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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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Long-term Outcome of Asymptomatic Esophageal Eosinophilia

Yugo Suzuki1 , Yorinari Ochiai1 , Daisuke Kikuchi1 , Mako Koseki1 , Kenichi Ohashi2 , Shu Hoteya1

1Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan; 2Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Correspondence to: Yugo Suzuki
ORCID https://orcid.org/0000-0001-9182-6286
E-mail yugo-suzuki@nms.ac.jp

Received: September 30, 2023; Revised: December 12, 2023; Accepted: December 20, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver.

Published online April 16, 2024

Copyright © Gut and Liver.

Background/Aims: Asymptomatic esophageal eosinophilia (aEE), characterized by eosinophil infiltration in the esophagus without clinical symptoms, has been reported as a precursor of eosinophilic esophagitis (EoE). Nevertheless, no report exists on the long-term clinical course of the disease. Therefore, this study aimed to investigate the long-term clinical course of aEE over 5 years, including the symptomatic conversion rate and the effect of treatments.
Methods: We reviewed 28 patients with aEE who had been followed up for over 5 years with endoscopic monitoring. The basal characteristics of patients were compared with those of 58 patients diagnosed with EoE during the same period. Patients’ clinicopathological findings were collected and examined.
Results: No significant differences in basal characteristics and histopathological findings were observed between the patients with aEE and those with EoE. The median follow-up duration was 64 months. Among the 28 patients with aEE, seven were treated with proton pump inhibitor or potassium-competitive acid blocker and the remaining 21 opted for follow-up with no medication. Among the treated patients, six (85.7%) exhibited endoscopic and pathologic improvements. Among the cases followed up without medication, the findings worsened in two (9.5%), improved spontaneously in seven (33.3%), and were unchanged in 12 (57.1%), and three (14.3%) developed symptoms at a mean time of 40 months. Symptoms developed in cases where endoscopic and pathologic findings remained unchanged or worsened during follow-up.
Conclusions: Some patients with aEE had improved findings without treatment, whereas others developed symptoms, emphasizing the importance of long-term monitoring and individualized treatment decisions.

Keywords: Eosinophilic esophagitis, Esophageal diseases, Endoscopy

Eosinophilic esophagitis (EoE) is a chronic immune-mediated esophageal disorder characterized by eosinophil-predominant inflammation in the esophagus. EoE often results from an exaggerated type 2 helper T-cell immune response to dietary or airborne allergens.1 This condition leads to various digestive symptoms, such as dysphagia and food impaction, presenting a major challenge to affected individuals. EoE prevalence is increasing worldwide, especially in Western countries, including Japan, likely because of improvements in hygiene and the widespread adoption of endoscopic examinations.2-5 Recent guidelines6,7 and the International Consensus Diagnostic Criteria8 define EoE as a condition characterized by symptoms resulting from esophageal dysfunction, with esophageal histology demonstrating an intraepithelial eosinophil infiltration of ≥15 eosinophils per high-power field (hpf). The histological remission is important for the improvement of EoE symptoms and its activity.9 Conversely, symptoms cannot accurately predict endoscopic and histologic remission in EoE.10,11 Recently, asymptomatic esophageal eosinophilia (aEE), characterized by eosinophil infiltration in the esophagus without clinical symptoms, has been reported as a similar entity or precursor of EoE.12,13 We evaluated the differences between EoE and aEE in the previous study to explore the pathogenesis and characteristics of aEE, and reported no significant clinicopathologic differences between the two.14 Nevertheless, aEE remains a relatively new concept with low prevalence, and data regarding symptomatic conversion rates and clinical risk factors are limited. Particularly, no report exists on the long-term clinical course of the disease and treatment effects with a proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB). Therefore, whether treatment is necessary for aEE remains uncertain, and treatment guidelines have not been established.

Therefore, this study aimed to investigate the long-term clinical course of aEE over 5 years to determine the natural history of aEE, including the symptomatic conversion rate and the effect of PPI or P-CAB treatments.

1. Patients and design

We retrospectively reviewed patients clinically and pathologically diagnosed with esophageal eosinophilia (EE) at Toranomon Hospital, Tokyo, Japan, between September 2011 and September 2018. Biopsies were performed on patients with endoscopic findings characteristic of EoE. We excluded patients who had previously undergone chemoradiotherapy or esophageal surgery and those with secondary EE that can cause eosinophil infiltration besides EoE, such as eosinophilic gastritis, gastroesophageal candida esophagitis, achalasia, graft versus host disease, and eosinophilic granulomatosis with polyangiitis. Patients with EE were defined as those having esophageal histology revealing a peak eosinophil count of ≥15 eosinophils/hpf, as stated in the guidelines for EoE.6-8 The symptoms were confirmed for patients with the histology demonstrating an eosinophil infiltration of ≥15 eosinophils/hpf. In this study, "asymptomatic" was defined as the absence of symptoms related to esophageal dysfunction within 3 months before diagnosis. Patients with aEE who had not been followed up for over 5 years and those who had not undergone endoscopy after initial diagnosis were excluded. The basal characteristics of patients with aEE were compared with those of patients diagnosed with EoE during the same period. This is a retrospective observational study. Clinical, endoscopic, and histopathological data were collected from medical records.

2. Endoscopic findings

Endoscopic findings characteristics of EoE, such as esophageal rings, white exudate, longitudinal furrows or ridges, edema, and stricture, were evaluated based on the EoE endoscopic reference scores, which were calculated for inflammation and fibrostenosis.15,16 The location of each finding and the endoscopic phenotype (diffuse or localized) were retrospectively evaluated for each case.17 Additionally, other findings that may influence gastrointestinal symptoms, including atrophic gastritis, hiatus hernia, and reflux esophagitis, were assessed based on the Los Angeles classification.18 Three board-certified endoscopists (Y.S., Y.O., and D.K.) of the Japan Gastroenterological Endoscopy Society retrospectively made the diagnoses.

3. Histopathological assessment

All biopsy specimens were fixed in 10% formalin, stained with hematoxylin and eosin, and pathologically assessed using the EoE histology scoring system.19 The EoE histology scoring system evaluates eosinophilic inflammation and other features, including epithelial basal zone hyperplasia, eosinophilic abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Specialist pathologists from the Japanese Society of Pathology determined the grades of abnormalities for each finding using a 4-point scale (0 for normal; 3 for maximum change).

4. Indications for treating aEE and its clinical course

Given the absence of diagnostic guidelines for aEE, treatment decisions were left to the discretion of the attending physician and were determined in consultation with the patients. When treatments were administered, patients received oral PPIs or P-CABs for at least 8 weeks in accordance with the EoE guidelines6-8 intending to improve the endoscopic and pathological findings. Endoscopies were performed 8 weeks after endoscopic treatment or later, and histological evaluations were performed using biopsy samples. Regardless of treatment status, all patients underwent endoscopic follow-up at least once every 2 years. Follow-up endoscopic findings were categorized as "worsened," "unchanged," or "improved" compared to findings at initial diagnosis. Symptom development was defined as the emergence of esophageal dysfunction-related symptoms, such as dysphagia, food impaction, heartburn, and chest pain, during the observation period. When patients with aEE developed symptoms related to the esophageal dysfunction, they were considered as a progression to EoE from the diagnostic criteria for the EoE.6-8 For patients who were lost to outpatient follow-up, the long-term outcome data were retrieved by request from the referring physicians or through a telephone interview.

5. Study endpoints

The primary endpoint was the rate of symptom development. Secondary endpoints included the course of endoscopic findings, response rates to treatment, and clinicopathological characteristics.

6. Statistical analyses

The data are presented as the median and interquartile range (IQR). The chi-square test and Fisher exact test were used to compare qualitative variables between groups, and the Mann-Whitney U test and t-test were used to compare quantitative variables. All statistical analyses were performed using SPSS version 29 (SPSS IBM statistics; IBM Corp., Armonk, NY, USA). Statistical significance was set at a p-value <0.05.

