Outcomes of Serum Food-Specific Immunoglobulin G 4 to Guide Elimination Diet in Patients With Eosinophilic Esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) is associated with atopy; however, recent studies have identified an association with food-specific immunoglobulin G 4 (FS-IgG 4 ) rather than immunoglobulin E antibodies. This study aimed to evaluate the role of serum FS-IgG 4 in guiding an elimination diet and its outcomes. METHODS: Patients with and without EoE were enrolled in a prospective, controlled, single tertiary center trial. Serum FS-IgG 4 titers, esophageal eosinophil counts, and dysphagia symptom questionnaire scores were assessed, and participants with elevated FS-IgG 4 (ImmunoCAP, cutoff of 10 mgA/L) commenced 6-week targeted elimination diet. Repeat serum FS-IgG 4 and endoscopic and histologic examination were performed at 6-week follow-up. RESULTS: Twenty-two patients with active EoE and 13 controls were recruited. Serum FS-IgG 4 to milk, wheat, soy, eggs, and nuts was significantly higher in EoE ( P = 0.0002, P = 0.002, P = 0.003, P = 0.012, and P < 0.001, respectively). Elevated serum FS-IgG 4 to 1 or more food groups (median 2) was identified in 21/22 (95.4%) patients with EoE; 20/21 underwent 6-week dietary elimination. Median reductions in dysphagia symptom questionnaire score and EoE endoscopic reference score after elimination were 8 ( P = 0.0007) and 1 ( P = 0.002), respectively. Nine (45%) patients had histological remission (<15 eosinophils per high-power field). Fall in median esophageal eosinophil count was not statistically significant (50 vs 23; P = 0.068). Serum FS-IgG 4 did not decline by 6-week follow-up. DISCUSSION: Serum FS-IgG 4 to milk, wheat, soy, egg, and nuts was present at higher levels in EoE, with targeted elimination resulting in 45% histologic remission rate. Serum FS-IgG 4 has potential as a noninvasive biomarker in EoE. When successful, FS-IgG 4 -led elimination diet can negate need for medications and be viewed more favorably by patients because of its smaller endoscopic burden compared with empirical elimination diets.

Medical Management of Eosinophilic Esophagitis in Pediatric Patients.

Eosinophilic esophagitis is an immune-mediated allergic disease of the esophagus that affects pediatric patients of all ages. The diagnosis is made by esophagogastroduodenoscopy demonstrating eosinophilic infiltrate of the esophagus. Approaches to treatment involve proton pump inhibitors (PPIs), swallowed topical steroid preparations, as well as dietary elimination. In this review we discuss the evidence and efficacy of each of these approaches.

Management of Eosinophilic Esophagitis: Dietary and Nondietary Approaches.

Eosinophilic esophagitis (EoE) is an allergen-driven chronic inflammatory condition, characterized by symptoms related to esophageal dysfunction and confirmed histologically by esophageal mucosal eosinophilia. Since its first description in the 1990s, the incidence and prevalence of EoE have been on the rise. It is known to affect all ages of various ethnic backgrounds and both sexes; however, it is most seen in White males. Children with EoE often present with abdominal pain, nausea, vomiting, and failure to thrive, whereas adults with EoE typically present with dysphagia and food impaction. Diagnosis of EoE requires histologic confirmation of elevated esophageal eosinophils in a symptomatic patient, and only after secondary causes have been excluded. Because EoE is a chronic and progressively fibrostenotic disease, treatment goals include resolution of symptoms, induction and maintenance of disease remission, and prevention and possibly reversal of fibrostenotic complications, while minimizing treatment-related adverse effects and improving quality of life. Treatment strategies include the "3 D's"-drugs, diet, and dilation. Standard drug therapies include proton-pump inhibitors and topical corticosteroids. Dietary therapies include elemental diet, allergy testing-directed elimination diet, and empiric elimination diets. Endoscopic esophageal dilation for EoE strictures can alleviate esophageal symptoms but has no effect on mucosal inflammation. Recent progress in EoE research has made possible evidence-based clinical guidelines. Ongoing pharmacologic trials show promise for novel biologic agents in the treatment of refractory EoE.

A Novel Allergen-Specific Immune Signature-Directed Approach to Dietary Elimination in Eosinophilic Esophagitis.

