Advancing the understanding of eosinophilic esophagitis: From pathogenesis to novel therapies

Abstract

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease characterized by inflammation in the esophagus, occurring in genetically predisposed individuals as a consequence of food antigen sensitization. EoE prevalence has increased exponentially in the last three decades to 40 per 100000 people worldwide, making it a common cause of dysphagia and food impaction in both children and adults. Diagnosis is made by esophageal biopsy showing eosinophilia (≥ 15 eosinophils per high-power field on biopsy). In children the presentation may be feeding intolerance, in adults a form of chronic solid food dysphagia. In EoE, in the absence of treatment, active inflammation inevitably progresses to fibrostenotic remodeling, highlighting the importance of early recognition and therapy. This review outlines the clinical criteria and pathophysiological mechanisms of EoE, biomarkers for the diagnosis of EoE, and the therapeutic strategies for EoE. EoE is characterized by epithelial barrier dysfunction, Th2 inflammation and eosinophil recruitment, with microbiome influences. Diagnosis is made by standard endoscopic biopsy, or by non-intrusive esophageal string test, Cytosponge, or by impedance planimetry. Treatment includes proton pump inhibitors, topical corticosteroids, dietary elimination therapy, endoscopic dilation, and the Food and Drug Administration approved biologic dupilumab. Emerging therapies such as precision medicine and artificial intelligence are also identified as areas for attention.

Key Words: Eosinophilic esophagitis; Dysphagia; Dupilumab; Biologic therapy; Elimination diet; Esophageal eosinophilia; Endoscopic dilation

Core Tip: Eosinophilic esophagitis is increasingly recognized as a progressive fibrostenotic disease in which symptom severity may not correlate with histologic activity, contributing to diagnostic delays and long-term esophageal remodeling. New imaging modalities including functional luminal imaging probe, Cytosponge, and artificial intelligence driven histologic scoring have shown promise in assessing disease beyond eosinophilic counts. Precision medicine approaches and endotype driven therapies are expected to transform patient management in the near future.

INTRODUCTION

Eosinophilic esophagitis (EoE) is a chronic immune-mediated inflammatory condition of the esophagus characterized by esophageal dysfunction and infiltration of eosinophils into the epithelium[1,2]. Both adult and pediatric populations are affected. A 2023 systematic review and meta-analysis of population-based studies reported a pooled global prevalence of approximately 40 per 100000 individuals and a global pooled incidence of approximately 5.31 per 100000 person-years, with adult-specific rates of 7.7 per 100000 reported in earlier meta-analyses[3,4]. Population-based studies document substantial temporal increases in disease burden, with a 316-fold rise in incidence reported in the Netherlands (0.01 to 3.16 per 100000 between 1995 and 2019) and substantial temporal increases in Denmark, with an approximately 20-fold rise over the period 1997-2012 and a 3-fold increase from 3.9 to 11.7 per 100000 between 2011 and 2018, depending on the study period examined[3,5]. EoE patients typically present with dysphagia, food impaction or symptoms resembling gastroesophageal reflux[4]. Diagnosis requires symptoms of esophageal dysfunction, histologic evidence of ≥ 15 eosinophils per high-power field on esophageal biopsy while ruling out alternative causes including proton pump inhibitor (PPI)-responsive esophageal eosinophilia[6]. EoE has contributed significantly to gastrointestinal morbidity over the last two decades[4]. Current treatment is centered on the “three Ds”: Drugs (topical corticosteroids), dietary therapy and endoscopic dilation[1]. Current treatments provide symptom control and histologic remission in many patients, although long-term efficacy in completely preventing fibrostenotic progression varies across individuals[7,8]. This highlights the unmet need for early diagnosis, reliable biomarkers, targeted therapies and standardized outcome measures to improve disease monitoring and patient quality of life[7]. The natural history of untreated EoE has shown a progression from an inflammatory phenotype to a fibrostenotic disease characterized by esophageal remodeling and stricture formation[9,10]. This review traces advances in the understanding of EoE pathogenesis and maps the translation of that knowledge into novel diagnostic tools and therapies, from early biologic drug development to current precision medicine approaches.

