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Eosinophilic esophagitis (EoE) is a chronic allergic condition that induces inflammation in the esophagus. Its diagnosis depends on the presentation of esophageal dysfunction symptoms coupled with the detection of a substantial eosinophil count (≥ 15 per high-power field [HPF]) within the esophagus.1-3 The prevalence of this condition has shown a marked rise, not only in Western countries but also in Asian nations, including Korea. This emerging trend emphasizes the urgency for further research to devise more effective diagnostic and treatment strategies.4-8
The EoE endoscopic reference score (EREFS) was developed to standardize the reporting of endoscopic features associated with EoE.9 EREFS is established based on the presence and severity of edema, rings, exudates, furrows, and strictures. EREFS has demonstrated commendable inter- and intra-observer agreement, positioning it as a prospective tool for diagnosing and assessing treatment responses in EoE patients.10 However, an optimal EREFS threshold for both diagnosis and treatment response evaluation remains to be definitively validated, particularly in Asian countries such as Korea.11-14 In this study, we aim to identify an optimal EREFS threshold for diagnosing and histologically evaluating treatment responses among Korean patients with EoE.
Patients with ≥ 15 eosinophils/HPF and symptoms of esophageal dysfunction were included retrospectively from a tertiary center in Korea between August 2007 and November 2021. Adult patients (≥ 18 years) who had undergone an endoscopic esophageal biopsy were enrolled. Exclusion criteria encompassed patients with alternative causes of esophageal eosinophilia, such as gastroesophageal reflux disease, parasitic infections, malignancies, collagen vascular diseases, hypersensitivity, and inflammatory bowel disease.15-18 Non-EoE controls constituted patients who failed to meet clinical and histologic diagnostic criteria for EoE following endoscopic esophageal biopsy. These controls were matched to EoE patients at a 1:1 ratio based on age and sex using a propensity score.
Baseline characteristics such as age, sex, and symptoms were compared between patients with EoE and non-EoE controls. A history of allergic diseases, including asthma, allergic rhinitis, food allergy, and atopic dermatitis, was assessed. Peripheral blood eosinophilia (> 500 eosinophils/μL) and elevated IgE levels (> 100 kU/L) were defined. Helicobacter pylori infection confirmation relied on positive results from rapid urease, urea breath, or serology test.
Comparative analysis of EREFS features and scores between the EoE and non-EoE control groups was conducted. An optimal EREFS threshold for histologic diagnosis (≥ 15 eosinophils/HPF) was determined based on sensitivity, specificity, and the Youden index. For optimal treatment response threshold identification, EREFS features, and scores, and peak eosinophil counts were evaluated before and after treatment. The optimal treatment response threshold was determined based on sensitivity, specificity, and the Youden index for histologic response (< 15 eosinophils/HPF). The Institutional Review Board of the Asan Medical Center approved this study (Approval No. 2022-0905).
Endoscopic examinations were performed utilizing a gastroduodenoscope (GIF H260 or HQ290; Olympus, Ltd, Tokyo, Japan) by 7 experienced gastroenterologists. An experienced gastroenterologist (K.W.J) retrospectively evaluated the EREFS of endoscopic images. Exudates were categorized as absent (grade 0), mild (occupying < 10% of the esophageal surface area; grade 1), or severe (occupying > 10% of the esophageal surface area; grade 2). Rings were classified as absent (grade 0), mild (subtle circumferential ridges; grade 1), moderate (distinct rings not obstructing endoscope passage; grade 2), or severe (distinct rings obstructing endoscope passage; grade 3). Edema was determined as absent (grade 0) or present (loss of vascular markings; grade 1). Furrows were recorded as absent (grade 0) or present (vertical lines; grade 1). Strictures were categorized as absent (grade 0) or present (grade 1). The inflammatory score included exudates, edema, and furrows, with scores ranging from 0 to 4. The fibrostenotic score encompassed rings and strictures, with scores ranging from 0 to 4. The total EREFS was calculated by summing scores for all 5 features, ranging from 0 to 8.7,19
Two pathologists, including a gastrointestinal specialist (B.A. and Y.S.P), independently re-evaluated all available hematoxylin and eosin-stained slides of esophageal biopsy specimens. They were blinded to clinicopathologic information. After scanning at a low power view, the HPF with the highest eosinophil count was selected for PEC evaluation (HPF = 0.237mm2).20
Treatment options encompassed proton pump inhibitors (PPIs) (standard dose, once daily), topical steroids (fluticasone from a multidose inhaler, 250-500 μg twice daily), or oral prednisolone (0.5 mg/kg/day for 6-8 weeks with dose tapering). After treatment, upper endoscopy with repeated esophageal biopsies was performed during follow-up. A histologic response was defined as a PEC of < 15 eosinophils/HPF on the follow-up biopsy.7
The χ2 test or Fisher’s exact test was used to compare categorical variables, whereas the Mann–Whitney U test was employed to assess continuous variables. Continuous variables were presented as means ± standard deviations or numbers (%) and categorical variables as numbers (%). A P-value of < 0.05 denoted statistical significance. R version 4.0.5 (R Foundation for Statistical Computing, Vienna, Austria) was utilized for all statistical analyses.
