Newly Developed and Validated Eosinophilic Esophagitis Histology Scoring System and Evidence that it Outperforms Peak Eosinophil Count for Disease Diagnosis and Monitoring

Eosinophilic esophagitis is diagnosed by symptoms, and at least 15 intraepithelial eosinophils per high power field in an esophageal biopsy. Other pathologic features have not been emphasized. We developed a histology scoring system for esophageal biopsies that evaluates eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells and lamina propria fibrosis. Severity (grade) and extent (stage) of abnormalities were scored using a 4 point scale (0 normal; 3 maximum change). Reliability was demonstrated by strong to moderate agreement among 3 pathologists who scored biopsies independently (p≤0.008). Several features were often abnormal in 201 biopsies (101 distal, 100 proximal) from 104 subjects (34 untreated, 167 treated). Median grade and stage scores were significantly higher in untreated compared to treated subjects (p≤0.0062). Grade scores for features independent of eosinophil counts were significantly higher in biopsies from untreated compared to treated subjects (basal zone hyperplasia p≤0.024 and dilated intercellular spaces p≤0.005), and were strongly correlated (r-square\u3e0.67). Principal components analysis identified 3 principal components that explained 78.2% of the variation in the features. In logistic regression models, 2 principal components more closely associated with treatment status than log distal peak eosinophil count (r-square 17, area under the curve 77.8 vs r-square 9, area under the curve 69.8). In summary, the eosinophilic esophagitis histology scoring system provides a method to objectively assess histologic changes in the esophagus beyond eosinophil number. Importantly, it discriminates treated from untreated patients, uses features commonly found in such biopsies, and is utilizable by pathologists after minimal training. These data provide rationales and a method to evaluate esophageal biopsies for features in addition to peak eosinophil count

Should wheat, barley, rye, and/or gluten be avoided in a 6-food elimination diet?

Eosinophilic esophagitis (EoE), a food antigen-mediated disease, is effectively treated with the dietary elimination of six foods commonly associated with food allergies (milk, wheat, egg, soy, tree nuts/peanuts and fish/shellfish). Because wheat shares homologous proteins (including gluten) with barley and rye and may also be processed with these grains, some clinicians have suggested barley and rye may also trigger EoE as a result of cross-reaction and/or cross-contamination with wheat. In this opinion paper, we discuss the theoretical risks of cross-reactivity and cross-contamination among wheat, barley, and rye proteins (including gluten), assess common practices at EoE treatment centers, and provide recommendations for dietary treatment and future studies of EoE

Budesonide Oral Suspension Improves Symptomatic, Endoscopic, and Histologic Parameters Compared With Placebo in Patients With Eosinophilic Esophagitis

BACKGROUND & AIMS: Pharmacologic treatment of eosinophilic esophagitis (EoE) is limited to off-label use of corticosteroids not optimized for esophageal delivery. We performed a randomized, controlled phase 2 trial to assess the ability of budesonide oral suspension (BOS), a novel muco-adherent topical steroid formulation, to reduce symptoms and esophageal eosinophilia in adolescents and adults with EoE. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 93 EoE patients between the ages of 11 and 40 years with dysphagia and active esophageal eosinophilia were randomized to receive either BOS 2 mg or placebo twice daily for 12 weeks. Co-primary outcomes were change in Dysphagia Symptom Questionnaire (DSQ) score from baseline, and proportion of patients with a histologic response (≤6 eosinophils/high-power field) after treatment. Endoscopic severity scores and safety parameters were assessed. RESULTS: At baseline, mean DSQ scores were 29.3 and 29.0, and mean peak eosinophil counts were 156 and 130 per hpf in the BOS and placebo groups, respectively. After treatment, DSQ scores were 15.0 and 21.5, and mean peak eosinophil counts were 39 and 113 per high-power field, respectively (P < .05 for all). For BOS vs placebo, change in DSQ score was -14.3 vs -7.5 (P = .0096), histologic response rates were 39% vs 3% (P < .0001), and change in endoscopic severity score was -3.8 vs 0.4 (P < .0001). Adverse events were similar between groups. CONCLUSIONS: Treatment with BOS was well tolerated in adolescent and young adult patients with EoE and resulted in improvement in symptomatic, endoscopic, and histologic parameters using validated outcome instruments. ClinicalTrials.gov ID NCT01642212

Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in European EoE cases and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replication of the 5q22 locus (meta-analysis p = 1.9×10−16), we identified association at 2p23 (encoding CAPN14, p = 2.5×10−10). CAPN14 was specifically expressed in the esophagus, dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to IL-13, and located in an epigenetic hotspot modified by IL-13. There was enriched esophageal expression for the genes neighboring the top 208 EoE sequence variants. Multiple allergic sensitization loci were associated with EoE susceptibility (4.8×10−2 < p < 5.1×10−11). We propose a model that elucidates the tissue specific nature of EoE that involves the interplay of allergic sensitization with an EoE-specific, IL-13–inducible esophageal response involving CAPN14

Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective contributions to heritability are unknown

MicroRNA Profiling in Mucosal Biopsies of Eosinophilic Esophagitis Patients Pre and Post Treatment with Steroids and Relationship with mRNA Targets

<div><h3>Background</h3><p>The characterization of miRNAs and their target mRNAs involved in regulation of the immune process is an area of intense research and relatively little is known governing these processes in allergic inflammation. Here we present novel findings defining the miRNA and mRNA transcriptome in eosinophilic esophagitis (EoE), an increasing recognized allergic disorder.</p> <h3>Methods</h3><p>Esophageal epithelial miRNA and mRNA from five paired biopsies pre- and post-treatment with glucocorticosteroids were profiled using Taqman and Affymetrix arrays. Validation was performed on additional paired biopsies, untreated EoE specimens and normal controls. Differentially regulated miRNAs and mRNAs were generated, within which miRNA-mRNA target pairs with high predicted confidence were identified.</p> <h3>Results</h3><p>Compared to the post-glucocorticoid treated esophageal mucosa, of all the 377 miRNA sequences examined, 32 miRNAs were significantly upregulated and four downregulated in the pre-treated biopsies. MiR-214 was the most upregulated (150 fold) and miR-146b-5b, 146a, 145, 142-3p and 21 were upregulated by at least 10 fold. Out of 12 miRNAs chosen for validation by qRT-PCR, five (miR-214, 146b-5p, 146a, 142-3p and 21) were confirmed and 11 shared the same trend. When the expression of the 12 miRNAs in the EoE mucosa was compared to unrelated normal mucosa, six (miR-214, 146b-5p, 146a, 21, 203, and 489) showed similar significant changes as in the paired samples and 10 of them shared the same trend. In the same five pairs of samples used to profile miRNA, 311 mRNAs were down-regulated and 35 were up-regulated in pre-treated EoE mucosa. Among them, 164 mRNAs were identified as potential targets of differentially regulated miRNAs. Further analysis revealed that immune-related genes, targeted and non-targeted by miRNAs, were among the most important genes involved in the pathogenesis of EoE.</p> <h3>Conclusions</h3><p>Our findings add to the accumulating body of data defining a regulatory role for miRNA in immune and allergic processes.</p> </div

Treatment-induced miRNA expression changes validated by qRT-PCR.

<p>Delta Ct values are used to represent selected miRNA expression levels in esophageal epithelium of 7 paired EoE patients pre- vs post-treatment (5 pairs used in miRNA profiling and 2 additional pairs; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040676#pone-0040676-t001" target="_blank">Table 1</a>). Asterisks indicate statistical significance (P<0.05).</p