Eosinophilic gastrointestinal disorder in an infant with feeding dysfunction

Feeding dysfunction (FD) has recently been considered to comprise a prevalent set of symptoms in eosinophilic gastrointestinal disorders (EGIDs) in young children. We report the case of an 8-month-old girl with an EGID who visited our hospital due to vomiting, poor weight gain and feeding difficulties; her condition was discovered during the examination of the symptoms including FD. Tracheal aspiration and reduced esophageal clearance showed up in a barium swallow test and upper gastrointestinal contrast radiography, respectively. Delayed clearance from the stomach was also detected on gastrointestinal scintigraphy. Gastrointestinal endoscopy and biopsies revealed esophagitis with some eosinophils and duodenitis with eosinophilic inflammation. She was not a likely candidate for eosinophilic esophagitis. On administration of an elemental diet, the patient gained weight. Esophageal and stomach clearance subsequently improved, although the vomiting and FD persisted to some extent. We conclude that it is important to consider other EGIDs as well as eosinophilic esophagitis in the differential diagnosis of FD.     

Pathophysiology, diagnosis and treatment of food protein-induced gastrointestinal diseases

PURPOSE OF REVIEW: Although our general understanding of food hypersensitivity has improved in recent years, gastrointestinal food protein-induced diseases still pose diagnostic and therapeutic dilemmas. RECENT FINDINGS: Food allergy in children and adults may involve any part of the gastrointestinal tract. Clinical presentations include protein-induced enterocolitis syndrome, enteropathy and proctocolitis, as well as eosinophilic gastroenteritis and related disorders. For many of these conditions, our understanding of the pathophysiology is incomplete. Manifestations are mostly non-IgE mediated, and skin prick testing and measurement of food-specific IgE antibody levels are of limited diagnostic value. Atopy patch testing may be of benefit in identifying food items associated with late-onset gastrointestinal reactions. A definitive diagnosis of gastrointestinal food allergy, however, still relies on formal food challenges. Depending on the clinical presentation, gastrointestinal biopsies may be required. In infancy, hypoallergenic formula or maternal elimination diets have been shown to effectively control the gastrointestinal manifestations of food allergies. Growth parameters and micronutrient levels need to be carefully monitored while on elimination diets for prolonged periods. In older children and adults with eosinophilic gastrointestinal disorders, the response to dietary restriction is variable. Corticosteroids may be required to control symptoms in those who failed to respond to hypoallergenic diets. In eosinophilic esophagitis, steroids can be administered topically in the form of swallowed aerosols. Leukotriene receptor antagonists and other novel therapies may be useful as steroid-sparing agents. SUMMARY: Early diagnosis and treatment of food protein-induced gastrointestinal diseases may prevent significant nutritional complications. Further research is needed to develop diagnostic tools for these mainly cell-mediated disorders.     

The pathology and causes of tissue eosinophilia in the gastrointestinal tract

Eosinophilic inflammation in the gastrointestinal tract may occur as a primary eosinophilic disorder or as a secondary response with other causes. Primary eosinophilic gastrointestinal disorders (EGIDs) are Th2‐mediated allergic diseases that overlap pathogenetically with atopic conditions involving other organs. The pathological diagnosis of primary EGIDs can be challenging, as the quantity of eosinophils considered to be ‘abnormal’ is difficult to define, and the diagnosis, by definition, requires exclusion of the far more common secondary causes. Our understanding of the basic biology and natural history of eosinophilic oesophagitis has advanced considerably over the last decade, whereas other EGIDs have proven more difficult to characterize; nonetheless, some recent advances have been made. This review summarizes current knowledge regarding the clinical presentation, diagnosis, natural history and treatment of EGIDs, including eosinophilic oesophagitis. We also draw attention to the numerous secondary causes of tissue eosinophilia in the gastrointestinal tract, and suggest a practical approach to the histological assessment, diagnosis and reporting of EGIDs.     