OBJECTIVES: Dietary elimination for treatment of eosinophilic esophagitis (EoE) is limited by lack of accuracy in current allergy tests. We aimed to develop an immunologic approach to identify dietary triggers and prospectively test allergen-specific immune signature-guided dietary elimination therapy. METHODS: In the first phase, we developed and assessed 2 methods for determining selected food triggers using samples from 24 adults with EoE: a CD4+ T-cell proliferation assay in peripheral blood and food-specific tissue IgG4 levels in esophageal biopsies. In the second phase, we clinically tested elimination diets created from these methods in a prospective cohort treated for 6 weeks (NCT02722148). Outcomes included peak eosinophil counts (eos/hpf), endoscopic findings (measured by the EoE Endoscopic Reference Score), and symptoms (measured by the EoE Symptom Activity Index). RESULTS: Parameters were optimized with a positive test on either assay, yielding agreements of 60%, 75%, 53%, 58%, and 53% between predicted and known triggers of peanut, egg, soy, wheat, and milk, respectively. In clinical testing, the mean number of foods eliminated based on the assays was 3.4, and 19 of 22 subjects were compliant with treatment. After treatment, median peak eosinophil counts decreased from 75 to 35 (P = 0.007); there were 4 histologic responders (21%). The EoE Endoscopic Reference Score and EoE Symptom Activity Index score also decreased after treatment (4.6 vs 3.0; P = 0.002; and 32.5 vs 25.0; P = 0.06, respectively). DISCUSSION: We successfully developed a new testing approach using CD4 T-cell proliferation and esophageal food-specific IgG4 levels, with promising accuracy rates. In clinical testing, this led to improvement in eosinophil counts, endoscopic severity, and symptoms of dysphagia, but a smaller than expected number of patients achieved histologic remission.

Triple Diagnosis of Crohn's Disease, Celiac Disease, and Eosinophilic Esophagitis in a Child With Siderius-Hamel Syndrome.

Siderius-Hamel syndrome is a rare condition characterized by intellectual disability and distinct facial features. Crohn's disease-related eosinophilic esophagitis (EoE) has been reported; however, an association between celiac disease and EoE remains controversial. We present a case of a child with Siderius-Hamel syndrome who had characteristic findings of all these conditions-Crohn's disease, celiac disease, and EoE-an occurrence that to our knowledge has not been reported previously. The purpose of this report is to make physicians aware of this rare occurrence, so that it can be kept in mind while evaluating a patient with Siderius-Hamel syndrome presenting with gastrointestinal complaints.

Pediatric eosinophilic esophagitis effectively treated with a short-term 6-food-group elimination diet and reintroduction therapy: A case report.

RATIONALE: Eosinophilic esophagitis (EoE) is an inflammatory disease diagnosed based on clinical symptoms and pathological findings. EoE is treated with proton pump inhibitors (PPIs), topical steroids, and elimination diet-reintroduction therapy. After remission is achieved with the elimination diet, foods can be reintroduced sequentially to identify specific food triggers; however, this reintroduction method was not previously standardized. PATIENT CONCERNS: A 12-year-old girl presented to our hospital with a 3-year history of epigastric pain. Esophagogastroduodenoscopy revealed linear furrows, esophageal rings, white exudates, and pallor throughout the esophagus. Histopathological findings revealed eosinophilic infiltration >15 eos/hpf on esophageal biopsy. There were no obvious abnormal findings in the stomach and duodenum. DIAGNOSES: EoE INTERVENTIONS AND OUTCOMES:: Because PPI was ineffective, we proposed a 6-food-group elimination diet (SFGED) and reintroduction therapy for EoE, which was initially planned out over a 6-week interval. However, a 5-day interval of SFGED and reintroduction therapy was performed instead. The treatment was effective and causative food antigens (egg and nuts) were identified. Since her symptoms recovered following short-term treatment, the nutritional impact was minimized, as was the duration of her hospitalization. Consequently, the patient's quality of life was well-preserved. LESSONS: SFGED and reintroduction therapy for EoE may be effective even for short-term treatments involving 5-day intervals.

Management of eosinophilic esophagitis is often discordant with guidelines and not patient-centered: results of a survey of gastroenterologists.

