Pediatric Eosinophilic Esophagitis Symptom Scores (PEESS v2.0) identify histologic and molecular correlates of the key clinical features of disease

Abstract

Background: The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS v2.0) measures patient-relevant outcomes. However, whether patient-identified domains (dysphagia, gastroesophageal reflux disease [GERD], nausea/vomiting, and pain) align with clinical symptomology and histopathologic and molecular features of eosinophilic esophagitis (EoE) is unclear.

Objective: The purpose of this study was to determine whether clinical features of EoE, measured through PEESS v2.0, associate with histopathologic and molecular features of EoE. This represents a novel approach for analysis of allergic diseases, given the availability of allergic tissue biopsy specimens.

Methods: We systematically recruited treated and untreated pediatric patients with EoE (aged 2-18 years) and examined parent proxy-reported symptoms using the PEESS v2.0. Clinical symptomology was collected by questionnaire. Esophageal biopsy samples were quantified for levels of eosinophils, eosinophil peroxidase (EPX) immunohistochemical staining, and mast cells. Molecular features were assessed by using the EoE Diagnostic Panel (94 EoE-related gene transcripts). Associations between domain scores and clinical symptoms and biological features were analyzed with Wilcoxon rank sum and Spearman correlation.

Results: The PEESS v2.0 domains correlated to specific parent-reported symptoms: dysphagia (P = .0012), GERD (P = .0001), and nausea/vomiting (P < .0001). Pain correlated with multiple symptoms (P < .0005). Dysphagia correlated most strongly with overall histopathology, particularly in the proximal esophagus (P ≤ .0049). Markers of esophageal activity (EPX) were significantly associated with dysphagia (strongest r = 0.37, P = .02). Eosinophil levels were more associated with pain (r = 0.27, P = .06) than dysphagia (r = 0.24, P = .13). The dysphagia domain correlated most with esophageal gene transcript levels, predominantly with mast cell-specific genes.

Conclusion: We have (1) established a validated, parent proxy-reported measure for pediatric EoE, the PEESS v2.0; (2) verified that the parent proxy effectively captures symptoms; (3) determined that the dysphagia domain most closely aligns with symptoms and tissue-based molecular biomarkers; (4) established that symptoms correlate with EPX staining; and (5) observed association between mast cells and dysphagia.

Keywords: Allergy; mast cells; microarray; molecular genetics; patient-reported outcomes; pediatrics; quality of life; reflux; surveys.

Conflict of interest statement

Conflicts of interest

LJM, JMG, AK, KAH, ME, HH, KM, JPA, JTG: None

Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. The relationships between gastrointestinal symptoms and PEESS® v2.0 scores

The x-axis represents the negative log10 p-value of the Wilcoxon Rank Sum test comparing individuals reporting the clinical symptom to those who do not report the clinical symptom. The x-axis columns in the figure are PEESS® v2.0 scores while the y-axis indicates clinical symptoms reported as yes/no. GERD, gastroesophageal reflux disease; GI, gastrointestinal; NV, nausea/vomiting domain.

Figure 2. Spearman correlations between PEESS® v2.0 scores and disease parameters

Strength of the association with a diagnostic subset of the eosinophilic esophagitis transcriptome is measured using Spearman’s ρ (text within cell). Darker red shades indicate stronger negative correlations, whereas darker blue shades indicate stronger positive correlations. Bolded values indicate correlations that are significant at p ≤ 0.05. CPA3, carboxypeptidase A3; Eos, eosinophil; EPX, eosinophil peroxidase; GERD, gastroesophageal reflux disease; NV, nausea/vomiting domain

Figure 3. Spearman correlations between PEESS® v2.0 scores and a diagnostic subset of the eosinophilic esophagitis transcriptome

Darker red shades indicate stronger negative correlations, whereas darker blue shades indicate stronger positive correlations. Correlations by functional groupings of genes.

Figure 4. The hierarchical relationships between domains based on gene expression profile correlations

Using the Spearman r for the correlation between a diagnostic subset of the eosinophilic esophagitis (EoE) transcriptome (EoE diagnostic panel) gene expression and PEESS® v2.0 domain scores, we created a clustering tree representing the hierarchical order of the domain’s representativeness and plotted it with the Spearman r–based heat-diagram for the correlation at gene level. Darker red shades indicate stronger negative correlations, whereas darker blue shades indicate stronger positive correlations. The shorter the distance (tree-branch length), the more similar the expression correlation for each domain is.

Figure 5. Associations between the PEESS® v2.0 dysphagia domain and a diagnostic subset of the eosinophilic esophagitis transcriptome

The x-axis represents the negative log10 p-value of the Spearman correlation between the dysphagia domain and a diagnostic subset of genes from the eosinophilic esophagitis (EoE) transcriptome (EoE diagnostic panel, EDP). The y-axis is organized by genes within functional groupings, color shading is for ease of interpretation only. Dashed line indicates p = 0.05.