Abstract
Eosinophilic Esophagitis (EoE) is a chronic inflammatory disorder with variable macroscopic and microscopic findings and clinical presentations, complicating management. This study examines esophageal sampling practices, segmental disease patterns, and longitudinal treatment trends and outcomes in pediatric EoE. We retrospectively reviewed charts of 138 pediatric EoE patients diagnosed between 2009 and 2023. EoE was defined as compatible symptoms and ≥ 15 eosinophils per high-power-field without alternative explanation. Diagnostic endoscopy was defined as the first endoscopy performed for evaluation of symptoms showing ≥ 15 eosinophils. Data included demographics, symptoms, macroscopic/microscopic findings, sampling methods, and treatments. Mean age at diagnosis was 8.33 ± 5.37 years, 75% male. Most common presenting symptoms were vomiting (39.28%), dysphagia (32.14%) and food impaction (28.57%). Among 112 diagnostic endoscopies, macroscopic abnormalities were most frequent in the lower esophagus (85.71%), with furrows (69.64%) and exudates (55.36%) predominating. Multi-level sampling in patients with ≥ 15 eosinophils in one field, revealed < 15 eosinophils in 21.11% of upper, 7.14% of middle, and 14.14% of lower esophageal samples. Microscopic findings despite normal endoscopic appearance were most common in the upper (26.4%, p < 0.001), and less frequently in the lower (9.8% p = 0.002) esophagus. Remission following first-line therapy was achieved in 44 patients (48.35%). Biologic therapy was initiated after multiple prior treatment failures and resulted in histologic remission in all treated patients (n = 9).
Conclusions: Findings indicate greater disease severity distally and underscore the need for multi-regional sampling, even in normal-appearing areas. Therapeutic responses are heterogenous and limited, and biologic therapies show promise but require validation in larger studies.
|
What is Known: • Pediatric eosinophilic esophagitis (EoE) is a chronic immune-mediated disease with variable endoscopic findings, requiring both compatible clinical features and histologic evidence of ≥15 eosinophils per high-power field. • Empiric elimination diets and proton pump inhibitors are considered first-line treatments, with variable remission rates. | |
|
What is New: • Pan-esophageal multi-level biopsies, including from normal-appearing mucosa, improve diagnostic accuracy. • While first-line therapies show mild success rates, real-world data demonstrate complete histologic remission with biologic therapy, supporting its promise for pediatric EoE. |
Supplementary Information
The online version contains supplementary material available at 10.1007/s00431-026-07270-1.
Keywords: Eosinophilic Esophagitis, Endoscopy, Histology, Management
Introduction
Eosinophilic Esophagitis (EoE) is a chronic, multifactorial, immune-mediated inflammatory disease of the esophagus [1–4]. The immunological process underlying EoE begins with esophageal exposure to food allergens [5, 6], resulting in a type 2 inflammation characterized by an accumulation of eosinophils in the esophageal mucosa. Over time, this chronic inflammation contributes to a cycle of barrier dysfunction and tissue remodeling, which can result in esophageal strictures and stenosis [5, 7, 8].
In recent years, there has been a sharp rise in incidence and prevalence of EoE [9, 10], now the leading cause of dysphagia and food impaction among children and young adults [1, 9]. Clinical manifestations of EoE vary by age, ranging from food refusal and failure to thrive (FTT) in infants, to dysphagia and food impaction in older children and young adults [11].
Diagnosis of EoE is based on clinical suspicion and confirmed through esophagoscopy. Due to its patchy characteristics, diagnostic criteria include the collection of at least six esophageal biopsies from at least two sites along the esophagus, with histological evidence of 15 or more eosinophils per high-power-field (HPF) in the absence of other explanations [1, 3, 12].
First-line treatment options include elimination diets, proton pump inhibitors (PPI), or topical corticosteroids (TCS), while systemic corticosteroids (SCS) and endoscopic dilatation may be required for severe cases [1, 3, 12]. An emerging treatment for EoE is Dupilumab, a monoclonal antibody that blocks interleukin-4 and interleukin-13 signaling [13–18]. Dupilumab demonstrated efficacy in patients above one year of age [13, 14, 18]. However, long-term, real-world data remain limited.
This study aimed to examine biopsy sampling practices, segmental disease patterns, therapeutic trajectories, including early real-world experience with biologic therapy, in a tertiary pediatric EoE cohort.
