Increase in distal esophageal wall thickness with time in adult patients with eosinophilic esophagitis

Abstract

Background and Aim

Eosinophilic esophagitis (EoE) is a chronic disease which may progress to a fibro‐stenotic phenotype due to esophageal sub‐epithelial fibrosis. Esophageal wall thickening in patients with EoE has been demonstrated in a few studies using endoscopic ultrasound (EUS). The aim of this study was to longitudinally assess the endoscopic appearance, wall thickness, histology, and dysphagia score of EoE patients.

Methods

Patients with EoE were recruited and studied between February 2012 and April 2021. Patients were evaluated on two separate occasions at least 12 months apart with endoscopy, EUS, and esophageal mucosal biopsies. The dysphagia score and epidemiology data were also assessed.

Results

A total of 16 EoE patients were included with a mean follow‐up duration of 2.2 ± 1.2 years. In 14/16 (88%) patients, the total wall thickness of the distal esophagus significantly increased (P = 0.0012) as a result of thickening of the muscularis propria (P = 0.0218). However, only 1/14 (7%) patient had an increase in the dysphagia score, while 8/14 (57%) and 5/14 (36%) had a stable and reduced dysphagia score, respectively. No differences were found in the total thickness of other esophageal regions, dysphagia score, endoscopic appearance, and eosinophil count over time.

Conclusion

Distal esophageal wall thickness increases with time in EoE patients, independent of the dysphagia score and eosinophil count.

16 eosinophilic esophagitis patients were studied over a 2.2 ± 1.2 year period. Distal oesophageal wall thickness was found to increase in 88% of patients independent of dysphagia score and eosinophil count.

Introduction

Eosinophilic esophagitis (EoE), which has been increasing in prevalence and incidence, is the most frequent eosinophilic gastrointestinal disorder and the second most common cause of chronic esophagitis and dysphagia after gastro‐esophageal reflux disease. ¹ , ² , ³ , ⁴ , ⁵ The natural history of EoE is incompletely understood, and it is yet unclear as to whether phenotypic variations exist or if these differences indicate a different disease pattern of responsiveness to therapy or prognosis. ⁶ , ⁷ Current data indicate that EoE is a chronic, progressive disease with persistence of dysphagia and long‐term complications such as stricture formation, food impaction, narrow‐caliber esophagus, and esophageal perforation. ⁶ , ⁸ , ⁹ , ¹⁰ , ¹¹

The prevalence of fibrotic strictures has been shown to increase with increasing duration of disease as well as diagnostic delay, suggesting that the natural history of EoE is a progression from an inflammatory to a fibro‐stenotic phenotype due to development of subepithelial fibrosis in the esophageal wall. ⁹ , ¹² , ¹³ Studies using endoscopic ultrasound (EUS) studies in EoE patients have been able demonstrate significant thickening of the esophageal wall due to this remodeling process. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ We therefore hypothesized that the esophageal wall thickness in EoE increases with time and can be detected using EUS. The aim of this study was to longitudinally assess the endoscopic appearance, wall thickness, histology, and dysphagia score of EoE patients.

Methods

This longitudinal study was performed at the Royal Adelaide Hospital and was approved by the Royal Adelaide Hospital Research Ethics Committee (protocol number: 111233).

In the initial assessment study, patients between 18 and 70 years of age with a diagnosis of EoE (defined as ≥15 eosinophils/high powered field with symptoms of esophageal dysfunction and exclusion of other causes of esophageal eosinophilia) were retrieved from a pre‐existing database and enrolled at their outpatient clinic/endoscopy appointments or via an invitation letter. ¹⁹ Enrolled patients underwent an endoscopy with EUS and mucosal biopsies and completed a dysphagia score. ¹⁹ Esophageal wall thickness was measured in a contracted state to avoid distortion caused by longitudinal furrows and ensure constant distensibility of the esophagus. ¹⁹ A non‐validated, modified version of the dysphagia score used by Straumann et al. in a randomized placebo‐controlled trial of oral viscous budesonide in adult EoE patients was used in the study. ²⁰ This score assessed the frequency (none [0] to several times per day [5]) and intensity of dysphagia (unhindered swallowing [0] to obstruction requiring endoscopic intervention [5]) with total scores ranging from 0 to 10. ¹⁹ These patients were then invited to return for a follow‐up endoscopy with EUS and mucosal biopsies along with completion of a dysphagia score ≥1 year after their initial assessment.

