Disorder Definitions

Eosinophils account for a small fraction of peripheral blood leukocytes and tissue resident cells under healthy conditions. However, they can accumulate in large numbers in the blood and/or tissues in a variety of diseases, including hypereosinophilic syndrome (HES), Churg-Strauss syndrome, helminth infections, allergies (including asthma), nasal polyposis, immunodeficiencies, and eosinophilic gastrointestinal disorders (EGIDs).

EGIDs comprise distinct diseases, including eosinophilic esophagitis (EoE), eosinophilic gastritis (EoG), eosinophilic enteritis (EoN, including eosinophilic duodenitis [EoD]), and eosinophilic colitis (EoC), defined by the anatomical location of eosinophil-rich inflammation along the gastrointestinal (GI) tract in the absence of known causes of eosinophilia (e.g., drug reactions, parasitic infections, or malignancy).

EoE, EoG, EoN, and EoC are chronic, primary immune-mediated disorders. While EoE is becoming increasingly recognized, non-EoE EGIDs remain rare. Diagnosis and management are complex and require multidisciplinary input from adult and pediatric specialists, including gastroenterologists, allergists, immunologists, and pathologists. Of the eosinophil-associated diseases, there has been growing attention on EoE, EoG, EoN, and EoC over the past decade, as these diseases are now recognized to be increasing in incidence and prevalence, associated with substantial morbidity and lacking satisfactory treatment.

The importance of these issues is underscored by an NIH report calling for increased research into these diseases. At present, there are only two U.S. Food and Drug Administration (FDA)-approved drugs for the treatment of EoE and none for non-EoE EGIDs. The NIH Division of Rare Diseases Research Innovation (DRDRI) lists EoE, EoG, EoN, and EoC under the broader classification of eosinophilic enteropathy. These distinct diseases have been grouped together for several reasons.

First, the diagnoses of these disorders share the common feature of eosinophilic inflammation infiltrating the GI wall as evidenced by microscopic analysis of tissue biopsies.
Second, the defining clinical constellation and molecular pathogenesis of these disorders remain poorly understood and are in urgent need of scientific and clinical advances. In fact, although we strive to distinguish these diseases, they can sometimes overlap, highlighting their relatedness and the need to develop diagnostic and prognostic markers.
Third, these diseases are characterized by prominent eosinophilic inflammation. However, recent clinical and translational research has demonstrated that eosinophils are not the sole drivers of disease. In fact, therapies targeting eosinophil recruitment do not reliably improve disease, and there are now increasingly appreciated roles for epithelial barrier dysfunction, mast cells, and cytokine signaling abnormalities in EGID pathology.
Fourth, while it is now well recognized that most forms of EoE are food antigen–driven, EGIDs are largely idiopathic. The pathogenesis of EoG and EoN is increasingly recognized to involve type 2 inflammation, whereas the mechanisms underlying EoC remain less well defined.
Fifth, current management includes roles for proton pump inhibitors, topical corticosteroids, biologic treatment, and dietary therapy, with a key role for shared decision making in determining the optimal therapy approach.
Sixth, targeted biologic therapies are increasingly used to treat allergic diseases, particularly dupilumab, which is now FDA-approved for the treatment of eosinophilic esophagitis.
Seventh, by improving our understanding of these rare diseases in which eosinophils are likely to be the primary cause of disease, our findings may contribute to our understanding of eosinophilia in more common diseases (e.g., asthma and allergic rhinitis).
Eighth, the FDA has begun to focus on how to best meet the needs of these disorders and has engaged our consortium members in a partnership, as outlined in recent workshops and articles.

The diagnoses of EoG, EoN, and EoC are generally reserved for cases with markedly increased numbers of eosinophils in which eosinophilic inflammation is a prominent histologic feature. Gastrointestinal segment-specific reference thresholds have been proposed in recent guidelines when evaluating tissue eosinophilia. Suggested peak eosinophil counts include ≥30 eosinophils/HPF in the gastric antrum; ≥50 eosinophils/HPF in the duodenum; ≥100 eosinophils/HPF in the ileum; and for the colon, ≥100 eosinophils/HPF in the right colon, ≥85 eosinophils/HPF in the transverse or descending colon, or ≥65 eosinophils/HPF in the sigmoid colon. These values should be interpreted in conjunction with clinical symptoms and the exclusion of secondary causes of gastrointestinal eosinophilia.