Allergy-associated colitis. Characterization of an entity and its differential diagnoses

There is substantial evidence that allergic reactions exist in the gastrointestinal tract (GI). However, patients with food allergy-related enteropathy pose a diagnostic challenge to physicians because the clinical features are variable, unspecific, occur in other gastrointestinal disorders, and specific diagnostic tools are missing. Several recent studies and reviews have focused on the function of eosinophilic granulocytes in GI disease. The role of eosinophils in the pathophysiology of GI hypersensitivity reactions is poorly defined. However, some findings have been reported that imply an involvement of eosinophils in allergic reactions of the gut. The presumptive histology of allergy-associated colitis in colonic and ileal biopsies is based on prominent pure eosinophilic infiltration of a normal lamina propria, submucosa and epithelium with variable degrees of degranulation. An immunoperoxidase stain for eosinophilic peroxidase is supportive in establishing the diagnosis if suspected. Neutrophils or mononuclear infiltrates are not significantly increased and damage to the intestinal tissue is not prominent. Despite characteristic histologic changes in colonic biopsy specimens, a final diagnosis depends on careful clinical examination and exclusion of several differential diagnoses.     

Immunomodulatory therapy of eosinophil‐associated gastrointestinal diseases

Eosinophil‐associated gastrointestinal disorders (EGIDs), including eosinophilic esophagitis (EE) and eosinophilic gastroenteritis (EG), are a spectrum of increasingly recognized inflammatory diseases characterized by gastrointestinal symptoms and eosinophilic infiltration of the gastrointestinal tract. Significant morbidity is associated with the development of esophageal strictures in some patients. Immune‐mediated reactions to food allergens appear to drive the inflammation in a subset of patients, especially those with solitary EE, but dietary interventions remain difficult in EE and are less effective in EG. Despite the increasing incidence of these disorders and their increased recognition by physicians, there are currently no medications that either United States or European Union regulatory agencies have specifically approved for use in EGIDs. This lack of safe and effective therapies for EGIDs is a major obstacle in the care of these patients and underscores the need for new therapeutic approaches. This review briefly discusses the currently available ‘off label’ drug treatments for EGIDs, most notably topical and systemic corticosteroids. Pathogenesis studies of EGIDs suggest possible therapeutic targets, and conversely, clinical trials of mechanistically‐targeted therapeutics give insight into disease pathogenesis. Thus, EGID pathogenesis is discussed as an introduction to mechanistically‐targeted immunotherapeutics. The two biologic categories that have been used in EGIDs, anti‐IgE (omalizumab) and anti‐IL‐5 (SCH55700/reslizumab and mepolizumab), are discussed. Because there are similarities in the pathogenesis of EGIDs with asthma and atopic dermatitis, biologic therapeutics currently in early trials for asthma management are also briefly discussed as potential therapeutic agents for EGIDs. Given the deficiencies of current therapeutics and the rapidly advancing knowledge of the pathogenesis of these disorders, EGIDs are an ideal model for translating recent advances in understanding immunopathogenesis into mechanistically‐based therapeutics. Further understanding of the early events in pathogenesis is also needed to develop preventive and disease‐modifying treatments.     

A review of eosinophilic gastroenteritis

Eosinophilic gastroenteritis (EG) is a rare disease of unknown etiology characterized by patchy or diffuse eosinophilic infiltration of the gastrointestinal tract wall with various gastrointestinal manifestations. As clinical presentation and radiological findings in EG are nonspecific, diagnosis requires a high index of suspicion and exclusion of other disorders that are associated with peripheral eosinophilia. This article reviews the history, current concepts of this complex disorder and the common symptoms. Because there is no gold standard for this disease, a wide variety of diagnostic criteria is presented.     

A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation

Although eosinophils have been implicated in the pathogenesis of gastrointestinal disorders, their function has not been established. Using a murine model of oral antigen-induced eosinophil-associated gastrointestinal disease, we report the pathological consequences of eosinophilic inflammation and the involvement of eotaxin and eosinophils. Exposure of mice to enteric-coated antigen promotes an extensive T helper 2-associated eosinophilic inflammatory response involving the esophagus, stomach, small intestine and Peyer's patches as well as the development of gastric dysmotility, gastromegaly and cachexia. Electron microscopy shows eosinophils in proximity to damaged axons, which indicated that eosinophils were mediating a pathologic response. In addition, mice deficient in eotaxin have impaired eosinophil recruitment and are protected from gastromegaly and cachexia. These results establish a critical pathological function for eotaxin and eosinophils in gastrointestinal allergic hypersensitivity.     