PATHOPHYSIOLOGY OF EOE

EoE pathogenesis involves epithelial barrier dysfunction, Th2-mediated inflammation, and progressive tissue remodeling (Figure 1)[1,2]. In genetically predisposed individuals, it is primarily caused by an immunological response to dietary antigens[3]. It typically begins as an inflammatory condition affecting esophageal function (e.g., vomiting, abdominal pain, and food refusal in the pediatric setting, dysphagia and food impaction in the adolescent/adult setting) and changes to fibrostenotic over the course of years[5]. The fibrostenotic phenotype is characterized by the presence of fixed rings, strictures, and esophageal narrowing. Natural history and relapse studies confirm that EoE is often a relapsing condition, and that cessation of therapy results in recurrent esophageal inflammation, remodeling and subsequent fibrostenotic sequelae, EoE is thus a chronic, life-long disease requiring active therapy directed at the underlying inflammation[11].

Figure 1 Pathogenesis of eosinophilic esophagitis with current and investigational therapeutic targets. The horizontal cascade depicts antigen exposure, epithelial barrier dysfunction with alarmin release [thymic stromal lymphopoietin, interleukin (IL)-33, IL-25], Th2/type 2 innate lymphoid cells immune activation with IL-4, IL-5, and IL-13 production, eosinophil recruitment and activation, and tissue remodeling/fibrostenosis. The therapeutic class intervening at each step is shown below the corresponding cascade step, including dietary elimination, anti-alarmin biologics (tezepelumab), Th2 cytokine-targeted biologics (dupilumab, cendakimab, mepolizumab, reslizumab, benralizumab, lirentelimab), topical corticosteroids and proton-pump inhibitors, and endoscopic dilation. DSG-1: Desmoglein-1; CAPN14: Calpain 14; TSLP: Thymic stromal lymphopoietin; IL: Interleukin; ILC2: Type 2 innate lymphoid cells; CCL26: Chemokine (C-C motif) ligand 26; eos: Eosinophil; HPF: High-power field; FED: Food elimination diet; FDA: Food and Drug Administration.

Epithelial barrier dysfunction

The initial step in EoE pathophysiology involves abnormalities in the esophageal epithelial barrier that permit allergen entry and trigger local reactions[3,6]. Patients with EoE exhibit reduced epithelial adhesion proteins including desmoglein-1 and E-cadherin[6,12]. Upon allergen exposure, epithelial cells release cytokines like Interleukin (IL)-33, which activate dendritic cells and type 2 innate lymphoid cells[6,12]. These antigen-presenting cells promote naive T cell differentiation into Th2 cells[2,3].

Th2 cytokine signaling and eosinophil recruitment

Activated Th2 cells and type 2 innate lymphoid cells release IL-4, IL-5, and IL-13, essential for pathophysiology[3,12]. IL-13 stimulates esophageal epithelial cells to produce eotaxin-3 [chemokine (C-C motif) ligand 26][3,12]. Eotaxin-3 facilitates eosinophil migration into esophageal mucosa by binding to C-C chemokine receptor type 3 receptors on eosinophils[3]. IL-5, released by Th2 cells and mast cells, is crucial for eosinophil activation and proliferation[3,12]. These cytokines, along with IL-4, maintain eosinophilic infiltration and amplify the inflammatory loop[2,6]. Mast cells and basophils release histamine and leukotrienes, further promoting inflammation[4,6]. Biologic agents targeting the IL-4/IL-13 axis (dupilumab), IL-5/IL-5 receptor axis (mepolizumab, benralizumab, reslizumab), and epithelial cytokines such as thymic stromal lymphopoietin (TSLP; tezepelumab) have emerged to directly affect the EoE disease process by blocking the recruitment and activation of eosinophils, as well as the chronic inflammatory remodeling that occurs in the esophageal wall[13]. Recent mechanistic reviews further consolidate the evidence linking Th2-driven cytokine networks to the rationale for these targeted therapies[14].

