Eosinophilic esophagitis

An allergic etiology of EoE is supported by several lines of evidence.

It is associated with other atopic conditions including asthma, atopic dermatitis, allergic rhinitis/sinusitis, and food allergies.[28] Up to 80% of children and 60% of adults with EoE have been reported to have concomitant allergic conditions.[31][32][33][34][35][36]

When patients are treated with a strictly hypoallergenic diet (e.g., elemental formula), symptoms and signs rapidly resolve, and when trigger foods are reintroduced, symptoms and signs recur.[37][38][39]

Aeroallergens have been correlated with disease activity in some patients. Although seasonal flares of EoE have been reported, associated with increased aeroallergen exposure (e.g., in spring, summer, and during pollen season), definite conclusions regarding causality cannot be drawn because most studies so far have been retrospective and no mechanistic correlation has been established.[4][40][41][42]

Allergen sensitization and subsequent exposure causes an EoE-like syndrome in animal models.[43][44]

Evidence of T helper cell type 2 (Th2)-mediated allergic inflammatory patterns has been demonstrated in tissue samples from patients.[45][46][47]

Despite the condition’s strong association with allergy, it is not yet known why an individual patient develops the condition. Studies have suggested that certain early life factors, such as antibiotic use in infancy and cesarean delivery, are associated with EoE.[48] This may be due to these factors causing changes in the microbiome. An inverse relationship between lack of Helicobacter pylori and EoE has been demonstrated, but other microbiome-based studies are in their early stages.[49][50][51]

In addition to male gender and atopy, EoE has been associated with living in cold and arid climate zones, and rural areas with low population density.[52][53]

To date, specific causative and modifiable factors, apart from food triggers, have not been identified. The 6 foods considered to be the top triggers for EoE are dairy, wheat, egg, soy, nuts, and seafood.[54][55][56][57] However, some evidence suggests that the contribution from seafood and nuts is minimal, and that legumes are a more frequent trigger.[58]

The condition is believed to be the result of a T helper cell type 2 (Th2)-mediated allergic process. After allergen exposure, T cells produce Th2 cytokines such as interleukin (IL)-5, IL-4, and IL-13 (all of which are potential therapeutic targets), which leads to eosinophilic infiltration of the esophageal mucosa.[46][59] This is mediated in a large part by eotaxin-3, an eosinophil chemokine and the most highly upregulated gene in patients with EoE.[60]

In addition, this inflammatory cascade is associated with an altered gene expression profile, the so-called EoE transcriptome.[60][61][62][63] The eosinophils, in turn, are activated in the esophagus and play several roles, including:

Causing direct cellular injury by degranulating. This, as well as altered expression of epithelial-related genes, compromises the normal barrier function of the esophageal mucosa, making it leaky[64][65][66]

Recruiting other inflammatory cells, in particular mast cells, and perpetuating ongoing inflammation[47][67][68]

Producing profibrotic factors (e.g., transforming growth factor beta) that can lead to smooth muscle dysfunction and collagen deposition, which leads clinically to swallowing dysfunction and esophageal stricture formation.[69][70][71][72][73]

Several genome-wide association studies have identified single nucleotide polymorphisms that are highly associated with EoE.[74][75][76] The inheritance pattern of EoE is complex, and there may be genetic predispositions that require environmental exposures to cause disease.[77] Two notable genes are thymic stromal lymphopoietin (TSLP), a regulatory cytokine involved in a number of atopic diseases, and calpain 14 (CAP14), a protein that has been localized to the esophageal epithelium and has a role in regulating barrier function.[75][76][78][79] Both of these factors may be future therapeutic targets.

Phenotypic classification

There are no accepted subclassifications of eosinophilic esophagitis; however, there is increased discussion of phenotypes based on clinical features.

For example, patients can be categorized by whether there are predominantly fibrostenotic features (indicated by esophageal remodeling resulting in focal strictures or diffuse narrowing), or inflammatory features (indicated by endoscopic findings of edema, white plaques or exudates, or linear furrows without strictures).[5][6][7] In general, younger patients and patients with a shorter disease duration tend to have inflammatory features, while older patients and those with a longer disease duration prior to diagnosis tend to have fibrostenotic features.

Other potential phenotypes include allergic versus nonallergic comorbidities, association with connective tissue diseases or autoimmunity, and treatment responsive versus unresponsive.[8][9][10]

Pathophysiology

Classification

Phenotypic classification