Dietary composition of adult eosinophilic esophagitis patients is related to disease severity.

BACKGROUND: In addition to the elimination diet, dietary composition may influence disease severity in patients with eosinophilic esophagitis (EoE) through modulation of the immune response. AIM: To explore the immunomodulatory role of nutrition before and during elimination diet in adult EoE patients. METHODS: Nutritional intake was assessed in 39 Dutch adult EoE patients participating in the Supplemental Elemental Trial (Dutch trial registry NL6014, NTR6778) using 3-day food diaries. In this randomized controlled trial, diagnosed patients received either a four-food elimination diet alone (FFED) or FFED with addition of an amino acid-based formula for 6 weeks. Multiple linear regression analyses were performed to assess associations between the intake of nutrients and food groups per 1000 kCal and peak eosinophil count/high power field (PEC), both at baseline and after 6 weeks. RESULTS: At baseline, we found a statistically significant negative (thus favorable) relationship between the intake of protein, total fat, phosphorus, zinc, vitamin B12, folate, and milk products and PEC (p < .05), while calcium (p = .058) and full-fat cheese/curd (p = .056) were borderline (favorably) significant. In contrast, total carbohydrates, prepacked fruit juice, and white bread were significantly positively (unfavorable) related to PEC (p < .05), while ultra-processed meals (p = .059) were borderline (unfavorably) significant. After dietary intervention, coffee/tea were significantly negatively (favorably) related to PEC, hummus/legumes were significantly positively (unfavorably) related with PEC, while peanuts were borderline significantly positively related (p = .058). CONCLUSION: Dietary composition may be related to inflammation in adult EoE patients. High-quality and anti-inflammatory diets may be a promising adjuvant therapy in the dietary management of EoE.

The New Therapeutic Frontiers in the Treatment of Eosinophilic Esophagitis: Biological Drugs.

Eosinophilic esophagitis (EoE) is a multifaceted disease characterized by a wide heterogeneity of clinical manifestations, endoscopic and histopathologic patterns, and responsiveness to therapy. From the perspective of an effective approach to the patient, the different inflammatory mechanisms involved in the pathogenesis of EoE and biologics, in particular monoclonal antibodies (mAbs), targeting these pathways are needed. Currently, the most relevant is dupilumab, which interferes with both interleukin (IL)-4 and IL-13 pathways by binding IL-4 receptor α, and is the only mAb approved by the European Medicine Agency and US Food and Drug Administration for the treatment of EoE. Other mAbs investigated include mepolizumab, reslizumab, and benralizumab (interfering with IL-5 axis), cendakimab and dectrekumab (anti-IL-13s), tezepelumab (anti-TSLP), lirentelimab (anti-SIGLEG-8), and many others. Despite the undeniable economic impact of biologic therapies, in the near future, there will be room for further reflection about the opportunity to prescribe biologic agents, not only as a last-line therapy in selected cases such as patients with comorbidities involving common pathways. Although recent findings are very encouraging, the road to permanent success in the treatment of EoE is still long, and further studies are needed to determine the long-term effects of mAbs and to discover new potential targets.

The Multiple Trajectories of the Allergic March

The allergic march comprises the sequential appearance of a series of allergic comorbidities. However, variability in the onset and progression of allergic diseases generates a heterogeneous scenario that does not follow a linear and single trajectory. Almost half of the pediatric population presents at least 1 allergy symptom. However, only 4%-6% present multimorbidity, with several allergic diseases co-occurring. It has recently been shown that although they share etiological mechanisms and risk factors, allergic diseases arise independently. In most cases, progression is not consecutive, or at least not the same in all patients. TH2-mediated inflammation, epithelial barrier dysfunction, and genetic predisposition play a fundamental role in the etiology of allergic diseases, on which the interaction with the exposome acts decisively. Therefore, studying diseases from an omics point of view is essential when attempting to describe the various trajectories of allergic progression and to propose effective interventions to prevent multimorbidity. In this narrative review, we provide an overview of the current perception of the allergic march, including clinical observations, omics data, risk factors, and measures aimed at modifying its course or even preventing its onset. (AU)