A total of 102 patients with EoE and 102 non-EoE controls were enrolled. Among the EoE patients, 74.5% were men, with a mean age of 46.9 years (Table 1). The most prevalent symptom among EoE patients was dysphagia or food impaction (27.5%), followed by dyspepsia (24.5%), and heartburn (23.5%). Allergic diseases were present in 32.4% of EoE patients, including asthma, allergic rhinitis, atopic dermatitis, or food allergy. Peripheral blood eosinophilia and elevated IgE level were observed in 12.4% (12/97) and 62.2% (23/37) of EoE patients, respectively. H. pylori infections were detected in 35.1% (20/57) of EoE patients.
Table 1 . Baseline Characteristics of Eosinophilic Esophagitis Patients and Non-eosinophilic Esophagitis Controls
Variables | Patients with EoE (n = 102) | Non-EoE controls (n = 102) | P-value |
---|---|---|---|
Sex | |||
Male | 76 (74.5) | 76 (74.5) | 1.000 |
Age (yr) | 46.9 ± 14.7 | 48.2 ± 14.5 | 0.531 |
Symptoms | |||
Dysphagia/food impaction | 28 (27.5) | 29 (28.4) | < 0.001 |
Dyspepsia | 25 (24.5) | 13 (12.7) | |
Heartburn | 24 (23.5) | 7 (6.9) | |
Epigastric pain | 21 (20.6) | 8 (7.8) | |
Nausea or vomiting | 3 (2.9) | 6 (5.9) | |
Chest pain | 1 (1.0) | 3 (2.9) | |
Globus | 0 (0.0) | 6 (5.9) | |
Regurgitation | 0 (0.0) | 5 (4.9) | |
Asymptomatic | 0 (0.0) | 25 (24.5) | |
Allergy profile | |||
Asthma | 15 (14.7) | 5 (4.9) | < 0.001 |
Allergic rhinitis | 12 (11.8) | 2 (2.0) | |
Food allergy | 4 (3.9) | 0 (0.0) | |
Atopic dermatitis | 2 (2.0) | 0 (0.0) | |
None | 69 (67.6) | 95 (93.1) | |
Smoking history | |||
Present | 39 (38.2) | 45 (44.1) | 0.398 |
None | 60 (58.8) | 52 (51.0) | |
Unknown | 3 (2.9) | 5 (4.9) | |
Alcohol consumption history | |||
Present | 39 (38.2) | 55 (53.9) | 0.022 |
None | 60 (58.8) | 42 (41.1) | |
Unknown | 3 (2.9) | 5 (4.9) | |
Peripheral blood eosinophilia | |||
Present | 12 (11.8) | 6 (5.9) | 0.318 |
None | 85 (83.3) | 81 (79.4) | |
Unknown | 5 (4.9) | 15 (14.7) | |
Elevated IgE | |||
Present | 23 (22.5) | 7 (6.9) | 0.639 |
None | 14 (13.7) | 7 (6.9) | |
Unknown | 65 (63.7) | 88 (86.3) | |
Helicobacter pylori infection | |||
Present | 20 (19.6) | 20 (19.6) | 0.807 |
None | 37 (36.3) | 31 (30.4) | |
Unknown | 45 (44.1) | 51 (50.0) |
EoE, eosinophilic esophagitis.
Peripheral eosinophilia was defined as > 500 eosinophils/μL; elevated IgE level was defined as > 100 kU/L.
Data are presented as n (%) or mean ± SD.
Among the 102 non-EoE controls, the most common symptom was dysphagia or food impaction (28.4%), and a higher proportion of asymptomatic patients were included compared to EoE patients (24.5% vs 0.0%, P < 0.001). Allergic diseases were more prevalent in EoE patients than in non-EoE controls (32.4% vs 6.9%, P < 0.001). The non-EoE control group included more patients with a history of alcohol consumption than the EoE control group (53.9% vs 38.2%, P = 0.022). Peripheral blood eosinophilia, elevated IgE levels, and H. pylori infection did not differ significantly between the groups.
