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Background:
Review

Noninvasive Biomarkers in Eosinophilic Esophagitis: Current Perspectives

by
Melissa Munroe
,
Nhat Hoang
,
Jon Marc Rhoads
and
Tu T. Mai
*
Department of Pediatrics, Division of Gastroenterology, University of Texas McGovern Medical School, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Appl. Sci. 2025, 15(16), 9083; https://doi.org/10.3390/app15169083
Submission received: 1 July 2025 / Revised: 15 August 2025 / Accepted: 15 August 2025 / Published: 18 August 2025
(This article belongs to the Section Applied Biosciences and Bioengineering)
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Abstract

Eosinophilic esophagitis (EoE) is an inflammatory disease of the esophagus, diagnosed based on clinical symptoms and elevated eosinophil counts in esophageal mucosal biopsies. While endoscopic biopsy remains the gold standard for diagnosing and monitoring this disease, the average child with EoE receives at minimum yearly endoscopy. There are risks and high costs associated with repeated procedures. Studies have been developed to evaluate less invasive methods for disease diagnosis and surveillance. We will be reviewing the current literature on noninvasive biomarkers in eosinophilic esophagitis, including specific levels of markers in blood, urine, stool, and saliva samples, as well as the esophageal string test. To date, there are no consensus statements recommending the use of noninvasive biomarkers in symptomatic patients or in asymptomatic patients. Only the esophageal string test has been formally accepted as a potential alternative to endoscopic surveillance by the American Society for Gastrointestinal Endoscopy Consensus Conference. Further studies need to be conducted to validate the use of biomarkers in diagnosing and monitoring this disease.

1. Introduction

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated condition of the esophagus, clinically characterized by symptoms of esophageal dysfunction and histologically defined by a peak eosinophil count of ≥15 eosinophils per high-power field (eos/hpf) on mucosal biopsies [1]. Currently, endoscopic biopsy with histologic assessment remains the gold standard for both diagnosis and monitoring. However, repeated endoscopic evaluations pose a substantial burden, especially in pediatric populations, due to procedural risks, anesthesia exposure, and healthcare costs [2,3]. Additionally, symptoms often fail to correlate with histologic disease activity, further complicating disease management [3]. In recent years, there has been growing interest in developing noninvasive biomarkers for EoE to reduce reliance on serial endoscopy. Several reviews have summarized aspects of this evolving field, particularly focusing on blood-based biomarkers or highlighting experimental techniques. However, our review aims to provide a more comprehensive and clinically oriented synthesis by: (1) evaluating biomarkers across all noninvasive sample types—including blood, urine, stool, saliva, and esophageal luminal secretions (Figure 1); (2) systematically appraising their diagnostic and monitoring utility; (3) analyzing their cost, availability, and feasibility in clinical settings; and (4) identifying the most promising candidates based on the strength of evidence and endorsement by professional guidelines.

2. Methodology

A comprehensive literature search was conducted in PubMed to identify relevant studies evaluating noninvasive biomarkers in EoE from January 2000 to May 2025. The following keywords and combinations were used: “eosinophilic esophagitis”, “EoE”, “biomarkers”, “noninvasive”, “serum markers”, “saliva”, “urine”, “stool”. Boolean operators (AND, OR) were applied to refine the search.
After removing duplicates, three independent reviewers screened the titles and abstracts to identify eligible studies. Full texts of potentially relevant articles were retrieved and reviewed.
Relevant data were extracted, including the study type and design, size, patient population, diagnostic or monitoring relevance, and key findings and limitations.

3. Blood-Based Biomarkers in Eosinophilic Esophagitis

Eosinophils are specialized bone marrow-derived myeloid cells that play important roles in the innate and adaptive immune system. In chronic eosinophil-mediated conditions such as EoE, eosinophils promote a chronic inflammatory state through the release of their enzymes and granular contents (including cytotoxic proteins and inflammatory mediators), which leads to tissue remodeling and morphologic and functional changes. Of the whole blood-based markers, there has been much interest in the absolute eosinophil count (AEC) and in granule-derived proteins, including eosinophilic cationic protein (ECP), eosinophil-derived neurotoxin (EDN), eosinophil peroxidase (EPO), and major basic protein (MBP).
Table 1 summarizes potential blood-based biomarkers identified in eosinophilic esophagitis (EoE), which may aid in diagnosis and monitoring of the disease.

3.1. Absolute Eosinophil Count (AEC)

Peripheral blood eosinophil counts vary by age. A normal AEC range in adults is generally cited as 50–350 eos/µL, whereas in infants, the upper limit of the normal range has been reported to be as high as 500 eos/µL [4,5,6,7]. The AEC is the most frequently studied biomarker in the EoE literature. Bullock [8] and Konikoff [9] noted significant differences between AEC in children and age-matched controls, while Min [10] noted significant differences in a combined group of adults and children with EoE and healthy controls. Bullock and Min also reported a significant difference in AEC between pediatric patients with active vs. treated EoE, while Johnsson [11], Colson [12], Conus [13], Domenech Witek [14], and Fujiwara [15] noted similar findings in adults. However, Strauman [16], Von Armnim [17], and Philpot [18] noted no difference between active and treated EoE in adults.
One of the largest studies of EoE by Thulin et al. (105 children divided into active EoE (n = 34), remission (n = 18), and healthy controls (n = 53)) revealed in the 3 groups average AECs of 540 eos/µL, 370 eos/µL, and 230 eos/µL, respectively [19]. However, AEC is a nonspecific biomarker that may be elevated in other atopic conditions, such as bronchial asthma, allergic rhinitis, and eczema, which underscores the importance of atopic controls in studies with EoE [20].
Although there is currently no definitive “cut-off value” to predict EoE, AEC is generally considered to be helpful in the workup for EoE, and there has been interest in whether this biomarker may predict response to therapy for individuals with EoE. Muftah et al. evaluated the ability of the baseline peripheral eosinophil count to predict the proton pump inhibitor response (PPI) in 183 patients with EoE [21]. They found that mean AEC was higher among PPI nonresponsive EoE patients compared to PPI responders (0.41 vs. 0.24 K/µL, p = 0.013) [21].