La marcha alérgica ha dado respuesta durante mucho tiempo a un escenario de aparición secuencial de diferentes comorbilidades alérgicas. Sin embargo, la variabilidad en la aparición y progresión de las diferentes enfermedades alérgicas dibuja un escenario heterogéneo que no responde a una trayectoria lineal y única. Aunque en la actualidad casi la mitad de la población infantil presenta al menos un síntoma de alergia, tan solo un 4-6% presenta multimorbilidad, coexistiendo varias entidades alérgicas. Recientemente se ha demostrado que, aunque compartiendo mecanismos etiológicos y factores de riesgo, estas enfermedades alérgicas surgen de manera independiente y que, en la mayoría de los casos, no se observa una progresión consecutiva, o al menos, no la misma en todos los pacientes. La inflamación mediada por células T helper de tipo 2 (Th2), la disfunción de la barrera epitelial y la predisposición genética juegan un papel fundamental en la etiología de estas enfermedades, sobre los que actúan de manera determinante la interacción con el exposoma. Por ello, el estudio de las enfermedades, desde un punto de vista de las ómicas, es fundamental para describir las diferentes trayectorias de la marcha alérgica y proponer intervenciones eficaces para evitar escenarios de multimorbilidad. En esta revisión narrativa se incluye una descripción general de la percepción actual de la marcha alérgica, incluidas observaciones clínicas, datos ómicos, factores de riesgo y medidas preventivas propuestas para modificar su curso o incluso prevenir su aparición. (AU)

Treatment of Pediatric Eosinophilic Esophagitis: Traditional and Novel Therapies.

PURPOSE OF REVIEW: This review presents and summarizes the existing studies on the treatment goals and options for pediatric eosinophilic esophagitis utilizing rigorous peer-reviewed literature. RECENT FINDINGS: In addition to traditional treatments, emerging biologic therapies continue to evolve the approach to treating pediatric eosinophilic esophagitis. Well defined treatment goals will aid the continued development of new therapies. Further, innovative assessment tools have changed how the clinician is able to assess the effectiveness of therapies with a trend toward less invasive options. The management of pediatric eosinophilic esophagitis continues to evolve with the advent of both novel treatment options and assessment tools. Treatment choices, with benefits and risks involved, should be presented to families upon diagnosis and tailored towards the individual patient and likelihood of adherence and success. Biologic therapy for EoE presents an exciting option for both first line therapy and escalation for those with severe or unresponsive disease.

Development of in-situ Raman diagnosis technique of eosinophil esophagitis.

The spectra of the live tissue with blood flow measured with 785 nm-excitation light showed a very weak signal due to hemoglobin (Hb). It suggested the possibility to detect eosinophil accumulation in the tissue with the 785 nm-excitation light. The excitation wavelength of 633 nm induced strong fluorescence of sapphire glass that is a material of the ball lens of BHRP (Ball lens top hollow optical fiber Raman probe). On the other hand, the previous study suggested that eosinophil including eosinophil peroxidase (EPO) that showed a strong resonance Raman effect with 633 nm-excitation light. The purpose of the present study is to collect basic information and to evaluate the viability of Raman spectroscopic analysis for the detection of eosinophil accumulation in the live esophagus. BHRP with a sapphire ball lens with 500 µm diameter was applied for measurement of live esophagus tissue of a mouse. In this study, Raman spectra of eosinophil were measured with 633 and 785 nm-excitation. The Raman spectra of eosinophil showed a strong contribution of EPO, suggested that a heme chromophore in EPO had pre-resonance enhancement via Q band with the 785 nm-excitation light. Principal component analysis (PCA) is applied for the analysis of Raman spectra of eosinophil, erythrocyte and other granulocytes. Eosinophil was successfully discriminated from other blood cells in the PCA score plots built for the datasets of the spectra measured with 633 and 785 nm-excitation wavelengths. Consequently, our study demonstrates that Raman spectroscopy with 785 nm-excitation had high viability for in situ analysis of eosinophilic esophagitis (EoE).

Histologic response to steroids in eosinophilic esophagitis is dependent on delivery compound.