All endoscopies and USs were performed by either of the two gastroenterology investigators (SW and NN).

Statistical analysis

Descriptive statistics were used to describe the results, with normality assessed using the Kolmogorov–Smirnov test. Paired t‐test was used to evaluate the parameters between the two assessments. Spearman's rank correlation coefficient (Spearman r) was used to detect any significant correlation between variables in each study group. Statistical significance was determined by a P‐value of <0.05. Analyses and graph construction were performed using IBM SPSS software, version 28, and GraphPad Prism software, version 9.

Results

Demographics and clinical characteristics

A total of 16 EoE patients were included in the study with a mean follow‐up duration of 2.2 ± 1.2 years. The demographics and clinical characteristics of our patient cohort are summarized in Table 1.

Table 1.

Demographics and clinical characteristics

	Initial assessment	Follow‐up assessment	P‐value
Age, median (IQR) years	43.5 (28)	45.4 (60.5)
Gender (Male: Female)	14 M:2F
Duration of disease, (median) IQR years	2.5 (7)
Mediations, n (%)	6 (38%)	5 (31%)	0.7505
PPI, n	6	5
Steroids, n	1	2
Refractory to therapy, n (%)	5 (83%)	2 (40%)
Dysphagia score, median (IQR)	4 (3.75)	3 (5)	0.8945
EREFS total, median (IQR)	2.5 (2.75)	3 (2.75)	0.5805
Fixed rings, n (%)	12 (75%)	14 (88%)
White plaques, n (%)	7 (44%)	8 (50%)
Longitudinal furrows, n (%)	15 (94%)	13 81%)
Peak eosinophil count/hpf, median (IQR)
Proximal	18 (25.5)	22.5 (25)	0.9248
Mid	25 (19.5)	25.5 (24)	0.3636
Distal	23.5 (16)	30 (37.5)	0.8168
Other histological findings, n
Eosinophil abscess	2	3
Basal zone hyperplasia	13	13
Dilated intracellular spaces	4	2
Lamina propria fibrosis	1	1
Eosinophil surface layering	6	6

Abbreviation: EREFS, endoscopic reference score.

Progression of esophageal wall thickness

Esophageal wall thickness measurements obtained via EUS are summarized in Table 2. In 14/16 (88%) patients, the total thickness of the distal esophageal wall significantly increased over the 2.2 ± 1.2 years (P = 0.0012) as a result of thickening of the muscularis propria layer (P = 0.0218). Of these, the majority had persistent dysphagia (9/14 [64%]), with only one of these patients having an increase in dysphagia score. Only five patients (36%) who had an increase in wall thickness experienced a reduction in dysphagia score (from 4 [3] to 0 [3]) (Fig. 1). In two patients who did not have thickening of the esophageal wall, the dysphagia scores remained stable at 5 and 8, respectively.

TABLE 2.

Esophageal wall thickness

Esophageal wall thickness	Initial assessment	Follow‐up assessment	P‐value
Proximal, median (IQR), mm
Total	2.6 (1.55)	3.15 (1.7)	0.0555
Muscularis propria	2 (0.3)	2.1 (1.6)	0.8955
Submucosa	1.55 (0.55)	1.3 (0.825)	0.5567
Mucosa	0.8 (0.9)	1.2 (0.6)	0.6452
Mid, median (IQR), mm
Total	2.85 (1.65)	3.65 (1.1)	0.0542
Muscularis propria	1.3 (1.2)	1.7 (1.1)	0.0259
Submucosa	1.85 (1.45)	1.45 (0.7)	0.4888
Mucosa	1.1 (0.6)	1 (0.4)	0.9510
Distal, median (IQR), mm
Total	3.9 (2.3)	5.6 (2)	0.0012
Muscularis propria	1.3 (1.3)	2.4 (0.8)	0.0218
Submucosa	2.4 (1.33)	2.7 (1.85)	0.5711
Mucosa	1.3 (1.1)	1.3 (0.35)	0.6470

Note: Bold indicates values that are statistically significant.