7. Ethical approval

The Institutional Review Board of Toranomon Hospital approved the study (approval number 1783), which was performed in accordance with the 1964 Declaration of Helsinki and its later revisions. All patients consented in writing to undergo the proposed procedure. Written informed consent for inclusion in the study was not mandatory owing to the retrospective observational nature of the research. However, patients were allowed to opt out via the website of the hospital.

1. Basic characteristics of patients and lesions

Fig. 1 illustrates the inclusion and exclusion criteria in a flowchart. Among the excluded 20 patients with aEE, 17 were not followed up for over 5 years, and three did not undergo endoscopy after initial diagnosis. Therefore, our analysis included 28 consecutive patients with aEE and 58 patients diagnosed with EoE during the study period. Of the 28 patients with aEE, 21 (75%) were noted on upper gastrointestinal endoscopy during the medical checkup. Table 1 presents the demographics and clinicopathological characteristics of the patients. The median age of the patients with aEE was 50 years (IQR, 42 to 57 years) with a man-to-woman ratio of 25:3. Lamina propria fibrosis could not be pathologically evaluated in six cases. The median total score for the EoE histology scoring system was 8 (IQR, 7 to 9.25), and the median total/full score was 0.35 (0.29 to 0.39). No significant difference in basal characteristics and histopathological findings was observed between the patients with aEE and those with EoE. However, patients with aEE had a significantly lower frequency of concurrent allergic diseases than those with EoE (46.4% vs 77.6%, respectively, p=0.002).

Figure 1.Patient flowchart. Among the 106 patients with EE, 48 were diagnosed with aEE and 58 with EoE. Twenty-eight patients with aEE were followed up for over 5 years with endoscopic monitoring. EE, esophageal eosinophilia; aEE, asymptomatic esophageal eosinophilia; EoE, eosinophilic esophagitis.

Table 1. Characteristics of Patients and Lesions

CharacteristicPatients with aEE (n=28)Patients with EoE (n=58)p-value
Age, median (IQR), yr50 (42–57)47 (42–55)0.647
Sex, No. (%)0.534
Male25 (89.3)47 (81.0)
Female3 (10.7)11 (19.0)
Body mass index, median (IQR), kg/m224.4 (22.6–26.4)23.2 (21.6–26.0)0.109
Brinkman index, median (IQR)0 (0–100)0 (0–215)0.599
Daily alcohol consumption, No. (%)12 (42.9)31 (53.4)0.159
Concurrent allergic diseases, No. (%)13 (46.4)45 (77.6)0.002*
Allergic rhinitis6 (21.4)19 (32.8)
Bronchial asthma4 (14.3)13 (22.4)
Atopic dermatitis4 (14.3)10 (17.2)
Food or other allergies44 (14.3)13 (22.4)
Peripheral blood eosinophil, median (IQR),/μL300 (182–392)253 (179–417)0.841
Non-specific IgE, median (IQR), IU/mL113 (64–167)200 (80–646)0.237
Helicobacter pylori infection, No. (%)0.531
Current infection3 (10.7)4 (6.9)
Past infection3 (10.7)12 (20.7)
Negative infection22 (78.6)42 (72.4)
PEC, median (IQR), eos/hpf56 (42–81)51.5 (30–93)0.658
EoEHSS grade score, median (IQR)
Eosinophilic inflammation2 (2–3)2 (2–3)0.889
Basal cell hyperplasia3 (3–3)3 (2–3)0.339
Dilated intercellular spaces3 (3–3)3 (3–3)0.946
Lamina propria fibrosis2 (2–2)2 (1–2)0.182
Eosinophilic abscess0 (0–0)0 (0–1)0.368
Eosinophil surface layering0 (0–0)0 (0–0)0.252
Surface epithelial alteration0.5 (0–2)0 (0–2)0.151
Dyskeratotic epithelial cells0 (0–0)0 (0–0)0.427
Total score/full score0.35 (0.29–0.39)0.38 (0.29–0.46)0.159

aEE, asymptomatic esophageal eosinophilia; EoE, eosinophilic esophagitis; IQR, interquartile range; IgE, immunoglobulin E; PEC, peak eosinophil count; eos/hpf, eosinophils per high-power field; EoEHSS, eosinophilic esophagitis histologic scoring system.

*p<0.05; Duplicates counted.



2. Endoscopic findings

Table 2 presents the endoscopic findings for patients with aEE. The median total, inflammatory, and fibrostenotic scores of patients with aEE were 3 (IQR, 2 to 4), 2 (IQR, 2 to 3), and 0 (IQR, 0 to 1), respectively. The diffuse phenotype was dominant (71.4% vs 28.6%), with lesions located in the upper to lower thoracic esophagus in 46.4% of the patients with aEE. No significant differences in EoE endoscopic reference score, phenotype, location, and other endoscopic findings were observed between patients with aEE and those with EoE. No significant difference in reflux esophagitis was observed between the two groups, with only one patient in each showing an A or higher in the Los Angeles classification.

Table 2. Endoscopic Findings

VariablePatients with aEE (n=28)Patient with EoE (n=58)p-value
Endoscopic findings, EREFS
Longitudinal furrows/ridges, No. (%)23 (82.1)53 (91.4)0.283
Median score (IQR)1 (1–1)1 (1–1)
Esophageal rings, No. (%)12 (42.9)33 (56.9)0.490
Median score (IQR)0 (0–1)1 (0–1)
White exudates, No. (%)16 (57.1)35 (60.3)0.818
Median score (IQR)1 (0–1)1 (0–1)
Stricture, No. (%)03 (5.2)0.548
Median score (IQR)0 (0–0)0 (0–0)
Edema, No. (%)26 (92.9)26 (93.1)1.000
Median score (IQR)1 (1–1)1 (1–1)
Inflammatory score, median (IQR)2 (2–3)3 (2–3)0.601
Fibrostenotic score, median (IQR)0 (0–1)1 (0–1)0.276
Total score, median (IQR)3 (2–4)3 (2–4)0.357
Phenotype0.793
Localized type8 (28.6)14 (24.1)
Diffuse type20 (71.4)44 (75.9)
Location, No. (%)0.468
Ut-Lt13 (46.4)19 (32.8)
Mt-Lt9 (32.1)24 (41.4)
Lt6 (21.4)15 (25.9)
Other endoscopic findings, No. (%)
Atrophic gastritis5 (17.9)9 (15.5)0.765
Reflux esophagitis, No. (%)0.548
LA classification: N-M27 (96.4)57 (98.3)
LA classification: A-D1 (3.6)1 (1.7)
A/B/C/D1/0/0/00/1/0/0
Hiatus hernia18 (64.3)33 (56.9)0.641

aEE, asymptomatic esophageal eosinophilia; EoE, eosinophilic esophagitis; EREFS, eosinophilic esophagitis endoscopic reference score; IQR, interquartile range; LA, Los Angeles; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; Ut, upper thoracic esophagus.



3. Clinical course and long-term outcome

Fig. 2 illustrates the clinical course and long-term outcomes of the patients with aEE. The median follow-up duration was 64 months (IQR, 60 to 79.5 months). Among the 28 patients with aEE, seven were treated with PPIs or P-CABs and the remaining 21 opted for follow-up with no medication. Among the treated patients, six (85.7%) exhibited endoscopic and pathologic improvements. Furthermore, among the six patients who achieved improvement, a temporal discontinuation of medication was attempted in three (50%). However, the three patients experienced worsened endoscopic findings. Table 3 presents the characteristics of patients with aEE treated with PPI or P-CABs. Five patients were treated with esomeprazole 20 mg or 10 mg, one with vonoprazan 20 mg, and one with rabeprazole 10 mg. The findings were unchanged in one case treated with esomeprazole 20 mg. After the initial diagnosis of aEE, the patient was started on PPI and followed up with periodic upper gastrointestinal endoscopy. The patient’s background, endoscopic and pathological findings at the time of initial examination did not differ from those of other aEE patients. In addition, the patient was evaluated by high-resolution manometry (HRM) and was diagnosed as a normal study according to the Chicago classification, version 3.0. Although the findings did not improve with treatment, the PPI was subsequently discontinued because no symptoms were observed during long-term follow-up. Endoscopic findings after discontinuation showed no exacerbation, and the intraepithelial eosinophil infiltration showed 42 eosinophils/hpf, unchanged from the initial diagnosis.