Published guidelines for the management of eosinophilic esophagitis (EoE) recommend an initial trial of proton pump inhibitors (PPI), histologic assessment for response to therapy, and tailoring treatments to patient needs and provider resources. Effectiveness studies directly comparing therapies are lacking, leaving a situation ripe for shared decision making. We aimed to assess gastroenterologists' adherence to guidelines and how they respond to EoE patients' preferences regarding management. We administered a web-based survey to practicing US gastroenterologists, assessing knowledge, and practice patterns in the management of EoE, including comfort with alternative treatments to steroids. Ninety-two providers responded, including 55% in private practice. Nearly half (47%) reported spending ≤10 minutes on initial education and counseling and 48% recommended PPI monotherapy prior to other strategies. Of those who did not start with PPI monotherapy, 55% chose topical steroids ± PPI and 26% dietary elimination ± PPI. Despite this, 90% felt comfortable allowing a patient to start dietary elimination instead of steroids, but less comfortable with dilation alone (39%) or no treatment (30%). Upon symptomatic resolution, 72% of academic providers recommended endoscopy with biopsies to demonstrate histologic response to treatment, compared to 27% in private practice. There are substantial variations in adherence to guidelines regarding PPI use and assessing response to therapy. Gastroenterologists prefer topical steroids over other treatment modalities and most spend little time educating and counseling, which may limit informed decision making. Strategies aimed at decreasing these variations in management and promoting shared decision making in EoE are needed.

Toll-like receptors-mediated pathways activate inflammatory responses in the esophageal mucosa of adult eosinophilic esophagitis.

OBJECTIVES: Esophageal microbiota and regulation of adaptive immunity are increasingly being investigated in eosinophilic esophagitis (EoE). Toll-like receptors (TLRs) play a central role in the initiation and maintenance of innate immune activity. Our objective was to characterize the esophageal and duodenal innate immune response in EoE and its modulation by dietary therapy. METHODS: Esophageal and duodenal biopsy samples were collected from 10 adults with untreated EoE, before and after effective treatment with a six-food elimination diet (SFED), and 10 controls with normal esophagus. In all cases, bacterial load (by mRNA expression of 16S), TLRs, mucins, transcription factors, interleukins, components of the NKG2D system, and innate immunity effectors were assessed by qPCR. Protein expression of TLRs were also determined by immunofluorescence. RESULTS: Bacterial load and TLR1, TLR2, TLR4, and TLR9 were overexpressed on biopsies with active EoE compared with controls. Muc1 and Muc5B genes were downregulated while Muc4 was overexpressed. Upregulation of MyD88 and NFκB was found together with IL-1ß, IL-6, IL-8, and IL-10 mediators and PER-1, iNOS, and GRZA effectors. NG-K2D components (KLRK1, IL-15, MICB) were also upregulated. In all cases, changes in active EoE were normalized following SFED and mucosal healing. Duodenal samples also showed increased expressions of TLR-1, TLR-2, and TLR-4, but not 16S or any other mediators nor effectors of inflammation. CONCLUSIONS: Esophageal TLR-dependent signaling pathways in EoE support the potential implication of microbiota and the innate immune system in the pathogenesis of this disease.

Combined and Alternating Topical Steroids and Food Elimination Diet for the Treatment of Eosinophilic Esophagitis.

BACKGROUND: Few studies have examined combined or alternating treatment algorithms in eosinophilic esophagitis. AIMS: We conducted a retrospective cohort study to ascertain the efficacy and adherence to a combined and alternating treatment approach with topical corticosteroids and 2-food elimination diet for pediatric EoE. METHODS: Patients were prescribed a 2-food elimination diet (milk and soy) and topical corticosteroid (fluticasone or oral viscous budesonide) for 3 months, after which the steroid was discontinued and 2-food elimination diet continued for 3 months. An EGD was performed at baseline, 3 and 6 months. Clinical, endoscopic, and histologic data were extracted from electronic medical records. Nonparametric tests assessed adherence and outcomes. RESULTS: Twenty-nine eosinophilic esophagitis cases were included (mean age 11.5 years, 61% male). Complete adherence to combined therapy and 2-food elimination diet alone was 75 and 79%, respectively. Median eosinophil counts decreased from 51 to 2 eosinophils/hpf (p < 0.001) after combined treatment and rebounded to 31 (p = 0.07) after 2FED alone. Dysphagia improved after both the combined and 2-food elimination diet alone treatment approaches (52 vs. 11% and 10%; p = 0.001, 0.005). Nonsignificant improvements in endoscopic findings were documented across the length of follow-up. CONCLUSIONS: An initial combined treatment approach resulted in significant improvements in symptoms and histologic findings. While symptomatic improvements continued with 2-food elimination diet alone, the histologic improvement was not maintained. While loss to follow-up may obscure the efficacy of 2-food elimination diet alone, a combined/alternating treatment approach merits assessment in a larger prospective study.

