Eosinophilic Esophagitis: the Potential Role of Biologics in its Treatment.

Eosinophilic esophagitis (EoE) is a chronic, relapsing inflammatory disease of the esophagus, characterized by the presence of significant esophageal mucosal eosinophilic infiltrates. The clinical presentation of EoE in childhood may include failure to thrive and feeding intolerance. The complication of food impaction is often related to the presence of strictures or narrow caliber esophagus. Over the last decade, there has been tremendous progress in the field of eosinophilic disorders, particularly eosinophilic esophagitis. Conventional treatment of eosinophilic esophagitis involves topical swallowed steroids, systemic steroids, elimination diets, and/or esophageal dilation. However, treatment outcomes with the above modalities are not satisfactory for all patients with EoE and alternative treatments are clearly needed. There has been ongoing research targeting the treatment-refractory population of patients with EoE and the population with long-term consequences of the disease and its treatment. With the significant eosinophilic infiltration that characterizes EoE, anti-IL-5 therapies designed to target eosinophilic inflammation have been some of the most studied anti-inflammatory biologic therapies in EoE. In the studies published to date, while various IL-5 inhibitors have decreased the numbers of esophageal eosinophils, they have not depleted them to the levels consistent with histologic remission of EoE. As additional biologics that modulate Th2-mediated immunity are trialed for the treatment of EoE, we stand to learn more about the inflammatory factors mediating this challenging condition. In this review, we discuss the alternative modes of therapy in EoE that have emerged, with a focus on anti-IL-5 therapies and other biologics, their variation of success, and ultimately, the future of treatment in this field.

Germination of pollen grains in the oesophagus of individuals with eosinophilic oesophagitis.

BACKGROUND: Eosinophilic oesophagitis (EoE) is characterized by oesophageal dysfunction and, histologically, by eosinophilic inflammation. There is no a clear aetiologic treatment. EoE exacerbations are often seasonal. We hypothesized that the inflammatory response of the oesophageal mucosa in patients with high levels of antibodies to pollen allergens and worsened seasonal EoE might be due to swallowing airborne pollen and the intrusion into the oesophageal mucosa of pollen allergens and pollen tubes, which encounter a pH and humidity resembling the stigma at pollination. OBJECTIVE: The aim of our study was to demonstrate the possible pathogenic role of environmental allergens in EoE through molecular and anatomopathological studies METHODS: One hundred and twenty-nine patients with EoE were tested for environmental and food allergens. Component resolved diagnosis (CRD), histological and botanical analysis was performed. Microscopic examination of oesophageal biopsies of 129 adults patients with EoE, 82 of them with seasonal exacerbation, and 100 controls, with gastroesophageal reflux without eosinophilic infiltrate, were made to verify the presence of callose (polysaccharide abundant in pollen tubes but absent in animal tissues) in the oesophagus. RESULTS: Component resolved diagnosis detected pollen allergens in 87.6% of patients with EoE. The predominant allergens were group 1 grass (55%), Art v 3 (11.3%) and lipid transfer proteins (LTPs) (19.4%) of common Mediterranean foods such as peach, hazelnuts, walnuts and wheat. Callose from pollen tubes was found in 65.6% of biopsies. CONCLUSION: Alteration of the mucosal barrier in EoE might cause the penetration of pollen grains into the oesophageal tissues. In EoE patients, anatomopathological studies searching for intrusion to plant foods and pollen, and specific-guided diet and immunotherapy after plant structures detection in biopsies, might be effective. CLINICAL RELEVANCE: It is possible to see the intrusion into animal tissues (oesophagus mucosa) of plant structures (pollen grains or pollen tubes) using an adecuate histologic botanical analysis. Molecular and anatomopathological studies can help to demonstrate a possible pathogenic role of environmental allergens in EoE.

Prenatal, intrapartum, and postnatal factors are associated with pediatric eosinophilic esophagitis.

