Introduction
Primary eosinophilic gastrointestinal disorders (EGID) are defined as diseases characterized by eosinophilic infiltration of the gastrointestinal wall in the absence of other known causes of tissue eosinophilia. Depending on the affected segment of the gastrointestinal tract, eosinophilic esophagitis (the most common form of EGID), eosinophilic gastritis and/or enteritis, and eosinophilic colitis are distinguished. Primary EGIDs are allergy-related [1].
Eosinophilic esophagitis (EoE) is a Th2 cell-driven disease caused by antigens in which chronic eosinophil-rich inflammation leads to esophageal dysfunction. Symptoms may include heartburn, regurgitation, vomiting, difficulty swallowing, food impaction and abdominal pain [2]. EoE was initially considered a rare condition. EoE is now recognized as a significant and increasingly common cause of upper gastrointestinal symptoms in both children and adults, with its incidence having markedly increased in the early 21st century [3]. To accurately diagnose a patient, it is important to distinguish between EoE and gastroesophageal reflux disease (GERD) as both conditions can cause similar clinical symptoms [4]. EoE is a secondary health problem that comes from a number of upper respiratory tract diseases that occur worldwide. This challenge places a heavy burden on the healthcare system [5]. EoE can reduce the quality of life of patients. This is due to, among others, restrictive diets and the need for regular endoscopic examinations [6]. Over the past decades, awareness of EoE has grown significantly, establishing it as a recognized inflammatory disease of the esophagus worldwide. EoE is considered the second most common cause of reflux-like symptoms after GERD and feeding difficulties in children, and it is commonly associated with food impaction and difficulty swallowing in adults. The condition affects approximately 4 in every 10,000 people, with males being three times more likely to be affected than females [7]. Eosinophilic gastritis and duodenitis are inflammatory diseases characterized by eosinophilic infiltration of the gastrointestinal wall. The mucous membrane and the muscle layer are affected [8]. Eosinophilic gastritis and duodenitis occur in people of all ages, from infants to the elderly, but most often affects people aged 30 to 50. There is also a slight preponderance of cases in men. Although cases of this disease have been reported worldwide, their exact incidence is not well established. Between January 1970 and July 2003, 31 new cases of eosinophilic gastroenteritis in Seoul were reported [9]. Eosinophilic colitis (EoC) is a rare primary eosinophilic disease of the gastrointestinal tract, characterized by two peaks of incidence - in neonates and young adults. Compared to the increasingly diagnosed eosinophilic esophagitis, EoC remains largely unknown. The clinical picture of EoC is very diverse and depends on whether the dominant inflammation occurs in the mucosa, in the entire thickness of the intestinal wall, or in the serous layer [10]. EoC is a rare condition with no specific diagnostic criteria, which makes it difficult to make a diagnosis. Typical symptoms of EoC include pain, cramps, diarrhea and weight loss. Because the presence of eosinophils in the colon may be associated with allergies, inflammatory bowel disease (IBD), and parasitic infections, the diagnosis of EoC requires the exclusion of other causes and correlations between colonic and laboratory results [11].
