Introduction
Eosinophilic esophagitis (EoE) is a clinicopathologic diagnosis requiring the integration of three criteria: symptoms of esophageal dysfunction, at least 15 eosinophils per high-power field (eos/HPF) on esophageal biopsy, and exclusion of non-EoE disorders that cause or potentially contribute to esophageal eosinophilia.1 In adolescents and adults, dysphagia and food impaction are the most common presenting symptoms, although heartburn and chest pain may also be present; notably, patients frequently adopt food avoidance and modification behaviors to minimize dysphagia, which can lead to significant diagnostic delays.1 Endoscopic evaluation is central to diagnosis, with typical findings including edema, fixed esophageal rings, white exudates, linear furrows, and strictures, systematically characterized using the EoE Endoscopic Reference Score; however, these findings are not pathognomonic and do not constitute formal diagnostic criteria.1 Because EoE is a patchy disease histologically, at least 6 biopsies from at least 2 esophageal levels are recommended, as fewer biopsies risk missing the diagnosis; with 6 or more biopsies, diagnostic sensitivity approaches 100%.1 The sole required histologic criterion remains the peak eosinophil count. However, additional features assessed by the EoE Histologic Scoring System, including basal zone hyperplasia, eosinophilic microabscesses, spongiosis, and eosinophil degranulation, are increasingly recognized as clinically relevant, as persistent basal zone hyperplasia and lamina propria fibrosis have been associated with ongoing symptoms even when eosinophil counts decline.1 Although the etiology of EoE remains to be fully elucidated, genetic, immune, and environmental factors have been associated with its pathogenesis. If left untreated, chronic inflammation can lead to esophageal remodeling, strictures, and perforation.2
The prevalence of EoE has been steadily increasing since it was first described in the 1990s.3 A recent multi-database analysis estimates a 5-fold increase in the prevalence of EoE since 2009. When standardized to the U.S. population, the prevalence rate is estimated at 142.5 cases per 100,000 people (approximately 1 in 700), or an estimated total of 472,380 cases.4 While the drivers of this increase remain incompletely understood, improved socioeconomic conditions and hygiene, which reduce early microbial exposure and promote atopic sensitization, are often cited.5
Within this context, the role of the gastric microbiome, specifically Helicobacter pylori, in EoE remains a subject of significant debate. Given the parallel rising prevalence of EoE and decreasing prevalence of H. pylori infection over the past two decades,6 some epidemiological studies have proposed an inverse association between H. pylori and atopy, allergy, and asthma, suggesting that H. pylori colonization may protect against atopy-associated conditions such as EoE via systemic immune modulation.5,7 However, clinical data are conflicting, including a systematic review that concluded that H. pylori merely functions as a biomarker for poor household hygiene and failed to demonstrate any protective effect against atopic and allergic conditions.8 Regarding EoE specifically, large multicenter studies have also found no protective effect.9
A critical gap in the literature further compounds this controversy: there are very limited data concerning the clinicopathologic features of EoE in the setting of gastric H. pylori infection. As a result, the specific clinicopathologic characteristics and therapeutic outcomes of patients with concurrent gastric H. pylori infection and EoE remain poorly defined. This study aimed to address this gap by retrospectively analyzing a cohort of patients with concurrent H. pylori infection and EoE at a single center.
Materials and methods
Study design and ethical approval
This single-center retrospective cohort study included esophageal and gastric biopsy specimens obtained between January 1, 2022, and December 30, 2025, at the University of South Alabama University Hospital, Mobile, Alabama. The study was conducted in accordance with the Declaration of Helsinki and was approved by the University of South Alabama Institutional Review Board (IRB Protocol No. 26-074). The requirement for informed consent was waived by the IRB because of the retrospective nature of the study and the use of existing, de-identified clinical pathology data. The study was reported in accordance with STROBE.
Case identification and selection
Cases were identified by searching for patients with esophageal eosinophilia on esophageal biopsy and/or H. pylori infection on gastric biopsy. Patients with a history of prior H. pylori eradication therapy (HPE) were excluded. Cases of eosinophilic gastrointestinal disease were also excluded. This was defined as the presence of gastrointestinal symptoms associated with pathologic eosinophilic infiltration of >20 eos/HPF in the gastrointestinal tract.
