Coexistence of gastroesophageal reflux and eosinophilic esophagitis in a single patient: case report

Introduction

The relationship between two commonly encountered esophageal pathologies, gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE) is a complex one that has gone through a series of modifications since EoE was first recognized as a distinct clinical entity (1). While GERD is usually, but not always, associated with reflux of gastric acid, the role of acid related esophageal changes in EoE has evolved over time. The original EoE guidelines, published in 2007, described the disorder as presenting with symptoms such as food impaction and dysphagia in adults, as well as feeding intolerance and GERD-like symptoms in children. It was characterized by esophageal pathology that either showed normal pH studies or did not respond to high-dose proton pump inhibitor (PPI) therapy (2). These guidelines included the need to exclude conditions with similar clinical, histological, or endoscopic features. In keeping with the predominant feeling at that time, it emphasized the necessity of excluding GERD.

In 2011, after additional information was available, an updated consensus recognized a subset of EoE as a novel disease phenotype, proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), which was distinguished from the majority of EoE (3). In 2018, a third consensus group, AGREE (A working Group on PPI-REE), reversed course. PPI-REE was considered a subgroup of EoE, defined by those who responded to acid suppression with resolution of both symptoms and eosinophilia (4). This unified perspective of EoE was supported by data showing that tissue from patients with EoE and PPI-REE shared the same active EoE transcriptome (5).

A number of publications have supported the position that GERD and EoE are distinct entities. One mini review recently concluded that erosive esophagitis and/or Barrett esophagus are exclusively seen in patients with GERD (6). Another recent review article also stated that erosive esophagitis is distinct from EoE (7). However, in clinical practice there are patients in which the diagnosis is less clear cut. The following presentation illustrates how the clinical, endoscopic and histologic characteristics of esophageal disease in a single patient may encompass features of both GERD and EoE at different times. Optimal therapy for these patients should therefore be directed at both conditions. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2024-620/rc).

Case presentation

A patient was referred for consultation at age 13 years, because of dysphagia and heartburn symptoms. Past medical history revealed that as an infant he experienced reflux and cow milk protein intolerance, that was addressed with a hydrolyzed cow milk formula. Shortly after a year of age, regular milk was reintroduced. He had no esophageal/swallowing/feeding issues until 6–7 months prior to the initial office visit, when he began to have the sensation of food getting stuck. Despite this complaint, he had no emesis and had been gaining weight. There was a strong past medical history of atopy. He had positive skin testing for cashews, pistachio, and hazelnuts and positive ImmunoCAP for sheep and goats’ milk, hazelnut, cashew, and almond. He also had a previous history of rhinitis that resolved after 4 years of immunotherapy for grass, trees, ragweed, and dust mites. In addition, an otolaryngologist had previously started him on Pepcid 20 milligrams (mg) BID (twice daily) for “reflux pharyngitis”. Family history was significant for his father having significant gastroesophageal reflux (GER), requiring acid suppression for years. He was recommended to begin a trial of PPI, but when the insurance denied paying for an over-the-counter medicine and the pharmacist told mom it would hurt his kidneys, this medicine was not started. A more extensive ImmunoCAP panel confirmed the previous sensitivities and was also positive for peanut, beta-lactoglobulin, casein, and sesame. His peripheral eosinophil per cent was 6.6% but his absolute eosinophil count was 450 cells/µL (microliter). Because of persistent emesis, PPI 20 mg was ultimately started and he was advised to stop having the 4–5 portions of dairy he was taking on a weekly basis. Physical exam revealed a well-developed, well-nourished young man with a normal exam aside from mild to moderate epigastric and subxiphoid pain. One month later he had his first endoscopy (see Table 1).