3.2. Eosinophil Cationic Protein (ECP)

ECP is a ribonuclease stored in eosinophil granules that has cytotoxic, neurotoxic, and profibrotic functions. Cengiz et al., in their study of 15 patients with EoE and 14 healthy controls, found that serum ECP levels were significantly higher in patients with EoE than in controls (20.4 vs. 8.8, p < 0.0001) [22]. They also found that a cut-off value of 13.9 mcg/mL had 92.8% specificity and 80% sensitivity for the diagnosis of EoE [22]. Min et al., in a larger study of 42 patients with EoE and 53 controls, found average ECP values of 26.98 vs. 5.20 ng/mL, respectively (p < 0.001) [10]. Schlag et al. assessed the baseline and post-treatment serum ECP levels in a group of 69 patients with EoE, 51 of whom received orally disintegrating budesonide, while the remainder received placebo [23]. They noted a significant decrease in serum ECP levels (45.5 ± 44.7 vs. 27.5 ± 25.0 μg/L, p = 0.0016) that correlated with histologic remission in the budesonide group vs. controls [23]. However, Wright et al. noted no significant differences in ECP levels between 19 EoE patients and 20 controls [24].

3.3. Eosinophil-Derived Neurotoxin (EDN)

EDN is primarily a neurotoxic protein that may also induce cytotoxicity, through its ribonuclease activity. Similar to ECP, evidence for the utility of EDN in the diagnosis and treatment of EoE is conflicting. Min et al. demonstrated significant differences in a cohort of 46 individuals with EoE and 69 controls, where the serum EDN levels were 31.70 vs. 14.18 ng/mL, respectively (p = 0.004) [10]. However, a cohort of 61 EoE cases and 87 controls evaluated by Dellon et al. demonstrated no difference in EDN levels [25].

3.4. Major Basic Protein (MBP)

MBP has cytotoxic functions through direct tissue injury and by promoting histamine release, complement activation, and neutrophil degranulation. Like other EDPs, there is no consensus for serum MBP in diagnosing or monitoring EoE. Sarbinowska found in a cohort of 16 EoE cases and 42 controls that MBP was significantly higher at approximately 700 ng/mL vs. 400 ng/mL in controls (p = 0.002) [26]. However, Dellon et al. and Wechsler JB et al. found no differences when comparing cases and controls [25,27].

3.5. Eosinophil Peroxidase (EPO)

EPO contributes to the formation of free radicals that lead to cellular injury. Several research groups have investigated tissue levels of EPO in EoE and have found markedly increased EPO deposition in the esophagus of patients with EoE [28,29]. However, studies investigating EPO as a serum marker are limited. One study of 19 treatment-naive EoE cases and 20 controls by Wright et al. demonstrated that despite no differences in absolute median serum EPO, ECP, and EDN levels, an inverse relationship existed between esophageal eosinophil density and peripheral EPO levels when normalized according to AECs [24]. EoE subjects had significantly lower median EPO levels at 2.56 vs. 6.96 ng/mL per eos/μL (p = 0.002). The authors surmised that this finding suggests that despite marked tissue eosinophil degranulation, most circulating eosinophils likely retain their granule proteins in EoE [24]. It bears noting that other studies where serum eosinophil granule proteins such as MBP and EDN were shown to be either elevated or not statistically different in EoE subjects and controls did not normalize for AEC. Therefore, it is possible that discrepancies among prior studies may be explained by relative differences in AEC between case and control groups.

3.6. Mast Cell Tryptase (MCT)

MCT is a serine protease stored in the secretory granules of mast cells and released upon activation. EoE patients exhibit increased mast cells in the esophageal epithelium and lamina propria [30]. Schlag et al., in a prospective observational study of 15 patients with EoE, demonstrated a significant decrease in mean MCT serum values (from 4.65 to 3.79 mg/L; p = 0.029) in response to fluticasone therapy [31]. However, they also noted that serum ECP was superior to MCT in predicting the response to steroids [31].

3.7. Eosinophil Surface Molecules

Perez-Lucendo et al. evaluated surface molecules expressed by eosinophils using flow cytometry in 12 active EoE cases, 7 inactive cases, 9 allergic controls, and 15 healthy controls, and found significantly lower expression of intercellular adhesion molecule 1 (ICAM-1) in active EoE cases (15.7%) compared to healthy controls (29.0%), allergic controls (29.2%), and inactive EoE cases (56.1%; p = 0.048) [32]. There were no statistically significant differences in expression of CD69, interleukin-5 receptor alpha (IL5RA), CD44, and CD63 [32].

Non-Eosinophil-Derived Biomarkers in EoE

Although the eosinophil is the primary effector cell in EoE, other immune cells are integral to the inflammatory process that leads to cellular injury [33]. Luminal antigens (food and some environmental) and irritants such as esophageal reflux fluid promote the release of epithelium-derived cytokines, thymic stromal lymphopoietin (TSLP), and interleukin (IL-13) [34]. Similarly, food antigens stimulate the T-helper 2 (Th2) local immune response, leading to the production of many cytokines, including eotaxin-3, alarmins (IL-25, IL-33, and TSLP), IL-4, IL-5, and IL-13, as well as the enhanced production of immunoglobulins (particularly IgG/IgG4). Additionally, the produced cytokines have direct effects on other allergic effector cells apart from the eosinophil, including mast cells, which then degranulate to release transforming growth factor A beta (TGF-β) and histamine. Below, we summarize the current research on the utility of these biomarkers in EoE, which are not derived from eosinophils.

