Delay in Diagnosis of Eosinophilic Esophagitis Increases Risk for Stricture Formation in a Time-Dependent Manner

TL;DR: The prevalence of esophageal strictures correlates with the duration of untreated disease and indicates the need to minimize delay in diagnosis of EoE.

About: This article is published in Gastroenterology.The article was published on 2013-12-01 and is currently open access. It has received 523 citations till now. The article focuses on the topics: Eosinophilic esophagitis.

Summary

INTRODUCTION

• Eosinophilic esophagitis (EoE) has recently been defined by an expert panel as “a chronic, immune/antigen-mediated, esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation”. [1].
• The endoscopic presentation of EoE is quite variable.
• For the purposes of this study, characteristic features of EoE were classified into two categories, the inflammatory and the fibrotic group of EoE features.
• The lack of data on stricture formation in EoE may be related to the fact that EoE is diagnosed with a longer diagnostic delay (time period from appearance of first symptoms to diagnosis, median 5 years in EoE) when compared with Crohn’s disease (median 0.75 years). [7,15].
• The authors also aimed to identify risk factors for stricture development.

Swiss EoE Database

• The authors performed a retrospective analysis of the Swiss EoE database (SEED) and an extensive review of all patient records.
• The data are stored in the Swiss EoE Clinic located in Olten, Switzerland.
• In order to minimize the limitations of the retrospective design of this study, only data gathered in structured manner on 323 patients, who personally attended the Swiss EoE Clinic, were used to carry out most of the analysis.
• Between 1989 and 2007, the diagnostic criterion for EoE was met, if ≥ 24 eosinophils per high power field (hpf) were observed in any of the fields examined.

Description of Endoscopic Findings

• Since 1989, the following endoscopic signs were consistently described: edema (defined as reduced vascular pattern), white exudates (defined as white spots of the esophageal surface), furrows (defined as vertical lines), rings, crêpe-paper esophagus , and strictures.
• The endoscopic features described in Swiss EoE Clinic visit records were identical to those that were used by Hirano et al. for a novel grading system for endoscopic esophageal features of EoE.[10].
• Stricture severity was classified as described elsewhere.[17].
• Briefly, a stricture was classified as low-grade if it could be passed with a standard endoscope (measured 9 mm in outer diameter) with some resistance, often M AN US CR IP T AC CE PT ED 8 inducing lacerations (also described as crêpe-paper esophagus).
• Stricturing rings were assigned a length of 0.5 cm.

Histologic Analyses

• The biopsies of all SEED patients followed up at the Swiss EoE Clinic were evaluated by CB.
• For the purposes of histologic examination, 4-µm sections were cut from the paraffin blocks and stained with H&E, van Gieson, Alcian blue and Periodic acid-Schiff stain.
• All histologic examinations were performed using a standard pathology microscope (Zeiss Axiophot, Plan-Neofluar 40, ocular magnification 10 ×, area of microscopic field 0.260 mm2).
• At least 10 sections of each esophageal biopsy specimen were surveyed, and the eosinophils in the most densely infiltrated area were counted (peak eosinophil count).
• The extent of subepithelial fibrosis was visualized using the van Gieson stain and semiquantiatively graded as either absent, mild/moderate, or severe.

Ethics

• The study was approved by the local ethics committee.
• Prior to inclusion into the SEED, a written informed consent was obtained from all patients.

Statistical Analysis

• Data from EpiData were imported into a statistical package program (STATA® version 12, College Station, Texas, USA).
• Categorical data M AN US CR IP T AC CE PT ED 9 were summarized as the percentage of the group total.
• Differences in quantitative data distributions between the groups were assessed by the Student’s t-test (for parametric data) and by the Wilcoxon rank-sum test (for non-parametric data).
• Univariate logistic regression modeling was performed to identify risk factors for the outcome “presence of stricture(s) at the time of EoE diagnosis”.