Figure 2.Clinical course of the patients with aEE. Among the 28 patients with aEE, seven were treated with PPIs or P-CABs and the remaining 21 opted for follow-up without medication. Findings were improved in six of the seven treated cases, worsened in two of the 21 untreated cases, improved spontaneously in seven cases, and were unchanged in 12 cases. Symptoms developed in three of the 21 untreated patients. aEE, asymptomatic esophageal eosinophilia; PPI, proton pump inhibitor; P-CAB, potassium-competitive acid blocker.

Table 3. Patients Treated with Proton Pump Inhibitor

No.Age, yrSexObservation
period, mo
LocationPhenotypeEoEHSS
(total/full)
Eosinophil
infiltration, eos/hpf
MedicationEndoscopic
findings
Eosinophile infiltration
after medication, eos/hpf
157F79Mt-LtLocalized0.3830Esomeprazole 20 mgImproved0–2
250M68Mt-LtDiffuse0.3385Esomeprazole 10 mgImproved60
356M65Mt-LtDiffuse0.0470Vonoprazan 20 mgImproved0
464F69Ut-LtDiffuse0.3821Esomeprazole 20 mgImproved0–2
544M62Ut-LtDiffuse0.33261Esomeprazole 20 mgImproved15
644M64Ut-LtDiffuse0.3840Esomeprazole 10 mgImproved6
739M60Ut-LtDiffuse0.3360Esomeprazole 20 mgUnchanged120
858M60Ut-LtDiffuse0.2951Rabeprazole 10 mgImproved0–2

EoEHSS, eosinophilic esophagitis histologic scoring system; eos/hpf, eosinophils per high-power field; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; Ut, upper thoracic esophagus.



Among the cases followed up without medication, the findings worsened in two (9.5%), improved spontaneously in seven (33.3%), and were unchanged in 12 (57.1%). One of the two patients with worsened findings was treated with PPI, which improved the findings; however, the other patient became symptomatic and was subsequently started on PPI, but the findings remained unchanged. Conversely, symptoms developed in two of the seven (28.6%) patients whose findings remained unchanged after the initial diagnosis. In one patient, the findings remained unchanged despite initiating subsequent PPI medication, whereas in the other patients, the findings and symptoms improved spontaneously without any medication.

Supplementary Fig. 1 shows the clinical course of the patients with EoE. In five of the 58 patients diagnosed with EoE, follow-up with upper gastrointestinal endoscopy was lost after the initial diagnosis. For the remaining 53 patients, five were followed up with no treatment due to patient's request, 47 were treated with PPIs or P-CABs, and one was on the elimination dietary therapy. Eight of the 19 patients with EoE who had inadequate improvement on PPIs or P-CABs received the additional treatment with topical corticosteroid, seven of whom showed endoscopic and histological improvements. Of the five patients with EoE who were followed up without treatment, three had no significant changes, but two had spontaneous improvement in the endoscopic findings. Out of the 48 patients who underwent therapeutic intervention and were followed up long-term with endoscopy, 32 were reevaluated histologically. Twenty-two patients (68.8%) achieved an eosinophil infiltration of <15, and all but one showed improvement in symptoms.

4. Patients with symptoms

Table 4 outlines the patients with aEE who developed digestive symptoms related to esophageal dysfunction. Among the patients followed up without treatment, three (14.3%) developed symptoms (all males) at a mean time of 40 months. Symptoms developed in cases where endoscopic and pathologic findings remained unchanged or worsened during follow-up. In case number 1, esophageal wall thickness was assessed using endoscopic ultrasound (EUS), and esophageal motility was assessed using HRM at symptom onset. EUS revealed a thickening of the lower esophagus with a total wall thickness of 3.6 and 2.8 mm from the surface to the muscular layer. HRM indicated ineffective esophageal motility based on the Chicago classification, version 3.0. However, the endoscopic and pathologic findings at the initial diagnosis were not more characteristic than those in other cases.

Table 4. Cases in Which Symptoms Developed

No.Age, yrSexObservation period, moTime to symptom development, moLocationPhenotypeEoEHSS
(total/full)
Eosinophil
infiltration, eos/hpf
SymptomsFindings after
initial diagnosis
Medication after
symptom development
Findings after
medication
142M10843LtLocalized0.33100Dysphasia, food impactionWorsenedEsomeprazole 20 mgUnchanged
237M6759Ut-LtDiffuse0.6350Dysphasia, heartburnUnchangedEsomeprazole 20 mgUnchanged
380M6118LtLocalized0.3842HeartburnUnchangedNo-

EoEHSS, eosinophilic esophagitis histologic scoring system; eos/hpf, eosinophils per high-power field; Lt, lower thoracic esophagus; Ut, upper thoracic esophagus.


Currently, no well-defined standards of practice for aEE exist, leaving treatment decisions to the discretion of clinicians. This study investigated patients with aEE for over 5 years, providing valuable long-term insights into the natural course of aEE and the incidence of symptom development. These longitudinal data can provide guidance for clinical practice and treatment decisions. In addition, the study presents individual cases and the outcomes of different treatment approaches, reflecting real-world practices. This allows insights into the variations in disease presentations and treatment responses among patients. The similar immunohistological profile of aEE and EoE and the similar clinical findings, including endoscopic findings,12-14 suggest that they may represent a continuum of diseases primarily differing in their stages of progression. The clinical findings suggest that the symptom development is associated with a younger age at initial onset,20 and esophageal wall thickening, primarily in the mucosal layer.21,22 Histopathologic findings suggest that mast cells and their receptors, PAR-2 and VPAC-1, may contribute to symptom onset.23 In addition, no previous studies have investigated follow-ups exceeding 5 years; however, the rate of symptom development in aEE has been reported to be 20.7%–31.0%.13,20 In this study, 14.3% of the untreated patients developed symptoms, and one case evaluated using EUS and HRM showed esophageal wall thickening and dysmotility. However, no other characteristic basal clinical findings were observed in the symptomatic conversion cases because of the small sample size.

Some patients in this study showed symptoms without treatment, with one-third demonstrating spontaneous improvements in endoscopic and histopathological findings without treatment. This spontaneous improvement in findings may be inferred from the timing of antigen exposure or changes in the immune response of the hosts. This indicates that aEE does not necessarily require immediate treatment, and follow-up with no treatment, including endoscopy, may be acceptable.

Management and follow-up goals for aEE are to prevent progression to EoE and subsequent esophageal remodeling leading to stricture formation.24 This focus does not aim to improve the quality of life, as no associated symptoms exist. When treating with PPIs or P-CABs, the short-term goal is to improve endoscopic and pathological findings. Despite the limited studies on aEE, aEE has been reported to progress to EoE at a certain rate. Consequently, endoscopic follow-up at least once a year after initial diagnosis is recommended. Some studies suggest that aEE should be regarded as asymptomatic EoE, and follow-up, including target biopsy, should be performed as in EoE.25,26 In addition, given that the usefulness of measuring esophageal body compliance for EoE using an endoluminal functional lumen imaging probe (EndoFLIP) has been demonstrated recently,27 esophagrams and EndoFLIP, if available, should be used alongside conventional endoscopy to evaluate potential fibrosis. Furthermore, EUS and HRM may be useful to evaluate fibrosis and symptom development,21,22 and close endoscopic monitoring should be considered if these tests predict fibrosis progression. Conversely, the follow-up interval can be extended in patients with aEE showing no signs of esophageal fibrosis.