Experimental analysis of eosinophil-associated gastrointestinal diseases

Eosinophil infiltration into the gastrointestinal tract occurs in a wide range of diseases. However, the underlying cellular and molecular mechanisms involved in eosinophil migration and the role of eosinophils in disease pathogenesis are largely unknown. Recent studies using experimental models of eosinophil-associated gastrointestinal allergy have revealed differential roles for IL-5 and eotaxin in the modulation of eosinophil accumulation into various regions of the gastrointestinal tract. Furthermore, such studies have revealed a possible role for eosinophils in the pathogenesis of gastrointestinal disorders. The present review describes the clinical manifestations of various eosinophil-associated gastrointestinal disorders and the current understanding of the role of IL-5 and eotaxin in the allergic inflammatory response, and the participation of the eosinophilic granulocyte in the expression of disease.     

Eosinophilic disorders

Eosinophilic inflammatory responses occur in association with multiple disorders. Although the initial cause and the affected organs vary among the different eosinophilic disorders, there are only 2 major pathways that mediate eosinophilia: (1) cytokine-mediated increased differentiation and survival of eosinophils (extrinsic eosinophilic disorders), and (2) mutation-mediated clonal expansion of eosinophils (intrinsic eosinophilic disorders). Independent from the original trigger, the most common cause of eosinophilia is the increased generation of IL-5-producing T cells. In some cases, tumor cells are the source of eosinophil hematopoietins. The intrinsic eosinophilic disorders are characterized by mutations in pluripotent or multipotent hematopoietic stem cells leading to chronic myeloid leukemias with eosinophils as part of the clone. Here, we propose a new classification of eosinophilic disorders on the basis of these obvious pathogenic differences between the 2 groups of patients. We then discuss many known eosinophilic disorders, which can be further subdivided by differences in T-cell activation mechanisms, origin of the cytokine-producing tumor cell, or potency of the mutated stem cell. Interestingly, many subgroups of patients originally thought to have the idiopathic hypereosinophilic syndrome can be integrated in this classification.     

The spectrum of eosinophilic infiltration of the gastrointestinal tract and its relationship to other disorders of angiitis and granulomatosis.

Six cases of eosinophilic infiltration of the gastrointestinal tract were studied. Three cases were of the diffuse infiltrative variety (eosinophilic enteritis, two cases; eosinophilic peritonitis, one case), and three cases were of the circumscribed variety (so-called inflammatory fibroid polyp). Two of the infiltrative lesions showed necrotizing granulomas identical to those described by Churg and Strauss; one of the two also showed active vasculitis. One circumscribed lesion occurred in a patient with polyarteritis nodosa. Necrotizing eosinophilic granulomas were also noted in this lesion. Our observations suggest that the two forms of eosinophilic infiltration of the gastrointestinal tract are parts of a disease spectrum. Supporting evidence in the literature is presented. The relationship of this group of eosinophilic lesions to the hypereosinophilic syndrome, allergic granulomatosis and angiitis of Churg and Strauss, and polyarteritis nodosa is discussed.     

Allergy and eosinophil-associated gastrointestinal disorders (EGID)

Eosinophil-associated gastrointestinal disorders (EGIDs) are characterized by an inappropriate accumulation of eosinophils within the gastrointestinal tract. The underlying etiology and pathophysiology that lead to the development of EGID are far from elucidated. However, there is growing evidence to support the role of aeroallergens and food allergens in the pathogenesis of these disorders. Recent advances have highlighted the role of Th2-driven cytokines in the development of EGID, and clinical studies have verified that children and adults with EGID often have positive skin testing to food allergens. The most common form of EGID, eosinophilic esophagitis (EE), has garnered intense investigation following an increased recognition over the past decade. Recently, there have been several important studies providing insight into both the cellular mechanisms governing EE and clinical therapies directed toward the treatment of EE. In the article herein, we will review the most recent scientific advances influencing our understanding of EGID with special emphasis on the role of allergens in the pathogenesis of EGID.     

The physiological and pathophysiological roles of eosinophils in the gastrointestinal tract

Eosinophils and the gastrointestinal tract interact in an intimate and enigmatic relationship. Under healthy conditions, the presence of eosinophils is limited almost exclusively to the digestive tract mucosa where they exert several effector and immunoregulatory functions. While their precise function in the gastrointestinal tract is not completely understood, it is likely that, together with different T cell subsets, eosinophils are involved in maintaining the immunologic homeostastis across the mucosal barrier under resting conditions. Eosinophils also play a role in several inflammatory conditions, such as intestinal infections, hypersensitivity reactions, primary eosinophilic inflammations and several other chronic intestinal disorders. Depending on the responsible trigger, their effects may be beneficial or detrimental. Here, we discuss the available information regarding the physiological and pathological functions of eosinophils within the gastrointestinal tract.     