The mean EREFS was 2.65 ± 1.41 for EoE patients and 0.52 ± 0.85 for non-EoE controls (P < 0.001). Furthermore, 91.2% (93/102) of EoE patients and 33.3% (34/102) of non-EoE controls had at least 1 endoscopic abnormality. Among EoE patients, 43.1% had rings, 63.7% had exudates, 74.5% had furrows, 63.7% had edema, and 5.9% had strictures. In contrast, among the non-EoE controls, 21.6% had rings, 4.0% had exudates, 8.8% had furrows, 15.7% had edema, and none had strictures (Table 2). All the EREFS features were significantly more frequent in EoE patients than in non-EoE controls. A score of ≥ 2 was the optimal diagnostic EREFS threshold, with a sensitivity of 79%, specificity of 86%, and the Youden index of 0.66 (Table 3).
Table 2 . Eosinophilic Esophagitis Endoscopic Reference Score Features and Scores of Eosinophilic Esophagitis Patients and Non-eosinophilic Esophagitis Controls
Endoscopic features and scores | Patients with EoE (n = 102) | Non-EoE controls (n = 102) | P-value |
---|---|---|---|
Exudates | |||
Grade 0: none | 37 (36.3) | 98 (96.1) | < 0.001 |
Grade 1: mild | 55 (53.9) | 2 (2.0) | |
Grade 2: severe | 10 (9.8) | 2 (2.0) | |
Score | 0.74 ± 0.63 | 0.06 ± 0.31 | < 0.001 |
Rings | |||
Grade 0: none | 58 (56.9) | 80 (78.4) | 0.003 |
Grade 1: mild | 39 (38.2) | 21 (20.6) | |
Grade 2: moderate | 5 (4.9) | 1 (1.0) | |
Grade 3: severe | 0 (0) | 0 (0) | |
Score | 0.48 ± 0.59 | 0.23 ± 0.44 | 0.001 |
Edema | |||
Grade 0: absent | 37 (36.3) | 86 (84.3) | <0.001 |
Grade 1: present | 65 (63.7) | 16 (15.7) | |
Score | 0.64 ± 0.48 | 0.16 ± 0.37 | <0.001 |
Furrows | |||
Grade 0: absent | 26 (25.5) | 93 (91.2) | <0.001 |
Grade 1: present | 76 (74.5) | 9 (8.8) | |
Score | 0.75 ± 0.44 | 0.09 ± 0.29 | <0.001 |
Strictures | |||
Grade 0: absent | 96 (94.1) | 102 (100.0) | 0.038 |
Grade 1: present | 6 (5.9) | 0 (0) | |
Score | 0.06 ± 0.24 | 0 ± 0 | 0.013 |
Inflammatory score | 2.14 ± 1.08 | 0.29 ± 0.62 | <0.001 |
Fibrostenotic score | 0.51 ± 0.67 | 0.23 ± 0.46 | 0.001 |
Total score | 2.65 ± 1.41 | 0.52 ± 0.85 | <0.001 |
EoE, eosinophilic esophagitis.
Data are presented as n (%) or mean ± SD.
Table 3 . Sensitivity, Specificity, Youden Index, Positive Predictive Value, Negative Predictive Value, and Accuracy of the Eosinophilic Esophagitis Endoscopic Reference Score Threshold for Diagnosis
EREFS threshold | Sensitivity (95% CI) | Specificity (95% CI) | Youden index (95% CI) | PPV (95% CI) | NPV (95% CI) | Accuracy (95% CI) |
---|---|---|---|---|---|---|
≥ 0 | 1.00 (0.96 to 1.00) | 0.00 (0.00 to 0.04) | 0.00 (–0.04 to 0.04) | 0.50 (0.43 to 0.57) | NA | 0.50 (0.43 to 0.57) |
≥ 1 | 0.91 (0.84 to 0.96) | 0.67 (0.57 to 0.76) | 0.58 (0.41 to 0.72) | 0.73 (0.65 to 0.81) | 0.88 (0.79 to 0.95) | 0.79 (0.73 to 0.84) |
≥ 2 | 0.79 (0.70 to 0.87) | 0.86 (0.78 to 0.92) | 0.66 (0.48 to 0.79) | 0.85 (0.77 to 0.92) | 0.81 (0.72 to 0.88) | 0.83 (0.77 to 0.88) |
≥ 3 | 0.56 (0.46 to 0.66) | 0.95 (0.89 to 0.98) | 0.51 (0.35 to 0.64) | 0.92 (0.82 to 0.97) | 0.68 (0.60 to 0.76) | 0.75 (0.69 to 0.81) |
≥ 4 | 0.28 (0.20 to 0.38) | 1.00 (0.96 to 1.00) | 0.28 (0.16 to 0.38) | 1.00 (0.88 to 1.00) | 0.58 (0.51 to 0.66) | 0.64 (0.57 to 0.71) |
≥ 5 | 0.09 (0.04 to 0.16) | 1.00 (0.96 to 1.00) | 0.09 (0.01 to 0.16) | 1.00 (0.66 to 1.00) | 0.52 (0.45 to 0.59) | 0.54 (0.47 to 0.61) |
≥ 6 | 0.01 (0.00 to 0.05) | 1.00 (0.96 to 1.00) | 0.01 (–0.04 to 0.05) | 1.00 (0.02 to 1.00) | 0.50 (0.43 to 0.57) | 0.50 (0.43 to 0.58) |
EREFS, eosinophilic esophagitis endoscopic reference score; PPV, positive predictive value; NPV, negative predictive value; CI, confidence interval; NA, not applicable.
