Abstract
Background & Aims:
Although eosinophil count is the standard used to monitor disease activity in patients with eosinophilic esophagitis (EoE), there are often disparities between patient-reported symptoms and eosinophil counts. We examined the prevalence of epithelial alterations, namely basal cell hyperplasia (BCH) and spongiosis, among patients with inactive EoE (eosinophil counts below 15 following therapy) and aimed to determine whether maintenance of these changes in epithelial morphology are associated with persistent clinical findings.
Methods:
Esophageal biopsies of 243 patients (mean age, 16.9 years) undergoing routine endoscopy at the University of Pennsylvania were evaluated for epithelial BCH and spongiosis. Univariable analysis was used to calculate the association between epithelial changes and symptoms as well as endoscopic findings and peak eosinophil count. We validated our findings using data from a cohort of patients at the University of North Carolina.
Results:
The discovery and validation cohorts each included patients with inactive EoE, based on histologic factors, but ongoing BCH and spongiosis. Ongoing BCH, but not spongiosis, in patients with inactive EoE was associated with symptoms (odds ratio, 2.14; 95% CI, 1.03–4.42; P=.041) and endoscopic findings (odds ratio, 7.10; 95% CI, 3.12–16.18; P<.001).
Conclusions:
In patients with EoE, the presence of BCH might indicate ongoing disease activity, independent of eosinophil count. This might account for the persistent symptoms in patients who are considered to be in remission based on histologic factors.
Keywords: esophagus, epithelium, inflammation, prognostic factor, outcome
Introduction
Eosinophilic Esophagitis (EoE) is a chronic, immune-mediated disease characterized by eosinophil-rich esophageal inflammation and symptoms including abdominal pain and dysphagia1. Fibrostenosis and stricture in EoE correlate with duration of untreated disease, highlighting the need for effective and accurate diagnosis and treatment2. Common epithelial changes in EoE include basal cell hyperplasia (BCH) characterized by expansion of basal keratinocytes and aberrant terminal differentiation (e.g. dyskeratosis)3, and dilated intercellular spaces (DIS)4, referred to as spongiosis, which has been implicated in paracellular permeability5. It remains elusive as to how histopathological changes in non-immune components may reflect EoE disease activity.
EoE diagnosis is defined by ≥15 eosinophils/high-power field (eos/hpf) in esophageal mucosa following 8–12 weeks of proton pump inhibitor (PPI)1. While this criterion is highly sensitive and specific for diagnosis6, 7, a portion of EoE patients in histologic remission (defined as <15 eos/hpf) continue to report symptoms and display tissue remodeling8–10. A scoring system comprised of 8 histologic features related to eosinophilia, epithelial architecture and lamina propria fibrosis was recently found to better differentiate between treated and untreated EoE compared to the gold standard of peak eosinophil count11. The relationship between these histologic findings and clinical activity remains understudied.
The goal of this study is to evaluate esophageal epithelial tissue alterations in patients with histologic EoE remission (<15 eos/hpf) and examine association of these alterations with clinical parameters. As it has been demonstrated that dyskeratosis is present in a small subset of treated EoE patients while BCH and spongiosis are highly prevalent12, we specifically focused on evaluation of BCH and spongiosis in the context of inactive EoE.
Methods
Study Population
Subjects were enrolled at the time of diagnostic esophagogastroduodenoscopy (EGD) through University of Pennsylvania, including patients from both Children’s Hospital of Philadelphia (CHOP) and Hospital of the University of Pennsylvania (HUP), or University of North Carolina (UNC) (IRB# 10–007737, 13–010552, #08–0773, 11–1122). Inclusion criteria included age >6 months and absence of other esophageal or inflammatory disease of the gastrointestinal (GI) tract. At UNC, incident adult EoE patients were recruited then re-scoped at regular intervals to evaluate therapy response, as previously described7,13 All patients were on PPI at time of diagnosis. EoE subjects were categorized as active (≥15 eos/hpf) or inactive (<15 eos/hpf) per standard diagnostic criteria1. Non-EoE subjects were comprised of subjects reporting symptoms warranting EGD with no previous EoE diagnosis or histopathologic abnormalities. Patients with PPI-treated gastro-esophageal reflux disease (GERD), defined as a history of reflux or erosive esophagitis and evidence of non-EoE inflammatory changes on histology, PPI-responsive esophageal eosinophilia, or other histologic changes that were not consistent with 2011 guidelines were excluded. At endoscopy, subjects were asked if, within the last 30 days, they had heartburn, dysphagia, regurgitation, history of impaction or abdominal pain.
