Maternal and Infant Antibiotic and Acid Suppressant Use and Risk of Eosinophilic Esophagitis.

Importance: Eosinophilic esophagitis (EoE), a chronic disease with significant patient and health care burden, has increased rapidly in incidence across many countries. Elucidating risk factors for disease development is a priority for health care practitioners and patients. Objective: To evaluate the association of maternal and infant use of antibiotics and acid suppressants with the development of EoE. Design, Setting, and Participants: This was a population-based, case-control study of pediatric EoE (1996-2019) in Denmark using pathology, prescription, birth, inpatient, and outpatient health registry data and with complete ascertainment of all EoE cases among Danish residents born between 1997 and 2018. Study data were analyzed from September 2020 to August 2023. Exposures: Maternal and infant use of antibiotics and acid suppressants, examining medication class, timing, and frequency of use. Main Outcome and Measure: Development of EoE. Results: Included in the study was a total of 392 cases and 3637 sex- and year of birth-matched controls with a median (IQR) age of 11.0 (6.0-15.0) years, 2772 male individuals (68.8%), and 1257 female individuals (31.2%). Compared with children with no antibiotic prescriptions filled during infancy, those with any use of an antibiotic had an associated 40% increase in risk of EoE (adjusted odds ratio [aOR], 1.4; 95% CI, 1.1-1.7). Those with 3 or more prescriptions had an associated 80% increase in risk of EoE (aOR, 1.8; 95% CI, 1.3-2.5). Frequency of maternal antibiotic use was associated with an increased risk (1 prescription: aOR, 1.4; 95% CI, 1.0-1.8; 3≤ prescriptions: aOR, 2.1; 95% CI, 1.4-3.2). Risk was highest for use in the third trimester and in the first 6 months from birth. Any acid suppressant use in infancy was associated with increased risk of EoE (aOR, 15.9; 95% CI, 9.1-27.7). Restriction of cases to those diagnosed at 5 years or older yielded similar results (aOR, 11.6; 95% CI, 5.5-24.8). For maternal use, 3 or more prescriptions were associated with an increased risk of EoE for her offspring (aOR, 5.1; 95% CI, 1.8-14.8). Conclusions and Relevance: Maternal and infant antibiotic use were associated with increased risk of developing EoE, in a dose-response manner, and the magnitude of association was highest for exposure near the time of delivery. Increased risk was also observed with maternal and infant acid suppressant use. Exposure during early life, a period of known developmental susceptibility, may confer the greatest risk and opportunity for risk mitigation.

Proton Pump Inhibitors in Allergy: Benefits and Risks.

Proton pump inhibitors (PPIs) are widely prescribed and are indicated for the treatment of several gastrointestinal disorders. Allergists may prescribe PPIs as a result of the coincidence of gastroesophageal reflux disease with asthma or rhinitis, or when gastroesophageal reflux disease presents as chronic cough. Furthermore, long-term, high-dose PPI therapy is a recommended option for managing eosinophilic esophagitis, resulting in histologic remission in approximately 40% of patients. Here, we discuss current recommendations for PPI use, its deescalation, and its side effect profile. We review evidence supporting the epidemiologic link between the use of acid-suppressant medication and the subsequent development of allergic disorders.

Non gastro-esophageal reflux disease related esophagitis: an overview with a histologic diagnostic approach.

Several pathological conditions, other than gastro-esophageal reflux disease and its complications, can affect the esophagus. While some of these can present with unspecific lesions (i.e. ulcers and epithelial damage) and require clinico-pathological correlation for diagnosis (i.e. drug-induced esophagitis and corrosive esophagitis) other conditions show distinctive histological lesions which enable the pathologist to reach the diagnosis (i.e. some specific infectious esophagites and Crohn's disease). In this context eosinophilic esophagitis is the condition which has been increasingly studied in the last two decades, while lymphocytic esophagitis, a relatively new entity, still represents an enigma. This overview will focus on and describe histologic lesions which allow pathologists to differentiate between these conditions.