Materials and methods
Ethics statement
This was a single-center retrospective study conducted at Hadassah University Medical Center in Jerusalem, Israel. The study was approved by the hospital's research ethics board (approval number: HMO-0326-23).
Study design and cohort
Medical charts of 383 children under 18 years of age seen in outpatient clinics or during inpatient admissions with a diagnosis of Esophagitis (ICD-9 code: 530, ICD-10 codes: K20 and K22) between February 2003 and October 2023 were reviewed.
EoE was defined based on clinical signs and symptoms, along with histopathological confirmation of ≥15 eosinophils per HPF anywhere in the esophagus, with no alternative diagnosis. Patients were included if they met the diagnostic criteria for EoE and had sufficient clinical and endoscopic data. A subgroup of 112 patients who underwent their diagnostic procedure at Hadassah University Medical Center (diagnostic sub-group) and fulfilled criteria of EoE were analyzed separately to ensure cohesive data from the time of diagnosis. Once patients were identified, their medical records were further reviewed for clinical course and outcomes through December 2024, as described below.
Histologic remission was defined as having fewer than 15 eosinophils per HPF at all sampled levels of the esophagus.
To minimize bias, this retrospective study utilized existing records, ensuring the analysis did not influence clinical decision-making.
The study size was determined by including all patients who met the predefined eligibility criteria during the study period, resulting in a comprehensive consecutive cohort.
Data collection
Data collected included the patient's age at diagnosis, sex, ethnicity, medical history and signs and symptoms leading to diagnosis. Information related to each procedure included age, diagnostic sampling methodology, treatment received priorly, and both endoscopic and pathologic findings.
Statistical methods
Continuous variables were summarized using mean ± standard deviation (SD), median or both, depending on data distribution and reporting requirements. To assess associations between two categorical variables, the Chi-square (χ2) test and Fisher’s exact test were used, as appropriate. Differences between paired categorical variables were evaluated using the McNemar test. Non-parametric tests were applied in cases of small sample size or when data were not normally distributed. All statistical tests were two-tailed, and a p-value of ≤0.05 was considered statistically significant.
Results
Patient characteristics and presenting symptoms
Of the 138 patients who met the inclusion criteria, 112 (81.16%) had available diagnostic endoscopy and pathology reports and were included in the diagnostic subgroup. The remaining 26 patients (18.84%) had undergone diagnostic endoscopy at external centers and were therefore included based on follow-up data only Fig. 1.
Fig. 1.
Patient selection flow diagram. A total of 383 patients were initially identified with various forms of esophagitis based on ICD-9 code 530 and ICD-10 codes K20 and K22. Of these, only patients meeting diagnostic criteria for EoE with sufficient clinical data were included in the final analysis (n = 138). A diagnostic subgroup was defined, consisting of patients with available data from the initial diagnostic endoscopy (n = 112). *Reflux (n = 52), Esophagitis Not otherwise specified (NOS) (n = 10), Caustic Injury (n = 9), Helicobacter Pylori/Peptic Ulcer Disease (PUD) (n = 6), Erosive Esophagitis (n = 5), Lymphocytic Esophagitis (n = 5), Candida (n = 5), Celiac disease (n = 3), Inflammatory Bowel Disease (IBD) (n = 3), Pill Esophagitis (n = 2), Graft vs Host Disease (GVHD) (n = 1), Aspiration Esophagitis (n = 1), Gastritis (n = 1)
The demographic characteristics of the entire cohort are summarized in Table 1. Males accounted for 75% of the cohort and 52.9% of the complete cohort had comorbid atopy including food allergy (41.30%), asthma (16.67%), atopic dermatitis (10.87%), environmental allergies (7.97%), and allergic rhinitis (5.07%) (Table 1).
Table 1.