Previous studies on EoE have reported endoscopic improvement in 50.% to 61.8% of cases after therapeutic intervention with PPIs.28-30 In addition, it has been reported that 75% of patients with EoE who show resistance to a PPI therapy respond to P-CAB in a small number of cases, suggesting a possible benefit of the therapeutic effect of P-CAB.31 On the other hand, temporary exacerbations of disease during PPI administration and relapse after PPI discontinuation should be noted.32,33 Although studies on aEE are scarce, the response rate to PPI is reported to be very high at 90.5%,13 with 83.3% of patients improving with PPI treatment even after symptom development.20 The response to PPIs/P-CABs in this study was 85.7% and 58.3% for aEE and EoE, respectively, consistent with previous reports. P-CAB was used as an antacid for aEE in two cases, and endoscopic findings were improved in both cases. A total of five of the 28 patients with aEE, two with no treatment and three with PPI interruption, experienced worsened endoscopic findings, of whom four (80%) responded well to PPI treatment. This observation indicates a relatively benign course of aEE and suggests a low need for therapeutic intervention immediately after diagnosis as prevention of progression to EoE in asymptomatic patients. Considering that approximately one-third of aEE cases in this study spontaneously resolved, conducting a regular follow-up rather than treating empirically after initial diagnosis is appropriate. Although it is difficult to establish clear criteria for the timing of therapeutic intervention, it may not be too late to initiate treatment when the endoscopic findings worsen during the follow-up. However, therapeutic intervention should be considered when findings suggesting esophageal fibrosis or clinical symptoms emerge during follow-up with endoscopic monitoring.

Additionally, none of the treated cases in this study developed symptoms after at least 5 years of follow-up. However, discontinuing PPI treatment may lead to symptom relapse during the course of the disease,13 as observed in three patients. Therefore, once PPI treatment is initiated, deciding whether to continue or discontinue treatment for asymptomatic patients is challenging, and treatment selection should be tailored to individual cases.

This study had some limitations. First, it had a retrospective single-center design with a limited sample size. Therefore, we were unable to examine risk factors related to symptom progression, and statistical analysis of treatment efficacy was limited. The patient sample in this study was obtained from a single medical institution, potentially limiting geographical, racial, and cultural diversity. The findings of EoE are milder in Japan than in Western countries owing to the prevalence of endoscopy and racial differences.34,35 Thus, caution is required when generalizing the results, and a larger-scale prospective study is needed to verify our findings. Second, treatment options and decision criteria were subject to the discretion of the physician. This may have led to different patients receiving different treatments, potentially affecting the consistency of the results and causing the patient selection bias. Additionally, the follow-up methods and intervals between examinations of the patients varied owing to the lack of clear practice guidelines. Therefore, guidelines for diagnosis and treatment of aEE should be established alongside those for EoE in the future. Third, the presence or absence of symptoms was subjective, and no quantitative evaluation, such as questionnaires, was used. Given the importance of symptoms in patients with EoE, including asymptomatic cases, developing a symptom-scoring system for EoE may be beneficial.

In conclusion, this study provides insights into the natural course of aEE and the effects of PPI or P-CAB treatment. Treatments led to improvement in most cases; however, discontinuation resulted in worsening in some cases. Some patients with aEE had improved findings without treatment, whereas others developed symptoms, emphasizing the importance of long-term monitoring and individualized treatment decisions.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Study concept and design: Y.S. Data acquisition: Y.S., Y.O., D.K., S.H. Data analysis and interpretation: Y.S., Y.O. Drafting of the manuscript: Y.S. Critical revision of the manuscript for important intellectual content: Y.S., D.K., M.K., K.O., S.H. Statistical analysis: Y.S. Approval of final manuscript: all authors.

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Article

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Gut and Liver

Published online April 16, 2024

Copyright © Gut and Liver.

Long-term Outcome of Asymptomatic Esophageal Eosinophilia

Yugo Suzuki1 , Yorinari Ochiai1 , Daisuke Kikuchi1 , Mako Koseki1 , Kenichi Ohashi2 , Shu Hoteya1

1Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan; 2Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Correspondence to:Yugo Suzuki
ORCID https://orcid.org/0000-0001-9182-6286
E-mail yugo-suzuki@nms.ac.jp

Received: September 30, 2023; Revised: December 12, 2023; Accepted: December 20, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: Asymptomatic esophageal eosinophilia (aEE), characterized by eosinophil infiltration in the esophagus without clinical symptoms, has been reported as a precursor of eosinophilic esophagitis (EoE). Nevertheless, no report exists on the long-term clinical course of the disease. Therefore, this study aimed to investigate the long-term clinical course of aEE over 5 years, including the symptomatic conversion rate and the effect of treatments.
Methods: We reviewed 28 patients with aEE who had been followed up for over 5 years with endoscopic monitoring. The basal characteristics of patients were compared with those of 58 patients diagnosed with EoE during the same period. Patients’ clinicopathological findings were collected and examined.
Results: No significant differences in basal characteristics and histopathological findings were observed between the patients with aEE and those with EoE. The median follow-up duration was 64 months. Among the 28 patients with aEE, seven were treated with proton pump inhibitor or potassium-competitive acid blocker and the remaining 21 opted for follow-up with no medication. Among the treated patients, six (85.7%) exhibited endoscopic and pathologic improvements. Among the cases followed up without medication, the findings worsened in two (9.5%), improved spontaneously in seven (33.3%), and were unchanged in 12 (57.1%), and three (14.3%) developed symptoms at a mean time of 40 months. Symptoms developed in cases where endoscopic and pathologic findings remained unchanged or worsened during follow-up.
Conclusions: Some patients with aEE had improved findings without treatment, whereas others developed symptoms, emphasizing the importance of long-term monitoring and individualized treatment decisions.

Keywords: Eosinophilic esophagitis, Esophageal diseases, Endoscopy

INTRODUCTION

Eosinophilic esophagitis (EoE) is a chronic immune-mediated esophageal disorder characterized by eosinophil-predominant inflammation in the esophagus. EoE often results from an exaggerated type 2 helper T-cell immune response to dietary or airborne allergens.1 This condition leads to various digestive symptoms, such as dysphagia and food impaction, presenting a major challenge to affected individuals. EoE prevalence is increasing worldwide, especially in Western countries, including Japan, likely because of improvements in hygiene and the widespread adoption of endoscopic examinations.2-5 Recent guidelines6,7 and the International Consensus Diagnostic Criteria8 define EoE as a condition characterized by symptoms resulting from esophageal dysfunction, with esophageal histology demonstrating an intraepithelial eosinophil infiltration of ≥15 eosinophils per high-power field (hpf). The histological remission is important for the improvement of EoE symptoms and its activity.9 Conversely, symptoms cannot accurately predict endoscopic and histologic remission in EoE.10,11 Recently, asymptomatic esophageal eosinophilia (aEE), characterized by eosinophil infiltration in the esophagus without clinical symptoms, has been reported as a similar entity or precursor of EoE.12,13 We evaluated the differences between EoE and aEE in the previous study to explore the pathogenesis and characteristics of aEE, and reported no significant clinicopathologic differences between the two.14 Nevertheless, aEE remains a relatively new concept with low prevalence, and data regarding symptomatic conversion rates and clinical risk factors are limited. Particularly, no report exists on the long-term clinical course of the disease and treatment effects with a proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB). Therefore, whether treatment is necessary for aEE remains uncertain, and treatment guidelines have not been established.

