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Original Article: Gastroenterology: Eosinophilic GI Disorders

Eosinophilic Esophagitis Histology Remission Score: Significant Relations to Measures of Disease Activity and Symptoms

Collins, Margaret H.; Martin, Lisa J.; Wen, Ting; Abonia, Juan Pablo; Putnam, Philip E.§; Mukkada, Vincent A.§; Rothenberg, Marc E.

Author Information
Journal of Pediatric Gastroenterology and Nutrition: May 2020 - Volume 70 - Issue 5 - p 598-603
doi: 10.1097/MPG.0000000000002637

Abstract

What Is Known

  • For diagnosis of eosinophilic esophagitis, consensus recommendations include a threshold of ≥15 eosinophils in at least 1 high power field of esophageal biopsies. Recommendations defining remission do not exist.
  • The eosinophilic esophagitis histology scoring system evaluates eosinophil inflammation and other pathologic features, and better identifies treatment status than peak eosinophil count.

What Is New

  • An eosinophilic esophagitis histology remission score is derived from the eosinophilic esophagitis histology scoring system.
  • The remission score significantly correlates with reduced symptoms scores and biomarker expression (eosinophil peroxidase deposition and mast cell markers) and therefore may be useful to define histologic remission.

Eosinophilic esophagitis (EoE) is a chronic disorder characterized by remissions and relapses. The goals of therapy in clinical care and research are to reduce eosinophil density below the threshold value for diagnosis, that is, 15 eosinophils per high power field (HPF), and to reduce symptoms. Although there are guidelines for diagnosis (1–6), guidelines for defining EoE remission, however, do not exist despite inconsistency in remission identification, and potentially inaccurate interstudy comparisons, especially of randomized clinical trials (7,8).

An EoE Histology Remission Score (EoEHRS) should signify improved pathology, including pathologic changes other than eosinophil density. We reported the validated EoE Histology Scoring System (EoEHSS) that evaluates multiple histopathologic features in esophageal biopsies and showed that it outperformed peak eosinophil count (PEC) to discriminate therapy-naïve patients from those who had received EoE treatment (9). We and others have reported very good to excellent interobserver agreement scores, demonstrating that the EoEHSS is reliable (9,10), and the EoEHSS may have broad applications such as studies of peanut allergy (11). The responsiveness of the EoEHSS has been documented in randomized clinical trials (12,13).

We therefore sought an EoEHRS derived from the EoEHSS that would correlate with reduced symptoms, and with other biomarkers of disease activity.

METHODS

We recently reported the validated PEESSv2.0 that asks 20 questions divided into domains based on user feedback: dysphagia, nausea and vomiting, gastroesophageal reflux disease, and pain (14). Frequency and severity of symptoms are reported; higher scores indicate greater symptom frequency and severity. We found that parent proxy PEESS v2.0 scores correlated significantly with patient scores (ρ = 0.58–0.78, P < 0.0001–0.005), a finding confirmed in our more recent study (15), and used parent proxy scores for the study reported herein. The EoEHSS instrument evaluates 8 features in esophageal biopsies (Supplemental Table 1, Supplemental Digital Content, https://links.lww.com/MPG/B770, lists features and shows definitions). The severity of the features (grade) and the extent of the alterations (stage) are scored separately. Biopsies obtained at the time PEESS v2.0 symptoms scores were acquired were evaluated in the usual manner for clinical care and were subsequently scored by 1 pathologist (M.H.C.) using the EoEHSS. The study was approved by the Institutional Review Board at Cincinnati Children's Hospital Medical Center.

Eosinophilic Esophagitis Histology Remission Score

Our goal was to identify a histology remission score using validated symptoms and histology scoring tools, and to compare the remission score to other activity biomarkers. A cohort having all these data comprised the subjects who participated in the construction of the PEESSv2.0 validated symptom scoring tool. Forty-two of those 46 subjects (14) completed PEESSv2.0 questionnaires ≤30 days of the date that biopsies used for this study were obtained (most were completed on the day of the concurrent endoscopy), and 16 subjects had 2 study visits meeting this criterion. Not all slides were available for review, and recut slides could not be obtained for some because of exhausted paraffin blocks. We therefore used data from 58 sets of biopsies (116 biopsies total) from 42 of 46 subjects (14) for the remission score analysis with symptoms correlations. We used the validated EoEHSS to define histology remission. Each feature in the EoEHSS is scored on a scale of 0 to 3 (0 = normal, 3 = most marked change). Extensive personal experience (M.H.C.) reviewing EoE biopsies reveals that a total grade or stage score ≤3 is frequent after therapy. A common goal for EoE therapy is to reduce eosinophil inflammation, specifically to PEC <15/HPF, the threshold value for EoE diagnosis. Therefore we decided that the remission score would include BOTH grade and stage scores ≤3 AND scores defining PEC <15/HPF. To accomplish this, grade score could be 0 (signifying no intraepithelial eosinophils) or 1 (signifying 1–14 eosinophils/HPF), but not >1 because those scores correspond to PEC ≥15/HPF (Supplemental Table 1, Supplemental Digital Content, https://links.lww.com/MPG/B770, shows EoEHSS scores for eosinophilic inflammation). The stage score for PEC <15/HPF is 0, and was required for remission. Eosinophil inflammation was the only EoEHSS score for which a limit was set to define remission; grade scores for all other features that exceeded 1 did not disqualify a biopsy from remission status so long as the total grade score was ≤3 (Supplemental Table 2, Supplemental Digital Content, https://links.lww.com/MPG/B770 illustrates remission calculations). To determine the effect on symptoms of remission at 1 versus both sites, full remission was defined as EoEHRS scores showing remission in proximal and distal biopsies, and partial remission was defined as an EoEHRS remission score in 1 but not both sites. To summarize, histology remission was defined as grade score ≤3 (score for eosinophil inflammation must be ≤1), and stage score ≤3 (score for eosinophil inflammation must be 0).