Histology
Hematoxylin & eosin (H&E)-stained esophageal biopsies were retrieved from Pathology Departments at CHOP, HUP or UNC. Specimens were scored by a pathologist with expertise in GI pathology (BJW) blinded to clinical history and diagnosis. Sections were scored for three parameters: (i) eos/hpf (400X) in the most affected area was reported as an exact number (for subjects with eosinophil counts <20 eos/hpf) or a range (21–30, 31–40, 41–50, 51–75, or >76 for subjects with >20 eos/hpf); (ii) BCH was assessed semi-quantitatively in relation to total epithelial thickness (Score 0=0–20% of epithelial thickness occupied by basal cells; Score 1=21–50%; Score 2=51–75%; Score 3=76–100%, Supplementary Figure S1); and (iii), spongiosis was assessed subjectively as negative (score 0), mild (desmosomes visible due to DIS, with epithelial integrity intact, score 1), or severe (intraepithelial vesicle formation or loss of epithelial integrity, score 2). For cases in which eosinophil count assigned by the study pathologist (BJW) was discrepant with eosinophil count in the patients’ records, a second pathologist (AKS) determined which eosinophil count was accurate.
Major basic protein (MBP) staining was performed using anti-human eosinophil MBP antibody (1:100, clone BMK 13, AbD Serotec, Kidlington, UK and Raleigh, NC) overnight at 4°C. Slides incubated with secondary antibody only served as negative controls. MBP staining was scored by AKS.
Statistical Analysis
Descriptive statistics are presented as mean ± standard deviation or median (minimum-maximum) for continuous variables and frequency counts (percentages) for categorical variables. Two-sample t-test or Wilcoxon rank-sum test and one-way analysis of variance or Kruskal-Wallis test comparing two and three groups, respectively for continuous variables and chi-square test or Fisher’s exact test for categorical variables were used.
Univariable logistic regression models were constructed to quantify the strength of associations between each of the covariates of interest (presence of BCH, presence of spongiosis, and eos/hpf) and binary outcome of presence of any symptoms and presence of EGD changes separately in the inactive patients. Adequacy was validated using the Hosmer-Lemeshow goodness-of-fit test. Sensitivity analyses were performed to examine potential outliers and influential points. Estimated odds ratio (OR) from logistic regression models were reported with corresponding 95% confidence intervals (CI) and p values. Statistical analyses were conducted using Stata 14.1 (StataCorp, College Station, TX) and the significance level was set at 0.05.
Results
Patient Characteristics
Among subjects recruited through the University of Pennsylvania, 243 met inclusion criteria. At the time of esophageal biopsy procurement, mean patient age was 16.9 years (range 1.6–66.3 years), 73.2% were male and 80.6% were white (Table 1). Of 196 patients with confirmed EoE diagnoses, 48 (24%) had ≥15 eos/hpf (47.38±26.94) at the time of analysis and were defined as “active EoE” while 148 displayed <15 eos/hpf (3.40±3.96) and were defined as “inactive EoE”. The remaining 47 subjects were defined as non-EoE controls and had no esophageal eosinophilia. Across all groups, 58.4% of subjects reported presence of heartburn, dysphagia, regurgitation, history of impaction or abdominal pain. Dysphagia was the most commonly reported symptom in active EoE patients (50.0%) while abdominal pain was most common in non-EoE subjects (51%). Inactive EoE patients most commonly reported either dysphagia (19.7%) or abdominal pain (19.7%). Endoscopic findings were reported in 2.1% of non-EoE, 87.2% of active EoE and 44.1% of inactive EoE subjects with furrows being documented most frequently across all groups. Among EoE patients, 12.5% of active and 4.7% of inactive subjects had history of esophageal dilation.