Characteristics of study cohort
| Diagnostic Sub-Group (n = 112) | Complete Cohort (N = 138) | |
|---|---|---|
| n (%) | n (%) | |
| Gender | ||
| Males | 84 (75) | 108 (78.26) |
| Females | 28 (25) | 30 (21.74) |
| Ethnicity | ||
| Jews | 86 (76.79) | 108 (78.26) |
| Arabs | 26 (23.21) | 30 (21.74) |
| Associated Disordersa | ||
| Food Allergy | 44 (39.29) | 57 (41.30) |
| Asthma | 16 (14.29) | 23 (16.67) |
| Atopic Dermatitis | 12 (10.71) | 15 (10.87) |
| Environmental Allergyb | 10 (8.93) | 11 (7.97) |
| Allergic Rhinitis | 5 (4.46) | 7 (5.07) |
| Celiac | 8 (7.14) | 10 (7.25) |
| IBDc | 5 (4.46) | 5 (3.62) |
| Drug Allergy | 4 (3.57) | 6 (4.35) |
| Symptoms Leading to Diagnosisa | ||
| Vomiting | 44 (39.28) | |
| Dysphagia | 36 (32.14) | |
| Food Impaction | 32 (28.57) | |
| FTTd | 27 (24.11) | |
| Eczema | 23 (20.54) | |
| Feeding Difficulty | 22 (19.64) | |
| Abdominal Pain | 17 (15.18) | |
| Diarrhea | 16 (14.29) | |
| GERe and Associated Symptoms | 14 (12.50) | |
| Constipation | 6 (5.36) | |
| Otherf | 11 (9.82) | |
aThe total percentage does not sum up to 100% due to patients with no/multiple Associated Disorders
bPollens, dust, animals
cInflammatory Bowel Disease
dFailure to Thrive
eGastroesophageal Reflux
fIncidental post foreign body removal (4), positive celiac antibodies (3), anemia (2), joint pain (1), melena (1), laryngomalacia (1), weight loss (1), peripheral eosinophilia (1), suspected ulcer (1)
EoE incidence rose over time (Online resource 1), peaking in 2022 with 17 new cases. Mean age at diagnosis was 8.33±5.37 years (range three weeks – 18 years) in the diagnostic subgroup. Most common symptoms leading to diagnosis (Table 1) were vomiting (39.28%), dysphagia (32.14%) and food impaction (28.57%).
Endoscopic evaluation
Macroscopic findings
Diagnostic endoscopy reports from the 112 patients in the diagnostic subgroup were analyzed for segmental macroscopic findings. Overall, 15 patients (13.39%) had no visible endoscopic abnormalities. Among those with reported findings, involvement was most frequent in the lower esophagus (85.71%), followed by the middle (75%) and upper segments (71.43%). Pan-esophageal overt involvement was reported in 67.86% of endoscopies. The most common macroscopic features were furrows (69.64%) and exudates (55.36%).
We evaluated segmental discordance in macroscopic findings between esophageal regions (Table 2). Exudates were more frequently identified in the middle esophagus despite being absent in the upper esophagus (p=0.016). Similarly, both furrows and exudates were more commonly observed in the lower esophagus while absent in the upper esophagus (p=0.004 and p<0.001, respectively) and the middle segments (p=0.013 and p=0.002, respectively). In contrast, trachealization was more often detected in the upper esophagus despite being absent in the lower esophagus (p=0.031). Notably, the upper and middle esophagus frequently appeared macroscopically normal, even when abnormalities were present in the lower esophagus (p<0.001 and p=0.003, respectively).
Table 2.
Segmental distribution of discrepancy in macroscopic findings in diagnostic sub-groupa
| Finding | Ub– Lc +/U + L- (p) | Md- L +/M + L- (p) | U- M +/U + M- (p) |
|---|---|---|---|
| Furrows | 16/3 (0.004) | 12/2 (0.013) | 5/2 (0.453) |
| Trachealization | 0/6 (0.031) | 0/2 (0.500) | 1/5 (0.219) |
| Exudates | 20/1 (< 0.001) | 13/1 (0.002) | 7/0 (0.016) |
| Edema | 2/0 (0.500) | 1/1 (1.000) | 2/0 (0.500) |
| Friable Mucosa | 1/1 (1.000) | 1/0 (1.000) | 0/1 (1.000) |
| Attenuated Vascular Pattern | 5/2 (0.453) | 4/1 (0.375) | 2/2 (1.000) |
| Normal | 2/17 (< 0.001) | 1/12 (0.003) | 3/7 (0.344) |
aEndoscopies in which findings were concordant between segments (either absent or present in both) are not shown
bUpper Esophagus
-Finding absent
cLower Esophagus
+ Finding Present
dMiddle Esophagus
Microscopic findings
We reviewed pathology reports from the 112 patients in the diagnostic subgroup, documenting microscopic findings in the upper, middle and lower esophagus. Microscopic abnormalities beyond eosinophilic infiltration were highly prevalent. Completely normal histology was rare, identified in only 3.33% of upper esophageal segments and 1.98% of lower segments, and was not observed in the middle esophagus.
The most prominent histologic abnormalities, in addition to eosinophilic infiltration, were basal cell hyperplasia (62.50%) and edema (12.50%).
