Seema S. Aceves

Oral Viscous Budesonide Is Effective in Children With Eosinophilic Esophagitis in a Randomized, Placebo-Controlled Trial

BACKGROUND & AIMS Eosinophilic esophagitis (EoE) is caused by immunologic reactions to ingested/inhaled allergens. The diagnosis is considered if >or=15 eosinophils per high-powered field (eos/hpf) are detected in mucosal biopsies. Placebo-controlled studies have not been conducted to evaluate the safety and efficacy of oral viscous budesonide (OVB). METHODS Children with EoE were randomly assigned to groups that were given OVB (n=15) or placebo (n=9). Patients<5 feet and >or=5 feet tall received 1 mg and 2 mg OVB daily, respectively. All patients received lansoprazole. Duration of treatment was 3 months, followed by repeat endoscopy and biopsies. Patients were classified as responders if their peak eosinophil counts were <or=6 eos/hpf, partial responders were 7-19 eos/hpf, and nonresponders were >or=20 eos/hpf. Baseline and post-treatment symptoms and endoscopic and histologic features were scored. RESULTS Thirteen (86.7%) children given OVB (P<.0001) and none who received placebo (P=.3) were classified as responders. Mean pre-/post-treatment peak eosinophil counts were 66.7 and 4.8 eos/hpf, respectively, in the group given OVB (P<.0001); they were 83.9 and 65.6 eos/hpf, respectively, in the group given placebo (P=.3). In the group given OVB, there were significant reductions from baseline values in proximal (P=.002), mid (P=.0003), and distal (P=.001) esophageal eosinophilia. After OVB therapy, compared with baseline, the mean symptom (P=.0007), endoscopy (P=.0005), and histology scores improved (P=.0035) significantly. CONCLUSIONS OVB is an effective treatment of pan-esophageal disease in children with EoE. OVB improves symptoms and endoscopic and histologic features. Proton pump inhibitor single therapy did not significantly improve esophageal eosinophilia or symptoms of EoE.

Common variants at 5q22 associate with pediatric eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the accumulation of eosinophils in the esophagus. We report association of EoE with variants at chromosome 5q22 encompassing TSLP and WDR36 (rs3806932, combined P = 3.19 × 10−9). TSLP is overexpressed in esophageal biopsies from individuals with EoE compared with unaffected individuals, whereas WDR36 expression is unaltered between the two groups. These data implicate the 5q22 locus in the pathogenesis of EoE and identify TSLP as the most likely candidate gene in the region.

Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids

Background:  Esophageal remodeling occurs in eosinophilic esophagitis (EE) patients but whether the components of remodeling in the subepithelium are reversible by administration of topical oral corticosteroids is unknown.

Oral Viscous Budesonide: A Potential New Therapy for Eosinophilic Esophagitis in Children

BACKGROUND:Eosinophilic esophagitis (EE) is a disorder characterized typically by pan-esophageal eosinophilia. We evaluate a palatable, long-acting topical corticosteroid preparation for the treatment of EE.STUDY DESIGN:This is a retrospective analysis of symptoms, endoscopic and histologic findings, efficacy, and safety of treatment in children with EE receiving oral viscous budesonide. Response to therapy was determined histologically by the number of eos/hpf. Patients were classified by histology into responders (0–7 eos/hpf), partial responders (8–23 eos/hpf), and nonresponders (≥24 eos/hpf). A symptom score (max. 14) and an EE endoscopy score (max. 8) were used to compare data.RESULTS:In 20 children (mean age 5.5 yr, median age 4.1 yr) the mean highest eosinophil count was 87 eos/hpf (range 30–170) before and 7 eos/hpf (range 0–50, P < 0.0001) after therapy. There were 16 (80%) responders, 1 partial responder, and 3 nonresponders. Commonest pretreatment symptoms were nausea, vomiting, pain, and heartburn. The mean symptom score fell from 4.4 to 0.8 (P < 0.0001) and the mean endoscopy score from 3.6 to 0.8 (P < 0.0001). No significant adverse events were reported. Morning cortisol levels were within normal limits.CONCLUSIONS:Topical viscous budesonide is a safe and effective therapy for EE in young children.