Therefore, this study aimed to investigate the long-term clinical course of aEE over 5 years to determine the natural history of aEE, including the symptomatic conversion rate and the effect of PPI or P-CAB treatments.

MATERIALS AND METHODS

1. Patients and design

We retrospectively reviewed patients clinically and pathologically diagnosed with esophageal eosinophilia (EE) at Toranomon Hospital, Tokyo, Japan, between September 2011 and September 2018. Biopsies were performed on patients with endoscopic findings characteristic of EoE. We excluded patients who had previously undergone chemoradiotherapy or esophageal surgery and those with secondary EE that can cause eosinophil infiltration besides EoE, such as eosinophilic gastritis, gastroesophageal candida esophagitis, achalasia, graft versus host disease, and eosinophilic granulomatosis with polyangiitis. Patients with EE were defined as those having esophageal histology revealing a peak eosinophil count of ≥15 eosinophils/hpf, as stated in the guidelines for EoE.6-8 The symptoms were confirmed for patients with the histology demonstrating an eosinophil infiltration of ≥15 eosinophils/hpf. In this study, "asymptomatic" was defined as the absence of symptoms related to esophageal dysfunction within 3 months before diagnosis. Patients with aEE who had not been followed up for over 5 years and those who had not undergone endoscopy after initial diagnosis were excluded. The basal characteristics of patients with aEE were compared with those of patients diagnosed with EoE during the same period. This is a retrospective observational study. Clinical, endoscopic, and histopathological data were collected from medical records.

2. Endoscopic findings

Endoscopic findings characteristics of EoE, such as esophageal rings, white exudate, longitudinal furrows or ridges, edema, and stricture, were evaluated based on the EoE endoscopic reference scores, which were calculated for inflammation and fibrostenosis.15,16 The location of each finding and the endoscopic phenotype (diffuse or localized) were retrospectively evaluated for each case.17 Additionally, other findings that may influence gastrointestinal symptoms, including atrophic gastritis, hiatus hernia, and reflux esophagitis, were assessed based on the Los Angeles classification.18 Three board-certified endoscopists (Y.S., Y.O., and D.K.) of the Japan Gastroenterological Endoscopy Society retrospectively made the diagnoses.

3. Histopathological assessment

All biopsy specimens were fixed in 10% formalin, stained with hematoxylin and eosin, and pathologically assessed using the EoE histology scoring system.19 The EoE histology scoring system evaluates eosinophilic inflammation and other features, including epithelial basal zone hyperplasia, eosinophilic abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Specialist pathologists from the Japanese Society of Pathology determined the grades of abnormalities for each finding using a 4-point scale (0 for normal; 3 for maximum change).

4. Indications for treating aEE and its clinical course

Given the absence of diagnostic guidelines for aEE, treatment decisions were left to the discretion of the attending physician and were determined in consultation with the patients. When treatments were administered, patients received oral PPIs or P-CABs for at least 8 weeks in accordance with the EoE guidelines6-8 intending to improve the endoscopic and pathological findings. Endoscopies were performed 8 weeks after endoscopic treatment or later, and histological evaluations were performed using biopsy samples. Regardless of treatment status, all patients underwent endoscopic follow-up at least once every 2 years. Follow-up endoscopic findings were categorized as "worsened," "unchanged," or "improved" compared to findings at initial diagnosis. Symptom development was defined as the emergence of esophageal dysfunction-related symptoms, such as dysphagia, food impaction, heartburn, and chest pain, during the observation period. When patients with aEE developed symptoms related to the esophageal dysfunction, they were considered as a progression to EoE from the diagnostic criteria for the EoE.6-8 For patients who were lost to outpatient follow-up, the long-term outcome data were retrieved by request from the referring physicians or through a telephone interview.

5. Study endpoints

The primary endpoint was the rate of symptom development. Secondary endpoints included the course of endoscopic findings, response rates to treatment, and clinicopathological characteristics.

6. Statistical analyses

The data are presented as the median and interquartile range (IQR). The chi-square test and Fisher exact test were used to compare qualitative variables between groups, and the Mann-Whitney U test and t-test were used to compare quantitative variables. All statistical analyses were performed using SPSS version 29 (SPSS IBM statistics; IBM Corp., Armonk, NY, USA). Statistical significance was set at a p-value <0.05.

7. Ethical approval

The Institutional Review Board of Toranomon Hospital approved the study (approval number 1783), which was performed in accordance with the 1964 Declaration of Helsinki and its later revisions. All patients consented in writing to undergo the proposed procedure. Written informed consent for inclusion in the study was not mandatory owing to the retrospective observational nature of the research. However, patients were allowed to opt out via the website of the hospital.

RESULTS

1. Basic characteristics of patients and lesions

Fig. 1 illustrates the inclusion and exclusion criteria in a flowchart. Among the excluded 20 patients with aEE, 17 were not followed up for over 5 years, and three did not undergo endoscopy after initial diagnosis. Therefore, our analysis included 28 consecutive patients with aEE and 58 patients diagnosed with EoE during the study period. Of the 28 patients with aEE, 21 (75%) were noted on upper gastrointestinal endoscopy during the medical checkup. Table 1 presents the demographics and clinicopathological characteristics of the patients. The median age of the patients with aEE was 50 years (IQR, 42 to 57 years) with a man-to-woman ratio of 25:3. Lamina propria fibrosis could not be pathologically evaluated in six cases. The median total score for the EoE histology scoring system was 8 (IQR, 7 to 9.25), and the median total/full score was 0.35 (0.29 to 0.39). No significant difference in basal characteristics and histopathological findings was observed between the patients with aEE and those with EoE. However, patients with aEE had a significantly lower frequency of concurrent allergic diseases than those with EoE (46.4% vs 77.6%, respectively, p=0.002).

Figure 1. Patient flowchart. Among the 106 patients with EE, 48 were diagnosed with aEE and 58 with EoE. Twenty-eight patients with aEE were followed up for over 5 years with endoscopic monitoring. EE, esophageal eosinophilia; aEE, asymptomatic esophageal eosinophilia; EoE, eosinophilic esophagitis.

Table 1 . Characteristics of Patients and Lesions.

CharacteristicPatients with aEE (n=28)Patients with EoE (n=58)p-value
Age, median (IQR), yr50 (42–57)47 (42–55)0.647
Sex, No. (%)0.534
Male25 (89.3)47 (81.0)
Female3 (10.7)11 (19.0)
Body mass index, median (IQR), kg/m224.4 (22.6–26.4)23.2 (21.6–26.0)0.109
Brinkman index, median (IQR)0 (0–100)0 (0–215)0.599
Daily alcohol consumption, No. (%)12 (42.9)31 (53.4)0.159
Concurrent allergic diseases, No. (%)13 (46.4)45 (77.6)0.002*
Allergic rhinitis6 (21.4)19 (32.8)
Bronchial asthma4 (14.3)13 (22.4)
Atopic dermatitis4 (14.3)10 (17.2)
Food or other allergies44 (14.3)13 (22.4)
Peripheral blood eosinophil, median (IQR),/μL300 (182–392)253 (179–417)0.841
Non-specific IgE, median (IQR), IU/mL113 (64–167)200 (80–646)0.237
Helicobacter pylori infection, No. (%)0.531
Current infection3 (10.7)4 (6.9)
Past infection3 (10.7)12 (20.7)
Negative infection22 (78.6)42 (72.4)
PEC, median (IQR), eos/hpf56 (42–81)51.5 (30–93)0.658
EoEHSS grade score, median (IQR)
Eosinophilic inflammation2 (2–3)2 (2–3)0.889
Basal cell hyperplasia3 (3–3)3 (2–3)0.339
Dilated intercellular spaces3 (3–3)3 (3–3)0.946
Lamina propria fibrosis2 (2–2)2 (1–2)0.182
Eosinophilic abscess0 (0–0)0 (0–1)0.368
Eosinophil surface layering0 (0–0)0 (0–0)0.252
Surface epithelial alteration0.5 (0–2)0 (0–2)0.151
Dyskeratotic epithelial cells0 (0–0)0 (0–0)0.427
Total score/full score0.35 (0.29–0.39)0.38 (0.29–0.46)0.159

aEE, asymptomatic esophageal eosinophilia; EoE, eosinophilic esophagitis; IQR, interquartile range; IgE, immunoglobulin E; PEC, peak eosinophil count; eos/hpf, eosinophils per high-power field; EoEHSS, eosinophilic esophagitis histologic scoring system..