The initial endoscopy, at 13 years (y) 10 months (m) revealed a hiatal hernia (Figure 1), moderate to severe features of esophagitis including edema, irregular mucosa and multiple linear erosions limited to the distal 7 cm (Figure 2). The distal edema was the only positive finding in the Eosinophilic Esophagitis Endoscopic Reference Score (EREFS; EREFS =1) feature present. His distal esophagus had up to 14 eosinophils per high power field (hpf) but, because of peripapillary lymphocytes and superficial squamous sloughing, the findings were considered more suggestive of GERD than EoE. Also consistent with GERD was the mid-esophagus, which was histologically unremarkable save a rare eosinophil (0–1 eosinophil/hpf). Given these findings, the PPI was increased to 20 mg BID (first row in Table 1). However, the allergist suggested stricter adherence to dietary restrictions instead, and the PPI was continued at 20 mg once daily for several months and then discontinued. One month later he had a follow-up esophagogastroduodenoscopy (second row in Table 1), age 14 y 2 m. The endoscopic impression was EoE with marked edema, scattered microabscesses, and subtle furrowing mainly limited to the distal esophagus, yielding an EREFS of 3 (Figure 3). Biopsies revealed 20, 50, and 20 eosinophils/hpf in distal, mid, and proximal esophagus, respectively, as well as other features most consistent with EoE (Figure 4).

Figure 1 Hiatal hernia (salmon colored gastric mucosa above the lower esophageal sphincter) was noted during endoscopy.

Figure 2 Distal esophageal erosions in the absence of any endoscopic features found in eosinophilic esophagitis aside from edema.

Figure 3 Endoscopic images from distal esophagus demonstrating features of eosinophilic esophagitis. The arrows are pointing to microabscesses also referred to as exudates. The dots are illustrating furrows, sometimes referred to as railroad tracks. The star is in one of several areas featuring edema, or lack of vascular markings. Each of these features would be assigned a value of one point in the standardized Eosinophilic Esophagitis Endoscopic Reference Score to yield a score of 3.

Figure 4 Esophageal biopsy specimens showing histologic features suggestive of eosinophilic esophagitis. (A) Mid esophageal tissue shows basal cell hyperplasia and an increased number of intraepithelial eosinophils are noted (H&E staining, ×400 magnification). (B) Dilated intracellular spaces and surface epithelial alteration were present in a different portion of the mid esophagus, with dark pink cytoplasm signaling aberrant “keratinization” at the surface (H&E staining, ×400 magnification). (C) The proximal esophageal specimen showed prominent lamina propria fibrosis with thick pink bands of sclerosis (H&E staining, ×400 magnification). H&E, hematoxylin and eosin.

As the patient had been on PPI therapy and dietary exclusion for 18 months (see Table 1) with ongoing dysphagia, and worsening of the eosinophilia throughout his esophagus, he was considered refractory to those modalities. After discussion and education of the family it was decided to introduce dupixent 2 milliliters (mL) (300 mg) subcutaneously each week. Because of the presence of GERD features, PPIs were also restarted at 40 mg daily. As the parents were quite concerned about the long-term effects of PPI, once his swallowing normalized and his heart burn symptoms resolved, his PPI was lowered to 20 mg daily. He had a single episode of food impaction in school and a teacher gave him a Heimlich maneuver. He was drinking additional water with meals and eating slower than his peers, but there were no additional episodes of impaction nor other manifestations of dysphagia. Five months later there was ongoing clinical improvement without any notable symptoms of dysphagia, pain, or emesis. In school, he felt he was capable of eating as fast as the other students. The follow-up endoscopy performed at 14 y 5 m (third row in the Table 1), after 5 months on the dupixent and 20 mg PPI, revealed several discrete erosions in the distal esophagus, the longest one being 8 mm as determined by comparison to the open forceps, and EREFS was 0. Biopsies revealed 10 eosinophils in the distal esophagus with ancillary histopathologic features, such as elongated vascular papillae and the absence of basal cell hyperplasia, more suggestive of reflux. The mid and proximal esophagus had normal histology without any eosinophilia (Figure 4). The medicines were continued as is, with ongoing monitoring of his symptoms. He continued to feel some chest pain, almost once per week. It occurred in school, and in the evening, but did not wake him up from sleeping. He also had a bad taste in his mouth and throat clearing but no triggers could be identified for any of these symptoms.