3.8. Eotaxin-3 (CCL26)

CCL26 is a potent eosinophil chemoattractant that signals through CCR3, a chemokine receptor expressed on activated eosinophils and mast cells. Blanchard et al. analyzed esophageal tissue via a genome-wide microarray expression analysis and noted that the gene encoding the eosinophil-specific chemoattractant eotaxin-3 (also known as CCL26) was the most highly induced gene product in EoE patients compared with healthy controls [35]. Furthermore, CCL26 messenger RNA (mRNA) and protein levels strongly correlated with tissue eosinophilia and mastocytosis. However, despite the increased esophageal expression of CCL26 at the tissue level, differences in circulation were not detected in multiple studies [26,27,36]. An exception is the study by Sarbinowska et al. of 16 patients with EoE and 42 controls, where there mean CCL26 levels were higher than in controls and approached statistical significance with p = 0.07 [26].

3.9. Cytokines

The cytokines released by Th2 lymphocytes have been shown to promote eosinophil proliferation; cells are subsequently recruited to esophageal mucosa, where they degranulate and lead to tissue injury. A number of cytokines, including interleukin IL-4, IL-5, and IL-13, have been shown to be elevated in the esophageal tissues of patients with EoE compared with controls [16,37,38,39]. IL-5 is one of the cytokines for which there has been significant interest due to its major role in eosinophil differentiation, maturation, and proliferation. Mepolizumab and benralizumab, two anti-IL-5 antibodies, have been explored in phase 2 trials as potential therapies for eosinophilic gastrointestinal disorders [40,41]. However, serum levels of IL-5 have not been found to be significantly different when comparing EoE cases and controls [10,26,39]. Furthermore, in a prospective study of noninvasive serum biomarker panel for the diagnosis and monitoring of EoE, Dellon et al., in the aforementioned cohort of 61 EoE cases and 87 adult controls, noted no significant difference in serum biomarker levels of interleukin IL-4, IL-5, IL-6, IL-9, IL-13, transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), TNF-α, eotaxin-1, eotaxin-2, eotaxin-3, and TSLP in active EoE cases compared with controls [25]. There was also no difference in these levels after treating EoE with topical corticosteroids compared to controls.
Similar studies have also shown no significant differences in serum cytokine levels in EoE vs. controls. Exceptions include a study by Blanchard et al., where blood levels of IL-4, IL-13, IL-5, IL-6, IL-12p70, CD40 ligand, IL-1α, and IL-17 differentiated 13 patients with EoE from 12 without with 100% specificity and 100% sensitivity [35]. Sarbinowska et al., in a group of 16 cases of EoE and 42 controls, also demonstrated significantly higher levels of TGF-β1 compared to controls (p = 0.04) [26].

3.10. Immunoglobulins

In a study that included 20 EoE cases and 10 controls, Wright et al. demonstrated that total IgG4 and food-specific IgG4 levels were elevated in the esophagus of EoE cases compared to controls and that food-specific IgG4 levels in the esophagus corelated with plasma levels [42]. More recent investigations, including a study by Lim et al. [43] of a similar number of patients (22 EoE and 13 controls), concluded that serum food-specific IgG4 levels (FS-IgG4) to milk, wheat, soy, eggs, and nuts were significantly higher in patients with EoE (p = 0.0002) who underwent a 6-week targeted dietary elimination. Similar findings were noted by Masuda and Wright et al. and in a larger study by McGowan et al. (2023) that included 93 patients with EoE and 30 controls [44,45].

3.11. Metabolic Markers in EoE

There have been a handful of studies to date that have investigated whether there are differences in metabolites that differentiate EoE from controls. Moye et al., in a cohort of 7 pediatric EoE cases and 17 controls, found that several metabolites related to arginine and its hydrolysis product (ornithine) (dimethylarginine, putrescine, and N-acetylputrescine) may serve as potential biomarkers for EoE [46]. This indicates alterations in the arginine–ornithine–polyamine pathway in affected patients, possibly due to the metabolic activation of leukocytes, including eosinophils and macrophages. Most recently, Josyabhatla et al. studied 21 children with active EoE, 16 with EoE in remission, and 91 healthy children without esophageal disease [47]. They found that 3 amino acids in plasma, i.e., citrulline, β-alanine, and cysteine, were higher in active EoE compared to controls (p < 0.05), while the polyamine spermine was lower in active EoE versus controls (p < 0.05). They also found that a combined score utilizing fractional exhaled nitric oxide (FeNO), β-ALA, CYS, and spermine had a receiver operator curve with an area under the curve (AUC) of 0.90 (95% CI: 0.80–0.96) in differentiating active EoE from controls and 0.87 (95% CI: 0.74–1.00) when differentiating active EoE from EoE in remission [47]. The researchers hypothesized that the upregulated metabolites may have been a consequence of chronic inflammation or due to tissue remodeling in the esophagus.
High-resolution metabolomics (HRM) is a technique that combines liquid chromatography with ultra-high-resolution mass spectrometry and advanced computational tools to assess levels of untargeted endogenous and exogenous metabolites. Using HRM, Sinclair et al., in a group of 14 pediatric EoE cases and 58 controls, showed that a precursor pathway of pro-inflammatory lipids (linoleic acid metabolism) and glycerophospholipid metabolism were significantly elevated in children with EoE (p < 0.01), similar to reports in other atopic conditions [48]. Additionally, they found that vitamin B6 metabolism was disrupted, with elevated levels of pyridoxine (p < 0.01) [48].
We underscore that while the current literature suggests that many blood-based biomarkers have had limited utility individually, several groups have investigated combinations of biomarkers, and the initial results show promise. For example, Thulin et al., in their cohort of 34 active cases, 18 remissions, and 53 controls, used a combination of biomarkers including AEC, EDN, serum IgE to egg white, and serum IgE to wheat in combination with clinical symptoms to create a scoring system with an AUC of 0.92, sensitivity of 88%, and specificity of 100% in distinguishing EoE (active and in remission) from healthy individuals [19].