Histological features that support the diagnosis include eosinophilic glandulitis or cryptitis, eosinophils within the muscularis mucosa or submucosa, fibrosis or fibroplasia of the lamina propria, eosinophil degranulation, and lymphoid aggregates. Architectural abnormalities such as crypt elongation, branching, or distortion may serve as confirmatory features, particularly when endoscopic findings are normal. Ongoing research continues to refine diagnostic criteria for these disorders.

Clinical presentation varies by site of tissue eosinophilia. EoE commonly presents with feeding difficulties and vomiting in young children and dysphagia or food impactions in adolescents and adults. EoG typically presents with upper abdominal pain, nausea, and vomiting, and EoC manifests with diarrhea, hematochezia, and lower abdominalor rectal pain. Despite suggestions of an EGID mini epidemic over the last decade, EoE, EoG, EoN, and EoC remain rare diseases. With the introduction of ICD-9-CM codes for these conditions, recent investigations by CEGIR Investigators were able to accurately estimate the prevalence of EGIDs. Using a highly specific case definition, the prevalence of EoE has been estimated to be between 39.0-56.7/100,000 in the USA, consistent with earlier work, with an extrapolated national prevalence of approximately 105,000-150,000 cases. In a separate study, the prevalence of EoG was found to be 6.4/100,000, extrapolated to approximately 17,000 cases in the USA, and the prevalence of EoC was estimated at 3.5/100,000, extrapolated to approximately 9,000 cases. Due to the rarity of these conditions, single centers are unable to compile sufficient patient numbers to study these diseases comprehensively. Although the etiologies of EoE, EoG, EoN, and EoC remain unknown, several lines of evidence support allergic, environmental, and genetic components in EoE. The high response rate to food elimination diets, especially amino acid–based elemental diets, and the frequent recurrence of disease with food reintroduction imply that EoE is mediated by immune sensitization to foods. Indeed, experimental EoE, EoG, or EoC in murine models can be induced by exposure to dietary or inhaled allergens or to the Th2-associated cytokine interleukin (IL-13) via a variety of entry points including the skin, respiratory tract, and GI tract. Consistent with an allergic etiology, swallowed GCs (SGCs) are effective for the treatment of EoE and elicit local changes in esophageal expression. However, better treatments are needed due to the substantial rates of GC resistance, high rates of disease relapse upon GC cessation, and/or relapse while on therapy. Unlike food anaphylaxis, which is typically caused by sensitization to a single food in a given individual, most patients with EoE have sensitization to a large panel of foods, requiring removal of several major food groups from their diet in order to achieve disease remission.

Even if remission is achieved, dietary restriction is typically a very challenging long-term therapeutic option.