In June 2024, after being on the dupixent for more than 10 months, he had a significant reaction after an injection that included pain in thigh where he had received the injection site, difficulty walking, and emesis. After missing a day of school, he returned to baseline, and he was seen for a follow-up. He had a normal exam. History revealed that he may have been dehydrated as he was training with an advanced degree martial arts routine multiple times per week and the weather was quite hot. He was restarted at half dose, 150 mg dupixent, told to pay more attention to oral rehydration, and has tolerated subsequent doses without further issues.

To evaluate further the efficacy of the lower dose of dupixent, a repeat endoscopy (fourth row in the Table 1) was performed several months later on 150 mg dose along with 20 mg PPI, at 15 y 2 m. There were multiple 3 and 4 mm erosions noted in the distal esophagus. EREFS was 1 for edema, which was limited to the distal esophagus. The biopsy specimens from the distal esophagus showed ulcer debris and other features of reflux, including peripapillary edema and lymphocytes with only rare eosinophils (2/hpf). The biopsy specimen from the proximal esophagus was histologically unremarkable. The mid esophageal biopsy, however, showed patchy basal cell hyperplasia, edema, and persistence of scattered eosinophils (2/hpf), suggestive of an overlap between distal reflux and proximal EoE in remission (Figure 5). The plan was to remain on the lowered dose of dupixent and attempt to slowly wean him off of the acid suppression, as the family remained concerned about the long-term impact of prolonged PPI. The plan included more stringent adherence to dietary restrictions and to ancillary reflux measures and the introduction of histamine 2 (H2) receptor antagonists and alginate. The patient himself is now tolerating the pharmacologic interventions without any issues and has remained virtually asymptomatic and satisfied with the plan.

Figure 5 Esophageal biopsies after dupixent highlight reflux esophageal changes (hematoxylin and eosin, ×400 magnification). (A) Distal esophageal tissue contains “reflux-type” changes, including frank ulcer debris. (B) A second section from the distal esophagus showed very mild peripapillary edema with scattered lymphocytes. (C) Portions of the mid esophageal biopsies include histologically unremarkable fragments of squamous epithelium. (D) Other mid esophageal tissue fragments show patchy features more consistent with eosinophilic esophagitis in remission, including mild basal cell hyperplasia and intraepithelial edema with the persistence of scattered eosinophils (2/hpf). hpf, high power field.

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient’s parent prior to every procedure which was performed with the acknowledgment that they were participating in an IRB approved research protocol. The parents have seen this manuscript and have provided verbal consent for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This adolescent had endoscopies which fulfilled the criteria of EoE by having increased eosinophils in his proximal and mid esophagus, an elevated EREFS score, as well as the characteristic symptom, dysphagia. That diagnosis was supported by a strong history of atopy having had cow milk protein intolerance as an infant, nasal rhinitis requiring immunotherapy for years, and positive allergens by ImmunoCAP and skin testing. His most dramatic esophageal histologic findings were seen after he stopped taking the PPI, so that he would be characterized as PPI-REE. He also has a profile that strongly supports a diagnosis of GERD with persistent pathology in the form of erosions limited to the distal esophagus without any eosinophils, the presence of a hiatal hernia, classical GERD symptoms, and a strong family history of a father who has required prolonged acid suppression. Histology from the erosion noted in the most recent endoscopy revealed severe acute and chronic inflammation in the ulcer bed with acutely inflamed granulation tissue. Long term management will be challenging as his symptoms and endoscopic/histologic features support aggressive medical therapy while the potential impact of decades of acid suppression must also be considered. In summary, this young man had esophageal pathologies at different times which would individually be conclusively consistent with either EoE or GERD. A recent comprehensive review substantiates the nuances of this relationship. While seeking to identify pharmacogenetic characteristics that could predict which EoE patients would respond to PPI, the authors concluded that whether an individual patient would respond to PPI depends on a number of different clinical, molecular, environmental, dietary, and genetic factors. Furthermore, as of this time, there is no integrative model that would enable an accurate prediction (8).