3.12. Serum RNA Sequencing

Circulating microRNAs are small noncoding RNAs in blood, serum, and plasma that play a role in cell-cell communication. Lu et al. demonstrated the potential utility of measuring circulating microRNAs in the setting of EoE with a group of 10 adult EoE cases and 8 controls [49]. These researchers found upregulated levels of microRNAs (miR-146a, miR-146b, and miR-223) in the plasma of EoE patients compared to controls, while miR-146a and miR-233 were downregulated in EoE in remission [49]. More recently Grueso-Navarro et al. [20] evaluated the utility of microNAs in plasma-derived extracellular vesicles as potential biomarkers for EoE. They noted in their cohort of 33 patients with EoE and 14 controls that 32 small RNAs (sRNAs) showed statistically significant differences between EoE and control subjects. They also identified 30 dysregulated sRNAs that differentiated active EoE from treated EoE. Several of the upregulated miRNAs in active EoE (miR-10b-5p, miR-125a-5p, miR-374-5p, and miR-30a-3p) alluded to the upregulation of genes involved in key molecular events for EoE, including disruption of the epithelial barrier (for example, AMP-activated protein kinase (AMPK) [50], mitogen-activated protein kinase (MAPK)), inflammation (Wnt signaling [51]), fibrosis (TGF-β signaling [52]), and eosinophil degranulation [53]. They concluded that pEVs could serve as informative mediators of some pathological processes underlying EoE.
Tarallo et al. [54] evaluated 13 pediatric patients with EoE and 8 controls and compared the expression of miR-21-5p and miR-223-3p in esophageal mucosa, in which they noted that the expression levels of both miR-21-5p and miR-223-3p were significantly higher in EoE vs. controls in both the esophageal mucosa and the plasma (p < 0.01) and suggested that plasma miR-21-5p and miR-223-3p levels reflect those found in esophageal mucosa. They further concluded that these microRNAs may have utility in monitoring EoE [54].
Venkateshaiah et al. [55] studied blood mRNA levels of T-cells and IgE receptors in 15 healthy controls, 33 EoE cases, and 19 children with gastroesophageal reflux disease (GERD). They found that mRNA levels of FCεRI are significantly decreased, and FCεRII, a low-affinity receptor for IgE, is increased in EoE patients compared to normal individuals and GERD patients, p < 0.001 [55].
Wu et al. [56] recently identified CXC chemochine receptor 2 (CXCR2) gene expression as a promising diagnostic indicator in EoE. They evaluated the 4 available EoE-associated gene expression datasets in children (GSE184182, GSE 197702, GSE55794, GSE173895) and used a protein interaction network to reveal candidate diagnostic markers for EoE. The CXCR2 gene showed diagnostic efficacy (AUC = ~1.00) in regional tissue and peripheral whole blood samples [56].
Sninsky et al. [57] evaluated 20 EoE cases and 20 controls for differential mRNA expression and noted differential expression of three genes. IL5RA expression was 2.36-fold higher (q = 0.03) and ribosomal protein L7a pseudogene 45 (RPL7AP45) was 1.83-fold higher (q = 0.03) in cases than in controls, while polypeptide N-acetylgalactosaminyltransferase-like 6 (GALNTL6) was 2.81-fold higher (q = 0.03) in controls compared with cases [57].
Table 1. Potential blood-based biomarkers in EoE.
Table 1. Potential blood-based biomarkers in EoE.
TestAvailability Cost (USD) FunctionRelevant StudiesUtility
SupportiveChallenging
AECReadily available at all commercial labs$25–50/testDiagnosticNANAModerate
MonitoringBulock [8], Min [10], Johnsson [11], Colson [12], Conus [13], Domenech Witek [14], Fujiwara [15], Thulin [19]Straumann [16], Von Arnim [17], and Philpot [18]
Predictive of diseaseBullock [8], Konikoff [9], Min [10], Thulin [19]NA
Predictive of PPI response Muftah [21] NA
ECPReadily available at most commercial labs $110–200/test Diagnostic Cengiz [22]Wright [24] Low
MonitoringSchlag [23,31]
EDN Limited availability, mainly specialty/research labs (the Mayo clinic) $220/test Diagnostic Min [10]Dellon [25]Low
EPO Limited availability, few commercial labs $260–700/48 well ELISA kit Diagnostic Wright [24] Low
MBP Very limited availability for serum test, mainly research labs $380–750/48 well ELISA kit Diagnostic Sarbinowska [26]Dellon [25], Wechsler [27]Low
Mast cell tryptase (MCT) Readily available, most commercial labs $49–185/test MonitoringSchlag [23] Low
Eotaxin-3 (CCL26) Limited availability, research labs $380–1000/48 well ELISA kit Diagnosis Sarbinowska [26] Low
Cytokines
IL-4 Readily available at all commercial labs $70–275/individual test Diagnostic/Monitoring Blanchard [35] noted that IL-4, IL-13, IL-5, IL-6, IL-12p70, CD40 ligand, IL-1α, and IL-17 differentiated EoE vs. controls
Sarbinowska [26] noted that TGF-b1 differentiated EoE from controls		Dellon [25] Low
IL-5 Available at all commercial labs Appr. $250–400/48 well ELISA kit
IL-6 Readily available at all commercial labs $145–630/48 well ELISA kit
IL-9 Limited availability, mainly research labs $200–600/48 well ELISA kit
IL-13 Research labs $100–500/48 well ELISA kit
TGF-α Research labs Appr. $499/96 wells ELISA kit
TGF-β Available at several commercial labs $158–280/test
Tumor necrosis factor–α Available at several commercial labs $85/300/test
TSLP Research labs $190–1500/48 well ELISA kit
Immunoglobulins
Total IgG-4 Readily available at all commercial labs $40–180/test DiagnosticNAWright [42] Low
Food specific IgG-4 Readily available at all commercial labs $200–450/test Diagnostic Lim [43], Thulin [19], Masud [44], McGowan [45]NAModerate
Plasma amino acids Readily available at all commercial labs $130–330/panel Diagnostic Moye [46], Josyabhatla [47] Moderate
Metabolomics Very limited only in a few research labs $200–450/panel Diagnostic Sinclair [48] Moderate
Circulating microRNAs Very limited only in a few research labs Unknown DiagnosticGruesso Navarro [20], Tarallo [54], Venkateshaiah [55] Moderate
Gene expression Very limited only in a few research labs Unknown DiagnosticWu [56] (CXCR2 gene expression), Sninsky [57] (IL5RA expression) Moderate
Abbreviations: AEC, absolute eosinophil count; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase; MBP, major basic protein; MCT, mast cell tryptase; IL, interleukin; TGF, transforming growth factors; CCL26, chemokine (C-C motif) ligand 26 (eotaxin-3); TSLP, thymic stromal lymphopoietin.