To evaluate segmental differences in microscopic findings, we analyzed cases in which two esophageal segments were sampled and demonstrated discordant histological results. Only one statistically significant difference was identified: basal cell hyperplasia was more frequently present in the lower esophagus despite being absent in the upper esophagus (p=0.013). No other significant segmental differences were observed, including eosinophilic infiltration, edema, or normal histology (Table 3).
Table 3.
Segmental distribution of discrepancy in microscopic findings in diagnostic sub-groupa
| Finding | Ub- Lc +/U + L- (p) | Md- L +/M + L- (p) | U- M +/U + M- (p) |
|---|---|---|---|
| ≥ 15 Infiltrated Eosinophils | 16/12 (0.572) | 2/4 (0.687) | 3/1 (0.625) |
| Infiltrated Eosinophils (any) | 3/2 (1.000) | 0/0 (NAe) | 0/0 (NA) |
| Basal Cell Hyperplasia | 14/3 (0.013) | 3/1 (0.625) | 3/2 (1.000) |
| Edema | 3/2 (1.000) | 0/0 (1.000) | 0/0 (1.000) |
| Normal | 2/3 (1.000) | 0/0 (NA) | 0/0 (NA) |
aEndoscopies in which findings were concordant between segments (either absent or present in both) are not shown
bUpper Esophagus
- Finding absent
cLower Esophagus
+ Finding Present
dMiddle Esophagus
eStatistical significance could not be determined as there was no variation in the findings between the two sites
Multi-regional sampling (≥2 regions) was performed in 100 (89.29%) patients. Among these, <15 eosinophils per HPF were identified in 19 of 90 (21.11%) upper esophageal samples, 2 of 28 (7.14%) middle samples, and 14 of 99 (14.14%) lower samples.
Analysis of multi-regional sampling was not possible in nine patients (8.04%) because multiple specimens were submitted unmarked within a single container. Additionally, three patients (2.68%) underwent urgent food bolus extraction with biopsy obtained from only one esophageal region.
Macroscopic-microscopic discrepancies in esophageal findings
We analyzed the association between macroscopic findings observed during endoscopy and microscopic findings in the corresponding esophageal segments. A total of 229 esophageal segments were biopsied during the diagnostic evaluation of 112 patients. Concordance between endoscopic appearance and histologic findings was observed in 80 (71.43%) diagnostic procedures. In contrast, macroscopic-microscopic discordance was identified in 44 segments (19.21%), corresponding to 32 (28.57%) patients within the cohort.
Among segments demonstrating macroscopic-microscopic discordance, histologic abnormalities despite a normal endoscopic appearance were most frequently observed in the upper esophagus (n=23, 25.56% of upper samples) and, to a lesser extent, in the lower esophagus (n=10, 9.9% of lower samples). These differences were statistically significant (p=<0.001 and p=0.002, respectively).
Treatment and follow-up
Standard treatment and follow-up
During the follow-up period, patients underwent 530 endoscopic procedures with biopsy sampling, including 112 diagnostic and 418 follow-up procedures. The mean number of procedures per patient was 3.84±2.56 (range 1–12). Treatment data were recorded prior to each endoscopy.
Among the 92 patients in the diagnostic subgroup who underwent a second procedure, the most commonly used first-line therapies were PPI (n=27, 29.35%) and elimination diet (n=26, 28.26%) achieving 55.56% and 53.85% success rates accordingly. Combined therapy with PPI and elimination diet was used in eight patients (8.7%) and was associated with a 37.5% success rate.
Overall, 70 patients (61.61%) in the diagnostic sub-group achieved histologic remission during the follow-up period. An average of 1.65 endoscopic procedures were required to reach initial remission. Following first-line therapy, remission was achieved in 44 patients (47.83%) among the 92 who underwent a second endoscopic evaluation.
The heat map shown in Fig. 2 demonstrates treatment-response patterns across the cohort. Overall, most therapeutic regimens were associated with remission rates below 50%. Notably, the use of TCS, either alone or in combination with other therapies, was not associated with higher remission rates.
Fig. 2.