The existence of both diseases in the same patient also provides some insight into their respective mechanisms and their relationship(s) with each other. Part of the evolving characterization and recommendations regarding acid suppression in EoE may be related to the observations that PPIs in EoE may not simply work by suppressing acid secretion but may also impact immune function by restoring the integrity of the epithelial barrier (9). One small study has demonstrated that PPI could only reverse the barrier integrity defect in EoE patients who are PPI-REE (10).

A number of publications have attempted to define the relationship between GERD and EoE, often by trying to establish distinguishing characteristics. The observation that positive food allergy testing and increased environmental allergens predicted a lower likelihood of histologic response to PPI in EoE was interpreted to suggest that an allergic phenotype of EoE that may be less likely to respond to PPI therapy (11). Conversely, a retrospective series comparing adult EoE patients to those with erosive esophagitis found that erosive esophagitis patients had a lower prevalence of atopy, and dysphagia (12). The minireview alluded to above postulates that erosive esophagitis creates macroscopic breaks in the esophageal barrier that permits egress of potential allergens from the esophageal lumen into the mucosa. In this setting, a secondary EoE-like picture develops that may be primarily incited by the acid refluxate. The authors recommend that when EoE and GERD are interacting, it may take time to determine which of the two entities is the most important which can then guide optimal therapy (6). A similar conclusion was expressed by another expert who also suggested that esophageal acid exposure can lead to disruption of the intact epithelial barrier and result in antigenic penetration with the consequential development of EoE (13).

A cohort of pediatric patients who are routinely exposed to excessive esophageal acid exposure are those who have had surgical correction of esophageal atresia (EA). These children are recognized to have abnormal esophageal motility, leading to impaired acid clearance, causing the prolonged acid exposure. Results from a questionnaire sent to over 400 EA patients with surgical correction, found that 76% of the respondents had GERD symptoms (14). A review article has highlighted the high prevalence of EoE (4–17%) reported in this cohort (15). One small retrospective study found that EoE children born with EA had a lower prevalence of allergies (23.5% vs. 80%, P<0.05), a lower age of presentation (3.1 vs. 12.2 years, P<0.05), and a higher resolution rate with PPI therapy (64.7% vs. 17.8%, P<0.05) compared to other EoE patients (16). These observations would be consistent with the aforementioned theory that prolonged acid exposure can compromise esophageal barrier integrity leading to inappropriate allergen penetration. Compromise of the esophageal barrier is believed to be a cornerstone of EoE pathogenesis.

The strength of this report is that comprehensive, standardized investigations were repeated by the same team involving the same patient to maximize the ability to compare different studies and highlight the essential overlap noted. As this is a single case report describing a single patient, additional examples of the described phenomenon would be desirable.

Conclusions

This case illustrates that EoE and GERD can exist in the same patient and thus can complicate successful management. Only by assessing all of the available information and keeping an open mind can these patients be adequately treated. In certain clinical settings, both conditions need to be recognized and to be treated for the optimal outcome. Finally, by appreciating the central role of esophageal epithelial integrity in minimizing EoE symptoms, endoscopic abnormalities, and histopathology, a greater understanding of the evolution of EoE and its successful treatment can be realized.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2024-620/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2024-620/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2024-620/coif). S.S.R. serves as an unpaid editorial board member of Translational Pediatrics from January 2024 to December 2025. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient’s parent prior to every procedure which was performed with the acknowledgment that they were participating in an IRB approved research protocol. The parents have seen this manuscript and have provided verbal consent for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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