4. Stool Biomarkers in Eosinophilic Esophagitis

Table 2 summarizes potential stool-based biomarkers that have been investigated in eosinophilic esophagitis (EoE).

4.1. Fecal Calprotectin (FCP)

FCP is a calcium-binding protein produced primarily by neutrophils and is a well-known marker of inflammation. Because FCP is highly resistant to degradation by digestive enzymes, its level is a useful screening tool for inflammatory disorders of the lower gastrointestinal tract [58]. Elevated FCP can be seen in various gastrointestinal disorders including infectious colitis, microscopic colitis, allergic colitis, intestinal polyps, and colorectal cancer [59]. In a cross-sectional study of 14 patients with eosinophilic colitis, the mean FCP decreased significantly from 448 μg/g at diagnosis to 201.9 μg/g after 3 months of treatment with dietary elimination [60]. However, the evidence for FCP in the diagnosis and monitoring of EoE is not promising. Goldi et al. [61] found no difference between FCP levels in patients with active EoE, inactive EoE, and GERD. There was also no difference between EoE treatment responders and nonresponders compared to baseline. Interestingly, this study showed that FCP was higher in the control group compared to those with active EoE (median 73.1 vs. 12.4 μg/g, p = 0.024) [61].

4.2. Fecal Eosinophil-Derived Neurotoxin (EDN)

EDN is a major protein within cytoplasmic granules and is released upon eosinophilic stimulation. It also mediates inflammation and tissue injury via antigen uptake and dendritic cell recruitment. EDN has been proposed as a marker for eosinophilic activity [34]. Thus far, the role of fecal EDN in the diagnosis and monitoring of EoE has not been substantiated. A prospective, longitudinal study by Subbarao et al. [39] found that stool EDN levels were not statistically different between children with EoE (n = 60) and non-EoE controls (n = 20). There was also no change in fecal EDN at baseline and 4 weeks after treatment with corticosteroids [39].
Similarly, Goldi et al. [61] found no difference in fecal EDN levels among patients with EoE (n = 38), GERD (n = 14), and controls (n = 17). Within the EoE group who received treatment and had follow-up tests, there was again no significant difference in fecal EDN before and after treatment. The study concluded that fecal EDN was unsuitable for the diagnosis or monitoring of disease [61].

4.3. Fecal Eosinophil Cationic Protein (ECP)

ECP, as discussed above, is a protein found in eosinophilic granules that is released during degranulation. ECP levels in serum and feces have been proposed as noninvasive markers of EoE disease activity. Witek et al. demonstrated a significant reduction in serum ECP in 19 patients with EoE following dietary elimination, with a pre-diet ECP mean of 37.3 ± 26.7 and post-diet ECP mean of 21.4 ± 10.6 (p < 0.001) [14].
A statistically significant correlation between fecal ECP and esophageal histology was demonstrated by Ghisa et al. [62] in a cohort of 29 EoE patients (active and in remission) and 72 control patients (EoE excluded). This study showed a correlation coefficient of 0.483 between fecal ECP and eos/hpf (p = 0.008). The mean fecal ECP levels in the EoE and control groups were 17.3 μg/L vs. 8.1 μg/L, respectively, and there was a significant difference between controls and active EoE (p = 0.02). However, the values were quite variable, with EoE patients having fecal ECP values of 0–172 μg/L and controls having fecal ECP values of 0–32 μg/L. There was also no significant difference in fecal ECP levels when comparing patients with active EoE and those in remission, nor between controls and EoE in remission [62].
In a cohort of 38 patients with EoE (29 active), 14 with GERD, and 17 controls, Goldi et al. [61] found no difference in fecal ECP in patients with active EoE, GERD, and controls. In patients with EoE who underwent treatment, there was no significant difference in fecal ECP between responders and nonresponders compared to baseline [61].
Table 2. Potential stool-based biomarkers in EoE.
Table 2. Potential stool-based biomarkers in EoE.
Test Availability Cost (USD) FunctionRelevant Studies Potential
SupportiveChallenging
ECP Very limited, only in a few research labs Unknown Diagnosis, monitoring response to therapyNAGoldi [61]Low
EDNVery limited, only in a few research labs $675/96 well ELISA kitDiagnosisNASubbarao [39], Goldi [61]Low
FCPReadily available at all commercial labs $30–120/test Diagnosis, monitoring response to therapy NAGhisa [62]Low
Abbreviations: ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; FCP, fecal calprotectin.

5. Urinary Biomarkers in Eosinophilic Esophagitis

Table 3 summarizes urinary biomarkers that have been previously studied in eosinophilic esophagitis (EoE).

5.1. Urine Osteopontin (OPN)

OPN is an integrin-binding cell adhesion molecule expressed by immune cells and upregulated with T-cell activation. A longitudinal pediatric study by Wechsler et al. found a significant difference in spot urine OPN levels of 41 patients with active EoE vs. 15 non-EoE controls (19.4 [12.0, 29.0] vs. 8.9 [6.0, 17.8] ng/mL, p < 0.05) [27]. However, in the 33 EoE patients with repeat endoscopy following treatment, there was no significant reduction in urine OPN before or after treatment in either histologic responders or non-responders. Note that some non-EoE controls in this study may have coexisting atopic conditions leading to endoscopic evaluation. Urine OPN was a weak predictor of tissue eosinophilia. The levels were not useful in differentiating between active and inactive disease. Due to the limited number of urine samples collected, further studies are needed to validate the use of urinary OPN as a screening biomarker of EoE.