*p<0.05; Duplicates counted..



2. Endoscopic findings

Table 2 presents the endoscopic findings for patients with aEE. The median total, inflammatory, and fibrostenotic scores of patients with aEE were 3 (IQR, 2 to 4), 2 (IQR, 2 to 3), and 0 (IQR, 0 to 1), respectively. The diffuse phenotype was dominant (71.4% vs 28.6%), with lesions located in the upper to lower thoracic esophagus in 46.4% of the patients with aEE. No significant differences in EoE endoscopic reference score, phenotype, location, and other endoscopic findings were observed between patients with aEE and those with EoE. No significant difference in reflux esophagitis was observed between the two groups, with only one patient in each showing an A or higher in the Los Angeles classification.

Table 2 . Endoscopic Findings.

VariablePatients with aEE (n=28)Patient with EoE (n=58)p-value
Endoscopic findings, EREFS
Longitudinal furrows/ridges, No. (%)23 (82.1)53 (91.4)0.283
Median score (IQR)1 (1–1)1 (1–1)
Esophageal rings, No. (%)12 (42.9)33 (56.9)0.490
Median score (IQR)0 (0–1)1 (0–1)
White exudates, No. (%)16 (57.1)35 (60.3)0.818
Median score (IQR)1 (0–1)1 (0–1)
Stricture, No. (%)03 (5.2)0.548
Median score (IQR)0 (0–0)0 (0–0)
Edema, No. (%)26 (92.9)26 (93.1)1.000
Median score (IQR)1 (1–1)1 (1–1)
Inflammatory score, median (IQR)2 (2–3)3 (2–3)0.601
Fibrostenotic score, median (IQR)0 (0–1)1 (0–1)0.276
Total score, median (IQR)3 (2–4)3 (2–4)0.357
Phenotype0.793
Localized type8 (28.6)14 (24.1)
Diffuse type20 (71.4)44 (75.9)
Location, No. (%)0.468
Ut-Lt13 (46.4)19 (32.8)
Mt-Lt9 (32.1)24 (41.4)
Lt6 (21.4)15 (25.9)
Other endoscopic findings, No. (%)
Atrophic gastritis5 (17.9)9 (15.5)0.765
Reflux esophagitis, No. (%)0.548
LA classification: N-M27 (96.4)57 (98.3)
LA classification: A-D1 (3.6)1 (1.7)
A/B/C/D1/0/0/00/1/0/0
Hiatus hernia18 (64.3)33 (56.9)0.641

aEE, asymptomatic esophageal eosinophilia; EoE, eosinophilic esophagitis; EREFS, eosinophilic esophagitis endoscopic reference score; IQR, interquartile range; LA, Los Angeles; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; Ut, upper thoracic esophagus..



3. Clinical course and long-term outcome

Fig. 2 illustrates the clinical course and long-term outcomes of the patients with aEE. The median follow-up duration was 64 months (IQR, 60 to 79.5 months). Among the 28 patients with aEE, seven were treated with PPIs or P-CABs and the remaining 21 opted for follow-up with no medication. Among the treated patients, six (85.7%) exhibited endoscopic and pathologic improvements. Furthermore, among the six patients who achieved improvement, a temporal discontinuation of medication was attempted in three (50%). However, the three patients experienced worsened endoscopic findings. Table 3 presents the characteristics of patients with aEE treated with PPI or P-CABs. Five patients were treated with esomeprazole 20 mg or 10 mg, one with vonoprazan 20 mg, and one with rabeprazole 10 mg. The findings were unchanged in one case treated with esomeprazole 20 mg. After the initial diagnosis of aEE, the patient was started on PPI and followed up with periodic upper gastrointestinal endoscopy. The patient’s background, endoscopic and pathological findings at the time of initial examination did not differ from those of other aEE patients. In addition, the patient was evaluated by high-resolution manometry (HRM) and was diagnosed as a normal study according to the Chicago classification, version 3.0. Although the findings did not improve with treatment, the PPI was subsequently discontinued because no symptoms were observed during long-term follow-up. Endoscopic findings after discontinuation showed no exacerbation, and the intraepithelial eosinophil infiltration showed 42 eosinophils/hpf, unchanged from the initial diagnosis.

Figure 2. Clinical course of the patients with aEE. Among the 28 patients with aEE, seven were treated with PPIs or P-CABs and the remaining 21 opted for follow-up without medication. Findings were improved in six of the seven treated cases, worsened in two of the 21 untreated cases, improved spontaneously in seven cases, and were unchanged in 12 cases. Symptoms developed in three of the 21 untreated patients. aEE, asymptomatic esophageal eosinophilia; PPI, proton pump inhibitor; P-CAB, potassium-competitive acid blocker.

Table 3 . Patients Treated with Proton Pump Inhibitor.

No.Age, yrSexObservation
period, mo
LocationPhenotypeEoEHSS
(total/full)
Eosinophil
infiltration, eos/hpf
MedicationEndoscopic
findings
Eosinophile infiltration
after medication, eos/hpf
157F79Mt-LtLocalized0.3830Esomeprazole 20 mgImproved0–2
250M68Mt-LtDiffuse0.3385Esomeprazole 10 mgImproved60
356M65Mt-LtDiffuse0.0470Vonoprazan 20 mgImproved0
464F69Ut-LtDiffuse0.3821Esomeprazole 20 mgImproved0–2
544M62Ut-LtDiffuse0.33261Esomeprazole 20 mgImproved15
644M64Ut-LtDiffuse0.3840Esomeprazole 10 mgImproved6
739M60Ut-LtDiffuse0.3360Esomeprazole 20 mgUnchanged120
858M60Ut-LtDiffuse0.2951Rabeprazole 10 mgImproved0–2

EoEHSS, eosinophilic esophagitis histologic scoring system; eos/hpf, eosinophils per high-power field; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; Ut, upper thoracic esophagus..



Among the cases followed up without medication, the findings worsened in two (9.5%), improved spontaneously in seven (33.3%), and were unchanged in 12 (57.1%). One of the two patients with worsened findings was treated with PPI, which improved the findings; however, the other patient became symptomatic and was subsequently started on PPI, but the findings remained unchanged. Conversely, symptoms developed in two of the seven (28.6%) patients whose findings remained unchanged after the initial diagnosis. In one patient, the findings remained unchanged despite initiating subsequent PPI medication, whereas in the other patients, the findings and symptoms improved spontaneously without any medication.

Supplementary Fig. 1 shows the clinical course of the patients with EoE. In five of the 58 patients diagnosed with EoE, follow-up with upper gastrointestinal endoscopy was lost after the initial diagnosis. For the remaining 53 patients, five were followed up with no treatment due to patient's request, 47 were treated with PPIs or P-CABs, and one was on the elimination dietary therapy. Eight of the 19 patients with EoE who had inadequate improvement on PPIs or P-CABs received the additional treatment with topical corticosteroid, seven of whom showed endoscopic and histological improvements. Of the five patients with EoE who were followed up without treatment, three had no significant changes, but two had spontaneous improvement in the endoscopic findings. Out of the 48 patients who underwent therapeutic intervention and were followed up long-term with endoscopy, 32 were reevaluated histologically. Twenty-two patients (68.8%) achieved an eosinophil infiltration of <15, and all but one showed improvement in symptoms.