The spectrum of therapeutic activity of mepolizumab

ABSTRACT

Introduction: The basis of the development of the anti-interleukin-5 monoclonal antibody mepolizumab was the acknowledgment of the crucial importance of this cytokine in promoting eosinophils production, activation, and survival, which is associated with the eosinophilic asthma phenotype, as well as with other disorders characterized by high levels of eosinophils.

Areas covered: All the available literature on the outcomes treatment with mepolizumab in eosinophilic disorders are reviewed, including asthma, chronic rhinosinusitis, esophagitis, granulomatosis with polyangiitis, eosinophilic chronic obstructive pulmonary disease, hypereosinophilic syndrome, and allergic bronchopulmonary aspergillosis.

Expert opinion: The efficacy of mepolizumab in eosinophilic asthma is clearly demonstrated by a number of controlled trials and by meta-analyses. Among other eosinophilic disorders, controlled trials are available for chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic chronic obstructive pulmonary disease. Allergic bronchopulmonary aspergillosis, as well as other minor eosinophilic disorders, are backed only by case reports and are waiting controlled trials to verify the therapeutic role of mepolizumab.     

Eosinophilic Gastroenteritis with Eosinophilic Dermatitis

Eosinophilic gastroenteritis (EG) is characterized by eosinophilic infiltration of the bowel wall and variable gastrointestinal manifestations. Clinicians should have a high index of suspicion for EG when faced with gastrointestinal symptoms and peripheral eosinophilia to avoid incorrect diagnosis and inappropriate treatments. A 24-year-old woman was admitted to our hospital complaining of acute right lower quadrant abdominal pain and a laparoscopic appendectomy performed for a presumed diagnosis of an acute appendicitis. However, the procedure revealed bowel edema and a moderate amount of ascites without evidence of a suppurative appendicitis. Postoperatively, she showed persistent and progressive eosinophilia, exudative eosinophilic ascites, eosinophilic infiltration of the resected appendix wall, and eosinophilic infiltration of gastroduodenal mucosa. A punch biopsy of the abdominal skin also revealed inflammation with marked eosinophilic infiltration of the skin. She recovered after the treatment with a low dose of steroid for the EG with eosinophilic dermatitis. EG with eosinophilic dermatitis has not been reported yet and is considered fortuitous in this case.     

Human milk-specific mucosal lymphocytes of the gastrointestinal tract display a TH2 cytokine profile

BACKGROUND: A number of gastrointestinal disorders, including allergic eosinophilic gastroenteritis and food protein-induced enteropathy, have been associated with milk hypersensitivity. The immunologic reactions appear to involve T cells that are activated by specific food proteins. OBJECTIVE: The present study was performed to examine the cytokine profiles of milk-specific lymphocytes from the duodenal lamina propria from children with milk-induced gastrointestinal diseases. METHODS: Duodenal biopsy specimens obtained from 10 patients with allergic eosinophilic gastroenteritis, food protein-induced enteropathy, or both and 12 control subjects were mechanically minced and cultured with either mitogens (i.e., polyclonal T-cell expansion) or milk proteins (i.e., milkspecific T-cell expansion). By using flow cytometry, expanded T cells were phenotyped with anti-CD4, anti-CD8, anti-IL-4, anti-IL-5, and anti-IFN-gamma mAbs. The milk specificity of the lines was evaluated by means of the lymphocyte proliferation assay. In addition, the release of T(H)1, T(H)2, and T(H)3 cytokines was determined after restimulation. RESULTS: In patients and control subjects polyclonal expansion of mucosal lymphocytes resulted in predominantly T(H)1 cells. Milk-specific mucosal T-cell lines could be established in 60% of the patients but in none of the control subjects. In contrast to the polyclonal expansion of T cells, the milk-specific expansion of mucosal T cells showed a clear T(H)2 cytokine profile. On restimulation with milk protein, these cells showed a high proliferative response. They released T(H)2 cytokines, predominately IL-13, but failed to release T(H)3 cytokines important in the development of oral tolerance. CONCLUSION: The release of T(H)2 cytokines after stimulation of milk-specific mucosal T cells may play a pathogenic role in the inflammatory changes seen in milk-induced gastrointestinal disorders.     