Histopathologic evaluation
All available hematoxylin and eosin- and immunohistochemistry-stained slides from eligible cases were independently re-reviewed by WX and JZ, who were blinded to the patients’ clinical outcomes and follow-up data. Any discrepancies were resolved by joint review and consensus. The current diagnostic criteria for EoE, defined by esophageal dysfunction and the presence of ≥15 eos/HPF in esophageal biopsy specimens, were used for the study. At least 6 esophageal biopsies were obtained from at least two different esophageal levels (typically proximal/mid and distal esophagus). Peak eosinophil count was assessed in the area of greatest eosinophil density. H. pylori infection was confirmed when organisms were identified on hematoxylin and eosin sections and detected by immunohistochemistry staining.
Clinical data collection and outcome assessment
Demographic, clinical, and histopathologic data were extracted from the electronic medical record. Clinical parameters reviewed included age, sex, presenting symptoms, concurrent atopic diseases, laboratory findings, endoscopic findings, and the extent of gastrointestinal involvement. Treatment regimens and clinical outcomes were also reviewed. Information regarding the use of medications that could interfere with H. pylori detection, including proton pump inhibitors (PPIs) and antibiotics, was carefully documented. Outcomes were assessed based on histologic response at follow-up biopsy, defined as resolution of esophageal eosinophilia (≤5 eos/HPF in adults and 0 eos/HPF in children) and clearance of H. pylori infection.
Statistical analysis
Descriptive statistics were used to characterize the cohort. Categorical variables were summarized as frequencies and percentages. The prevalence of EoE, gastric H. pylori infection, and concurrent disease was calculated with corresponding 95% confidence intervals (CIs). The association between EoE and gastric H. pylori infection was evaluated using a two-tailed Fisher’s exact test. Odds ratios (ORs) with 95% CIs were calculated to estimate the strength of association. A two-sided P-value < 0.05 was considered statistically significant.
Results
Patients were identified through the electronic medical record system (Fig. 1). Among 5,443 patients undergoing concurrent esophageal and gastric biopsy evaluation, 197 (3.6%, 95% CI, 3.1–4.1%) met the diagnostic criteria for EoE, and 286 (5.3%, 95% CI, 4.7–5.9%) had gastric H. pylori infection. Twenty-eight patients with concurrent EoE and gastric H. pylori infection were initially identified, corresponding to an H. pylori prevalence of 14.2% (28/197) among patients with EoE. A significant association was identified between EoE and H. pylori infection (odds ratio, 3.20; 95% CI, 2.11–4.87; Fisher’s exact test, P < 0.001) (Table 1). After exclusion of 1 patient with eosinophilic gastrointestinal disease and 3 patients with prior H. pylori treatment, 24 patients met the study inclusion criteria for the subsequent clinicopathologic analysis.
| Variable | Estimate | 95% CI |
|---|
| EoE prevalence | 197/5443 = 3.6% | 3.1–4.1% |
| H. pylori prevalence | 286/5443 = 5.3% | 4.7–5.9% |
| H. pylori among EoE patients | 28/197 = 14.2% | 10–19.8% |
| Concurrent EoE and H. pylori | 28/5443 = 0.51% | 0.34–0.74% |
| Association between EoE and H. pylori | OR = 3.20 | 2.11–4.87 |
The clinical characteristics of patients with concurrent EoE and H. pylori infection are summarized in Table 2. The cohort consisted of 24 patients with a marked male predominance (male-to-female ratio, 7:1) and a mean age of 29.5 years (range, 8-82 years). Eight patients (33%) were pediatric (<18 years). The most common presenting symptoms were abdominal pain in children and dysphagia in adults, accounting for 75% (n = 18) of cases overall. Obesity and atopic diseases were documented in 6 (25%) and 7 (29%) patients, respectively.