Microbiome and EoE development

The role of esophageal and early life microbiome dysbiosis in EoE is supported by increasing evidence, and is consistent with the microbiome-immune axis of EoE pathogenesis. Human, animal, and multi omics studies have consistently demonstrated esophageal dysbiosis in active EoE, with bacterial overload and enrichment of Haemophilus and other Proteobacteria, and depletion of Firmicutes including Streptococcus and Lactobacillales[15]. Multi omics approaches have pointed to dysbiosis as a hallmark of the pathobiology of EoE. The association between microbial signatures and antigen-driven inflammation has been suggested[16]. Some meta-analyses have shown an inverse relationship between Helicobacter pylori colonization and EoE, which might be due to Helicobacter pylori suppression of Th2 immunity. However, potential studies have provided inconsistent results[17]. Mechanistically, the Haemophilus influenzae lipopolysaccharide colocalizes with toll like receptor 4 in active EoE, suggesting microbiome mediated epithelial and natural immune system activation[15]. Experimental neonatal antibiotic induced dysbiosis, resulting in a decrease in esophageal Lactobacillales and a concomitant increase in type 2 inflammation, consistent with clinical findings in human EoE[18]. Epidemiological studies have supported a hygiene/microbiome hypothesis, as small EoE risks are shown to be associated with antibiotic exposure in infancy, delivery via cesarean section, prematurity and Neonatal Intensive Care Unit admission[19]. In children with esophageal atresia, extended high dose PPI therapy and early exposure to antibiotics both independently increase EoE risk[20]. Therapeutically PPIs, topical steroids and elimination diets have reproducibly modified the esophageal microbiome, usually to a control like profile; microbiome modulation and probiotics remain investigational adjuncts[15,18].

Genetic and environmental contributors

In EoE, genetic susceptibility and environmental exposures act synergistically rather than independently. Family and twin studies suggest strong aggregative familial clustering, modest heritability, and environmental exposures in early life contribute to most of the population risk[21,22]. Within loci, genes related to epithelial barrier function (filaggrin, desmoglein 1, calpain 14, serine peptidase inhibitor Kazal type 7 may predispose the esophagus to barrier dysfunction in response to allergens, while genes related to Th2 immune signaling [chemokine (C-C motif) ligand 26, periostin, TSLP] may predispose the esophagus to allergic inflammatory response[23,24]. Most variants are located in regulatory regions and are thought to mediate altered gene expression in esophageal and immune cells[25]. In addition, there is strong evidence for an environmental component in EoE, given the substantially increasing incidence since the 1990s. Other environmental exposures found to be associated with EoE risk include dietary exposure, aeroallergens, antibiotics, acid suppressant exposure, cesarean delivery, Neonatal Intensive Care Unit admission and early life microbiome[26,27]. Gene-environment interaction studies suggest that some environmental exposures are associated with EoE risk only among genetically susceptible individuals, for example, breastfeeding and EoE inversely associated among children with calpain 14 risk alleles[27,28]. Together, these data support a multifactorial “nature and nurture” model of genetically driven epithelial and immune pathways which when coupled with environmental exposure led to chronic antigen-driven eosinophilic inflammation and progressive esophageal dysfunction[22,29].

CLINICAL PRESENTATION AND DIAGNOSTIC CHALLENGES

Diagnosing EoE presents significant challenges due to variable clinical presentations. Adults primarily present with solid food dysphagia and episodic food impaction[1]. Pediatric presentations differ markedly, with generalized feeding difficulties, food refusal, or poor growth without obvious explanations[2]. Recent comparative reviews of pediatric and adult EoE emphasize how these age-dependent presentations influence diagnostic timing and the choice of management strategy[30].

Adults frequently develop compensatory eating behaviors over time without conscious realization, complicating early EoE detection. Patients report extended chewing times and increased water consumption during meals, patterns that appear minor but indicate long-standing symptom compensation[17].

Pathological-clinical dissociation

Pathological findings and clinical symptoms don't always correlate. Patients with higher eosinophilic counts may experience milder symptoms than those with severe dysphagia but lower counts. This dissociation occurs because EoE involves both inflammation and structural changes like fibrosis and narrowing developing gradually over years[31].

Functional lumen imaging probe (FLIP) technology illuminates this discrepancy. FLIP demonstrates that patients with reduced esophageal distensibility despite modest mucosal disease correlate better with dysphagia severity than eosinophil counts alone[32]. Consequently, many patients receive prolonged acid suppressant therapy before formal diagnosis[33].

Endoscopic findings and scoring

Endoscopy remains critical for EoE diagnosis, though many patients present with normal-appearing esophagus during endoscopy[34]. Endoscopic abnormalities include trachealized appearance, vertical furrows, white plaques (eosinophilic microabscesses), or fragile mucosa. These findings constitute the EoE Endoscopic Reference Score, a standardized framework improving disease recognition and reporting[35]. Findings categorize into inflammatory features (edema, exudates) and fibrostenotic features (rings, strictures), signaling different disease phases[34].