Eosinophilic esophagitis
EoE is the most common EGID [12]. It is an antigen-mediated Th-2-type inflammatory disease influencing the esophagus [13, 14]. Commonly, patients with EoE suffer from other allergic diseases such as allergic rhinitis, asthma and atopic dermatitis [5, 14, 15]. Presence of EoE in families increases an individual’s risk [5]. As it is an allergic disease, food and environmental allergens can stimulate EoE [16]. Chehade et al. have reported that out of 705 EoE patients, 90.6% had an allergic disorder with 67% having a food allergy, 60.3% – allergic rhinitis, 46.4% – atopic dermatitis, 45.4% – asthma, 31.2% – allergic conjunctivitis, 26.2% – urticaria, 27.1% – food anaphylaxis and 13.2% – angioedema [17]. Smoking and alcohol consumption does not amplify the risk of EoE [14]. The disease can appear at any age and is more frequent in Caucasians and in males. It has been reported that a remodeling of the epithelium, lamina propria, vasculature and deeper esophageal layer, as well as esophageal dysmotility may occur [18]. The symptoms of EoE are non-specific and can vary. Therefore EoE is often misdiagnosed. Patients can meet diagnostic delays because of the delay in referral to the gastroenterologist, delayed esophagogastroduodenoscopy and insufficient biopsy collection for histopathologic analysis [19]. A common manifestation of EoE in adults is esophageal dysphagia. Heartburn and non-cardiac chest pain can be present. Patients often involuntarily change their eating habits in order to reduce symptoms [5]. To describe this behavior an IMPACT acronym has been created. Symptoms expressed in the acronym include: imbibe fluids with meals, modifying food, prolonged mealtimes, avoidance of hard textured foods, chewing excessively, turning away pills. Young children’s symptoms include feeding difficulties, regurgitation and faltering growth. Therefore, in this age group EoE has similar symptoms to GERD. In consequence they are treated with anti-GERD medications such as proton pump inhibitor (PPI) [20]. Endoscopy is a crucial diagnostic method of EoE [21]. In the endoscopic image EoE is often manifested by crêpe paper mucosa, mucosal rings, longitudinal furrowing, white exudates and edema [5, 14]. An EoE endoscopic reference score (EREFS) has been created. It includes the following discoveries: edema, rings, exudates, furrows and strictures. Edema, exudates and furrows are characteristic of inflammation, whereas rings and strictures of fibrostenosis [5, 14, 21]. Higher numbers of intraepithelial eosinophils can be detected in the esophagus. Elevated collagen deposition in the lamina propria can lead to the presence of rings and strictures [5, 14]. The diagnosis of EoE is based on three criteria: symptoms characteristic to the dysfunction of esophagus, peak eosinophil value of ≥ 15 eosinophils per high-power field and exclusion of different diseases with eosinophilia in esophagus, such as GERD, Crohn’s disease, achalasia, pill esophagitis, connective tissue diseases, infections, hypereosinophilic syndrome, drug hypersensitivity [22]. The level of esophageal eosinophils is not a reliable marker of disease severity as similar eosinophils levels can be detected in different stages of the disease [21]. Untreated and long lasting EoE causes fibrosis with wall thickening with unnatural frailty and strictures, which can lead to complications such as acute food bolus impaction [14]. The Index of Severity for Eosinophilic Esophagitis (I-SEE) has been created to determine the severity of EoE. It consists of symptoms and complications, inflammatory and fibrostenotic features. Here the symptom severity should be defined by its frequency, the inflammatory features by both histologic methods and endoscopic images of edema, furrows, exudates; and the fibrostenotic features by images of esophageal rings and strictures in the endoscopy [21]. EoE is treated by dietary lifestyle changes and/or medications [23]. The treatment plan is individualized for each patient depending on their age, food allergies, general health and the severity of the disease [19]. Introducing a diet is an important therapeutic option and can be a successful long lasting treatment. There are three diet strategies: an elemental diet, targeted elimination diet and an empiric elimination diet. Empiric elimination diet is an important aspect of the treatment as it showed a 74% histologic remission of EoE in children with similar results in adults [2, 14]. A “six food elimination diet” (6FED) can be introduced, in which patients should abstain from eating dairy, wheat, eggs, soy, peanuts, tree nuts, fish and shellfish [5, 14]. In 6FED a reintroduction of these products requires endoscopies [14]. Another dietary method is starting with a 2-food elimination diet (2FED) – in which patients avoid dairy and wheat – and later proceed to a 4FED (elimination of dairy, wheat, eggs and soy) and to a 6FED [22]. The usage of PPI was formerly a diagnostic method of EoE, however PPIs are currently a primary treatment. PPIs are overall safe to use, yet the response is lower than in steroid treatment. Swallowed topical steroids (STS), such as budesonide, are