Topical steroids are commonly used in treatment of eosinophilic esophagitis (EoE), but currently there is lack of data to clarify most effective regimen. We aimed to study the achievement of histologic remission using the same dose of budesonide in two different delivery formulations. Patients with established EoE treated with pharmacy compounded budesonide capsule or budesonide Rincinol gel (both 3 mg twice daily) were studied retrospectively. Those with pre-treatment and post-treatment histologic assessment were included with main endpoint being histologic remission. 103 patients (62 gel, 41 capsule) were included, with higher rate of histologic remission with gel (84 vs. 59%, P=0.004). A subset of patients in both groups had lack of steroid response (<50% drop in eosinophils) (15% for gel, 32% for capsule). Formulation/delivery vehicle of steroid treatments to esophageal mucosa in EoE appears important for treatment efficacy, with budesonide gel having higher likelihood of histologic remission compared to budesonide capsules in our population. A truly steroid refractory group appears likely in our population. Larger, prospective studies may help clarify best regimen of topical steroids in EoE and may work to identify patients likely to benefit from alternative therapies.

Nutritional and Psychological Considerations for Dietary Therapy in Eosinophilic Esophagitis.

The step-up empiric elimination diet, starting from one/two food groups of most local allergens remains the current gold standard for a dietary approach in eosinophilic esophagitis (EoE) patients. Milk, followed by wheat and egg, is the most frequent food that triggers EoE in pediatric and adult patients. Elimination diets, with restrictions over four food groups, may be limited to highly motivated patients, in which nutritional counseling is recommended. Malnourishment is uncommon in EoE patients and likely multifactorial (concomitant gastrointestinal eosinophilic disorders or IgE-mediated food allergies, feeding difficulties, abnormal feeding behavior). Avoidant/restrictive food intake disorder in EoE children on highly restrictive diets was lately described and may warrant specific psychological support. As for adults, quality of life may be impaired by symptom severity and dietary restrictions, aside from recently reported food impaction-related specific anxiety in up to 43% of patients. Severe symptoms, feeding dysfunction, and diet restrictions may negatively influence psychosocial adjustment for patients and their caregivers.

Diagnosing Pollen-food Allergy Syndrome Allergologically in a Patient with Suspected Eosinophilic Gastroenteritis.

Pollen-food allergy syndrome (PFAS) consists of type I allergy to pollen and multiple food items that are cross-reactive to the pollen. PFAS typically occurs in the oral cavity and can co-occur with eosinophilic esophagitis. However, it is infrequently reported to present with symptoms of eosinophilic gastroenteritis (EGE), such as abdominal pain and eosinophilic infiltration of the gastrointestinal tract. We herein report a patient with a condition initially suspected of being EGE based on symptoms and pathological findings that was later diagnosed as PFAS associated with birch pollen. PFAS should be considered as a differential diagnosis in patients with EGE-like symptoms.

Computational analysis to define efficacy & molecular mechanisms of 7, 4'- Dihydroxyflavone on eosinophilic esophagitis: Ex-vivo validation in human esophagus biopsies.

Introduction: Eosinophilic Esophagitis (EoE) is a chronic condition characterized by eosinophilic inflammation of the esophagus which leads to esophageal dysfunction with common symptoms including vomiting, feeding difficulty, dysphagia, abdominal pain. Current main treatment options of EoE include dietary elimination and swallowed steroids. Diet elimination approach could lead to identifying the trigger food(s), but it often requires repeated upper endoscopy with general anesthesia and potentially could negatively affect nutrition intake and growth of the child and individuals' quality of life. Although the swallowed steroid treatment of effective, the EoE will universally recur after discontinuation of the treatment. Digestive Tea formula (DTF) has been used by the Traditional Chinese Medicine (TCM) practice to improve GI symptoms in EoE patients, including abdominal pain, GE reflux, and abnormal bowel movement. Previously, a flavonoid small molecule compound 7, 4 dihydroxy flavone (DHF) from Glycyrrhiza uralensis in DTF inhibited eotaxin, Th2 cytokine and IgE production in vitro and in vivo. Method: This study comprehensively evaluates the potential therapeutic and immunological mechanisms underlying DHF improvement of symptoms related to EoE using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analyses, in silico molecular docking and dynamic simulation followed by ex-vivo target validation by qRT-PCR using cultured human esophagus biopsy specimen with or without DHF from patients with EoE. Results: Computational analyses defined 29 common targets of DHF on EoE, among which TNF-α, IL-6, IL1ß, MAPK1, MAPK3 and AKT1 were most important. Docking analysis and dynamic simulation revealed that DHF directly binds TNF-α with a free binding energy of -7.7 kcal/mol with greater stability and flexibility. Subsequently, in the human esophagus biopsy culture system, significant reduction in levels of TNF-α, IL-6, IL-8 and IL1-ß was found in the supernatant of biopsy sample cultured with DHF. Furthermore, the gene expression profile showed significant reduction in levels of TNF-α, IL1-ß, IL-6, CCND and MAPK1 in the esophagus biopsy sample cultured with DHF. Discussion: Taken together, the current study provides us an insight into the molecular mechanisms underlying multi-targeted benefits of DHF in the treatment of EoE and paves the way for facilitating more effective EoE therapies.

