Eosinophilic gastrointestinal disorders (EGIDs) are emerging inflammatory diseases which may involve any part of the gastrointestinal (GI) tract and lead to the eosinophilic mucosal infiltration in the absence of secondary causes of intestinal eosinophilia (1, 2). Based on the site of the eosinophil inflammations, EGIDs are classified into eosinophilic esophagitis (EoE) and nonesophageal EGIDs (1). While nonesophageal EGIDs still represent a clinical enigma for clinicians, EoE is considered the prototype of EGIDs with standardized guidelines (1, 3). EoE is a chronic/remittent, allergen-mediated disease characterized by esophageal dysfunction and eosinophilic infiltration, affecting both children and adults, with a male-female ratio of 3:1 (4). The prevalence of EoE is significantly increased in the last decade; indeed, it is currently considered one of the most common causes of upper gastrointestinal morbidity (4,5). EoE diagnosis requires 15 eosinophils per high power field in tissue biopsies endoscopically obtained, without concomitant eosinophilic infiltration in other GI tracts (3). To date, the GI endoscopy is the gold standard for the diagnosis and follow-up of patients with EGIDs. The need for several endoscopies to monitor the disease and the absence of validated non-invasive biomarkers or tools are the main reasons for a significant burden on affected patients and the healthcare system (6). Therefore, there is a critical need for non-invasive biomarkers to replace such invasive monitoring. Several efforts have been made to identify potential non-invasive biomarkers for diagnosing and monitoring the disease in the last years.

Recently Votto et al. published a review showing promising non-invasive biomarkers for diagnosing and monitoring EGIDs, despite none of these have been incorporated into guideline recommendations. Absolute eosinophil count, circulating eosinophil progenitors, and eosinophil granule proteins (eosinophil cationic protein [ECP], eosinophil-derived neurotoxin [EDN], eosinophil peroxidase [EPX]), and galectin-10 (GAL-10) have been identified as the most specific biomarkers of active EoE, especially if used in combination. In a recent pediatric case-control study, Wechsler et al. showed that plasma GAL-10, ECP, EDN, Eotaxin-3, major basic protein-1 (MBP-1) are significantly increased in EoE compared to healthy controls. Thus, the combination of this novel panel of eosinophil-associated proteins results as a potential non-invasive tool to identify untreated EoE patients from non-EoE controls.

Furthermore, several studies reported that EoE patients had a marked change in tissue-specific gene expression. Lu et al. investigated esophageal miRNA expression profile in patients with active disease and responsive to steroids, finding that the expression levels of specific miRNAs (miR-21, miR-223, and miR-375) strongly correlated with esophageal eosinophil levels (7). Other epigenetic mechanisms such as DNA methylation have been recently assessed. Pediatric patients with EoE showed differences in mucosal DNA methylation profiles compared to controls (8).

EoE is a multifactorial disease. Although recent evidence suggested a fundamental pathogenetic role of the environmental factors, several studies have also reported that genetic predisposition is a significant risk factor in the development of EoE (9). Different studies, including candidate-gene identification and genome-wide association studies, have identified gene loci that have been associated explicitly with EoE (10). In this context, the Cincinnati Children's Hospital researchers developed a specific diagnostic panel comprising a 96-gene quantitative PCR array to identify patients with EoE monitor the disease and response to therapy (11).

The future of EGIDs is exciting from both a diagnostic and therapeutic standpoint. The growing number of genetic, molecular expression, and immunologic analyses, in conjunction with increased differentiation of clinical phenotypes and biomarker-supported endotypes, will help clinicians explain differing therapeutic responses, predict clinical response, guide individual therapies, and improve patient outcomes. Therefore, further research is required to confirm phenotypes and histological or serological biomarkers to provide a novel endotype classification based on different cytokine or genetic signatures.

Summary
Votto Martina, De Filippo Maria, Marseglia Gian Luigi and Licari Amelia; 
Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy 

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Votto et al., Acta Biomed. 2021 Nov 29;92(S7):e2021530. doi: 10.23750/abm.v92iS7.12401.