5.2. Urine 3-Bromotyrosine (3-BT)

3-BT is a product of eosinophil activation. Activated eosinophils produce eosinophil peroxidase, which oxidizes tyrosine residues by bromine. The subsequent degradation of protein-bound 3-BT releases free 3-BT. Through this mechanism, 3-BT can be used as a marker of eosinophil degranulation to reflect EoE disease activity. A proof-of-concept study by Cunnion et al. demonstrated that spot urinary 3-BT levels were 93 times higher in EoE patients (n = 27) compared to nonatopic controls (n = 24) (169.5 pg vs. 1.81 pg/400 mg Cr; p = 0.01) [63]. There was also a significant 13-fold increase in 3-BT in EoE patients compared to atopic controls (n = 24) (169.5 pg vs. 12.87 pg/400 mg Cr; p = 0.01). Using a 3-BT cut-off of 17 in EoE vs. nonatopic controls resulted in 81% sensitivity, 100% specificity, and 100% NPV, while a higher cut-off of 145 in EoE vs. atopic controls resulted in 67% sensitivity, 79% specificity, and 90% NPV. Although urinary samples cannot differentiate among the sources of eosinophilic inflammation, the results of this study suggest that elevated urinary 3-BT is more strongly associated with EoE compared to other atopic diseases, and 3-BT may be useful as a screening tool.
Table 3. Potential urine-based biomarkers in EoE.
Table 3. Potential urine-based biomarkers in EoE.
Test Availability Cost (USD) Function Relevant Studies Potential
SupportiveChallenging
OPNVery limited, only in a few research labs Unknown DiagnosisWechsler [27]NAModerate
Monitoring response to therapy NAWechsler [27]Low
3-BTLimited to research labsUnknown Diagnosis Cunnion [63]NAModerate
Abbreviations: OPN, osteopontin; 3-BT, 3-bromotyrosine.

6. Salivary Biomarkers in Eosinophilic Esophagitis

In a study in children with 26 EoE patients and 19 non-EoE patients, saliva samples were collected, and the salivary microbiomes were profiled using 16S rRNA gene sequencing for microbiota analyses. A decreasing trend in microbial richness and alpha diversity was observed in children with EoE. Haemophilus was significantly more abundant in children with active EoE compared with inactive disease (q value = 0.0008). These findings suggest the salivary microbiome can be used as an adjunctive noninvasive marker [64]. As with many of the previous studies, one of the limitations of this study includes the small sample size. Use of the salivary microbiome for EoE monitoring is not currently recommended beyond research purposes by one reviewer, although further work may clarify a role for the microbiome in EoE [65].
Hiremath et al. [66] recently conducted the first investigation of untargeted salivary metabolomics in children with EoE. These investigations included 19 children with EoE and 9 controls without EoE but similar symptoms of esophageal dysfunction. They identified eight salivary metabolites with significant differences (defined as at least a 3-fold difference with p < 0.05) in children with EoE compared to controls. Specifically, nucleotide molecules (including deoxyadenosine, deoxycytidine, adenosine, deoxyguanosine, and guanosine) showed significant negative changes in EoE compared to controls, while in contrast, the organic acids and derivatives (such as urea, N-heptanolyglycine, and L-arginine) were significantly increased in active EoE compared to controls. Urea was significantly higher in active EoE versus inactive EoE, and the dipeptide serylarginine (L-Ser-L-Arg) was significantly higher in inactive compared with active EoE [66]. Larger studies are necessary to validate these potentially important findings.

7. Esophageal String Test

The esophageal string test (EST) is not a biomarker test but it represents a minimally invasive procedure to collect biomarkers from the esophagus. During this procedure, patients swallow a gelatin-coated capsule attached to a nylon string, which is held outside of the mouth with the string left in the esophagus. The string absorbs inflammatory mediators over one hour and is then removed and analyzed [67]. An initial study showed that the eosinophil-derived protein biomarkers measured in esophageal string scrapings were highly correlated with the same biomarkers measured in biopsy samples obtained from endoscopic procedures. These levels were able to differentiate between the normal esophagus, active EoE, EoE in remission, and GERD. The biomarkers measured included MBP, EDN, ECP, EPO, and Charcot–Leyden crystal protein/galectin-10 (CLC/Gal-10).
A 1 h EST was later developed. All eosinophil-associated biomarkers including eotaxin-2, eotaxin-3, MBP, and others from the 1 h EST correlated with peak eosinophils and the high-power field and the same eosinophil-derived protein biomarkers obtained from mucosal biopsies (with p < 0.0001 for all measures). In the follow-up survey, 98% of children and 96% of parents were willing to repeat the EST, and 74% of the children and 78% of parents who participated stated they would prefer the 1 h EST over sedated endoscopy [68]. Ackerman et al. recently demonstrated that eosinophil counts and EoE scores significantly correlate during treatment distinguishing patients with active EoE from inactive disease from 94% of strong tests performed in a cohort of 14 patients with EoE from who underwent repeat endoscopies and also had EST performed [69]. The EST is available commercially as EnteroTrack™, which is manufactured by EnteroTrack LLC in Aurora, Colorado, United States of America. This string-based, minimally invasive study is performed in office and can then be sent to reference laboratories for an analysis of disease relevant biomarkers.
The limitations of the EST include difficulty administering it in patients who are not able to swallow pills, in patients with esophageal narrowing, or in patients with an allergy to the gelatin capsule. Eosinophil-derived proteins derived from nasal, pulmonary, or ocular secretions could potentially adhere to the string and increase the measurement of the stated biomarkers, although one study did not find any correlation between self-reported comorbid allergic disease and increased biomarkers measured by EST [67]. Humorously, a recent review stated the 1 h EST may be the clinical test that we have been waiting for, where all strings are attached [70].
The use of the EST to monitor EoE disease activity and response to treatment in asymptomatic patients has been suggested by the American Society for Gastrointestinal Endoscopy Consensus Conferences as a suitable modality for interval surveillance in asymptomatic patients. In their 2022 consensus paper, they cautioned that “the absence of symptoms is not a guarantee of endoscopic or histologic remission”, and recommended periodic assessments of inflammatory activity using endoscopy or less invasive modalities such as a string or sponge test in symptom-free patients [36].
Table 4 presents potential biomarkers identified in oral and esophageal secretions in eosinophilic esophagitis (EoE).
Table 4. Potential oral and esophageal secretion-based biomarkers in EoE.
Table 4. Potential oral and esophageal secretion-based biomarkers in EoE.
Test Availability Cost (USD) Function Relevant Studies Potential
SupportiveChallenging
EST Limited availability $120–550/exam Diagnostic, monitoring response to treatmentAckerman [68,69], Venkatesh [70], Furuta, G [67], Furuta [71]NAHigh
16S rRNA gene sequencing (salivary microbiome)Very Limited$75–130/testDiagnostic Hiremath [64]NALow–moderate
Salivary metabolomeVery limited UnknownUnknownDiagnosis, monitoring response to treatmentHiremath [66]NAModerate
Abbreviation: EST, esophageal string test.