Histologic confirmation challenges

Patchy eosinophilic infiltration makes inadequate tissue sampling the most frequent cause of missed diagnosis[36]. Current recommendations advise obtaining at least six biopsies across two or more esophageal regions[37]. Prior PPI treatment can transiently suppress eosinophilia, causing false-negative biopsies if endoscopy occurs shortly after PPI initiation[33].

Clinical consequences of diagnostic delays

Diagnostic delays carry significant clinical consequences. Cohort studies demonstrate longer delays correlate with increased stricture prevalence at presentation[5]. In adults, acute food impaction often serves as the sentinel event prompting endoscopic evaluation[17]. Food impaction, particularly with fibrous foods like meat or bread, indicates chronic stenosis and should prompt endoscopy with biopsies[17]. Diagnostic delays have improved recently through increased clinician awareness and standardized biopsy protocols[38].

CURRENT DIAGNOSTIC AND TREATMENT APPROACHES

The definitive diagnostic method for EoE remains identifying increased intraepithelial esophageal eosinophil counts through biopsy, without eosinophilic infiltration in stomach or duodenum[1]. According to American College of Gastroenterology 2025, British Society of Gastroenterology, and British Society of Paediatric Gastroenterology, Hepatology and Nutrition guidelines, EoE diagnosis requires esophageal dysfunction symptoms and minimum 15 eosinophils per high-power field on biopsy, after excluding other esophageal eosinophilia causes[2].

Evolving diagnostic technologies

Endoscopy remains invasive, prompting development of less invasive diagnostic methods. The esophageal string test employs an absorptive string capsule that unravels in the esophagus. Research involving 134 participants demonstrated 80% sensitivity and 75% specificity for disease activity, with diagnostic performance based on quantification of eosinophil-derived proteins including eotaxin-3 and major basic protein-1, correlating strongly with biopsy outcomes[4].

The Cytosponge technique involves swallowing a capsule containing mesh sponge connected to string. Histological examination revealed 75% sensitivity and 86% specificity for disease activity in multicenter studies[4]. Transnasal endoscopy, performed without sedation, allows biopsies in children as young as six, utilizing virtual reality goggles for distraction[4].

Pharmacological treatment options

Pharmacological treatments include PPIs, topical corticosteroids, and biologics[1,2]. A 2023 systematic review and network meta-analysis examining 15 randomized controlled trials (1813 patients) compared treatment effectiveness. For histological remission (≤ 6 eosinophils/high-power field), low-dose lirentelimab ranked first, followed by budesonide orally disintegrating tablet and benralizumab[39].

PPIs achieve histologic remission in 30%-50% of patients within 8-12 weeks, likely through anti-inflammatory effects beyond acid reduction[1,2]. Topical corticosteroids achieve histologic remission rates of 60%-95% and alleviate symptoms in children and adults[1,2].

Biologic therapies

Biologic therapy for EoE currently centers on dupilumab, the first and only monoclonal antibody approved specifically for EoE. It blocks IL-4/IL-13 signaling by binding the epitope on the IL-4Rα chain of IL-4 and IL-13 receptors. On May 20, 2022, dupilumab was approved by the United States Food and Drug Administration at dosing of 300 mg weekly for patients 12 years and older who weigh 40 kg[40,41]. The European Medicines Agency also approves dupilumab for EoE in patients 12 years and older with a weight of at least 40 kg, usually in patients who have had a failure of standard therapy[13]. Approval was based on 2 pivotal studies (phase 2 and 3 LIBERTY EoE TREET) showing higher rates of histologic remission (histologic remission: Defined as ≤ 6 eosinophils/high-power field, 60% vs 5% placebo; peak eosinophil counts were reduced > 95% in each study; meaningful and sustained clinical improvements in dysphagia score, endoscopic severity, and esophageal distensibility throughout 52 weeks of weekly dosing)[42,43]. Post-marketing studies and meta analyzes report high rates of symptomatic improvement (approximately 89%), histologic response, and endoscopic improvement. The most common side effects include pain at the site of injection[44]. Investigational biologics targeting IL-5/IL-5R (mepolizumab, reslizumab, benralizumab), IL-13 (cendakimab, dectrekumab), TSLP (tezepelumab), and sialic acid-binding immunoglobulin-like lectin 8 (lirentelimab) are used in EoE therapy. No biologics have consistently shown statistically important improvement in dysphagia and endoscopic findings in EoE, although IL-5/IL-5R targeting biologics have shown improvement in eosinophilia. With the exception of dupilumab, these agents have not been approved for treatment by the Food and Drug Administration[13,40]. At this time, dupilumab is the only licensed treatment for EoE and is usually reserved for patients who have failed PPI, topical steroid or dietary therapy. Other agents are being studied as potential treatments and for long-term disease modulation[13,45].