Disodium cromoglycate treatment reduces TH2 immune response and immunohistopathological features in a murine model of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is an emergent chronic disease of the esophagus. The immunopathological process in EoE is characterized by Th2 immune response and prominent eosinophilic influx, in response to common food allergens. The classical treatment consists of allergen elimination diet and systemic/topical corticosteroid therapy. Nevertheless, patients do not always comply to treatment, and the prolonged corticosteroid therapy can cause side effects, therefore, there is an immediate need for new therapeutic approach for EoE. Disodium cromoglicate (DSCG) is a substance broadly used in allergic asthma treatment, and a well-known mast cell activation stabilizer. However, its effect in EoE have not been evaluated yet. This study aimed to assess the effects of DSCG treatment in an EoE experimental model. Male Balb/C mice were subcutaneously sensitized for five days with OVA, and subsequently orally OVA-challenged, DSCG administration was performed between the OVA-challenges. DSCG treatment not only reduced eosinophilic and mast cell influx, as well as reduced fibrosis. In addition, tslp, GATA3, IL-5, FoxP3 and IL-10 mRNA expression were reduced in esophageal mucosa, associated with lower Th2 (CD3+CD4+GATA3+IL4+) and B cells (CD19+CD40+) number in peripheral lymphoid organs. In conclusion, the data demonstrate DSCG treatment was effective in reducing mast cell activation and Th2 immune response, important immunopathological EoE features. Therefore, the use of DSCG as an EoE treatment can be considered a promising therapeutic approach to treat this disease.

High-fat diet-induced obesity worsens TH2 immune response and immunopathologic characteristics in murine model of eosinophilic oesophagitis.

BACKGROUND: Eosinophilic oesophagitis (EoE) is an emergent chronic immune-mediated disease of the oesophagus, which affects both children and adults. It is clinically characterized by dysphagia, food impaction and oesophageal eosinophilia. Epidemiological studies indicate that obesity can worsen allergic symptoms; however, its effect on EoE immunopathological response has not been evaluated yet. This study aimed to assess the effect of obesity on allergic inflammation and T helper-2 profile in an EoE experimental model. METHODS: Obesity was induced by high-fat feeding. After 7 weeks of diet, male BALB/c mice were subcutaneously sensitized and orally challenged with OVA. RESULTS: Obesity itself induced a significant mast cell and eosinophil accumulation in the oesophagus, trachea, gut and lung. After allergy induction, this number was higher, when compared to lean-allergic mice. Moreover, obese-allergic mice showed higher remodelling area, in the oesophagus, associated with higher IL-5 and TSLP mRNA expression. In contrast, FoxP3 and IL-10 were less expressed in comparison with lean-allergic mice. In addition, the amount of CD11c+ MHCII+ PDL1+ dendritic cells was reduced, while the number of CD11c+ MHCII+ CD80+ DCs and CD3+ CD4+ GATA3+ IL-4+ cells was increased in obese-allergic mice in the spleen and lymph nodes when compared to lean-allergic mice. CONCLUSION: Obesity aggravated the immune histopathological characteristics in the EoE experimental model, which was associated with the reduction in the regulatory profile, and the increased inflammatory cells influx, related to the TH 2 profile. Altogether, the data provide new knowledge about obesity as a risk factor, worsening EoE symptoms, and contribute for future treatment strategies for this specific profile.

Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice.

We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL-13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development.