8. Discussion

The diagnosis and monitoring of EoE continues to rely heavily on invasive endoscopic biopsy, despite increasing awareness of its limitations—including procedural risks, sedation exposure, and financial burden. In this review, we comprehensively evaluated the evidence for noninvasive biomarkers across a range of biologic samples—blood, stool, urine, saliva, and esophageal luminal secretions. The findings underscore the complexity of biomarker development in EoE and highlight both the promise and current limitations of this evolving field.
Among blood-based biomarkers, AEC and ECP are the most frequently studied. While elevated levels are commonly associated with active disease, inconsistent thresholds, poor specificity, and overlap with other atopic conditions limit their utility. Granule proteins such as EDN, EPO, and MBP show variable results, with no consensus emerging on cut-off values or predictive performance. Several studies have noted that EoE subjects have elevated absolute serum or plasma ECP and EDN levels [9,10,39]. However, these granule proteins are not specific to EoE and may be released in other atopic conditions. However, it is possible that eosinophil granule proteins may have clinical utility when normalized by AEC [24]. Non-eosinophil-derived markers—including eotaxin-3, interleukins (e.g., IL-5, IL-13), and immunoglobulin profiles—also show conflicting data when comparing EoE patients with controls, in part due to small study cohorts and heterogeneity in patient phenotypes. Nevertheless, emerging evidence suggests that certain combinations of these markers, when evaluated together, may lead to improved diagnostic performance, as seen in studies leveraging scoring systems incorporating AEC, EDN, and allergen-specific IgE [19].
Urine-based biomarkers such as 3-BT and OPN offer a promising avenue, particularly because of the noninvasive nature of collection. Urinary 3-BT, a byproduct of EPO activity, demonstrated high specificity and sensitivity in differentiating EoE from both atopic and nonatopic controls, although it cannot distinguish between EoE and other eosinophilic GI diseases [63]. Similarly, metabolomics has yielded intriguing insights, identifying upregulated citrulline, β-alanine, and cysteine in active EoE [47]. These changes likely reflect underlying metabolic alterations related to inflammation and tissue remodeling. However, their interpretation is still constrained by limited sample sizes, potential, and the need for external validation.
Salivary metabolomics and microbiome profiling, while in early stages of exploration, have shown disease-specific trends, including altered nucleotide and organic acid levels and reduced microbial diversity in EoE patients [64,66]. These findings raise the possibility of using saliva as a noninvasive surveillance medium in the future. However, methodological standardization and large-scale reproducibility studies are needed before clinical integration.
Stool-based markers—such as FCP, ECP, and EDN—demonstrated low diagnostic value, with multiple studies failing to show significant differences between EoE and control groups. Given the origin of EoE in the upper GI tract, the dilution of eosinophil-derived proteins during intestinal transit may account for this lack of specificity and sensitivity, rendering fecal biomarkers suboptimal for clinical use at this time.
The most promising modality to date is the EST, which allows sampling of luminal secretions enriched with eosinophil granule proteins. Multiple studies show strong correlations between EST biomarker levels and histologic eosinophil counts, with the added advantage of being well-tolerated in pediatric populations [67,71]. Its commercial availability and endorsement by consensus guidelines further strengthen its candidacy as a minimally invasive surveillance tool, particularly in asymptomatic patients where clinical symptoms poorly correlate with disease activity.
It is also important to contextualize these biomarker developments within a broader clinical framework. Given the complex pathophysiology of EoE involving Th2 cytokines, epithelial barrier dysfunction, and fibrostenotic progression, it is unlikely that a single biomarker will sufficiently capture the multifaceted nature of disease activity. Future approaches may benefit from composite panels that integrate molecular, clinical, and demographic variables, and from longitudinal studies that evaluate changes in biomarker profiles over time and in response to treatment.
In addition, the rapid advancement of omics technologies—transcriptomics, proteomics, and metabolomics—offers a frontier for discovering multi-analyte biosignatures. For example, circulating microRNAs and plasma-derived extracellular vesicle profiles have shown preliminary but promising capacity to distinguish between active and inactive disease [20,55,57]. Although such technologies are not yet widely accessible, they underscore the shifting landscape of biomarker research and the potential for precision medicine in EoE.
In conclusion, despite an expanding repertoire of candidate biomarkers for EoE, none currently surpass endoscopy in diagnostic accuracy or reliability. However, several modalities—especially the EST, urinary 3-BT, and targeted metabolomics—have demonstrated enough promise to warrant further prospective studies with standardized protocols, inclusion of atopic controls, and exploration of multi-biomarker models. As research matures, the ultimate goal remains the development of a reliable, noninvasive, and accessible biomarker-based strategy that can reduce the burden of repeated endoscopy and allow for personalized disease monitoring.