What influences complementary medicine use for children with eosinophilic esophagitis? Findings from a cross-sectional survey.

BACKGROUND AND PURPOSE: Utilization of complementary medicines (CMs) amongst children with eosinophilic esophagitis (EoE) in Australia is high. Carers' beliefs, perceptions and use of CM can influence the decision to use CM in children in their care. This study explores the factors influencing the use of CM for a child's EoE when the carer also uses CM. MATERIALS AND METHODS: Carers of children aged 0-18 years with EoE participated in a national cross-sectional online survey, conducted in Australia between September 2018 and February 2019. Data analysis included bivariate analysis, Cramer's V, backwards stepwise logistic regression and binomial logistic regression. RESULTS: Of the 181 total survey responses, 165 (91.2 %) respondents indicated they had utilized some form of CM for themselves. Children whose carer had used some form of CM for themselves were more likely to have used CM than children whose carer had not used CM (OR 4.6; p = 0.001). Of the CM self-using carers, 125 (75.8 %) had also chosen to utilize CM for their child's EoE. Use of CM in children was more likely amongst children who had used a pharmaceutical for their EoE (OR 7.51; p = 0.010), and those whose carer had consulted with "other health practitioners or health workers" for their child's EoE (OR 5.34; p < 0.001) or had consulted with a chiropractor for themselves (OR 2.70; p = 0.029). CONCLUSION: High CM self-use amongst carers is associated with their decision to also use CM for their child's EoE, a concern given the absence of evidence for CM's safety and efficacy in this population. CM use in this population warrants further attention. Effective conventional medicines for EoE are limited and utilization of CM amongst children with EoE in Australia is high. The recommendation of CM for children with EoE warrants further attention given the substantial concomitant pharmaceutical care, and the absence of evidence for CM's safety and efficacy in this population. Further research into the role of CM practitioners, products, and therapies in an integrative model between CM and conventional healthcare must be undertaken.

Role of microbial dysbiosis in the pathogenesis of esophageal mucosal disease: A paradigm shift from acid to bacteria?

Genomic sequencing, bioinformatics, and initial speciation (e.g., relative abundance) of the commensal microbiome have revolutionized the way we think about the "human" body in health and disease. The interactions between the gut bacteria and the immune system of the host play a key role in the pathogenesis of gastrointestinal diseases, including those impacting the esophagus. Although relatively stable, there are a number of factors that may disrupt the delicate balance between the luminal esophageal microbiome (EM) and the host. These changes are thought to be a product of age, diet, antibiotic and other medication use, oral hygiene, smoking, and/or expression of antibiotic products (bacteriocins) by other flora. These effects may lead to persistent dysbiosis which in turn increases the risk of local inflammation, systemic inflammation, and ultimately disease progression. Research has suggested that the etiology of gastroesophageal reflux disease-related esophagitis includes a cytokine-mediated inflammatory component and is, therefore, not merely the result of esophageal mucosal exposure to corrosives (i.e., acid). Emerging evidence also suggests that the EM plays a major role in the pathogenesis of disease by inciting an immunogenic response which ultimately propagates the inflammatory cascade. Here, we discuss the potential role for manipulating the EM as a therapeutic option for treating the root cause of various esophageal disease rather than just providing symptomatic relief (i.e., acid suppression).

Eosinophilic esophagitis due to red yeast rice (Monacoline K) in a dietary supplement for hypercholesterolemia.

We present a case of eosinophilic esophagitis (EoE) with positive skin-prick testing for type I allergy to red yeast rice (RYR, Artechol®). RYR is an over-the-counter supplement for hypercholesterolemia, since years famous in Asian countries and now also more and more popular in Western countries. The clinical relevance of IgE-mediated inflammation was proven by a rapid clearance of EoE-symptoms upon discontinuation of RYR. The role of skin-prick testing and allergy testing in general in EoE is controversial, but was of high importance in our patient. It demonstrates that in cases of a clear-cut allergy history, together with positive skin-prick (IgE) testing, a broad elimination diet can thus be avoided.