Increased acid responsiveness in vagal sensory neurons in a guinea pig model of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is characterized with eosinophils and mast cells predominated allergic inflammation in the esophagus and present with esophageal dysfunctions such as dysphagia, food impaction, and heartburn. However, the underlying mechanism of esophageal dysfunctions is unclear. This study aims to determine whether neurons in the vagal sensory ganglia are modulated in a guinea pig model of EoE. Animals were actively sensitized by ovalbumin (OVA) and then challenged with aerosol OVA inhalation for 2 wk. This results in a mild esophagitis with increases in mast cells and eosinophils in the esophageal wall. Vagal nodose and jugular neurons were disassociated, and their responses to acid, capsaicin, and transient receptor potential vanilloid type 1 (TRPV1) antagonist AMG-9810 were studied by calcium imaging and whole cell patch-clamp recording. Compared with naïve animals, antigen challenge significantly increased acid responsiveness in both nodose and jugular neurons. Their responses to capsaicin were also increased after antigen challenge. AMG-9810, at a concentration that blocked capsaicin-evoked calcium influx, abolished the increase in acid-induced activation in both nodose and jugular neurons. Vagotomy strongly attenuated those increased responses of nodose and jugular neurons to both acid and capsaicin induced by antigen challenge. These data for the first time demonstrated that prolonged antigen challenge significantly increases acid responsiveness in vagal nodose and jugular ganglia neurons. This sensitization effect is mediated largely through TRPV1 and initiated at sensory nerve endings in the peripheral tissues. Allergen-induced enhancement of responsiveness to noxious stimulation by acid in sensory nerve may contribute to the development of esophageal dysfunctions such as heartburn in EoE.

Smad3-deficient mice have reduced esophageal fibrosis and angiogenesis in a model of egg-induced eosinophilic esophagitis.

OBJECTIVES: Eosinophilic esophagitis (EoE) is a food-triggered disease associated with esophageal fibrosis and stricture formation in a subset of patients. In the present study we used a murine model of egg (ovalbumin [OVA])-induced EoE to determine whether inhibiting transforming growth factor-ß1 (TGF-ß1) signaling through the Smad3 pathway would inhibit features of esophageal remodeling including fibrosis, angiogenesis, and basal zone hyperplasia. METHODS: Wild-type (WT) and Smad3-deficient (KO [knockout]) mice were sensitized intraperitoneally and then challenged chronically with intraesophageal OVA for 1 month. Levels of esophageal eosinophils, esophageal TGF-ß1+ and vascular endothelial growth factor (VEGF)+ cells, and features of esophageal remodeling (fibrosis, angiogenesis, basal zone hyperplasia) were quantitated by immunohistochemistry and image analysis. RESULTS: OVA challenge induced a similar increase in the levels of esophageal major basic protein (MBP)+ eosinophils and esophageal TGF-ß1+ cells in WT and Smad3 KO mice. Smad3 KO mice challenged with OVA had significantly less esophageal fibrosis and esophageal angiogenesis compared with OVA-challenged WT mice. The reduced esophageal angiogenesis in Smad3 KO mice was associated with reduced numbers of VEGF+ cells in the esophagus. There was a trend toward OVA-challenged Smad3 KO to have reduced basal zone hyperplasia, but this was not statistically significant. CONCLUSIONS: In a mouse model of egg-induced EoE, Smad3-deficient mice have significantly less esophageal remodeling, especially fibrosis and angiogenesis that is associated with reduced expression of VEGF. Targeting the TGF-ß1/Smad3 pathway may be a novel strategy to reduce esophageal fibrosis and its associated complications such as esophageal strictures in EoE.

The changing geoepidemiology of food allergies.

The science of food allergy has been rapidly evolving before our eyes in the past half century. Like other allergic disorders, the prevalence of food allergies has dramatically increased, and coupled with the increased public awareness of anaphylaxis due to food allergy, this has driven an explosion in basic and clinical research in this extremely broad subject. Treatment of food allergies has evolved and practices such as food challenges have become an integral part of an allergy practice. The impact of the increase of food allergy has driven package labeling laws, legislation on emergency treatment availability in schools and other public places, and school policy. But to this day, our knowledge of the pathogenesis of food allergy is still incomplete. There are the most obvious IgE-mediated immediate hypersensitivity reactions, but then multiple previously unidentified conditions such as eosinophilic esophagitis, food protein-induced enterocolitis syndrome, milk protein allergy, food-induced atopic dermatitis, oral allergy syndrome, and others have complicated the diagnosis and management of many of our patients who are unable to tolerate certain foods. Many of these conditions are not IgE-mediated, but may be T cell-driven diseases. The role of T regulatory cells and immune tolerance and the newly discovered immunological role of vitamin D have shed light on the variable clinical presentation of food allergy and the development of new methods of immunotherapy in an example of bench-to-bedside research. Component-resolved diagnostic techniques have already begun to allow us to more precisely define the epitopes that are targeted in food allergic patients. The development of biological modulators, research on genomics and proteomics, and epigenetic techniques all offer promising avenues for new modes of therapy of food allergy in the twenty-first century.