Patient Characteristics

• Of 783 patients included into SEED, 323 were diagnosed by the senior author according to standardized protocols for assessment of clinical, endoscopic, histologic, and laboratory disease activity.
• The remaining 200 EoE patients had complete datasets on clinical, endoscopic, histologic, and laboratory disease activity and were included for further analysis.
• Diagnostic delay was longest in the young patient population (≤ 20 years of age) and decreased with increasing age .
• Due to the limited and non-standardized data available for this group of patients, only data for the occurrence of strictures over time, which was available for 359 patients, was used in this manuscript.

Endoscopic, Histologic, and Laboratory Characteristics at EoE Diagnosis

• The key endoscopic, histologic, and laboratory findings at the time of EoE diagnosis are illustrated in Table 2.
• Further details on the number and other characteristics of esophageal strictures are provided in Table 3.
• No perforation was observed in dilated patients.

Evolution of Endoscopic Features Over Time

• Whitish exudates, furrows and/or edema were considered as inflammatory features, whereas corrugated rings, strictures and/or crêpe paper esophagus were considered as fibrotic features.
• Furthermore, the prevalence of purely inflammatory features decreased with increasing duration of diagnostic delay period (p = 0.019).
• The prevalence of esophageal strictures positively correlated with the presence of endoscopic fibrotic features (Spearman’s rho 0.3226, p < 0.001) and subepithelial fibrosis (rho 0.1927, p < 0.001).

Duration of Diagnostic Delay

• The authors evaluated the prevalence of strictures at the time of EoE diagnosis stratified according to the length of the diagnostic delay periods.
• The CochranArmitage trend test revealed a significant increase in the prevalence of strictures with the increasing length of diagnostic delay period (p < 0.001).
• Therefore, the authors performed logistic regression modeling evaluating gender, presence of allergies, length of diagnostic delay period, presence of EoE family history, presence of blood eosinophilia, and elevated IgE levels as risk factors for the presence of strictures at the time of EoE diagnosis.
• These results are depicted in Supplementary Table 1.
• Using the Cochran-Armitage trend test, the authors found that the prevalence of strictures at the time of EoE diagnosis increased with the increasing length of diagnostic delay period (p < 0.001) also in the externally diagnosed EoE patients.

Risk Factors for Stricture Formation

• Using logistic regression modeling, the authors evaluated whether some patients are at higher risk than others to develop strictures.
• The dependent variables for the outcome “presence of stricture(s) at the time of EoE diagnosis” are described in the methods section.
• The results of the logistic regression modeling are shown in Supplementary Table 2.
• To evaluate a relationship between peak eosinophil counts in esophageal biopsies and stricture formation, the authors calculated the Spearman’s correlation coefficient.

DISCUSSION

• The authors were able to demonstrate that patients are more likely to present with purely inflammatory endoscopic EoE features early in the disease course and then progress to develop fibrotic endoscopic features, in addition to inflammatory features.
• The authors found that the length of diagnostic delay was positively correlated with the M AN US CR IP T AC CE PT ED 15 prevalence of esophageal strictures.
• In Switzerland, approximately 250 board-certified gastroenterologists, working in university hospitals, general hospitals and private practices provide gastroenterological care.
• Thus, the presence of strictures is likely under-estimated in this study.
• In conclusion, their analysis of a large group of untreated EoE patients demonstrates that the prevalence of strictures is directly correlated with the length of diagnostic delay.

FIGURE LEGEND

• TABLES M AN US CR IP T AC CE PT ED Table 4: Prevalence of strictures in patients diagnosed with EoE after a diagnostic delay period that ranged from 0 - > 20 years.
• M AN US CR IP T AC CE PT ED Supplementary Table 1: Logistic regression modeling evaluating risk factors for the presence of strictures at EoE diagnosis stratified according to age at symptom onset.
• The Odds Ratio (OR) is computed on the underlined outcome of the dependent variable of the logistic regression model.
• The variable “diagnostic delay” is entered as continuous variable.