Table 1:
Demographics in University of Pennsylvania subjects (n=243)
| Non-EoE (n=47) |
Active EoE (n=48) |
Inactive EoE (n=148) |
Total (n=243) |
|
|---|---|---|---|---|
| Age (Mean years ± SD) | 16.5 ± 14.3 | 22.7 ± 14.05 | 14.5 ± 11.55 | 16.9 ± 13.16 |
| White Race, n (%) | 39 (82.9) | 41 (85.4) | 117 (79.6) | 196 (80.6) |
| Male, n (%) | 28 (59.5) | 34 (70.8) | 116 (78.9) | 179 (73.2) |
| Symptoms, n (%) | 46 (97) | 32 (66.7) | 64 (45.1) | 142 (58.4) |
| Heartburn, n (%) | 17 (36) | 13 (27.7) | 12 (8.5) | 42 (17.2) |
| Dysphagia, n (%) | 25 (27.2) | 24 (50.0) | 28 (19.7) | 77 (31) |
| Regurgitation, n (%) | 19 (40) | 9 (18.8) | 22 (15.5) | 50 (20.5) |
| Hx impaction, n (%) | 2 (4) | 5 (10.4) | 1 (0.7) | 8 (3.2) |
| Abdominal pain, n (%) | 24 (51) | 10 (20.8) | 28 (19.7) | 62 (25.5) |
| Endoscopic findings, n (%) | 1 (2.1) | 41 (87.2) | 64 (44.1) | 106 (43.6) |
| Furrows, n (%) | 1(2.1) | 34 (70.8) | 37 (25) | 72 (29.6) |
| Pseudoabscess, n (%) | 0 (0) | 17 (35.4) | 10 (6.8) | 27 (11) |
| Rings, n (%) | 0 (0) | 18 (37.5) | 17 (11.5) | 35 (14.4) |
| Stricture, n (%) | 0 (0) | 1 (2.0) | 1 (0) | 2 (0) |
| Eosinophil count (Mean ± SD) | 0 (0) | 47.38 ± 26.49 | 3.40 ± 3.96 | 11.52 ± 21.35 |
| Dilation performed, n (%) | 0 (0) | 6 (12.5) | 7 (4.7) | 13 (5) |
BCH, basal cell hyperplasia; EoE, eosinophilic esophagitis; Hx, history; SD, standard deviation.
Prevalence of epithelial changes in inactive EoE
To determine the prevalence of epithelial alterations in the context of histologic EoE remission, we evaluated BCH and spongiosis in esophageal biopsy specimens from inactive EoE patients recruited through University of Pennsylvania. Of 148 inactive EoE patients, 105 (70.9%) had a BCH score of 0 (Table 2). Among the 43 BCH-positive inactive patients, 41 had a BCH score of 1 and 2 had a BCH score of 2. Notably, 94.2% of non-EoE subjects had a BCH score of 0 while BCH was highly prevalent in active EoE patients (Table 2).
Table 2:
Prevalence of BCH and spongiosis in relation to disease status in University of Pennsylvania subjects.
| Non-EoE n (%) |
Active EoE n (%) |
Inactive EoE n (%) |
All groups |
Inactive EoE vs. Non-EoE |
Inactive EoE vs. Active EoE |
|
|---|---|---|---|---|---|---|
| BCH Score | ||||||
| 0 | 49 (94.2%) | 1 (2.1%) | 105 (70.9%) | |||
| 1 | 3 (5.8%) | 22 (45.8%) | 41 (27.7%) | |||
| 2 | 0 (0.0%) | 20 (41.7%) | 2 (1.4%) | |||
| 3 | 0 (0.0%) | 5 (10.4%) | 0 (0.0%) | |||
| BCH | ||||||
| Absent | 49 (94.2%) | 1 (2.1%) | 105 (70.9%) | p<0.001 | p<0.001 | p<0.001 |
| Present | 3 (5.8%) | 47 (97.9%) | 43 (29.1%) | |||
| Spongiosis Score | ||||||
| 0 | 35 (67.3%) | 0 (0.0%) | 39 (26.4%) | |||
| 1 | 17 (32.7%) | 27 (56.3%) | 109 (73.6%) | |||
| 2 | 0 (0.0%) | 21(43.8%) | 0 (0.0%) | |||
| Spongiosis | ||||||
| Absent | 35 (67.3%) | 0 (0.0%) | 39 (26.4%) | p<0.001 | p<0.001 | p<0.001 |
| Present | 17 (32.7%) | 48 (100.0%) | 109 (73.6%) | |||
BCH, basal cell hyperplasia; EoE, eosinophilic esophagitis
With regard to spongiosis in University of Pennsylvania subjects, prevalence among inactive EoE patients was 73.6% with mild spongiosis noted in 109 patients (Table 2). Unlike BCH which was largely absent in non-EoE subjects, spongiosis was identified in 32.7% of patients from this cohort with spongiosis-positive subjects exclusively exhibiting mild DIS (Table 2). Spongiosis was further detected in 100% of active EoE patients (Table 2).