Can We Use Diet to Effectively Treat Esophageal Disease? A Review of the Current Literature.

PURPOSE OF REVIEW: Esophageal diseases represent a wide variety of conditions affecting esophageal anatomy, physiology, and motility. Therapy focuses on pharmacotherapy and endoscopic or surgical management. Dietary therapy can be considered in management algorithms for specific esophageal diseases. This review focuses on outlining the literature related to dietary therapy in gastroesophageal reflux disease, eosinophilic esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. RECENT FINDINGS: Currently, data are strongest for dietary manipulation in eosinophilic esophagitis, specifically the six-food elimination diet. Dietary effects on gastroesophageal reflux disease are less clear, though newer research indicates that increased fiber with reduction in simple sugar intake may improve symptoms. In terms of Barrett's esophagus and esophageal adenocarcinoma, antioxidant intake may affect carcinogenesis, though to an unknown degree. Outcomes data regarding dietary manipulation for the management of esophageal diseases is heterogeneous. Given the rising interest in non-pharmacological treatment options for these patients, continued research is warranted.

Esophageal and Small Intestinal Mucosal Integrity in Eosinophilic Esophagitis and Response to an Elemental Diet.

OBJECTIVES: The esophageal mucosal integrity is impaired in eosinophilic esophagitis (EoE) and it has been suggested that the duodenal permeability is increased. The absence of food allergens may restore the integrity. The aims of this study were to assess duodenal permeability in EoE and to evaluate the effect of an elemental diet on the esophageal and duodenal integrity. METHODS: In this prospective study 17 adult EoE patients and 8 healthy controls (HC) were included. Esophageal biopsy specimens were sampled before and after 4 weeks of elemental diet to measure eosinophil counts and gene expression of tight junction and barrier integrity proteins. Esophageal and duodenal impedance were measured by electrical tissue impedance spectroscopy and Ussing chambers were used to measure transepithelial resistance (TER) and transepithelial molecule flux. Small intestinal permeability was measured using a test, measuring lactulose/mannitol (L/M) ratios. RESULTS: In EoE patients, the esophageal but not the duodenal integrity was impaired, compared with HC. We observed no significant difference between L/M ratios of HC and EoE patients. After diet, eosinophil counts decreased significantly, which was paralleled by normalization of esophageal impedance and transepithelial molecule flux. The esophageal TER improved significantly, but did not reach values seen in HC. Esophageal expression of genes encoding for barrier integrity proteins filaggrin and desmoglein-1 was impaired at baseline and restored after diet. CONCLUSIONS: An elemental diet restores esophageal integrity, suggesting that it is at least partly secondary to allergen exposure. Duodenal integrity seems not to be affected in EoE, and possibly plays a minor role in its pathophysiology.

Rol del manejo dietario y farmacológico en la esofagitis eosinofílica / Diet and pharmacological treatment in eosinophilic esophagitis

Eosinophilic esophagitis is an inflammation of the esophagus, causing dysfunction and fibrosis. Dysphagia or food impaction are common symptoms, that do not respond to proton pump inhibitors. Initial management must include an evaluation for food allergies .Emerging data in adults suggest that the elimination of six types of food from the diet can improve symptoms and esophageal eosinophilia. Pharmacological therapy should start with topical use of fluticasone, if lack of response is observed; budesonide is a good next step. The combination of steroids with proton pump inhibitors is reasonable if reflux is suspected to be contributing to symptoms. Further research will be necessary to find the best combination of tailored diets, proton pump inhibitors and steroids to achieve better control of the disease.