Heat map representing response rates to different treatment modalities. For each documented procedure, the corresponding treatment regimen was recorded, and the remission rate was calculated as the proportion of procedures demonstrating < 15 eosinophils throughout the esophagus under that specific treatment. *Patients who were diagnosed in another medical center and were already treated when firstly performed a procedure at Hadassah University Medical Center. †Proton Pump Inhibitors ‡Topical Corticosteroids §Systemic Corticosteroids ¶ketogenic diet (n = 2), antacids (n = 1) ||Review of the medical record did not allow determination of the specific administered treatment
Considering all endoscopic procedures performed, the most frequently employed therapeutic strategy was elimination diet (n=142, 33.89%), followed by PPI (n=60, 14.32%), combined PPI and elimination diet (n=50, 11.93%), and TCS (n=35, 8.35%). Across treatment strategies, success rates ranged from 37.14% with TCS to 46.67% with PPI.
When analyzed both as monotherapy and in combination with other modalities, elimination diet achieved an overall success rate of 43.7% (100/229 treatment exposures), with individual response rates ranging from 33.3% to 66.7%. PPI therapy demonstrated an overall success rate of 44.7% (71/159 exposures), with response rates ranging from 0% to 100%. TCS achieved an overall success rate of 45.4% (39/86 exposures), with response rates ranging from 0% to 61.1%. SCS were rarely used as a treatment modality (n=7, 1.67%) but yielded remission in six out of seven procedures.
Biologic therapy
Data on biologic therapy were available for nine patients who initiated treatment with subcutaneous Dupilumab. In all cases, biologic therapy was initiated after failure of prior treatments, and six patients had discontinued corticosteroids due to adverse effects, including growth restriction, mood changes and facial swelling. Notably, over the past two years (n=112 follow-up procedures), the use of biologic therapies has increased to 15.18% (n=17) of applied therapies (Online resource 2). The number of endoscopic procedures performed prior to initiation of biologic therapy ranged from 4 to 7.
Among patients treated with Dupilumab, age at EoE diagnosis ranged from 1 to 13 years, whereas initiation of biologic therapy occurred between 3 and 16 years of age. All nine patients had atopic comorbidities: nine (100%) had food allergy, five (55.56%) had atopic dermatitis and three (33.33%) had asthma. Following initiation of biologic therapy, seven patients (77.78%) achieved histologic remission at the first follow-up endoscopy, performed two to five months after treatment induction. All patients (n=9, 100%) achieved remission at least once while receiving biologic therapy, and eight (88.89%) maintained remission throughout the follow up period. Mild, self-limited adverse events were reported, including conjunctivitis (n=3, 33.33%), and pruritis with pharyngitis in one patient (11.11%).
Discussion
In this study, we characterized the clinical course and diagnostic patterns of pediatric EoE, from initial diagnostic endoscopic evaluation through conventional treatments to the advent of biologic therapies.
We observed a significant increase in the annual incidence of newly diagnosed pediatric EoE cases at our center. This finding is consistent with the global rise in EoE diagnoses reported over the past two decades [9, 10]. While heightened disease awareness among clinicians and families, improved diagnostic practices and evolving endoscopic and histopathologic criteria may have contributed to this, it is also likely that potential changes in environmental exposures that influence allergic sensitization and immune dysregulation have emerged as well [12, 19–21].
In assessing the macroscopic manifestations of the disease, we identified significant differences between esophageal segments, with distal segments more frequently exhibiting macroscopic findings. Furthermore, the pattern of abnormalities also varied by location, with exudates being more prominent in the lower esophagus and trachealization more frequent in the upper esophagus. These findings may reflect regional differences in local pathophysiology and mechanical influences along the esophagus. The distal esophagus is more frequently exposed to gastroesophageal refluxate, which may contribute to epithelial injury, heightened eosinophilic infiltration, and the development of exudative changes. In contrast, the proximal esophagus is structurally distinct, with a greater concentration of submucosal glands and exposure to mechanical stresses related to swallowing and peristalsis [22]. These factors may predispose to remodeling and fibrostenotic changes, manifesting endoscopically as trachealization or fixed rings in the upper esophagus. Further studies examining segment-specific histopathologic, molecular, and functional changes could provide deeper insights into these observed patterns.
In contrast to the segmental variability observed in macroscopic endoscopic findings, histopathologic analysis revealed relatively uniform microscopic abnormalities throughout the esophagus. Importantly, a substantial discordance was identified between macroscopic endoscopic appearance and histologic findings, with several mucosal segments that appeared grossly normal, both proximally and distally, exhibiting marked eosinophilic infiltration and structural changes on microscopic evaluation. Notably, even among patients who ultimately met diagnostic criteria for EoE, a substantial proportion demonstrated fewer than 15 eosinophils per HPF in at least one sampled esophageal segment. Altogether, these findings underscore the importance of obtaining systematic biopsies from both abnormal – and normal – appearing mucosa when EoE is suspected. EoE demonstrates a patchy and segment-dependent endoscopic phenotype, suggesting that reliance on targeted biopsy from visibly affected areas alone may lead to under-diagnosis or underestimation of disease extent.