Biologics other than dupilumab are being studied for EoE in trials targeting multiple type 2 inflammatory pathways with an emphasis on IL-13 blockade. Cendakimab, a monoclonal antibody against IL-13, has undergone a phase 2 study which transitioned to a multicenter phase 3 registrational study (NCT04753697) in approximately 399 adolescents and adults with EoE comparing dosing strategies to placebo for 48 weeks. Both primary endpoints of dysphagia symptom severity and histologic response at week 24 were met[46]. Sustained improvement was observed at week 48[47]. In a separate 52-week extension study, early IL-13 blockade with RPC4046 resulted in important histologic and endoscopic improvement[48]. Benralizumab (anti-IL-5Rα) is undergoing phase 3 study (NCT04543409)[40]. Other biologics in study include mepolizumab, reslizumab, lirentelimab, and tezepelumab, while a 128-week phase IV study (REMODEL) is studying the effect of treatment with dupilumab on fibrostenosis disease progression using endoluminal FLIP and histologic, endoscopic and molecular endpoints[40,45,49].

Dietary management

A 2023 systematic review and meta-analysis (34 studies, 1762 participants) reported 53.8% overall histologic remission with dietary elimination. Effectiveness rates were: Six-food elimination diet (61.3%), four-food elimination (49.4%), one-food elimination (51.4%), and targeted elimination (45.7%), with no statistically significant differences. Primary triggers identified were dairy (70.5%), wheat (48.0%), and eggs (27.6%)[35].

Dietary therapy is the main disease modifying therapy for EoE given the pathophysiology is thought to be driven by food antigens and remits after food exclusion[50]. Elemental diets based on amino acid formulas are the most effective, with histologic remission in 90% to 95% of patients, but are limited by poor taste, expense, and adverse effects on quality of life. Elemental diets are reserved for refractory cases[50]. Empiric elimination diets (6 foods, 4 foods, 2 foods, and milk only elimination diets) induce high rates of histologic and clinical remission and are the dietary gold standard for EoE and are typically done in a step-up approach[50]. A 2023 systematic review and meta-analysis (34 studies, 1762 participants) reported 53.8% overall histologic remission with dietary elimination. Effectiveness rates were: Six-food elimination diet (61.3%), four-food elimination (49.4%), one-food elimination (51.4%), and targeted elimination (45.7%), with no statistically significant differences. Primary triggers identified were dairy (70.5%), wheat (48.0%), and eggs (27.6%)[51]. Allergy test or targeted elimination diets that employ skin prick tests, atopy patch tests, and/or serum specific IgE are not recommended as they are not superior to empiric elimination diets and have a low to moderate predictive value for true EoE food triggers[52]. Consequently, current recommendations no longer support routine skin-testing to guide diet therapy in EoE although treatment for associated IgE mediated food allergies, respiratory allergies and risk of anaphylaxis following prolonged elimination diet in people with EoE is recommended to be undertaken with an allergist[52].

Global consensus: Unifying guidelines for EoE management

Major gastroenterology organizations have developed evidence-based guidelines using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The American Gastroenterology Association with joint task force on Allergy-Immunology Practice Parameters published guidelines in May 2020[27]. The American College of Gastroenterology updated their 2013 guidelines in 2025, incorporating paradigm-shifting changes in diagnosis and management[2]. The British Society of Gastroenterology and British Society of Paediatric Gastroenterology released joint consensus guidelines in 2022[23].