4. Patients with symptoms

Table 4 outlines the patients with aEE who developed digestive symptoms related to esophageal dysfunction. Among the patients followed up without treatment, three (14.3%) developed symptoms (all males) at a mean time of 40 months. Symptoms developed in cases where endoscopic and pathologic findings remained unchanged or worsened during follow-up. In case number 1, esophageal wall thickness was assessed using endoscopic ultrasound (EUS), and esophageal motility was assessed using HRM at symptom onset. EUS revealed a thickening of the lower esophagus with a total wall thickness of 3.6 and 2.8 mm from the surface to the muscular layer. HRM indicated ineffective esophageal motility based on the Chicago classification, version 3.0. However, the endoscopic and pathologic findings at the initial diagnosis were not more characteristic than those in other cases.

Table 4 . Cases in Which Symptoms Developed.

No.Age, yrSexObservation period, moTime to symptom development, moLocationPhenotypeEoEHSS
(total/full)
Eosinophil
infiltration, eos/hpf
SymptomsFindings after
initial diagnosis
Medication after
symptom development
Findings after
medication
142M10843LtLocalized0.33100Dysphasia, food impactionWorsenedEsomeprazole 20 mgUnchanged
237M6759Ut-LtDiffuse0.6350Dysphasia, heartburnUnchangedEsomeprazole 20 mgUnchanged
380M6118LtLocalized0.3842HeartburnUnchangedNo-

EoEHSS, eosinophilic esophagitis histologic scoring system; eos/hpf, eosinophils per high-power field; Lt, lower thoracic esophagus; Ut, upper thoracic esophagus..


DISCUSSION

Currently, no well-defined standards of practice for aEE exist, leaving treatment decisions to the discretion of clinicians. This study investigated patients with aEE for over 5 years, providing valuable long-term insights into the natural course of aEE and the incidence of symptom development. These longitudinal data can provide guidance for clinical practice and treatment decisions. In addition, the study presents individual cases and the outcomes of different treatment approaches, reflecting real-world practices. This allows insights into the variations in disease presentations and treatment responses among patients. The similar immunohistological profile of aEE and EoE and the similar clinical findings, including endoscopic findings,12-14 suggest that they may represent a continuum of diseases primarily differing in their stages of progression. The clinical findings suggest that the symptom development is associated with a younger age at initial onset,20 and esophageal wall thickening, primarily in the mucosal layer.21,22 Histopathologic findings suggest that mast cells and their receptors, PAR-2 and VPAC-1, may contribute to symptom onset.23 In addition, no previous studies have investigated follow-ups exceeding 5 years; however, the rate of symptom development in aEE has been reported to be 20.7%–31.0%.13,20 In this study, 14.3% of the untreated patients developed symptoms, and one case evaluated using EUS and HRM showed esophageal wall thickening and dysmotility. However, no other characteristic basal clinical findings were observed in the symptomatic conversion cases because of the small sample size.

Some patients in this study showed symptoms without treatment, with one-third demonstrating spontaneous improvements in endoscopic and histopathological findings without treatment. This spontaneous improvement in findings may be inferred from the timing of antigen exposure or changes in the immune response of the hosts. This indicates that aEE does not necessarily require immediate treatment, and follow-up with no treatment, including endoscopy, may be acceptable.

Management and follow-up goals for aEE are to prevent progression to EoE and subsequent esophageal remodeling leading to stricture formation.24 This focus does not aim to improve the quality of life, as no associated symptoms exist. When treating with PPIs or P-CABs, the short-term goal is to improve endoscopic and pathological findings. Despite the limited studies on aEE, aEE has been reported to progress to EoE at a certain rate. Consequently, endoscopic follow-up at least once a year after initial diagnosis is recommended. Some studies suggest that aEE should be regarded as asymptomatic EoE, and follow-up, including target biopsy, should be performed as in EoE.25,26 In addition, given that the usefulness of measuring esophageal body compliance for EoE using an endoluminal functional lumen imaging probe (EndoFLIP) has been demonstrated recently,27 esophagrams and EndoFLIP, if available, should be used alongside conventional endoscopy to evaluate potential fibrosis. Furthermore, EUS and HRM may be useful to evaluate fibrosis and symptom development,21,22 and close endoscopic monitoring should be considered if these tests predict fibrosis progression. Conversely, the follow-up interval can be extended in patients with aEE showing no signs of esophageal fibrosis.

Previous studies on EoE have reported endoscopic improvement in 50.% to 61.8% of cases after therapeutic intervention with PPIs.28-30 In addition, it has been reported that 75% of patients with EoE who show resistance to a PPI therapy respond to P-CAB in a small number of cases, suggesting a possible benefit of the therapeutic effect of P-CAB.31 On the other hand, temporary exacerbations of disease during PPI administration and relapse after PPI discontinuation should be noted.32,33 Although studies on aEE are scarce, the response rate to PPI is reported to be very high at 90.5%,13 with 83.3% of patients improving with PPI treatment even after symptom development.20 The response to PPIs/P-CABs in this study was 85.7% and 58.3% for aEE and EoE, respectively, consistent with previous reports. P-CAB was used as an antacid for aEE in two cases, and endoscopic findings were improved in both cases. A total of five of the 28 patients with aEE, two with no treatment and three with PPI interruption, experienced worsened endoscopic findings, of whom four (80%) responded well to PPI treatment. This observation indicates a relatively benign course of aEE and suggests a low need for therapeutic intervention immediately after diagnosis as prevention of progression to EoE in asymptomatic patients. Considering that approximately one-third of aEE cases in this study spontaneously resolved, conducting a regular follow-up rather than treating empirically after initial diagnosis is appropriate. Although it is difficult to establish clear criteria for the timing of therapeutic intervention, it may not be too late to initiate treatment when the endoscopic findings worsen during the follow-up. However, therapeutic intervention should be considered when findings suggesting esophageal fibrosis or clinical symptoms emerge during follow-up with endoscopic monitoring.

Additionally, none of the treated cases in this study developed symptoms after at least 5 years of follow-up. However, discontinuing PPI treatment may lead to symptom relapse during the course of the disease,13 as observed in three patients. Therefore, once PPI treatment is initiated, deciding whether to continue or discontinue treatment for asymptomatic patients is challenging, and treatment selection should be tailored to individual cases.

This study had some limitations. First, it had a retrospective single-center design with a limited sample size. Therefore, we were unable to examine risk factors related to symptom progression, and statistical analysis of treatment efficacy was limited. The patient sample in this study was obtained from a single medical institution, potentially limiting geographical, racial, and cultural diversity. The findings of EoE are milder in Japan than in Western countries owing to the prevalence of endoscopy and racial differences.34,35 Thus, caution is required when generalizing the results, and a larger-scale prospective study is needed to verify our findings. Second, treatment options and decision criteria were subject to the discretion of the physician. This may have led to different patients receiving different treatments, potentially affecting the consistency of the results and causing the patient selection bias. Additionally, the follow-up methods and intervals between examinations of the patients varied owing to the lack of clear practice guidelines. Therefore, guidelines for diagnosis and treatment of aEE should be established alongside those for EoE in the future. Third, the presence or absence of symptoms was subjective, and no quantitative evaluation, such as questionnaires, was used. Given the importance of symptoms in patients with EoE, including asymptomatic cases, developing a symptom-scoring system for EoE may be beneficial.

In conclusion, this study provides insights into the natural course of aEE and the effects of PPI or P-CAB treatment. Treatments led to improvement in most cases; however, discontinuation resulted in worsening in some cases. Some patients with aEE had improved findings without treatment, whereas others developed symptoms, emphasizing the importance of long-term monitoring and individualized treatment decisions.

SUPPLEMENTARY MATERIALS

Supplementary materials can be accessed at https://doi.org/10.5009/gnl230398.

