al ⁸⁶ noted three patterns: 42% of patients suffered a single outbreak of eosinophilic gastroenteritis shorter than 3 months, 37% patients experienced intermittent flares, and 21% had persistent active symptoms.

Morbidity and mortality

Morbidity includes malnutrition and intestinal obstruction and perforation​. Fatal outcomes are rare, gastrointestinal obstruction is the most common complication, and the risk of cancer is not increased.

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