For patients with dysphagia and esophageal strictures, American Society for Gastrointestinal Endoscopy suggests esophageal dilation combined with medical treatment[36]. A consolidated comparison of diagnostic, therapeutic, monitoring, and long-term management recommendations across the major international guidelines is presented in Table 1[2,10,53-57].

Table 1 Consolidated comparison of major international guidelines for the diagnosis and management of eosinophilic esophagitis.

Guideline body and year	Population	Key recommendations
American College of Gastroenterology, 2025[2]	Children and adults	Diagnosis: Symptoms of esophageal dysfunction and ≥ 15 eosinophils/HPF on biopsy, after excluding other causes. Treatment: First-line options include PPIs, swallowed topical corticosteroids and empiric step-up elimination diets (2 foods or 4 foods preferred over elemental). Monitoring: Regular clinical, endoscopic and histologic assessment. Long term: Maintenance therapy and multidisciplinary care recommended
European Society for Paediatric Gastroenterology, Hepatology and Nutrition, 2024[53]	Children	Diagnosis: Updated protocol with multiple biopsies, exclusion of other causes. Treatment: Topical corticosteroids, simplified empiric steps up elimination diets (start with single food), biologics for refractory cases and systemic steroids only for severe strictures. Monitoring: Emphasis on quality of life, transition to adult care, regular endoscopic/histologic follow up
EoETALY, 2024; Italian Society of Gastroenterology; Italian Society of Neurogastroenterology and Motility; Italian Society of Allergology, Asthma, and Clinical Immunology[54]	Children and adults	Diagnosis: ≥ 15 eosinophils/HPF, exclude other causes. Treatment: PPIs, topical corticosteroids, step-up empiric elimination diets, biologics for refractory cases and systemic steroids not for routine use. Monitoring: SCOPE (Symptoms, Control, Observation, Pathological Evaluation) scheme for comprehensive assessment. Emphasis on early diagnosis, multidisciplinary and lifelong management
American Society for Gastrointestinal Endoscopy, 2022[55]	Children and adults	Diagnosis: Endoscopy is essential for diagnosis, assessment of response and monitoring. Tissue sampling: Multiple biopsies from different esophageal sites recommended. Therapy: Endoscopic dilation for strictures; dilation is safe and effective for fibrostenotic disease. Monitoring: Endoscopy remains the gold standard for disease activity and remission; fewer invasive tests not yet established
British Society of Gastroenterology, British Society of Paediatric Gastroenterology, Hepatology and Nutrition, 2022[56]	Children and adults	Diagnosis: ≥ 15 eosinophils/HPF, exclude other causes. Treatment: PPIs, topical corticosteroids, empiric step up elimination diets and esophageal dilation for strictures. Monitoring: Regular clinical, endoscopic and histologic review. Long-term: Maintenance therapy and multidisciplinary team involvement
American Gastroenterological Association institute and the joint task force, 2020[57]	Children and adults	Diagnosis: Symptoms plus ≥ 15 eosinophils/HPF, after excluding other causes. Treatment: Topical corticosteroids (moderate certainty for induction), PPIs (very low certainty for induction), multiple dietary strategies (elemental, empiric 2 foods, 4 foods, 6 foods elimination; moderate to low certainty), allergy-based testing diets not recommended. Dilation: Safe for strictures but does not reduce eosinophil counts. Maintenance: Very low certainty for long term steroid use
United European Gastroenterology, European Society of Pediatric Gastroenterology, Hepatology and Nutrition, European Academy of Allergy and Clinical Immunology, European Society of Eosinophilic Oesophagitis, 2017[10]	Children and adults	Diagnosis: Symptoms of esophageal dysfunction and ≥ 15 eosinophils/HPF on biopsy, after excluding other causes. Treatment: First-line options include PPIs, swallowed topical corticosteroids, empiric step-up elimination diets (2 foods or 4 foods preferred over elemental). Monitoring: Regular clinical, endoscopic and histologic assessment. Long-term: Maintenance therapy and multidisciplinary care recommended

HPF: High-power field; PPI: Proton pump inhibitor.

NOVEL THERAPIES AND FUTURE DIRECTIONS

Emerging diagnostic technologies

Future diagnostic strategies in EoE are increasingly focused on minimally invasive longitudinal monitoring and functional assessment of esophageal remodeling[32].

The EndoFLIP probe assesses esophageal strictures, providing precise diameter and pressure measurements. In EoE patients, endoluminal FLIP demonstrates greater sensitivity than endoscopy for identifying fibrotic alterations[32].