Figure 1.

Characteristics of patients showing an increase in distal esophageal wall thickness at follow‐up assessment based on the dysphagia score. *Median (IQR).

The muscularis propria layer of the mid esophagus was thicker (P = 0.0259) on follow‐up assessment, but the total thickness alone showed a trend towards statistical significance (P = 0.0542).

No correlation was found between the dysphagia score and proximal (P = 0.78, r = –0.08), mid (P = 0.58, r = 0.15), and distal (P = 0.14, r = 0.39) esophageal wall thickness at follow‐up assessment. There was also no significant correlation between the change in dysphagia score and distal esophageal wall thickness at follow‐up assessment (P = 0.41, r = –0.22).

Discussion

This is the first longitudinal study to assess esophageal wall thickness, endoscopic appearance, histology, and dysphagia score in adult EoE patients over a mean duration of 2.2 years. Our data show that the total distal esophageal wall thickness significantly increased over time as a result of thickening of the muscularis propria layer in 88% of patients and was independent of the dysphagia score. No significant difference was found in the endoscopic reference score (EREFS), eosinophil count, and total wall thickness in the mid and proximal esophagus between the initial and follow‐up assessment.

Previous studies assessing the esophageal wall in EoE patients have shown significant thickening involving the mucosa, submucosa, and muscularis propria on EUS, supporting the occurrence of a chronic remodeling process. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁸ , ²¹ Additionally, an assessment of full‐thickness esophageal samples in 12 EoE patients showed that histological changes and mediators of EoE pathogenesis were present in both the submucosa and muscularis propria. ²² Our study shows that remodeling and development of esophageal wall thickening appears to be progressive with disease duration but is limited to the muscularis propria layer. This layer may thus be the source of esophageal non‐compliance and stiffness seen in studies using the endoluminal functional imaging system (FLIP). ²³ , ²⁴

The precise mechanism of dysphagia in EoE patients without strictures is unclear. ⁷ , ²⁵ It is hypothesized that dysphagia is due to the remodeling process as described in the previous paragraph, which leads to irreversible structural changes and subsequent loss of function. ⁹ , ²⁵ , ²⁶ The correlation between severity of symptoms and histological and endoscopic findings is unclear given conflicting study results. ¹ , ⁷ , ⁹ , ²⁵ , ²⁷ , ²⁸ , ²⁹ Relying on symptoms alone is therefore inadequate to allow for either a diagnosis or assessment of efficacy of therapy. ¹ Standard esophageal biopsies may also be an insufficient way of assessing overall disease severity given that the changes of EoE involve the sub epithelium of the esophagus. ³⁰ Our finding that esophageal wall thickening progresses independent of the dysphagia score and eosinophil count is thus not unexpected given this poor correlation and the lack of a readily available, validated symptom score for EoE.

The strength of our study is that it is a comprehensive longitudinal study assessing esophageal wall thickness in adult EoE patients. The main limitation of our study is the small sample size where type II errors may occur. We did not have a standardized treatment protocol; however, most of our patients (approximately 70%) were not on treatment due to noncompliance. The duration of our study may not have been adequate to allow changes in the esophageal wall thickness to have an impact on the symptom of dysphagia. Additionally, biopsies of the submucosa and muscularis propria were unobtainable and thus we were unable to depict the histological findings of this layer.

Conclusion

Distal esophageal wall thickness increases with time in EoE patients, independent of the dysphagia score and eosinophil count. Larger studies are required to confirm this finding and assess its impact on clinical management of these patients.