Successful Management of Eosinophilic Esophagitis Using Traditional Chinese Medicine: A Case Report.

Eosinophilic Esophagitis (EoE) is a relatively recently described condition, with rapidly increasing prevalence over the past several years. There is unfortunately no cure for EoE, and treatment involves food elimination and off-label use of topical steroids. These treatments can have significant impacts on quality of life for patients. Traditional Chinese Medicine (TCM) has been shown to decrease Th2 cytokines which are implicated in the pathophysiology of EoE. We present an 11-year-old male with severe EoE who was treated with TCM and able to achieve complete remission. Further modalities of treatment for EoE should continue to be pursued.

Targeted Anti-IL-5 Therapies and Future Therapeutics for Hypereosinophilic Syndrome and Rare Eosinophilic Conditions.

Eosinophilic inflammation is a component of many atopic diseases such as asthma, and biologics targeting eosinophils have been shown to be effective in subsets of these patients. However, there also are conditions in which eosinophils are the key inflammatory cells responsible for driving tissue damage. In these eosinophilic diseases such as hyper-eosinophilic syndrome, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis (EGPA), the development of biologics inhibiting eosinophilic inflammation have offered targeted therapeutic strategies for patients that have not responded well to typical first line drugs, which often have significant adverse side effects with poor disease modification or recurrent relapse with significant morbidity. IL-5 has long been recognized as the key inflammatory cytokine involved in the priming and survival of eosinophils and their proliferation and maturation in eosinophilic disease. There are a number of trials and case series demonstrating the immunomodulatory benefits of anti-IL-5 therapies in these diseases with good clinical responses. Yet, due to the heterogeneity and rarity of these conditions, anti-IL-5 therapies have not resulted in disease remission for all patients. Clearly, further research into the use of anti-IL-5 therapies in various eosinophilic diseases is needed and ongoing investigation into other immune mechanisms underlying chronic eosinophilic diseases may provide alternative therapies for these challenging conditions.

Tutorial: Nutrition Therapy in Eosinophilic Esophagitis-Outcomes and Deficiencies.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease that presents with symptoms of esophageal dysfunction, which vary by age. Diagnosis is made by upper endoscopy with esophageal biopsies to identify dense eosinophilic inflammation with at least 15 eosinophils per high-power field. Untreated, EoE can progress from inflammatory to esophageal remodeling with fibrosis and stricture formation. Food antigens are the primary trigger of inflammation in EoE. The most common food antigen triggers are dairy, wheat, egg, and soy. EoE can be managed with steroids or dietary elimination of food triggers. Elimination diets differ by the number of foods removed with specific nutrition implications for each diet. In addition, patients receiving swallowed steroids may have feeding dysfunction and need support for growth and nutrition intake. A multidisciplinary approach to care, including a dietitian, is integral to EoE management.

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.

Pharmacological treatments for eosinophilic esophagitis: current options and emerging therapies.

Introduction: The epidemiology of eosinophilic esophagitis (EoE) has increased rapidly to represent a common cause of chronic and recurrent esophageal symptoms. Current treatment options have limitations so the development of novel therapies is a matter of growing interest.Areas covered: This article provides an up-to-date discussion of current therapies and investigational options for EoE. Established anti-inflammatory treatments for EoE at present include dietary therapy, proton pump inhibitors and swallowed topic steroids, which should be combined with endoscopic dilation in case of strictures. Refractoriness, high recurrence rates, and need for long-term therapies have promoted the investigation of novel, esophageal-targeted formulas of topic corticosteroids, and monoclonal antibodies (including mepolizumab, reslizumab, QAX576, RPC4046, dupilumab, omalizumab, infliximab, and vedolizumab) for EoE, with some having been demonstrated as effective and safe in the short term. Several additional promising therapies are also discussed.Expert opinion: Several therapeutic targets have shown efficacy and will be approved to treat EoE, especially corticosteroid-sparing options and those for patients with multiple Th2-associated diseases. Personalized therapeutic strategies for initial and maintenance treatments of EoE must be rationally designed, to reduce the burden of disease and answer meaningfully the needs of all stakeholders involved in EoE.