Beyond diagnostic considerations, we evaluated treatment strategies and longitudinal outcomes over a 15-year period, generating a comprehensive real-world dataset. This analysis revealed several notable trends emerged with relevance for both individualized care and future guideline development.
Elimination diets were the most frequently employed treatment modality in our pediatric EoE cohort and remained consistently used throughout the study period. This observation aligns with international practice patterns, in which empiric or targeted food elimination remains a cornerstone of initial therapy in children [9, 12, 23]. Reported histological remission rates with elimination diets in both children and adults range from 45% to 91%, depending on the dietary strategy used (e.g., six-food elimination vs. targeted elimination) and patient adherence [24]. In our cohort, remission rates with elimination diet monotherapy ranged from 34% to 67% and were notably higher when used in combination with other modalities, including TCS or biologic agents. It is possible that the relatively modest success rates observed with elimination diets reflect challenges with long-term adherence, particularly given the practical complexity and psychosocial burden of dietary restrictions in children and adolescents.
PPI therapy as monotherapy achieved a remission rate of 45%, comparable to that of elimination diet, supporting current pediatric EoE guidelines that identify both as acceptable first-line treatment options [12, 23]. However, combining PPI with elimination diet did not appear to enhance treatment efficacy in our cohort, raising questions about the utility of this combination approach.
Steroid-based therapies, particularly SCS, were used infrequently in our pediatric population, likely reflecting concerns regarding potential adverse effects, especially impaired growth, and the availability of alternative therapeutic options. TCS were used more frequently than SCS in our cohort but were associated with relatively modest remission rates. This may reflect a selection bias, whereby patients with more severe or treatment-refractory disease were more likely to receive steroid therapy. Unfortunately, even among this subgroup, TCS therapy did not appear to achieve satisfactory remission rates. Conversely, SCS – while used as a monotherapy in only five procedures – were effective in all cases, with a 100% remission rate. While their use is limited by concerns regarding adverse effects and is not suitable for long-term management in children, short courses of SCS may be considered in selected situations requiring rapid disease control, such as severe exacerbations or as a bridge to maintenance therapy.
Our cohort provides early real-world experience with biologic therapy for EoE. Despite the small sample size, all patients treated with biologics achieved histologic remission. We propose that the superiority of biologic agents lies not only in their targeted mechanism of action but also in the controlled administration setting (e.g., injection-based, supervised delivery), which may mitigate the compliance challenges inherent in other therapies.
These preliminary findings highlight the need for large-scale, prospective studies to better define the long-term efficacy and safety of biologic therapies and to inform future access policies. At present, biologic treatment is often restricted to patients with prior treatment failure. No significant adverse effects were observed in our cohort, however, these findings should be interpreted cautiously given the small sample size and relatively short duration of follow-up.
The primary limitation of this study is its retrospective design. Patient identification relied on contemporary diagnostic criteria and may therefore have failed to capture patients who were previously misclassified. Data extraction was also constrained by variability in the quality and completeness of clinical documentation. In particular, macroscopic endoscopic findings were inherently subjective and dependent on the level of detail recorded by the endoscopist. This contrasts with prospective studies that employ standardized data collection tools. Furthermore, the lack of repeat endoscopic evaluation in some patients limited our ability to confirm sustained histologic remission. As a single-center study, our findings may be influenced by selection bias and may not be fully generalizable to other populations. The absence of a control group also limits the analytical depth, rendering much of the data descriptive in nature.
Conclusion
In this longitudinal real-world cohort of pediatric EoE, we demonstrate marked segmental variability in macroscopic disease expression alongside relatively diffuse microscopic inflammation and frequent discordance between endoscopic appearance and histologic activity. These findings reinforce the importance of systematic multi-level biopsy sampling to ensure accurate diagnosis and disease monitoring. Conventional therapies were associated with variable and often modest remission rates, highlighting the chronic and treatment-refractory nature of the disease in a substantial proportion of patients. In contrast, biologic escalation was associated with encouraging early response and the absence of microscopic evidence of inflammation on repeated biopsies. Together, these observations support a more individualized, proactive management strategy that integrates comprehensive diagnostic assessment with timely therapeutic optimization. Further prospective, multicenter studies are needed to refine treatment algorithms and define the long-term role of biologic therapies in pediatric EoE.