Among the 102 patients, post-treatment data on endoscopic findings and histology were available for 30 patients. This subgroup primarily comprised men (76.7%), with dysphagia or food impaction as the predominant symptom (46.7%). Moreover, 36.6% of patients had a history of allergic diseases (Supplementary Table 1). The baseline mean EREFS was 2.83 ± 1.49, with 60.0% exhibiting rings, 50.0% exudates, 73.3% furrows, 70.0% edema, and 13.3% strictures.
Thirty patients received treatment at the physician’s discretion, including 19 on PPI, 4 on topical steroids, 5 on PPI plus topical steroids, and 2 on PPI plus oral steroid. Post-treatment, the mean total EREFS decreased from 2.83 ± 1.49 to 1.60 ± 1.69 (P = 0.004). Of the 5 EREFS features, edema, furrows, and strictures exhibited significant decrease in scores, whereas exudates and rings did not. The inflammatory score showed a significant decrease, whereas the fibrostenotic score did not (Supplementary Table 2). The mean peak eosinophil counts dropped from 67.27 ± 106.94 to 13.67 ± 21.49 (P = 0.009). A histologic response was achieved in 73.3% (22/30) of patients.
Following treatment, histologic responders (n = 22) showed a notable decrease in mean EREFS (from 2.59 ± 1.37 to 0.91 ± 1.19), whereas histologic non-responders (n = 8) did not (from 3.50 ± 1.69 to 3.50 ± 1.41). The responders received PPI (n = 13), topical steroids (n = 4), PPI plus topical steroids (n = 4), and PPI plus oral steroids (n = 1) as treatment. The post-treatment inflammatory and fibrostenotic scores, along with the total EREFS for responders were 0.64 ± 0.90, 0.27 ± 0.46, and 0.91 ± 1.19, respectively. The corresponding scores for non-responders were 2.62 ± 1.19, 0.88 ± 0.64, and 3.50 ± 1.41, respectively.
An EREFS of ≤ 3 was the optimal therapeutic response threshold for histologic response, with a sensitivity of 95%, a specificity of 88%, and the Youden index of 0.83. An EREFS of 0 exhibited specificity (88%) but lacked sensitivity (55%), while an EREFS of ≤ 4 demonstrated sensitivity (100%) but lacked specificity (0%) for a histologic response (Table 4).
Table 4 . Sensitivity, Specificity, Youden Index, Positive Predictive Value, Negative Predictive Value, and Accuracy of the Eosinophilic Esophagitis Endoscopic Reference Score Threshold for Histologic Response (< 15 Eosinophils/High Power Field)
EREFS threshold | Sensitivity (95% CI) | Specificity (95% CI) | Youden index (95% CI) | PPV (95% CI) | NPV (95% CI) | Accuracy (95% CI) |
---|---|---|---|---|---|---|
0 | 0.55 (0.32 to 0.76) | 0.88 (0.47 to 1.00) | 0.42 (–0.20 to 0.75) | 0.92 (0.64 to 1.00) | 0.41 (0.18 to 0.67) | 0.63 (0.44 to 0.80) |
≤ 1 | 0.68 (0.45, 0.86) | 0.88 (0.47 to 1.00) | 0.56 (–0.08 to 0.86) | 0.94 (0.70 to 1.00) | 0.50 (0.23 to 0.77) | 0.73 (0.54 to 0.88) |
≤ 2 | 0.91 (0.71 to 0.99) | 0.88 (0.47 to 1.00) | 0.78 (0.18 to 0.99) | 0.95 (0.76 to 1.00) | 0.78 (0.40 to 0.97) | 0.90 (0.73 to 0.98) |
≤ 3 | 0.95 (0.77 to1.00) | 0.88 (0.47 to1.00) | 0.83 (0.25 to 1.00) | 0.95 (0.77 to 1.00) | 0.88 (0.47 to 1.00) | 0.93 (0.78 to 0.99) |
≤ 4 | 1.00 (0.85 to 1.00) | 0.00 (0.00 to 0.37) | 0.00 (–0.15 to 0.37) | 0.73 (0.54 to 0.88) | NA | 0.73 (0.54 to 0.88) |
EREFS, eosinophilic esophagitis endoscopic reference score; PPV, positive predictive value; NPV, negative predictive value; CI, confidence interval; NA, not applicable.