An Antibody Against IL-5 Reduces Numbers of Esophageal Intraepithelial Eosinophils in Children With Eosinophilic Esophagitis

BACKGROUND & AIMS The role of interleukin (IL)-5 in the pathogenesis of eosinophilic esophagitis (EoE) has been established in animal models; anti-IL-5 therapy has been reported to be effective in adults. We investigated whether IL-5 has a role in accumulation of esophageal eosinophils in children with EoE and whether therapy with mepolizumab, an antibody against IL-5, reduces the number of esophageal intraepithelial eosinophils in children with EoE. METHODS We performed an international, multicenter, double-blind, randomized, prospective study of 59 children with EoE, defined as baseline peak count of esophageal intraepithelial eosinophils of ≥ 20 in at least 1 high-power field (hpf). Patients received an infusion every 4 weeks (a total of 3 infusions) of 0.55, 2.5, or 10 mg/kg mepolizumab. No placebo group was used. RESULTS Baseline peak and mean esophageal intraepithelial eosinophil counts were (mean ± SE) 122.5 ± 8.78 and 39.1 ± 3.63 per hpf, respectively. Four weeks after the third infusion, peak eosinophil counts were <5 per hpf in 5 of 57 children (8.8%); we did not observe differences among groups given different doses of mepolizumab. Reduced peak and mean eosinophil counts, to <20 per hpf, were observed in 18 of 57 (31.6%) and 51 of 57 (89.5%) children, respectively. Peak and mean esophageal intraepithelial eosinophil counts decreased significantly to 40.2 ± 5.17 and 9.3 ± 1.25 per hpf, respectively (P < .0001). An analysis to evaluate predictors of response associated a higher mean baseline esophageal intraepithelial eosinophil count with a greater reduction in mean count (P < .0001). CONCLUSIONS IL-5 is involved in the pathogenesis of EoE in children. Mepolizumab, an antibody against IL-5, reduces esophageal eosinophilic inflammation in these patients.

Pediatric and adult eosinophilic esophagitis: similarities and differences

Early in the 1990s, several case series described adults suffering from dysphagia and children with refractory reflux symptoms, both accompanied by an eosinophil‐predominant infiltration, thereby conclusively distinguishing it from gastroesophageal reflux disease. Eosinophilic esophagitis (EoE) was recognized as its own entity in the adult and in the pediatric literature. In the last decade, evidence has accumulated that EoE represents a T‐helper (Th)2‐type inflammatory disease. Remodeling of the esophagus is a hallmark of EoE, leading to esophageal dysfunction and bolus impaction. Familial occurrence and disease association with single‐nucleotide polymorphisms underscore the influence of genetics in this disease. Eosinophilic esophagitis may affect individuals at any age, although the clinical presentation is highly age dependent. There is a significant allergic bias in the EoE population, with the majority of patients having concurrent allergic rhinitis, asthma, eczema, and/or a history of atopy. One noteworthy difference is that in children, EoE seems to be primarily a food antigen–driven disease, whereas in adults, mainly aeroallergen sensitization has been observed. Treatment modalities for EoE include the 3Ds: drugs, diet, and dilation. The crucial question of whether adult and pediatric EoE are different phenotypes of one single entity or whether we are confronted with two different diseases is still open. Here, we review similarities and differences between EoE in adults and children.

Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction

BACKGROUND Increased numbers of mast cells are present in the esophageal epithelium in patients with eosinophilic esophagitis (EE). However, mast cell infiltration into the esophageal lamina propria (LP) and smooth muscle (SM) and the effects of their products on SM function has not been determined. OBJECTIVE We investigated mast cell localization and characterization in esophageal SM, the functional significance of mast cell TGF-β1 expression to contraction of human esophageal smooth muscle (HESM) cells in vitro, and the effect of topical corticosteroids on the number of tryptase-positive (MC(T)) and chymase-positive (MC(C)) mast cells in patients with EE. METHODS MC(T)- and MC(C)-positive mast cell numbers were quantitated in the epithelium, the LP before and after topical corticosteroid therapy, and the muscularis mucosa in patients with EE and control subjects by using immunohistology. Double immunofluorescence was used to assess mast cell production of TGF-β1. The ability of TGF-β1 to influence HESM cell contractility was assessed in vitro. RESULTS In the SM in patients with EE, significantly increased numbers of MC(T)- and TGF-β1-positive cells (but only low levels of eosinophils) were detected compared with those seen in control subjects. MC(T) expressed TGF-β1, which increased the contractility of cultured primary HESM cells in vitro. Topical corticosteroid therapy in patients with EE significantly reduced epithelial MC(T) numbers but not LP tryptase-chymase-positive mast cell numbers. CONCLUSIONS MC(T) numbers, rather than eosinophil numbers, are increased in the SM in patients with EE, express TGF-β1, and increase the contractility of HESM cells in vitro. As such, mast cells localized to SM in patients with EE might modulate esophageal contractility.

Transcriptome analysis of proton pump inhibitor–responsive esophageal eosinophilia reveals proton pump inhibitor–reversible allergic inflammation

BACKGROUND Esophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery. OBJECTIVE In this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities. METHODS We evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE. RESULTS The EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis (eotaxin 3, CCL26), barrier molecules (desmoglein 1, DSG1), tissue remodeling (periostin, POSTN), and mast cells (carboxypeptidase A, CPA3). PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment. CONCLUSION These findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated with classic features of allergic inflammation, provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia.

Distinguishing eosinophilic esophagitis in pediatric patients: clinical, endoscopic, and histologic features of an emerging disorder.

Goals To determine the clinical, endoscopic, and histologic criteria that distinguish children with eosinophilic esophagitis (EE) from those with non-EE diagnoses. Background EE is a disease of escalating incidence. Distinguishing children with EE from those with non-EE diagnosis can be difficult before endoscopy. Study A retrospective case-control study was performed for children with any degree of esophageal eosinophilic inflammation who underwent esophageal biopsy at Childrens Hospital San Diego from January 1998 to December 2002. A database containing children who met histologic criteria for EE and an equivalent number of children who had milder esophageal eosinophilia (non-EE patients) was created to compare the 2 groups. Results The number of EE cases increased from 15 in 1998 to 35 in 2002. EE patients were predominantly school-aged boys; 5 of 102 were suspected to have EE before biopsy. Although EE and non-EE patients complained of vomiting and abdominal pain at equivalent rates, EE patients were 3 times more likely to complain of dysphagia [odds ratio (OR)=3.11, 95% confidence interval (CI) 1.55-6.65] and twice as likely to have stricture formation (OR=2.43, 95% CI 0.72-11.75). On endoscopy, patients with EE were 19-times more likely than non-EE patients to have endoscopic abnormalities (OR=19, 95% CI 9.0-45.88). Histologically, EE patients were more likely to have basal zone hyperplasia and degranulated eosinophils (OR=45 and 157, respectively). Conclusions We demonstrate that school-aged children, particularly boys, who complain of dysphagia should raise the index of suspicion for EE. We also suggest that EE-associated strictures are more common than peptic strictures in children.

Relationships Between Eosinophilic Inflammation, Tissue Remodeling and Fibrosis in Eosinophilic Esophagitis

The clinical and pathologic features of eosinophilic esophagitis (EE) include extensive tissue remodeling. Increasing evidence supports a key role for the eosinophil in multiple aspects of the esophageal remodeling and fibrosis seen in this allergic disease. This article reviews the clinical implications of esophageal remodeling and fibrosis in EE and discusses the possible pathogenic mechanisms inducing and regulating these responses. The focus is specifically on eosinophil and cytokine interactions with the esophageal epithelium, vascular endothelium, resident fibroblasts, and smooth muscle. Current and potential therapeutic interventions are discussed that may impact the development or resolution of chronic esophageal remodeling and fibrosis in EE.