There were statistically significant associations between the presence of both BCH and spongiosis and disease status (p<0.001) in University of Pennsylvania subjects (Table 2). Prevalence of BCH or spongiosis in inactive EoE patients was significantly higher than that found in non-EoE subjects (p<0.001) and also significantly lower than that in found active EoE patients (p<0.001) (Table 2).
BCH is predictive of symptoms and EGD findings in inactive EoE
To determine whether maintained esophageal epithelial alterations may be associated with clinical findings in University of Pennsylvania subjects, we performed logistic regression analysis. Inactive EoE patients with ongoing BCH (score ≥1) were significantly more likely to report symptoms (OR 2.14, 95% CI 1.03–4.42; p=0.041) or display endoscopic findings (OR 7.10, 95% CI 3.12–16.18; p<0.001) as compared to inactive patients in which BCH resolved (Table 3). Evaluation of the relationship between BCH and specific symptoms revealed trends for increased frequency of heartburn, dysphagia, regurgitation and abdominal pain in inactive EoE patients with BCH (Figure 1). By contrast, a DIS score ≥1 in inactive EoE patients was not associated with persistent symptoms (OR 0.82, 95% CI 0.39–1.71; p=0.591) and was only marginally associated with endoscopic findings (OR 2.17, 95% CI 0.99–4.72; p=0.052) (Table 3). Additionally, eosinophil count was not predictive of symptoms in inactive EoE patients (OR 1.04, 95% CI 0.96–1.13; p=0.353), but was associated with the presence of endoscopic findings (OR 1.17, 95% CI 1.07–1.28; p=0.001) (Table 3).
Table 3:
Univariable logistic regression analysis evaluating histologic findings in inactive EoE patients from University of Pennsylvania as predictors of clinical outcomes
| Predictor | n | OR (95% CI) | p | |
|---|---|---|---|---|
| Symptoms | ||||
| BCH | 142 | 2.14 (1.03–4.42) | 0.041 | |
| Spongiosis | 142 | 0.82 (0.39–1.71) | 0.591 | |
| Eosinophil count | 142 | 1.04 (0.96–1.13) | 0.353 | |
| EGD findings | ||||
| BCH | 145 | 7.10 (3.12–16.18) | <0.001 | |
| Spongiosis | 145 | 2.17 (0.99–4.72) | 0.052 | |
| Eosinophil count | 145 | 1.17 (1.07–1.28) | 0.001 | |
BCH, basal cell hyperplasia; CI, 95% confidence interval; EGD, esophagogastroduodenoscopy; OR, odds ratio
Figure 1: Relationship between basal cell hyperplasia (BCH) and specific symptoms in inactive patients.
At time of endoscopy. Inactive EoE patients were surveyed about symptomatology. Bar diagram represents the percentage of inactive EoE patients reporting any symptom or each individual symptom In relation to patient BCH status. Note that a greater percentage of Inactive patients displaying BCH reported symptoms.
Validation of BCH in inactive EoE
Given that BCH in inactive EoE patients is uniquely associated with presence of both symptoms and endoscopic findings, we aimed to further validate this phenotype. We first confirmed the accuracy of H&E-based eosinophil scoring via immunostaining for eosinophil major basic protein (Supplementary Figure S2A, B). Data acquired from the University of Pennsylvania inactive EoE cohort fails to account for duration of disease inactivity, a potential confounding variable. Importantly, time since last active scope in this cross-sectional inactive EoE cohort was comparable in patients with (Median 240 days, Range 63–3033) and without BCH (Median 250 days, Range 63–2245) (p=0.820) (Supplementary Figure S3). Finally, longitudinal analysis of an independent patient cohort recruited at UNC upon incident EoE diagnosis (Table 4) revealed that 26% of patients displaying histologic therapeutic response (<15 eos/hpf) maintained a BCH score of 1 (Table 5). BCH was highly prevalent in patients with active EoE, with 84% of EoE cases at baseline and 86% of post-therapeutic non-responders (≥15 eos/hpf) displaying a BCH score ≥1. Frequency of BCH-positive patients was significantly different when comparing responders to non-responders (p<0.001) (Table 5), validating maintenance of BCH in a subset of inactive EoE patients. Notably, maintained spongiosis was also documented in 77% of UNC non-responders (Table 5).