| Features | n (%) |
|---|
| Age (mean, median, range) (y) | 29.5, 23, 8–82 |
| Children (age <18 y) | 8 (33%) |
| Male | 21 (87.5%) |
| Obesity | 6 (25%) |
| Atopic disorders | 7 (29%) |
| Esophagogastroduodenoscopy indication | |
| Dysphagia | 13 (54%) |
| Abdominal pain/dyspepsia | 5 (21%) |
| Heartburn | 2 (8%) |
| Others | 4 (17%) |
| Endoscopic abnormality | 19 (79%) |
| Peak eosinophil count (/HPF) | |
| 15–40 | 16 (67%) |
| 45–80 | 6 (25%) |
| 85–105 | 1 (4%) |
| 110–200 | 1 (4%) |
| PPI as first-line treatment | 24 (100%) |
| HPE regimen | 13 (54%) |
| Steroid use | 8 (33%) |
| Candida infection | 2 (20%)* |
| Resolution rate (H. pylori-, EoE-) | 3 (30%)* |
Endoscopic findings frequently included linear furrows, esophageal rings, stricture, and edema, with at least one of these features observed in approximately 80% (n = 19) of cases. Histologically, all cases demonstrated eosinophil degranulation and dilated intercellular spaces within the esophageal squamous epithelium. Additional features included basal cell hyperplasia, elongation of lamina propria papillae, and lamina propria fibrosis. Five cases (21%) showed dense eosinophilic infiltration with superficial layering and eosinophilic microabscess formation, consistent with classic EoE. In contrast, the remaining 19 cases (79%) demonstrated lower eosinophil density with a relatively even distribution throughout the squamous epithelium, representing a distinct, nonclassic histologic pattern observed in the setting of H. pylori infection (Fig. 2).
All pediatric patients in this cohort were educated on an elimination diet. PPI therapy was used as first-line treatment in all patients. Overall treatment regimens included HPE alone (n = 7, 29%), PPI therapy alone (n = 9, 37.5%), HPE combined with corticosteroids (n = 6, 25%), and PPI combined with corticosteroids (n = 2, 8%). HPE therapy in this cohort primarily consisted of standard bismuth-based quadruple regimens (PPI, bismuth, tetracycline, and metronidazole) or clarithromycin-based triple therapy (PPI, amoxicillin, and clarithromycin), administered for 14 days. Follow-up data were available for 10 patients: 3 (30%) achieved histologic resolution of both H. pylori infection and EoE following HPE with or without corticosteroids. Five (50%) patients had persistent H. pylori infection with persistent or relapsing EoE; notably, 3 of these belonged to the nonclassic group and did not receive HPE. Two (20%) patients became H. pylori-negative but had persistent EoE; both were treated with PPI alone and had a single follow-up. Fungal infection developed in 2 of 4 patients (50%) treated with combined HPE and corticosteroids (Fig. 3). One additional patient underwent a single follow-up with gastric biopsy only (without a concurrent esophageal biopsy) and was therefore excluded from the follow-up outcome analysis, which required assessment of both H. pylori infection and EoE status.
Discussion
EoE is considered an immune-mediated disease characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa (≥15 eos/HPF), with exclusion of other causes of eosinophilia. Like many immunologic entities, the exact etiology of EoE remains unknown, and it is believed to be secondary to a combination of environmental triggers (food, medication, infection, etc.), genetic predisposition, and host immune response. Whether H. pylori infection represents one such trigger has not been well characterized. This retrospective cohort study describes the clinicopathologic characteristics and treatment outcomes of patients with EoE and concurrent gastric H. pylori infection. Our findings suggest that H. pylori infection may be associated with a subset of EoE that, histologically, tends to differ slightly from classic EoE and is characterized by lower eosinophil density and a relatively even distribution of eosinophils within the squamous epithelium. This H. pylori-associated EoE might also respond to targeted eradication therapy.
The most recent meta-analysis reported a prevalence of H. pylori infection among patients with EoE ranging from 1.6% to 37.4%, with an overall prevalence of 5.03%.10 The 14.2% observed in our cohort falls within this range. While some studies have proposed an inverse association, suggesting that H. pylori may exert a protective effect on EoE,5 others have attributed this relationship to coincidental divergence in disease trends or confounding factors such as socioeconomic status and hygiene, rather than a true biologic effect.6,9 The significant association observed in our cohort supports a close relationship between these conditions. However, rather than demonstrating a protective effect, our findings, particularly the predominance of nonclassic histologic features in 79% of cases, raise the possibility of a pathogen-associated mechanism of esophageal eosinophilia that is distinct from classic immune-mediated EoE.11 To our knowledge, the predominance of this nonclassic histologic pattern in patients with concurrent gastric H. pylori infection has not been previously described.