9. Conclusions

Although a variety of potential biomarkers for EoE have been studied, none have yet reached the threshold of evidence-based clinical application. Most studies to date are limited by small sample sizes, variability in study design, and issues of biomarker specificity and reproducibility (Table 1, Table 2, Table 3 and Table 4). While no single biomarker currently offers sufficient reliability to replace endoscopic biopsy, several promising candidates have emerged—particularly urine 3-BT, plasma metabolites, and circulating microRNAs.
The EST, in particular, has shown a strong correlation with mucosal eosinophil burden and has demonstrated feasibility and patient acceptance in pediatric populations. It remains the only noninvasive tool formally endorsed by professional guidelines as a potential alternative to surveillance endoscopy in asymptomatic patients.
Future research should prioritize the validation of these biomarkers in larger, multicenter cohorts and explore integrated multimarker models that reflect the complex immunologic and molecular landscape of EoE. With continued investigation, the goal of a reliable, noninvasive diagnostic and monitoring strategy for EoE may soon be within reach.

Author Contributions

T.T.M.: Conceptualization, methodology, investigation, writing—original draft, writing—review and editing, supervision, project administration, corresponding author. M.M.: Writing—original draft, writing—review and editing. N.H.: Writing—original draft, writing—review and editing. J.M.R.: Conceptualization, investigation, writing—original draft, writing—review and editing, supervision, project administration. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AECAbsolute Eosinophil Count
AUCArea Under the Curve
AMPKAMP-Activated Protein Kinase
BTBromotyrosine (as in 3-BT)
CCL26Chemokine (C-C motif) Ligand 26 (Eotaxin-3)
CDCluster of Differentiation
CLC/Gal-10Charcot–Leyden Crystal Protein/Galectin-10
CXCR2CXC Chemokine Receptor 2
CYSCysteine
DNADeoxyribonucleic Acid
ECPEosinophil Cationic Protein
EDNEosinophil-Derived Neurotoxin
ELISAEnzyme-Linked Immunosorbent Assay
EoEEosinophilic Esophagitis
EosEosinophils
EPOEosinophil Peroxidase
ESTEsophageal String Test
FCPFecal Calprotectin
FeNOFractional Exhaled Nitric Oxide
FS-IgG4Food-Specific Immunoglobulin G4
FCεRI/FCεRIIHigh/Low-Affinity Receptors for Immunoglobulin E
GALNTL6Polypeptide N-Acetylgalactosaminyltransferase-Like 6
GERDGastroesophageal Reflux Disease
GSEGene Expression Omnibus Series
hpfHigh-Power Field
ICAM-1Intercellular Adhesion Molecule 1
IgE/IgG/IgG4Immunoglobulin E/G/G4
ILInterleukin (e.g., IL-4, IL-5, etc.)
IL5RAInterleukin-5 Receptor Alpha
MAPKMitogen-Activated Protein Kinase
MBPMajor Basic Protein
MCTMast Cell Tryptase
miRmicroRNA
mRNAMessenger RNA
NPVNegative Predictive Value
OPNOsteopontin
PAAPlasma Amino Acids
pEVsPlasma-Derived Extracellular Vesicles
PPIProton Pump Inhibitor
RNARibonucleic Acid
RPL7AP45Ribosomal Protein L7a Pseudogene 45
sRNASmall RNA
TGF-α/TGF-βTransforming Growth Factor Alpha/Beta
Th2T-Helper Type 2
TSLPThymic Stromal Lymphopoietin

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Applsci 15 09083 g001
Figure 1. Noninvasive biomarkers in eosinophilic esophagitis. Abbreviations: AEC, absolute eosinophil count; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase; MBP, major basic protein; MCT, mast cell tryptase; CCL26, eotaxin-3; TSLP, thymic stromal lymphopoietin; OPN, osteopontin; 3-BT, 3-bromotyrosine; FCP, fecal calprotectin; CLC/Gal-10, Charcot–Leyden crystal protein/galectin-10.
Figure 1. Noninvasive biomarkers in eosinophilic esophagitis. Abbreviations: AEC, absolute eosinophil count; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase; MBP, major basic protein; MCT, mast cell tryptase; CCL26, eotaxin-3; TSLP, thymic stromal lymphopoietin; OPN, osteopontin; 3-BT, 3-bromotyrosine; FCP, fecal calprotectin; CLC/Gal-10, Charcot–Leyden crystal protein/galectin-10.
Applsci 15 09083 g001
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Munroe, M.; Hoang, N.; Rhoads, J.M.; Mai, T.T. Noninvasive Biomarkers in Eosinophilic Esophagitis: Current Perspectives. Appl. Sci. 2025, 15, 9083. https://doi.org/10.3390/app15169083

AMA Style

Munroe M, Hoang N, Rhoads JM, Mai TT. Noninvasive Biomarkers in Eosinophilic Esophagitis: Current Perspectives. Applied Sciences. 2025; 15(16):9083. https://doi.org/10.3390/app15169083

Chicago/Turabian Style

Munroe, Melissa, Nhat Hoang, Jon Marc Rhoads, and Tu T. Mai. 2025. "Noninvasive Biomarkers in Eosinophilic Esophagitis: Current Perspectives" Applied Sciences 15, no. 16: 9083. https://doi.org/10.3390/app15169083

APA Style

Munroe, M., Hoang, N., Rhoads, J. M., & Mai, T. T. (2025). Noninvasive Biomarkers in Eosinophilic Esophagitis: Current Perspectives. Applied Sciences, 15(16), 9083. https://doi.org/10.3390/app15169083

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