Table 4:
Demographics in University of North Carolina subjects (n=99)
| Non-EoE controls (n=50) | EoE cases (n=49) | |
|---|---|---|
| Age (Mean yrs ± SD) | 48.8 ± 15.1 | 38.7 ± 13.8 |
| White (n, %) | 35 (70) | 48 (98) |
| Male (n, %) | 17 (34) | 32 (65) |
| Dysphagia, n (%) | 34 (68) | 47 (96) |
| Heartburn | 26 (52) | 10 (20) |
| Dysphagia, n (%) | 34 (68) | 47 (96) |
| Nausea/vomiting | 4 (8) | 1 (2) |
| Abdominal pain | 4 (8) | 5 (10) |
| Eosinophil count (Mean ± SD) | 0 ± 0 | 123.2 ± 81.1 |
| Dilation performed | 5 (10) | 16 (33) |
EoE, eosinophilic esophagitis; SD, standard deviation
Table 5:
Prevalence of BCH and spongiosis in incident EoE cases and post-therapeutic responders or non-responders in UNC cohort
| Incident EoE (n=49) |
Non-responders (n=14) |
Responders (n=35) |
Incident EoE vs. Non-responders |
Non-Responders vs. Responders |
|
|---|---|---|---|---|---|
| Eosinophil Count (Mean ± SD) | 145.6 ± 130.8 | 154.3 ± 69.0 | 6.9 ± 17.6 | 0.83 | < 0.001 |
| BCH Score |
Incident EoE n (%) |
Non-responders n (%) |
Responders n (%) |
||
| 0 | 8 (16) | 2 (14) | 26 (74) | ||
| 1 | 28 (57) | 5 (36) | 9 (26) | ||
| 2 | 12 (24) | 6 (43) | 0 (0) | ||
| 3 | 1 (2) | 1 (7) | 0 (0) | ||
| BCH | |||||
| Present | 41 (84) | 12 (86) | 9 (26) | 1 | < 0.001 |
| Spongiosis Score | Incident EoE n (%) | Non-responders n (%) | Responders n (%) | ||
| 0 | 1 (2) | 0 (0) | 8 (23) | ||
| 1 | 35 (71) | 7 (50) | 26 (74) | ||
| 2 | 13 (27) | 7 (50) | 1 (3) | ||
| Spongiosis | |||||
| Present | 48 (98) | 14 (100) | 27 (77) | 1 | 0.05 |
BCH, basal cell hyperplasia, SD, standard deviation
Discussion
Measuring EoE treatment response is challenging, and may not be fully accounted for by peak eosinophil count11. Indeed, symptoms and endoscopic findings often do not correlate with eosinophil count in treated patients10,14,15,9. Here, we identify a significant population of EoE patients in histologic remission (defined by peak eosinophil count <15 eos/hpf) who continue to display symptoms along with epithelial changes and endoscopic findings. We provide evidence that BCH-positive inactive EoE patients are significantly more likely to exhibit ongoing symptoms and endoscopic findings. Thus, utilizing BCH as a histologic read-out in addition to eosinophil count, may better reflect overall histologic activity as well as the patient’s global state.
Accuracy of eosinophil count as the sole diagnostic and therapeutic parameter in EoE has been questioned16, 17. An histologic scoring system using 8 features of EoE (EoEHSS) was recently developed12 and validated18 to better identify treatment status. Our study complements this work, focusing upon the clinical relevance of maintained alterations specifically in esophageal epithelium of EoE patients in clinical remission. In the common clinical conundrum of low eosinophil counts and continued symptoms, it may be useful to consider a more in-depth look at epithelial tissue architecture and BCH presence may warrant treatment escalation. While we specifically investigate 3 of the 8 components of EoEHSS, these were the 3 most common findings in the EoE esophagus, allowing for more broad applicability.