La esofagitis eosinofílica es una inflamación del esófago que causa disfunción y fibrosis. La presencia de disfagia o impactación alimentaria son síntomas comunes que no responden al uso de inhibidores de bomba de protones. El manejo inicial debe incluir una evaluación para alergias alimentarias. Datos emergentes en adultos sugieren que una dieta con eliminación de seis alimentos puede mejorar los síntomas y la eosinofilia esofágica. El tratamiento farmacológico debería comenzar con fluticasona tópica; si hay falta de respuesta a esta opción un paso siguiente adecuado es la budesonida. La combinación de esteroides con inhibidores de la bomba de protones es razonable si se sospecha que el reflujo contribuye a la sintomatología. Se requiere conocimiento adicional para encontrar la mejor combinación de dietas individualizadas, esteroides e inhibidores de bomba de protones para conseguir el mejor control de la enfermedad.

Dietary treatment modulates mast cell phenotype, density, and activity in adult eosinophilic oesophagitis.

BACKGROUND: Mast cells (MCs) are abundant in the inflammatory infiltrate in eosinophilic oesophagitis (EoE), but decrease with disease remission. However, their phenotype, role in the pathophysiology of the disease, and modulation after effective dietary therapy are still unclear. OBJECTIVE: To define the phenotype of oesophageal MCs, their modulation through dietary therapy, and their association with clinical manifestations of EoE. METHODS: Oesophageal mucosal samples from 10 adult patients with EoE obtained before and after effective six-food elimination diet (SFED) therapy, as well as from 10 control subjects were analysed. Eosinophil and MC density were quantified. Gene expression of chemoattractants for eosinophils (CCL11, CCL24, and CCL26), MCs (SCF), and their receptors (CCR3 and SCFR, respectively) were assessed by means of qPCR. Gene and protein expression of specific MC proteases (CPA3, CMA, and TPSB2) were evaluated with qPCR and immunofluorescence. Clinical manifestations and atopic background were recorded. RESULTS: MC density was significantly increased in EoE compared with controls, decreasing after dietary treatment (18.6 to 1.44 cells/hpf, respectively; P < 0.001). The MCTC subtype predominated in the oesophageal mucosa (90%) in both patients with EoE and controls. Gene expression of MC-related proteases, eotaxins, and SCF were up-regulated in patients with EoE, but significantly decreased after therapy, regardless of atopic background. Epithelial peaks of MCs and eosinophils were significantly associated (ρ = 0.80) in EoE and correlated with the symptom score (ρ = 0.78). Gene expression of MC proteases and eotaxins also correlated with the symptom score (P < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: MC and its proteases seem to play a relevant role in the pathophysiology and symptoms of EoE, which can be reversed after effective dietary treatment.

[Oesophageal diseases: gastroesophageal reflux disease, Barrett's disease, achalasia and eosinophilic oesophagitis]. / Enfermedades esofágicas: enfermedad por reflujo gastroesofágico, Barrett, acalasia y esofagitis eosinofílica.

The most important novel findings presented on oesophageal disease in DDW 2015 were the following: 1) GERD: a) hypervigilance seems to be a key pathogenic factor in reflux symptoms refractory to PPI; b) post-reflux swallowing-induced peristaltic waves could be an excellent diagnostic criterion for GERD; c) laryngeal pH-metry is not useful in the diagnosis of extra-oesophageal symptoms; d) the recommendation of weight loss adequately recorded in the clinical reports of patients with GERD and obesity or overweight is an excellent quality indicator and is associated with better outcomes. 2) Barrett's oesophagus: a) persistent low-grade dysplasia in more than one endoscopy and a diagnosis of "indefinite for dysplasia" are associated with a high risk of neoplastic progression; b) narrow-band imaging allows areas of dysplasia on Barrett's oesophagus to be identified with high sensitivity and specificity; c) initial endoscopy fails to identify a high percentage of advanced neoplasms in Barrett's oesophagus. Early re-endoscopy should be considered; d) endoscopists specialized in Barret's oesophagus obtain a much higher yield in the diagnosis of advanced lesions. Patients at high risk-men, older patients, smokers and those with long-segment Barrett's oesophagus-could benefit from follow-up in a referral center. 3) Achalasia: POEM seems safe and effective, independently from patient characteristics (age, comorbidity) and the technical variations used. 4) Eosinophilic esophagitis: topical budesonide and exclusion diets are reasonably effective in PPI non-responders.