Figures

Table 1: Demographic and disease-specific characteristics of included EoE patients.

Table 2: Endoscopic, histologic, and laboratory characteristics of EoE patients at the time of diagnosis.

Figure 1: Diagnostic delay (time from first symptoms to diagnosis) in relation to age at

Figure 2: Types of the endoscopic features present at the time of EoE diagnosis

Table 3: Characterization of esophageal strictures found at the time of EoE diagnosis in 75 EoE patients.

Figure 3: Percentage of patients without strictures over the diagnostic delay period encompassing > 20 years.

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation, in a time-dependent manner" ?

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Q2. What is the risk factor for strictures in eosinophilic es?

Diagnostic delay was the only risk factor for strictures at the time of EoE diagnosis (odds ratio, 1.08; 95% confidence interval, 1.040–1.122; P<.001). 

Q3. How many board-certified gastroenterologists work in Switzerland?

In Switzerland, approximately 250 board-certified gastroenterologists, working in university hospitals, general hospitals and private practices provide gastroenterological care. 

Q4. How many patients are treated in the Swiss EoE Clinic?

Of 783 patients, 323 patients (41.3 %) are followed-up and treated on a regular basis in the Swiss EoE Clinic by the senior author. 

Q5. What is the length of the delay in the study?

Estimation of the length of diagnostic delay in their study was based on patient’s reported outcomes, which is a subject to a recall bias. 

Q6. How many patients underwent endoscopic bolus removal?

An endoscopic bolus removal was performed in 56 (28.0 %) patients; 28 patients underwent this procedure prior to and 28 at the time of EoE diagnosis. 

Q7. How long did the delay period be associated with strictures?

Using univariate logistic modeling, the authors found that length of diagnostic delay (OR 1.080 per year, 95% CI 1.040 - 1.122, p < 0.001) was the only factor significantly associated with the presence of strictures at the time of EoE diagnosis. 

Q8. What is the main risk factor for strictures?

It is well established that strictures contribute to symptom generation as well as occurrence of potentially dangerous food bolus impactions. 

Q9. How many patients are currently in the SEED database?

The SEED has been founded in 1989 by the senior author (AS) and currently includes data on 783 EoE patients from all over Switzerland. 

Q10. What was the prevalence of fibrotic features at the time of EoE diagnosis?

the prevalence of purely inflammatory features decreased with increasing duration of diagnostic delay period (p = 0.019). 

Q11. Why are physicians reluctant to refer children for endoscopy?

The long diagnostic delay in children/young adults might be related to the fact that an upper endoscopy needs to be performed under general anesthesia, and, hence, physicians are more reluctant to refer children for endoscopy. 

Q12. What was the prevalence of esophageal strictures?

The prevalence of esophageal strictures positively correlated with the presence of endoscopic fibrotic features (Spearman’s rho 0.3226, p < 0.001) and subepithelial fibrosis (rho 0.1927, p < 0.001). 

Q13. How long did the delay period for EoE diagnosis be?

Using the Cochran-Armitage trend test, the authors found that the prevalence of strictures at the time of EoE diagnosis increased with the increasing length of diagnostic delay period (p < 0.001) also in the externally diagnosed EoE patients. 

Q14. What criteria were used to determine whether a patient had eosinophilic ?

whose data were included into the SEED, had to meet the following criteria: 1) report the presence of symptoms of esophageal dysfunction, 2) exhibit predominant eosinophilic esophageal inflammation, 3) either test negative by 24-hour pH-metric study or have esophageal eosinophilia that did not resolve following a completion of at least a 6-week double-dose PPI trial. 

Q15. What is the relationship between the length of the delay between the esophageal strict?

the risk of developing esophageal strictures is significantly associated with the length of diagnostic delay, a time period from appearance of first symptoms to establishment of EoE diagnosis.