Patients with improved histologic findings have more favorable long-term outcomes in EoE19–21. We show that there are ongoing epithelial changes in up to 73% of inactive patients. Tolerance of modest pathologic findings in the esophagus is likely due to economic and social burdens associated with EoE therapy22–25; however, it is unknown whether this degree of disease activity halts fibrostenotic progression26. We have previously shown that esophageal keratinocytes stimulate subepithelial fibroblasts to produce profibrotic cytokines27, 28. Additionally, esophageal keratinocytes stimulated with transforming growth factor-β produce enhanced plasminogen activator inhibitor-129 which correlates with BCH and fibrosis. These findings suggest biologic activity of esophageal epithelium and a potential role in the development of EoE complications, specifically fibrosis. While the current study only evaluates the epithelium, the most readily available esophageal tissue, eosinophils are present in lamina propria of EoE patients30, raising the possibility that ongoing eosinophilia in the lamina propria is promoting symptoms and epithelial changes in inactive EoE. As technology advances to interrogate lamina propria, evaluating the role of submucosa EoE in symptomatology could be an interesting area of research19,31,32.
There are a number of possible limitations to this study. BCH is a feature of inflammatory conditions in the esophagus, including GERD and nonerosive esophageal reflux disease. As the current study does not include patients these conditions, it remains to be determined whether BCH will prove useful in distinguishing EoE from other types of esophageal inflammation. Notably, all patients in our study were on high-dose PPI at the time of biopsy procurement, making it unlikely that reflux esophagitis was the cause of maintained BCH, symptoms, and EGD findings in inactive EoE. The use of human subjects reporting symptoms warranting EGD, yet displaying no abnormalities in esophageal mucosa as “non-EoE” controls may also be interpreted as a weakness. An ideal control for this study would be healthy human subjects with no esophageal symptoms; however, acquisition of endoscopic biopsies from such individuals, for example healthy volunteers, is associated with significant cost as well as ethical issues associated with elective administration of general anesthesia, particularly in pediatric subjects. An EoE-specific scoring system, such as Pediatric Eosinophilic Esophagitis Symptom Scores33 was not used for symptom assessment, and many endoscopic reports that were reviewed did not use EoE Endoscopic Reference Score34, 35. At the time of study design and data collection, these assessment tools had not been published and were not routinely used. Notably, our data may be more reflective of general clinical practice given that many gastroenterologists may not use assessment tools regularly. Although we validated maintained BCH in a subset of inactive EoE patients in two independent cohorts, the age distribution in these cohorts differed with pediatric and adult subjects comprising University of Pennsylvania subjects whereas the UNC cohort consisted exclusively of adults. Validation of findings in age-matched cohorts should be performed.
Likelihood of fibrotic remodeling increases with age in EoE26 and has been attributed to disease chronicity and not inherent age-associated differences in EoE as disease entity; however, studies comparing BCH as a predictor of maintained symptoms and EGD findings in pediatric and adult subjects may prove interesting. Symptoms and EGD findings were both associated with BCH on a binary (present versus absent) basis in the current study. While this draws the question of whether BCH is predictive of specific symptoms or macroscopic mucosal alterations, such studies may prove complicated. Indeed, as many young patients are not able to report symptoms themselves, we relied upon parental report which has recently been shown to accurately reflect patient symptoms.36 More in-depth studies into the relationship between BCH and EGD findings may be impacted by inter-observer variability as one study indicated fair to good inter-observer agreement with rings and plaques, but poor agreement in terms of plaques and no findings37.
This study also has numerous strengths. Utilizing a large number of pediatric and adult patients, we demonstrate that BCH and DIS remain prevalent in inactive EoE, defined as <15 eos per hpf. We include a longitudinal cohort from an independent institution, further supporting the principle that BCH is a relevant indicator of EoE disease activity. We performed dedicated histopathologic review for this study and utilized a histologic evaluation of BCH and DIS that can be easily adapted by pathologists in the clinical setting without special stains. We rigorously validated eosinophil counts with by immunohistochemistry.