Artificial intelligence and biomarkers

Digital pathology and artificial intelligence (AI) systems show promise as adjuncts to standard histology results. AI digital pathology models trained on EoE histology scoring system features can precisely recognize, quantify, and grade peak eosinophil count and other EoE findings in biopsy sections of EoE with a performance similar to expert gastrointestinal pathologists and with high accuracy for both active disease and disease severity[58]. Other AI systems that analyze whole slide images have inferred spatial biomarkers including eosinophil peak count, basal zone metrics, and distribution scores. These correlate with histologic disease severity and EoE histology scoring system, allowing quantitative assessment at a higher level of detail and reproducibility than manual counting[59]. Endoscopic AI models trained on EoE Endoscopic Reference Score features have demonstrated high sensitivity and specificity detecting EoE, and may help standardize endoscopic disease evaluation, outperforming novice endoscopists[60]. In addition to biopsies, active EoE is associated with elevated peripheral absolute eosinophil count (AEC) and eosinophil derived proteins, which decrease with treatment and remission[61]. In children, serum panels that include AEC, induced eosinophil derived neurotoxin and food specific immunoglobulin E/specific immunoglobulin G4 to egg, wheat, and milk can distinguish active EoE from both remission and healthy controls with high precision, and decrease with remission[61]. In adults, AEC remains an accessible and limited response biomarker, although its validity requires additional assessment in individuals with different atopic backgrounds[62]. Collectively, AI driven histology and emerging blood and food allergen specific immunoglobulin biomarkers are promising alternatives to biopsy in EoE biomarker monitoring, although further validation is required[62]. However, the current research is subject to important methodological and practical limitations that obstruct its applicability to clinical practice. Most EoE AI research is based on small, heterogeneous datasets with varying outcomes and assessment methods, which may limit generalizability and increase the risk of overfitting and bias[63]. In addition to not performing validation on external datasets, other challenges include proper management of missing data, evaluating model performance, and avoiding over and underfitting, as identified in various studies[63]. Other issues surrounding the use of algorithms in clinical practice, such as algorithmic bias, interpretability, patient data privacy, and integration into clinical workflows, will have to be addressed. Large, multicenter, real world validation studies are needed[63].

Next-generation therapeutics

Specialized esophageal formulations like orally dispersible tablets (budesonide orally disintegrating tablet/fluticasone oral tablet) and oral suspensions provide enhanced mucosal contact with robust efficacy and reassuring safety profiles[53]. Tezepelumab, targeting thymic stromal lymphopoietin, recently received orphan drug status for EoE treatment[64].

Clinical trials explore next-generation biologics targeting IL-5 or sialic acid-binding immunoglobulin-like lectin 8. Cendakimab shows promise in early trials for treatment-resistant patients. Lirentelimab (AK002) and CALY-002 (anti-IL-15 monoclonal antibody) undergo evaluation for safety, tolerability, and pharmacodynamics[64].

Interventional advances

The commercially available esophageal FLIP employs rigid balloon technology creating controlled endoluminal pressure for managing esophageal narrowing. High-resolution impedance planimetry provides real-time graphical esophageal lumen depiction during dilation, improving efficacy while minimizing fluoroscopy requirements[65].

Precision medicine approaches

Precision medicine principles emphasize recognizing unique “endotypes” for each EoE patient, reflecting distinct molecular disease fingerprints[54]. Future applications may include genetic or transcriptomic testing to predict individual responses to specific drugs or foods.

CONCLUSION

EoE has evolved from a poorly understood rare condition to a well-characterized disease with clear clinical guidelines and targeted therapies. Management sophistication has increased through understanding of underlying immune mechanisms while diagnostics enable easier, detailed, and frequent monitoring. The future of EoE management depends on interdisciplinary collaboration among allergists, gastroenterologists, pathologists, and dietitians. This multidisciplinary approach optimizes prevention of disease progression and complications. Future progress in EoE management will likely depend on integration of minimally invasive diagnostics, biomarker-guided monitoring, and targeted therapies within multidisciplinary care models.

ACKNOWLEDGEMENTS

The authors would like to acknowledge the contributions of all researchers and clinicians whose foundational work in EoE provided the foundation for this review.