Similarly, H. pylori has previously been reported in association with symptomatic eosinophilic gastritis and hypereosinophilia, both of which have been reported to resolve completely with eradication therapy alone.12,13 These observations provide a plausible mechanism by which chronic H. pylori infection may potentiate eosinophilic inflammation in susceptible individuals.14 Interestingly, H. pylori eradication has also been associated with improvement or resolution of chronic urticaria, a separate non-IgE-mediated allergic condition, with anti-H. pylori IgG levels being significantly elevated in affected patients compared with controls.15 While the mechanisms may differ, these observations suggest that H. pylori can modulate immune pathways across non-IgE-mediated allergic conditions. EoE is widely considered an atopic disease based on evidence from animal models, genetic studies, the frequency of comorbid allergic disorders, and the clinical efficacy of elimination diets.8 However, evidence suggests that EoE is not primarily IgE-mediated but rather represents a Th2-mediated immune response in which interleukin (IL)-4, IL-5, and IL-13 induce expression of eotaxin-3, a potent chemokine responsible for eosinophil migration and activation.16 Activated eosinophils subsequently release additional factors such as transforming growth factor-beta, which contributes to chronic injury and fibrostenotic remodeling of the epithelium.17,18
Treatment outcomes in our cohort further support this proposed mechanism. Among patients achieving H. pylori eradication, several demonstrated concurrent resolution of EoE, whereas persistent H. pylori infection was associated with relapsing or refractory EoE. A clinically notable finding was the development of fungal infection in 2 of 4 patients treated with corticosteroids. Although esophageal candidiasis is a recognized complication of topical steroid therapy in EoE,19,20 the relatively high frequency observed in this small cohort raises the possibility that concurrent mucosal inflammation, epithelial barrier dysfunction, or immune alterations associated with H. pylori infection may contribute to susceptibility in some patients.21 We propose, in these cases, targeted HPE as the primary treatment approach and reserve steroids for persistent eosinophilia after confirmed H. pylori eradication. Of note, the entire cohort was treated first-line with PPI alone or as a component of other regimens, which is in line with current international consensus guidelines for EoE management; the potential confounding effect of PPI therapy on esophageal eosinophilia cannot be excluded.22,23 Moreover, Okimoto et al.24 reported that more than 60% of patients who discontinued PPI therapy experienced recurrence of symptoms and/or esophageal eosinophilia. It is plausible that persistent gastric H. pylori infection may contribute to EoE persistence or recurrence in a subset of these patients.
Although our findings raise the possibility of a pathogen-associated pattern of EoE in the setting of gastric H. pylori infection, this proposed mechanism remains speculative. H. pylori infection is known to promote chronic mucosal inflammation through activation of innate and adaptive immune pathways, including Th1-, Th17-, and epithelial-derived cytokine responses.25 These immune effects may alter epithelial barrier function, antigen presentation, and downstream inflammatory signaling.26 Such immune modulation could theoretically influence esophageal inflammation by affecting type 2 immune pathways, eosinophil recruitment, or epithelial barrier integrity.11,26 However, H. pylori is also known to exert complex and sometimes opposing effects on host immunity.14 Due to the small cohort size and observational nature of this study, our findings should not be interpreted as proof of causality but rather as hypothesis-generating evidence that gastric H. pylori infection might contribute to eosinophilic esophageal inflammation in a subset of patients. Future prospective studies incorporating cytokine profiling, tissue-based immune markers, microbiome analysis, and standardized post-eradication follow-up are needed to clarify whether this association reflects a true pathogen-driven mechanism.