In conclusion, we have identified persistent BCH and DIS in patients with EoE defined to be in remission based upon peak eosinophil count. BCH specifically correlates with ongoing symptoms and endoscopic findings. These findings may impact EoE clinical practice by offering BCH as an easily assessable histologic parameter that can be used to define disease activity and assist in decision making, particularly in EoE patients exhibiting <15 eos/hpf following therapeutic intervention.
Supplementary Material
Human esophageal endoscopic biopsy specimens stained with Hematoxylin & Eosln were evaluated for basal cell content. BCH score 0 Indicates that >20% of epithelial thickness is compnsed of basal cells. BCH score 1 indicates that 20–50% of epithelial thickness Is comprised of basal cells. BCH score 2 indicates that 50–75% of the epithelial thickness is comprised of basal cells. BCH score 3 indicates that 76–100% of epithelial thickness is comprised of basal cells. Representative bright field images for each score. Scale bar. 100 μm.
Need to Know.
Background:
Although eosinophil count is used to monitor disease activity in patients with eosinophilic esophagitis (EoE), there are often disparities between patients’ symptoms and eosinophil counts. We studied the prevalence of epithelial alterations, such as basal cell hyperplasia (BCH) and spongiosis, in patients with EoE considered to be in remission (peak eosinophil counts below 15).
Findings:
We identified patients in 2 different cohorts who had inactive EoE, based on histologic factors, but ongoing BCH and spongiosis. Ongoing BCH, but not spongiosis, in patients with inactive EoE was associated with symptoms.
Implications for Patient Care:
In patients with EoE, the presence of BCH might indicate continued disease activity, regardless of eosinophil count. This might account for the persistent symptoms in patients who are considered to be in remission based on histologic factors.
Acknowledgements:
We appreciate the support of Dr. Anil K. Rustgi and the members of his laboratory. We thank Ben Rhodes, Yuriko Kimura and Kana Harada for technical support. We thank Hamid Moattari and the CHOP Pathology division for assisting us in obtaining patient biopsies.
Grant Support: This study was supported by the following NIH Grants: T32 DK007066 (KAW, BG) R01DK114436 (HN), K01DK103953 (KAW), R03DK118304 (KAW), K08DK106444 (ABM), K08DK099379 (BJW), K23DK90073 (ESD), Molecular Pathology and Imaging Core, Host-Microbial Analytic and Repository Core and Cell Culture and iPS Core Facilities at the NIH/NIDDK P30-DK050306 Center of Molecular Studies in Digestive and Liver Diseases (P30DK050306) and Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)(U54AI117804). CEGIR is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. CEGIR is also supported by patient advocacy groups including APFED CURED and EFC. Additional support was provided by GEGIR Trainee Award (ABM), NASPGHAN FOUNDATION/Takeda Pharmaceutical Products Inc. Research Innovation Award (HN) and University of Pennsylvania Center for Molecular Studies in Digestive and Liver Diseases Pilot and Feasibility Grants (KAW, HN).
Abbreviations:
- BCH
basal cell hyperplasia
- CHOP
Children’s Hospital of Philadelphia
- DIS
dilated intercellular spaces
- EGD
esophagogastroduodenoscopy
- EoE
eosinophilic esophagitis
- Eos/hpf
eosinophils per high-powered field
- GERD
gastro-esophageal reflux disease
- GI
gastrointestinal
- H&E
Hematoxylin and Eosin
- HUP
Hospital of the University of Pennsylvania
- IHC
immunohistochemistry
- MBP
major basic protein
- PPI
proton pump inhibitor
- UNC
University of Carolina
Footnotes
Disclosures None
Ethics approval Human patient studies were approved by the Institutional Review Board at Children’s Hospital of Pennsylvania, Hospital of the University of Pennsylvania and University of North Carolina.
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Supplementary Materials
Human esophageal endoscopic biopsy specimens stained with Hematoxylin & Eosln were evaluated for basal cell content. BCH score 0 Indicates that >20% of epithelial thickness is compnsed of basal cells. BCH score 1 indicates that 20–50% of epithelial thickness Is comprised of basal cells. BCH score 2 indicates that 50–75% of the epithelial thickness is comprised of basal cells. BCH score 3 indicates that 76–100% of epithelial thickness is comprised of basal cells. Representative bright field images for each score. Scale bar. 100 μm.