Supplementary Information
Below is the link to the electronic supplementary material.
Abbreviations
- EoE
Eosinophilic esophagitis
- FTT
Failure to thrive
- HPF
High power field
- PPI
Proton pump inhibitors
- TCS
Topical corticosteroids
- SCS
Systemic corticosteroids
- SD
Standard deviation
- IBD
Inflammatory bowel disease
- GER
Gastro-esophageal reflux
- NA
Not applicable
- NOS
Not otherwise specified
- PUD
Peptic ulcer disease
- GVHD
Graft vs host disease
Authors' contributions
S.G. and L.B.S conceived and designed the study and interpreted data. L.B.S supervised this work. The first draft of the manuscript was written by S.G.; S.G., Z.D., P.M., S.R., A.E., O.P. and L.B.S reviewed and edited the paper. All authors acquired data. All authors read and approved the final manuscript.
Funding
Open access funding provided by Hebrew University of Jerusalem.
Data availability
The data that support the findings of this study were obtained from the Hadassah Medical Center electronic medical records system. These data are stored on secure Hadassah institutional servers and are not publicly available due to privacy and institutional restrictions. Access to the data may be granted upon reasonable request to the corresponding author.
Declarations
Ethical approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Hadassah University Medical Center (Date: 26/10/2023 No: HMO-0326–23). Informed consent was waived due to the study’s retrospective observational nature.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Barni S, Arasi S, Mastrorilli C, Pecoraro L, Giovannini M, Mori F, Liotti L, Saretta F, Castagnoli R, Caminiti L et al (2021) Pediatric eosinophilic esophagitis: a review for the clinician. Ital J Pediatr 47(1):230. 10.1186/s13052-021-01178-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Furuta GT, Katzka DA (2015) Eosinophilic esophagitis. N Engl J Med 373(17):1640–1648. 10.1056/NEJMra1502863 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Muir A, Falk GW (2021) Eosinophilic esophagitis: a review. JAMA 326(13):1310–1318. 10.1001/jama.2021.14920 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Mukkada V, Falk GW, Eichinger CS, King D, Todorova L, Shaheen NJ (2018) Health-related quality of life and costs associated with eosinophilic esophagitis: a systematic review. Clin Gastroenterol Hepatol 16(4):495-503.e8. 10.1016/j.cgh.2017.06.036 [DOI] [PubMed] [Google Scholar]
- 5.O’Shea KM, Aceves SS, Dellon ES, Gupta SK, Spergel JM, Furuta GT, Rothenberg ME (2018) Pathophysiology of eosinophilic esophagitis. Gastroenterology 154(2):333–345. 10.1053/j.gastro.2017.06.065 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lyles JL, Martin LJ, Shoda T, Collins MH, Trimarchi MP, He H, Kottyan LC, Mukkada VA, Rothenberg ME (2021) Very early onset eosinophilic esophagitis is common, responds to standard therapy, and demonstrates enrichment for CAPN14 genetic variants. J Allergy Clin Immunol 147(1):244-254.e6. 10.1016/j.jaci.2020.10.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hirano I, Aceves SS (2014) Clinical implications and pathogenesis of esophageal remodeling in eosinophilic esophagitis. Gastroenterol Clin North Am 43(2):297–316. 10.1016/j.gtc.2014.02.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Warners MJ, Oude Nijhuis RAB, de Wijkerslooth LRH, Smout AJPM, Bredenoord AJ (2018) The natural course of eosinophilic esophagitis and long-term consequences of undiagnosed disease in a large cohort. Am J Gastroenterol 113(6):836–844. 10.1038/s41395-018-0052-5 [DOI] [PubMed] [Google Scholar]
- 9.Dellon ES, Hirano I (2018) Epidemiology and natural history of eosinophilic esophagitis. Gastroenterology 154(2):319-332.e3. 10.1053/j.gastro.2017.06.067 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Navarro P, Arias Á, Arias-González L, Laserna-Mendieta EJ, Ruiz-Ponce M, Lucendo AJ (2019) Systematic review with meta-analysis: the growing incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies. Aliment Pharmacol Ther 49(9):1116–1125. 10.1111/apt.15231 [DOI] [PubMed] [Google Scholar]