The limitations of dietary and glucocorticoid therapy, compounded by the absence of FDA-approved therapies for non-EoE EGIDs, highlight the pressing unmet medical needs of patients with these diseases. The impact of EGIDs on patients and their families is underscored by data collected by APFED. Over 30% of APFED members who responded to a survey reported traveling more than 100 miles from their home for treatment. Over 30% reported that EGIDs had an adverse impact on their finances, 30% reported an effect on their marriage, over 55% reported an effect on school, and over 60% reported an effect on their job CURED has also emphasized the desperate need to provide medical formula for patient with EGID. Most patients using elemental formula do not have insurance coverage or have only partial coverage for medical foods, even though more than half of these patients use elemental formula as a supplement for a severely restricted diet (six or fewer foods). The annual expense for elemental formula typically exceeds $15,000, and the annual out-of-pocket cost for most families with EGIDs is at least $2,000 not including formula. Administration of elemental formula often requires placement of feeding tubes. Collectively, there is substantial evidence for the growing unmet medical needs of patients and families suffering from EoE, EoG, EoN, and EoC. Knowledge gaps remain regarding the natural history and pathophysiological mechanisms of EGIDs, especially non-EoE EGIDs, for which FDA-approved drugs do not exist. Although elevated eosinophil levels are required for diagnosis of these diseases and generally accepted to correlate with disease activity, few studies have directly addressed whether eosinophils are the histological component that best correlates with clinical symptoms, and these studies have been primarily limited to EoE. Evaluating the fundamental assumption that tissue eosinophil counts correlate with disease activity is a major focus of the CEGIR consortium. A number of issues are likely contributing to the uncertainty about the best tissue features to monitor for correlation with clinical symptoms. These include 1) limited validated metrics to assess whether symptoms or patient-reported outcomes (PROs) align with tissue histology measures; 2) limited prospective, randomized, placebo controlled trials that have utilized the same primary outcome variables; 3) limited studies that have cohort sizes that are truly powered to find correlations between symptoms and tissue histology elements; 4) the intermittent nature of symptoms and the ability of patients to institute behavioral and lifestyle changes to compensate for their symptoms; and 5) inconsistent histological measurement methodologies of tissue eosinophil counts in various studies. We will overcome many of the limitations of prior studies by 1) utilizing a series of diverse clinical outcome measures (COMs); 2) conducting multisite prospective trials with well-defined entry criteria; 3) increasing cohort sizes; and 4) standardizing our histological methodologies. The histological assessment of EoE is relatively straightforward as the normal esophagus is void of mucosal eosinophils. In contrast, the diagnosis of EoG, EoN, and EoC are particularly complex as eosinophils are normal resident cells in the GI mucosa. Importantly, increased mucosal eosinophils are not pathognomonic for EoE, EoG, EoN, or EoC, as mucosal eosinophilia can be seen in other diseases including reflux esophagitis, food allergy, IBD, celiac, and malignancies. Therefore, definitions of key clinical and histological features, especially for patients with EoG, EoN, and EoC, are urgently needed. Currently, on the basis of limited data and clinical experiences, it has been proposed that the diagnostic criteria for EoG, EoN, and EoC includes the histological finding of at least twice the normal peak eosinophils/HPF reported in different regions of the non-diseased stomach and/or colon. Through this project, we seek to advance the field by determining the relationships between COMs and mucosal eosinophilia, which will ultimately assist in developing diagnostic criteria, understanding mechanisms and identifying endpoints for treatment efficacy of each of the three rare diseases (EoE, EoG, EoN, and EoC). Pathophysiological mechanisms defining EoE have made great strides in the last decade. For instance, a number of studies identified dysregulation of the allergic arm of the immune system in EoE pathogenesis. This etiology is supported by the reversibility of EoE following dietary avoidance of specific foods, the reoccurrence of EoE upon re-introduction of the removed foods, the induction of the EoE-like disease in mice by exposure to both food allergens and aeroallergens, and genome-wide transcriptome analysis of esophageal tissue implicating interplay between the innate and adaptive immune responses. EoE has a strong hereditary component with a large sibling risk ratio (λs~80).

Early genetic analyses have identified susceptibility loci in the regions that contain candidate genes expressed in epithelial cells and strongly implicated in antigen recognition (TSLP, thymic stromal lymphopoietin), inflammatory cell recruitment/activation (CCL26, eotaxin-3), and calpain 14 (CAPN14), an esophageal-specific enzyme. The Th2 cytokine IL-13 program’s transcription of key EoE-related genes and pathways and transforming growth factor (TGF)-β1 have been proposed to be a regulator of EoE pathogenesis. In contrast, our understanding of EoG, EoN, and EoC is in its infancy, with current murine model studies suggesting roles for the eosinophil-associated cytokines eotaxin-1 and IL-5. Thus, while early evidence suggests that EoE, EoG, EoN, and EoC occur as a result of immune dysfunction, specific targets and biomarkers remain to be fully recognized.