a popular line of therapy [23]. STS were found to be prosperous in EoE treatment in children after an unsuccessful proton pump inhibitor (PPI) treatment. STS can also be used as an adjunct to PPI therapy [24]. A maintenance therapy is recommended as there is a high relapse rate after terminating STS therapy [13]. Long-term side effects of STS can include Candida infections in oropharynx and esophagus, adrenal insufficiency [5, 23]. Esophageal dilation may be necessary in cases of persistent dysphagia, yet it does not affect underlying eosinophilic inflammation [5, 14]. In this treatment Savary dilators, bougie or hydrostatic balloons are used. A monoclonal antibody, dupilumab, blocks IL-14 and IL-13 signaling. These pathways are present in EoE. The usage of dupilumab showed propitious in relieving symptoms, histological and endoscopic manifestations [19]. More research is needed for other targeted biologics such as mepolizumab, an IL-5 antibody. Phase 2 or 3 trials revealed notable histologic response rates in comparison to placebo, yet the symptom response was not notably higher than placebo [22]. Omalizumab, a monoclonal antibody targeting IgE, has demonstrated effectiveness in reducing the need for inhaled and oral corticosteroids and alleviating asthma symptoms in patients with allergic asthma. However, in a study involving patients with eosinophilic esophagitis (EoE), omalizumab did not lead to any significant improvement in symptoms or a decrease in tissue eosinophil levels compared to placebo [22, 25].
Eosinophilic gastritis and duodenitis
Eosinophilic gastritis and duodenitis are uncommon conditions characterized by inflammatory infiltrates in the gastrointestinal wall, predominantly composed of eosinophils. According to existing studies, patients with eosinophilic gastritis and duodenitis commonly present with concurrent allergic diseases like rhinitis, asthma, food allergies, or eczema/atopic dermatitis. Peripheral eosinophilia and/ or esophageal eosinophilia often accompany these conditions. More severe instances may involve malabsorption or protein-losing enteropathy symptoms [26]. The symptoms of eosinophilic gastritis and duodenitis can significantly affect the quality of life of patients. The clinical manifestations are varied and depend on the location of eosinophilic infiltration and the affected layers of the gastrointestinal wall. Eosinophilic gastritis and duodenitis are generally categorized into three types: mucosal, muscular, and serosal disease. All of these disease phenotypes can manifest as abdominal pain [25]. Mucosal involvement, the most frequently occurring form, can result in symptoms such as abdominal pain, vomiting, nausea, and weight loss. When the muscular layer is affected, it leads to thickening of the gut wall, which may cause gastrointestinal obstruction. Serosal involvement is the rarest form and is often associated with pleural effusion and ascites. These three types can also occur concurrently [25, 27].
There are three diagnostic criteria for eosinophilic gastritis and duodenitis in adults, which are commonly used: the presence of gastrointestinal symptoms, histological evidence showing eosinophilic infiltration of the gastrointestinal tract or a high eosinophil count in ascitic fluid, and the exclusion of other causes of tissue eosinophilia through differential diagnosis [8]. To confirm the diagnosis, biopsies should be performed from five to six different sites within each affected segment (e.g., stomach, duodenum) as endoscopic findings might appear normal. The presence of eosinophils in the ascitic fluid can also be diagnostic. The diagnosis of eosinophilic gastritis and duodenitis is more likely if pseudo-polyps, eosinophils in specific tissue layers, eosinophilic clusters in abscesses, or eosinophilic aggregations in the lamina propria are identified [28]. Other non-specific but potentially informative features include the presence of eosinophil microabscesses, surface eosinophil layering, basal layer hyperplasia, papillary elongation, eosinophil degranulation, and fibrosis [29]. The primary treatment strategies for eosinophilic gastritis and duodenitis include dietary modifications and the use of oral steroids. Treatment aims to alleviate clinical symptoms, achieve histologic remission, and prevent long-term complications such as bowel remodeling and stricture formation. However, long-term steroid use is associated with potential adverse effects, making dietary management a viable alternative. Dietary interventions may involve an exclusive elemental diet with a complete amino acid-based liquid formula, an elimination diet based on allergy testing, or an empirical elimination diet that removes common trigger foods. Currently, there are no prospective studies that directly compare the effectiveness of these dietary strategies for treating eosinophilic gastritis and duodenitis [25, 29]. Therapeutic strategies for eosinophilic gastritis (EoG) may also incorporate mast cell stabilizers, such as cromolyn, antihistamines as ketotifen and leukotriene receptor antagonists, like montelukast, to modulate inflammatory pathways associated with the disease [25, 30].