DATA AVAILABILITY STATEMENT

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Study concept and design: Y.S. Data acquisition: Y.S., Y.O., D.K., S.H. Data analysis and interpretation: Y.S., Y.O. Drafting of the manuscript: Y.S. Critical revision of the manuscript for important intellectual content: Y.S., D.K., M.K., K.O., S.H. Statistical analysis: Y.S. Approval of final manuscript: all authors.

Fig 1.

Figure 1.Patient flowchart. Among the 106 patients with EE, 48 were diagnosed with aEE and 58 with EoE. Twenty-eight patients with aEE were followed up for over 5 years with endoscopic monitoring. EE, esophageal eosinophilia; aEE, asymptomatic esophageal eosinophilia; EoE, eosinophilic esophagitis.
Gut and Liver 2024; :

Fig 2.

Figure 2.Clinical course of the patients with aEE. Among the 28 patients with aEE, seven were treated with PPIs or P-CABs and the remaining 21 opted for follow-up without medication. Findings were improved in six of the seven treated cases, worsened in two of the 21 untreated cases, improved spontaneously in seven cases, and were unchanged in 12 cases. Symptoms developed in three of the 21 untreated patients. aEE, asymptomatic esophageal eosinophilia; PPI, proton pump inhibitor; P-CAB, potassium-competitive acid blocker.
Gut and Liver 2024; :

Table 1 Characteristics of Patients and Lesions

CharacteristicPatients with aEE (n=28)Patients with EoE (n=58)p-value
Age, median (IQR), yr50 (42–57)47 (42–55)0.647
Sex, No. (%)0.534
Male25 (89.3)47 (81.0)
Female3 (10.7)11 (19.0)
Body mass index, median (IQR), kg/m224.4 (22.6–26.4)23.2 (21.6–26.0)0.109
Brinkman index, median (IQR)0 (0–100)0 (0–215)0.599
Daily alcohol consumption, No. (%)12 (42.9)31 (53.4)0.159
Concurrent allergic diseases, No. (%)13 (46.4)45 (77.6)0.002*
Allergic rhinitis6 (21.4)19 (32.8)
Bronchial asthma4 (14.3)13 (22.4)
Atopic dermatitis4 (14.3)10 (17.2)
Food or other allergies44 (14.3)13 (22.4)
Peripheral blood eosinophil, median (IQR),/μL300 (182–392)253 (179–417)0.841
Non-specific IgE, median (IQR), IU/mL113 (64–167)200 (80–646)0.237
Helicobacter pylori infection, No. (%)0.531
Current infection3 (10.7)4 (6.9)
Past infection3 (10.7)12 (20.7)
Negative infection22 (78.6)42 (72.4)
PEC, median (IQR), eos/hpf56 (42–81)51.5 (30–93)0.658
EoEHSS grade score, median (IQR)
Eosinophilic inflammation2 (2–3)2 (2–3)0.889
Basal cell hyperplasia3 (3–3)3 (2–3)0.339
Dilated intercellular spaces3 (3–3)3 (3–3)0.946
Lamina propria fibrosis2 (2–2)2 (1–2)0.182
Eosinophilic abscess0 (0–0)0 (0–1)0.368
Eosinophil surface layering0 (0–0)0 (0–0)0.252
Surface epithelial alteration0.5 (0–2)0 (0–2)0.151
Dyskeratotic epithelial cells0 (0–0)0 (0–0)0.427
Total score/full score0.35 (0.29–0.39)0.38 (0.29–0.46)0.159

aEE, asymptomatic esophageal eosinophilia; EoE, eosinophilic esophagitis; IQR, interquartile range; IgE, immunoglobulin E; PEC, peak eosinophil count; eos/hpf, eosinophils per high-power field; EoEHSS, eosinophilic esophagitis histologic scoring system.

*p<0.05; Duplicates counted.


Table 2 Endoscopic Findings

VariablePatients with aEE (n=28)Patient with EoE (n=58)p-value
Endoscopic findings, EREFS
Longitudinal furrows/ridges, No. (%)23 (82.1)53 (91.4)0.283
Median score (IQR)1 (1–1)1 (1–1)
Esophageal rings, No. (%)12 (42.9)33 (56.9)0.490
Median score (IQR)0 (0–1)1 (0–1)
White exudates, No. (%)16 (57.1)35 (60.3)0.818
Median score (IQR)1 (0–1)1 (0–1)
Stricture, No. (%)03 (5.2)0.548
Median score (IQR)0 (0–0)0 (0–0)
Edema, No. (%)26 (92.9)26 (93.1)1.000
Median score (IQR)1 (1–1)1 (1–1)
Inflammatory score, median (IQR)2 (2–3)3 (2–3)0.601
Fibrostenotic score, median (IQR)0 (0–1)1 (0–1)0.276
Total score, median (IQR)3 (2–4)3 (2–4)0.357
Phenotype0.793
Localized type8 (28.6)14 (24.1)
Diffuse type20 (71.4)44 (75.9)
Location, No. (%)0.468
Ut-Lt13 (46.4)19 (32.8)
Mt-Lt9 (32.1)24 (41.4)
Lt6 (21.4)15 (25.9)
Other endoscopic findings, No. (%)
Atrophic gastritis5 (17.9)9 (15.5)0.765
Reflux esophagitis, No. (%)0.548
LA classification: N-M27 (96.4)57 (98.3)
LA classification: A-D1 (3.6)1 (1.7)
A/B/C/D1/0/0/00/1/0/0
Hiatus hernia18 (64.3)33 (56.9)0.641

aEE, asymptomatic esophageal eosinophilia; EoE, eosinophilic esophagitis; EREFS, eosinophilic esophagitis endoscopic reference score; IQR, interquartile range; LA, Los Angeles; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; Ut, upper thoracic esophagus.


Table 3 Patients Treated with Proton Pump Inhibitor

No.Age, yrSexObservation
period, mo
LocationPhenotypeEoEHSS
(total/full)
Eosinophil
infiltration, eos/hpf
MedicationEndoscopic
findings
Eosinophile infiltration
after medication, eos/hpf
157F79Mt-LtLocalized0.3830Esomeprazole 20 mgImproved0–2
250M68Mt-LtDiffuse0.3385Esomeprazole 10 mgImproved60
356M65Mt-LtDiffuse0.0470Vonoprazan 20 mgImproved0
464F69Ut-LtDiffuse0.3821Esomeprazole 20 mgImproved0–2
544M62Ut-LtDiffuse0.33261Esomeprazole 20 mgImproved15
644M64Ut-LtDiffuse0.3840Esomeprazole 10 mgImproved6
739M60Ut-LtDiffuse0.3360Esomeprazole 20 mgUnchanged120
858M60Ut-LtDiffuse0.2951Rabeprazole 10 mgImproved0–2

EoEHSS, eosinophilic esophagitis histologic scoring system; eos/hpf, eosinophils per high-power field; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; Ut, upper thoracic esophagus.


Table 4 Cases in Which Symptoms Developed

No.Age, yrSexObservation period, moTime to symptom development, moLocationPhenotypeEoEHSS
(total/full)
Eosinophil
infiltration, eos/hpf
SymptomsFindings after
initial diagnosis
Medication after
symptom development
Findings after
medication
142M10843LtLocalized0.33100Dysphasia, food impactionWorsenedEsomeprazole 20 mgUnchanged
237M6759Ut-LtDiffuse0.6350Dysphasia, heartburnUnchangedEsomeprazole 20 mgUnchanged
380M6118LtLocalized0.3842HeartburnUnchangedNo-

EoEHSS, eosinophilic esophagitis histologic scoring system; eos/hpf, eosinophils per high-power field; Lt, lower thoracic esophagus; Ut, upper thoracic esophagus.


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Vol.18 No.3
May, 2024

pISSN 1976-2283
eISSN 2005-1212

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