BACKGROUND: Multiple lines of evidence point to the potential importance of early-life environmental factors in the rapid increase in the incidence of eosinophilic esophagitis (EoE), but potential exposures have not been extensively studied. OBJECTIVE: We sought to assess the association between prenatal, intrapartum, and postnatal factors and the development of pediatric EoE using a case-control study. METHODS: Patients with EoE were recruited from an existing registry at Cincinnati Children's Hospital Medical Center (CCHMC). Population-based community control subjects were identified from a separate CCHMC registry. Mothers of study subjects were contacted and completed a Web-based questionnaire. Crude and adjusted models were used to estimate associations. RESULTS: Mothers of 127 cases and 121 control subjects were included. We observed a positive association between several early-life factors and EoE, including prenatal (maternal fever: adjusted odds ratio [aOR], 3.18; 95% CI, 1.27-7.98; preterm labor: aOR, 2.18; 95% CI, 1.06-4.48), intrapartum (cesarean delivery: aOR, 1.77; 95% CI, 1.01, 3.09), and infancy (antibiotic use: aOR, 2.30; 95% CI, 1.21-4.38; use of an acid suppressant: aOR, 6.05; 95% CI, 2.55-14.40) factors. We observed an inverse association between having a furry pet in infancy and EoE (aOR, 0.58; 95% CI, 0.34-0.97). No associations were observed for breast-feeding or maternal multivitamin or folic acid supplement use. CONCLUSION: Early-life factors, including maternal fever, preterm labor, cesarean delivery, and antibiotic or acid suppressant use in infancy, were associated with risk of pediatric EoE; having a pet in the home was protective. These results add to growing evidence that implicate early-life exposures in EoE pathogenesis.

Correlation Between Aeroallergen Levels and New Diagnosis of Eosinophilic Esophagitis in New York City.

OBJECTIVE: The relation between food allergies and eosinophilic esophagitis (EoE) is well established. Aeroallergens may also contribute to the development of EoE; however, there are limited data to support or refute this hypothesis. The objectives of this pilot study were to determine whether there is a seasonal variation in the onset of symptoms and/or diagnosis of EoE and whether these variations correlate with a specific pollen concentration within New York City. METHODS: We performed a retrospective chart review to identify all pediatric patients at New York Presbyterian Weill Cornell Medical Center diagnosed with EoE between 2002 and 2012. Sixty-six patients were identified and 28 were excluded. Cases were classified by both date of initial symptoms and date of histologic diagnosis. Pollen counts from a certified New York City counting station and the percentage of EoE cases were collated monthly and seasonally and compared. RESULTS: There was a seasonal variation in onset of symptoms and diagnosis of EoE, with the highest number of patients reporting onset of symptoms of EoE in July to September, and those being diagnosed with EoE in October to December. There was a seasonal correlation between peak levels of grass pollen and peak onset of EoE symptoms, which were both highest in July to September. The diagnosis of EoE peaked one season later. CONCLUSIONS: The study findings suggest that there is a correlation between specific aeroallergens and both the onset of symptoms and time of diagnosis of patients with EoE.

Significance of para-esophageal lymph nodes in food or aeroallergen-induced iNKT cell-mediated experimental eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder driven by food hypersensitivity; however, the specific foods and mechanisms involved are unclear. In patients with EoE, we have found that hypersensitivities to corn and peanuts are the most common. Accordingly, we sensitized and exposed mice either intranasally or intragastrically with corn or peanut extract or saline. Esophageal eosinophilia, the genes of eosinophil-directed cytokines, and allergen-induced antibodies were examined in mice challenged with corn or peanut extract or saline. A high number of esophageal lamina propria eosinophils as well as eosinophilic microabscesses, intraepithelial eosinophils, extracellular eosinophilic granules, thickened and disrupted epithelial mucosa, and mast cell hyperplasia were observed in the esophagus of peanut or corn allergen-challenged mice. Mechanistic analysis indicated that para-esophageal lymph nodes might be critical in the trafficking of eosinophils to the esophagus and in EoE association to airway eosinophilia. Furthermore, experimentation with gene-targeted mice revealed that peanut allergen-induced EoE was dependent on eotaxin and invariant natural killer T (iNKT) cells, as CD1d and eotaxin-1/2 gene-deficient mice were protected from disease induction. Thus we provide evidence that para-esophageal lymph nodes are involved in food- or aeroallergen-induced eosinophilia and patchy EoE pathogenesis, likely a mechanism dependent on eotaxins and iNKT cells.