Eosinophilic colitis
EoC is regarded as the rarest EGID. The pathophysiology of EoC has not been fully explained, yet it is connected with the Th-2 type CD4+ mechanism [25]. A typical symptom in children is bloody diarrhea. In adults EoC is a chronic disease with manifestations such as abdominal pain, persistent diarrhea, heartburn, weight loss, nausea, ascites, and gastrointestinal perforation [31]. There are three types of EoC: mucosal, transmural (muscular) and subserosal. The mucosal type is the most common one and is characterized by abdominal pain, nausea, vomiting, early fullness after eating and diarrhea. Common, chronic symptoms of the muscular type are nausea, vomiting and abdominal distention, all due to the obstruction of the intestine. The subserosal type may be depicted by eosinophilic ascites [25, 31, 32]. The diagnosis of EoC is made when the three criteria are met: gastrointestinal symptoms, histologic image of eosinophilic infiltration and exclusion of different diseases with eosinophilia [31]. Most patients have an increased peripheral eosinophilia (> 500 eosinophils/μl) [33]. The endoscopy image is generally not characteristic. The usual vascular pattern might be absent, with signs of erythema, a granular appearance, and surface-level ulcerations. In adults, the CT scan often reveals bowel wall thickening, strictures, mucosal fold thickening, a rigid ileocecal valve prone to reflux, and the presence of ulcerative and polypoid lesions. The “halo sign”, visible from a stratification of the bowel wall, can also be revealed. Treatment of EoC includes glucocorticoids and azathioprine, and montelukast. Induction therapy in adults usually consists of prednisone and budesonide as steroidal anti-inflammatory drugs are inhibitors of eosinophil growth factors: IL-3, IL-5 and GM-CSF. Azathioprine and 6-mercaptopurine are a medication of choice in the maintenance therapy for patients with steroid-dependent disease [25]. Montelukast is an inhibitor of LTD4 on the receptor Cys-LT1, which lowers the infiltration of eosinophils to the gastrointestinal tract. It is also beneficial in patients with steroid-dependent disease [11].
Conclusions
Primary EGIDs are a group of diseases characterized by eosinophilic infiltration of the gastrointestinal tract in the absence of other known causes of tissue eosinophilia. The main subtypes include EoE, the most common, followed by eosinophilic gastritis and duodenitis and the rarest, EoC. They are common in patients with other allergic diseases. These disorders frequently coexist with allergic diseases and are driven by Th2-type responses to food and environmental antigens. EoE presents with esophageal dysfunction – dysphagia, heartburn, non-cardiac chest pain and is diagnosed via endoscopy and biopsy. Treatment involves PPIs, topical steroids, and dietary modifications. Eosinophilic gastritis and duodenitis and EoC share similar immunopathology, with symptoms like abdominal pain, diarrhea, and weight loss. Management typically includes corticosteroids, elimination diets, and immunomodulators. Given their rising prevalence and impact on quality of life, especially in EoE, early diagnosis and individualized treatment are essential. Advances in understanding EGID pathogenesis have improved diagnosis and therapy, but further research is needed to optimize outcomes.