- 11.De Matteis A, Pagliaro G, Corleto VD, Pacchiarotti C, Di Giulio E, Villa MP, Parisi P, Vassallo F, Ziparo C, Di Nardo G (2020) Eosinophilic esophagitis in children: clinical findings and diagnostic approach. Curr Pediatr Rev 16(3):206–214. 10.2174/1573396315666191004110549 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Amil-Dias J, Oliva S, Papadopoulou A, Thomson M, Gutiérrez-Junquera C, Kalach N, Orel R, Auth MKH, Nijenhuis-Hendriks D, Strisciuglio C et al (2024) Diagnosis and management of eosinophilic esophagitis in children: an update from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 79(2):394–437. 10.1002/jpn3.12188 [DOI] [PubMed] [Google Scholar]
- 13.Chehade M, Dellon ES, Spergel JM, Collins MH, Rothenberg ME, Pesek RD, Hirano I, Liu R, Laws E, Mortensen E et al (2024) Dupilumab for eosinophilic esophagitis in patients 1 to 11 years of age. N Engl J Med 390(24):2239–2251. 10.1056/NEJMoa2312282 [DOI] [PubMed] [Google Scholar]
- 14.Dellon ES, Rothenberg ME, Collins MH, Hirano I, Chehade M, Bredenoord AJ, Lucendo AJ, Spergel JM, Aceves S, Sun X et al (2022) Dupilumab in adults and adolescents with eosinophilic esophagitis. N Engl J Med 387(25):2317–2330. 10.1056/NEJMoa2205982 [DOI] [PubMed] [Google Scholar]
- 15.Hirano I, Dellon ES, Hamilton JD, Collins MH, Peterson K, Chehade M, Schoepfer AM, Safroneeva E, Rothenberg ME, Falk GW et al (2020) Efficacy of Dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis. Gastroenterology 158(1):111-122.e10. 10.1053/j.gastro.2019.09.042 [DOI] [PubMed] [Google Scholar]
- 16.Gandhi NA, Pirozzi G, Graham NMH (2017) Commonality of the IL-4/IL-13 pathway in atopic diseases. Expert Rev Clin Immunol 13(5):425–437. 10.1080/1744666X.2017.1298443 [DOI] [PubMed] [Google Scholar]
- 17.Le Floc’h A, Allinne J, Nagashima K, Scott G, Birchard D, Asrat S, Bai Y, Lim WK, Martin J, Huang T et al (2020) Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation. Allergy 75(5):1188–1204. 10.1111/all.14151 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Rothenberg ME, Dellon ES, Collins MH, Hirano I, Chehade M, Bredenoord AJ, Lucendo AJ, Spergel JM, Sun X, Hamilton JD et al (2023) Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 8(11):990–1004. 10.1016/S2468-1253(23)00204-2 [DOI] [PubMed] [Google Scholar]
- 19.Mona R, Hruz P (2025) Epidemiology of eosinophilic esophagitis: really a novel and evolving disease? Inflamm Intest Dis 10(1):34–40. 10.1159/000543022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Jensen ET, Dellon ES (2015) Environmental and infectious factors in eosinophilic esophagitis. Best Pract Res Clin Gastroenterol 29(5):721–729. 10.1016/j.bpg.2015.06.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Alexander ES, Martin LJ, Collins MH, Kottyan LC, Sucharew H, He H, Mukkada VA, Succop PA, Abonia JP, Foote H et al (2014) Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J Allergy Clin Immunol 134(5):1084-1092.e1. 10.1016/j.jaci.2014.07.021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Blevins CH, Iyer PG, Vela MF, Katzka DA (2018) The esophageal epithelial barrier in health and disease. Clin Gastroenterol Hepatol 16(5):608–617. 10.1016/j.cgh.2017.06.035 [DOI] [PubMed] [Google Scholar]
- 23.Hirano I, Furuta GT (2020) Approaches and challenges to management of pediatric and adult patients with eosinophilic esophagitis. Gastroenterology 158(4):840–851. 10.1053/j.gastro.2019.09.052 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Lucendo AJ (2015) Meta-analysis-based guidance for dietary management in eosinophilic esophagitis. Curr Gastroenterol Rep. 10.1007/s11894-015-0464-y [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study were obtained from the Hadassah Medical Center electronic medical records system. These data are stored on secure Hadassah institutional servers and are not publicly available due to privacy and institutional restrictions. Access to the data may be granted upon reasonable request to the corresponding author.