Eosinophile Ösophagitis

Eosinophilic esophagitis is a chronic, clinically and histologically defined, inflammatory condition of the esophagus. The histological hallmark of eosinophilic esophagitis is a relevant, often patchy infiltration of the esophageal mucosa with eosinophils. In a consensus report a threshold value of approximately 120 eosinophils per mm² was arbitrarily fixed as a diagnostic criterion. Noteworthy for the quantification of the eosinophilic infiltration are several technical facts, for instance size and covering extent of the biopsy specimen of the high-power field (hpf) and quality of embedding of biopsy specimens have to be considered. In order to establish the histological diagnosis several additional abnormalities must be included in the assessment and gastrointestinal reflux disease is the main differential diagnosis of eosinophilic esophagitis. Finally it is emphasized that for an affirmative diagnosis of eosinophilic esophagitis, in addition to the histological findings the clinical facts must be included.     

Eosinophilic gastrointestinal diseases—clinically diverse and histopathologically confounding

Eosinophilic gastrointestinal diseases are a group of chronic diseases characterized by a range of symptoms caused by eosinophilic inflammation of various parts of the gastrointestinal tract. Other causes for eosinophilia need to be ruled out prior to making the diagnosis of EGIDs. The most common form of EGID is eosinophilic esophagitis (EoE), an antigen-driven disease that afflicts children and adults and has been identified across the world. Histological features include dense eosinophilia of the esophageal mucosa, eosinophil degranulation, eosinophil microabscess formation, and other features of epithelial inflammation including basal zone hyperplasia and rete pege elongation. Treatments include dietary exclusions and topical corticosteroids.     

Gastrointestinal eosinophilia

Gastrointestinal eosinophilia, a broad term for abnormal eosinophil accumulation in the gastrointestinal tract, involves many different disease identities. These diseases include primary eosinophil associated gastrointestinal diseases, gastrointestinal eosinophilia in hypereosinophilic syndrome, and all gastrointestinal eosinophilic states associated with known causes. Each of these diseases has its unique features but there is no absolute boundary between them. All three groups of gastrointestinal eosinophila are described in this article, although the focus is on primary gastrointestinal eosinophilia.     

Future therapies for eosinophilic gastrointestinal disorders

ObjectiveTo review novel therapeutics in development for treatment of eosinophilic gastrointestinal disorders (EGIDs).Data SourcesClinical trial data (clinicaltrials.gov) and literature search on PubMed.Study SelectionsStudies on treatment and clinical trials in EGIDs were included in this review.ResultsDuring the past decade, significant progress has been made in understanding disease mechanisms in EGIDs. As a result, a variety of novel therapeutics have been developed for treatment of these disorders. Several monoclonal antibodies against targets, including interleukin (IL) 4, IL-5, IL-13, integrins, and siglec-8, have shown promise in early trials. Novel formulations of corticosteroids are also in development.ConclusionThe field of EGID research has advanced rapidly, and disease-modifying therapeutics are closer to clinical application.     

Eosinophilic pancreatitis: a rare entity that can mimic a pancreatic neoplasm

Eosinophilic pancreatitis is a rare disorder that is frequently diagnosed only after pancreatic resection for suspected pancreatic tumor. It typically occurs in the setting of either eosinophilic gastroenteritis or the hypereosinophilic syndrome. Isolated eosinophilic infiltration of the pancreas is less common. We describe a case of a 36-year-old man who presented with the clinical symptoms of acute pancreatitis. Radiologic evaluation revealed an obstructive pancreatic lesion suspicious for carcinoma. Pathologic examination of the resection specimen revealed a dense infiltrate of eosinophils in the pancreas. Although an uncommon condition, eosinophilic pancreatitis is a syndrome lacking well-defined causes that can be associated with eosinophilic gastroenteritis, a treatable condition, or the potentially fatal hypereosinophilic syndrome. While the radiographic features of this condition can vary widely, eosinophilic infiltration of the pancreas with or without involvement of the gastrointestinal tract is the pathologic feature common to all of the previously reported cases.