EREFS has proven its validity and reliability as an endoscopic scoring system in EoE, as evidenced by studies conducted in Western countries. However, the establishment of optimal diagnostic and treatment response thresholds for EREFS remains incomplete, particularly in Asian countries such as Korea. Our study aimed to establish these thresholds for Korean EoE patients.12,21,22 Specifically, we identified that an optimal diagnostic threshold for EREFS was ≥ 2, while an optimal therapeutic response threshold was ≤ 3.
To determine the optimal diagnostic EREFS threshold, we compared patients with EoE and age- and sex-matched non-EoE controls. The EoE group exhibited higher proportions of symptomatic patients and those with a history of allergic diseases. However, there were no significant differences between the groups in terms of peripheral eosinophilia, elevated IgE levels, or H. pylori infections. Notably, both endoscopic and histologic severity were more pronounced in EoE patients than in their non-EoE controls. Our study found that the total EREFS showed commendable diagnostic accuracy for EoE. The optimal diagnostic threshold of EREFS was ≥ 2 (sensitivity of 79%; specificity, 86%; and the Youden index, 0.66). This finding aligns with literature reports indicating that a total EREFS of ≥ 2 was optimal with a sensitivity of 88%, specificity of 92%, and area under the curve (AUC) of 0.934.12
After treatment, a notable reduction in the total EREFS was observed, primarily attributed to the decrease in the inflammatory score. Although the fibrostenotic score did not display a significant decrease, histologic responders exhibited a more substantial decline in EREFS compared with non-responders. Previous studies also highlighted the responsiveness of EREFS to treatments and its utility as a clinical outcome measure.21,23,24 Regarding histologic response, we identified EREFS ≤ 3 as the optimal therapeutic response threshold (95% sensitivity, 88% specificity, and Youden index of 0.83). Cotton et al22 recently indicated that an EREFS ≤ 2 was the optimal clinical threshold, demonstrating a sensitivity of 80%, specificity of 83%, and an AUC of 0.793 for a histologic response (< 15 eosinophils/HPF). Some of the sub-analyses in this study suggested potential optimal thresholds of EREFS of 1 or 3, which aligns with our findings.
Our study had certain limitations. The retrospective design introduces the possibility of selection bias; however, in comparison with related studies, our research encompassed the largest cohort of Korean EoE patients. Rigorous adherence to protocols in EoE diagnosis and treatment, combined with comprehensive review of medical records and endoscopic images by trained professionals, was implemented to mitigate selection bias. Furthermore, the number of treated and followed-up patients was relatively limited owing to the rarity of EoE in Asian countries. Nonetheless, our data reflects the increasing prevalence and incidence of EoE in Korea.6,7 Ultimately, our study contributes valuable insights into EoE in the Korean context.
In conclusion, our study establishes that an EREFS of ≥ 2 serves as the optimal diagnostic threshold, whereas an EREFS of ≤ 3 represents the optimal treatment response threshold. Further studies involving a larger EoE patient population are necessary to validate the outcomes of our study.
None.
None.
Conception and design: Kee Wook Jung; pathologic review: Bokyung Ahn, and Young Soo Park; data analysis and interpretation: Kwangbeom Park, Jun Su Lee, Ga Hee Kim, Hee Kyong Na, Ji Yong Ahn, Jeong Hoon Lee, Do Hoon Kim, Kee Don Choi, Ho June Song, Gin Hyug Lee, and Hwoon-Yong Jung; drafting the article: Kwangbeom Park, and Bokyung Ahn; and critical revision for intellectual content: Kee Wook Jung, and Young Soo Park.
Note: To access the supplementary tables mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm23172.