Allergic Comorbidity in Eosinophilic Esophagitis: Mechanistic Relevance and Clinical Implications

Abstract

Allergic eosinophilic esophagitis (EoE) is a chronic, allergen-mediated inflammatory disease of the esophagus, and the most common cause of prolonged dysphagia in children and young adults in the developed world. While initially undistinguished from gastroesophageal reflux disease-associated esophageal eosinophilia, EoE is now recognized as a clinically distinct entity that shares fundamental inflammatory features of other allergic conditions and is similarly increasing in incidence and prevalence. The clinical and epidemiologic associations between EoE and other allergic manifestations are well established. In addition to exaggerated rates of atopic dermatitis, IgE-mediated food allergy, asthma, and allergic rhinitis in EoE patients, each of these allergic manifestations imparts individual and cumulative risk for subsequent EoE diagnosis. As such, EoE may be a member of the "allergic march"-the natural history of allergic manifestations during childhood. Several determinants likely contribute to the relationship between these conditions, including shared genetic, environmental, and immunologic factors. Herein, we present a comprehensive review of allergic comorbidity in EoE. We discuss areas of the genome associated with both EoE and other allergic diseases, including the well-studied variants encoding thymic stromal lymphopoietin and calpain 14, among other "atopic" regions. We summarize ways that environmental factors (such as microbiome-altering pressures and aeroallergen exposure) may predispose to multiple allergic conditions including EoE. Finally, we touch on some fundamental features of type 2 inflammation, and the resulting implications for the development of multiple allergic manifestations. We conclude with an analysis of the "type 2" biologics, and how mechanistic similarities between EoE and the other allergic manifestations have important implications for screening and treatment of the allergic patient.

Keywords: Allergic rhinitis; Asthma; Atopic dermatitis; Eosinophilic esophagitis; Food allergy.

Fig 1.

Frequency of allergic diseases in patients with eosinophilic esophagitis from 2015-2019 studies. Prevalence rates shown in parentheses. [^-]

Fig 2.

Model of allergy development. The epithelium (whether it be the airway, skin, or GI tract) is constantly exposed to protease and non-protease allergens (A). Exogenous protease exposure, up-regulation of endogenous proteases, and down-regulation of protease inhibitors is associated with impaired barrier integrity (B). Breakdown of the epithelial barrier allows allergen entry, and causes secretion of alarmin cytokines including IL-25, IL-33, and TSLP that recruit and activate innate lymphoid cells (ILC) and granulocytes (C). Innate cells are potent sources of type 2 cytokines that can help to activate naive dendritic cells (DC) to process antigen, and promote development of type 2 helper T (T_H2) cell responses (D). T_H2 cells can home back to the site of inflammation via up-regulation of specific chemokine receptors and integrins, or enter the circulation along with allergen-specific IgE-producing plasma blasts to exert effects at distant tissue sites (E).

Fig 3.

Factors underlying the development of EoE. Cumulative influence of an individual’s genetics (A), environment (B), and existing type 2 inflammation (C) on risk of EoE development.

Fig 4.

Simplified model of the pathologic relationship between EoE and the other allergic manifestations. Allergy often is initiated at a site of barrier defect such as is the case in atopic dermatitis (AD) (A). There are two broad checkpoints at which antigen-specific activation or tolerance can occur: the T cell and the B cell (B). Should T and B cell tolerance fail, an IgE-mediated disease such as IgE-mediated food allergy (IgE-FA) or allergic rhinitis (AR) ensues (C). In the presence of B cell tolerance, allergen-specific T cells can cause eosinophilic esophagitis (EoE) (D). Mixed IgE/T cell-mediated disease can also occur, such as is the case with asthma (E).