The relationship among EoE, gastroesophageal reflux disease (GERD), and PPI-responsive esophageal eosinophilia remains complex and incompletely understood.16 Contemporary guidelines recognize substantial overlap among these entities, and PPI responsiveness is no longer considered sufficient to exclude a diagnosis of EoE.1 Because objective reflux testing was not routinely performed and PPI therapy was administered as first-line treatment in all patients, the independent contribution of GERD and acid suppression cannot be fully determined. Consequently, PPI-responsive esophageal eosinophilia and reflux-associated eosinophilia cannot be completely excluded in some cases. However, all patients had symptoms of esophageal dysfunction, endoscopic findings typical of EoE (furrows, rings, or strictures), and peak eosinophil counts ≥15 eos/HPF, and the majority demonstrated additional histologic features characteristic of EoE, including eosinophil degranulation, basal zone hyperplasia, and lamina propria fibrosis. Therefore, while PPI therapy and GERD may have contributed to esophageal eosinophilia in a subset of patients,27 they are unlikely to fully account for the clinicopathologic patterns observed in this cohort.
Limitations
We acknowledge several limitations of this study. First, this is a single-center study with a limited number of cases, and a relatively high rate of loss to follow-up was observed, suggesting that this condition may be underrecognized or not consistently managed in routine clinical practice. Unfortunately, as this was a retrospective study, the specific reasons for loss to follow-up could not be reliably determined from the medical records. Possible explanations include transfer of care, failure to return for scheduled follow-up, symptom resolution, or care received outside our health care system. Furthermore, the relatively small cohort, wide age range, and limited follow-up constrain the interpretation of treatment response and long-term clinical outcomes. Therefore, analysis for potential confounding using multivariable regression was not performed. Second, some may argue that the nonclassic cases represent reflux-associated eosinophilia. In our opinion, these entities are not mutually exclusive, and it may not be feasible to fully distinguish them in routine clinical practice. Supporting this, the LOTUS trial included 1.8% (9 of 512) of GERD patients with EoE-type pathology at baseline.28 O’Connor has further suggested that the increasing prevalence of EoE may be partially driven by elevated gastric acid secretion associated with the rising prevalence of GERD.29 Third, we strictly adhered to the ≥15 eos/HPF threshold for EoE diagnosis, which may have excluded cases with EoE morphologic features but lower eosinophil counts. In practice, repeat biopsy may be warranted in such cases given the patchy distribution of eosinophilic infiltration in EoE.30,31 Finally, as this study focuses on patients with concurrent diseases, direct comparison with EoE patients without H. pylori infection was not contributory and thus was not performed.
Conclusions
Our findings identify gastric H. pylori infection as a potential contributor in a subset of patients with EoE and describe a distinctive clinicopathologic pattern characterized by relatively lower eosinophil counts and a more uniform distribution of eosinophilic inflammation. Although confirmation in larger prospective studies is warranted, this study expands the current understanding of EoE and highlights a potentially underrecognized, clinically relevant subtype associated with H. pylori infection.
Declarations
Acknowledgments
Prior Presentation: This study was presented in abstract form at the United States and Canadian Academy of Pathology (USCAP) Annual Meeting, San Antonio, Texas, March 2026, and published in the Laboratory Investigation abstract supplement.
Funding
This research did not receive any funding from public, commercial, or not-for-profit sectors.
Conflict of interest
WX is a member of the Editorial Board of the Journal of Clinical and Translational Pathology. Other authors have no conflict of interest related to this publication.
Author contributions
Writing – review & editing (JZ, KJJ, WX), writing – original draft (JZ, KJJ, WX), methodology (JZ, WX), formal analysis (JZ, WX), data curation (JZ), conceptualization (JZ, WX), resources (WX), investigation (WX), and supervision (WX). All authors have approved the final version and publication of the manuscript.
Ethical statement
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2024). Ethical approval was obtained from the Institutional Review Board of the University of South Alabama (IRB Protocol No. 26-074). The requirement for informed consent was waived by the IRB because of the retrospective nature of the study and the use of existing, de-identified clinical pathology data.
Data sharing statement
The datasets generated and analyzed during the current study are not publicly available because they contain protected health information and are subject to institutional review board and privacy restrictions. De-identified data may be made available from the corresponding author upon reasonable request and with appropriate institutional approval.