Targeting AMCase reduces esophageal eosinophilic inflammation and remodeling in a mouse model of egg induced eosinophilic esophagitis.

Studies of AMCase inhibition in mouse models of lung eosinophilic inflammation have produced conflicting results with some studies demonstrating inhibition of eosinophilic inflammation and others not. No studies have investigated the role of AMCase inhibition in eosinophilic esophagitis (EoE). We have used a mouse model of egg (OVA) induced EoE to determine whether pharmacologic inhibition of AMCase with allosamidin reduced eosinophilic inflammation and remodeling in the esophagus in EoE. Administration of intra-esophageal OVA for 6weeks to BALB/c mice induced increased levels of esophageal eosinophils, mast cells, and features of esophageal remodeling (fibrosis, basal zone hyperplasia, deposition of the extracellular matrix protein fibronectin). Administration of intraperitoneal (ip) allosamidin to BALB/c mice significantly inhibited AMCase enzymatic activity in the esophagus. Pharmacologic inhibition of AMCase with ip allosamidin inhibited both OVA induced increases in esophageal eosinophilic inflammation and OVA induced esophageal remodeling (fibrosis, epithelial basal zone hyperplasia, extracellular matrix deposition of fibronectin). This inhibition of eosinophilic inflammation in the esophagus by ip allosamidin was associated with reduced eotaxin-1 expression in the esophagus. Oral allosamidin inhibited eosinophilic inflammation in the epithelium but did not inhibit esophageal remodeling. These studies suggest that pharmacologic inhibition of AMCase results in inhibition of eosinophilic inflammation and remodeling in the esophagus in a mouse model of egg induced EoE partially through effects in the esophagus on reducing chemokines (i.e. eotaxin-1) implicated in the pathogenesis of EoE.

Early life exposures as risk factors for pediatric eosinophilic esophagitis.

OBJECTIVES: Few etiologic studies of eosinophilic esophagitis (EoE) have been conducted. Early life exposures have been shown to predispose to other allergic disease, but their role has not been assessed in EoE. The present study sought to explore early life exposures as possible risk factors for developing EoE in the pediatric population. METHODS: This was a 2-phase case-control study conducted at the University of North Carolina. The first phase consisted of survey development for early life exposures via cognitive interview. In the second phase, a telephone-based questionnaire was administered to cases with EoE (n = 31) and 2 sets of controls, patients with gastroesophageal reflux disease, and siblings of nonsyndromic cleft lip/palate patients (n = 26 in each). Different controls were explored to identify controls reflective of the source population of the cases. Siblings of cleft lip/palate patients were identified as the more suitable control population. Odds ratios were calculated to evaluate the association between early life exposures and the development of pediatric EoE. RESULTS: Early life exposures were associated with increased odds of developing pediatric-onset EoE. Antibiotic use in infancy was associated with 6 times the odds of having EoE (95% confidence interval 1.7-20.8). Cesarean delivery, preterm birth, and formula-only or mixed (infant formula and breast milk) feeding also have trends toward increased odds for developing EoE. CONCLUSIONS: A number of early life exposures may be associated with the development of EoE. These are potentially modifiable risk factors that if confirmed would have implications for improved understanding of EoE pathogenesis and disease prevention.