Biologic Measures of Disease Activity

These methods are reported in detail in the supplemental information of our prior work and included mast cell evaluations and eosinophil protein deposition scoring (14). For these analyses, paraffin blocks from both proximal and distal biopsies were available for 40 of 42 subjects. Briefly, slides were stained with antibody to tryptase (Cell Marque, Rocklin, CA) or chymase (AbD Serotec, Raleigh, NC). Immunohistochemistry for eosinophil peroxidase was performed as previously described using an eosinophil-specific mouse monoclonal antibody (Clone: MM25–82.2.1) (16). For genetic markers of disease activity, total RNA was extracted from distal esophageal biopsies collected in RNA later (Qiagen, Valencia, CA, 76104) using the miRNeasy RNA Extraction Kit (Qiagen, 217004) and an aliquot of 500 ng of RNA was acquired by the iScript cDNA Synthesis Kit (BioRad Laboratories Hercules, CA 170-8891) following the manufacturer's manual protocol. Taqman real-time PCR amplification for tryptase and CPA3 was performed on an ABI 7900HT System (Applied Biosystems, Foster City, CA). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an expression control.

Statistical Analyses

To evaluate the relationship between EoEHSS and PEESS v2.0 scores, we used Spearman nonparametric correlation. EoEHSS individual features and composites of features were compared with PEESS v2.0 mean and domain scores. Composite EoEHSS scores included mean grade or mean stage scores across all features; eosinophil composite score consisting of the mean grade or mean stage scores for the features that include eosinophils in the definition (eosinophil inflammation, eosinophil abscess, eosinophil surface layering, and surface epithelial alteration), and noneosinophil composite score consisting of the mean grade or mean stage scores for the features that do not evaluate eosinophils (basal zone hyperplasia, dilated intercellular spaces, dyskeratotic epithelial cells, lamina propria fibrosis). Correlation coefficient range 0.00 to 0.30 was considered weak, 0.31 to 0.50 moderate, 0.51 to 0.80 strong, and 0.81 to 1.00 very strong. We employed P value threshold of ≤0.05 for significance since the EoEHSS features and PEESS domains exhibited substantial correlation. To compare subjects whose biopsies met remission criteria to subjects whose biopsies did not, Wilcoxon rank-sum tests were used.

RESULTS

Demographics

All 42 subjects were boys and 41 of 42 (98%) were white. Median age at diagnosis was 4.04 (interquartile range [IQR] 2.5–8.5, range 0. 8–15.2) years, and median age at participation in this study was 6.8 (IQR 4. 9–11.3, 2.4–16.4) years. Most subjects (41/42, 98%) were receiving therapies to treat EoE (swallowed steroids, diet modifications, or both).

Eosinophilic Esophagitis Histology Scoring System Scores Correlated More Strongly Than Peak Eosinophil Count With PEESS v2.0 Scores

Spearman correlations between the EoEHSS scores and the PEESSv2.0 domains revealed associations between total, dysphagia, pain, and gastroesophageal reflux disease (GERD), but not nausea and vomiting, scores and multiple scores of the EoEHSS (Table 1 shows significant correlations at P≤ 0.01; Supplemental Table 3, Supplemental Digital Content, https://links.lww.com/MPG/B770, shows significant correlations at P≤ 0.05, and Supplemental Table 4, Supplemental Digital Content, https://links.lww.com/MPG/B770, shows strongest symptom correlations for each EoEHSS feature). Specifically, moderate correlations occurred with the grade and stage scores for the overall grade composite score and the eosinophil composite score. Six individual features associated with symptoms, most frequently involving grade and stage scores for surface layering and eosinophil inflammation. Notably, pain scores correlated moderately with scores for both composites (0.48–0.37, P = <0.01) and for 4 individual features (surface epithelial alteration, surface layering, eosinophil inflammation, and eosinophil abscesses) (0.45–0.34, P≤ 0.01). Notably, PEC exhibited moderate and significant correlations with total scores, and pain and GERD domains that generally were weaker than the EoEHSS correlations; PEC also correlated weakly and insignificantly with dysphagia in contrast to the moderate and significant correlations of EoEHSS scores. The consistent correlations of EoEHSS composite and individual scores with several symptoms domain scores suggest that pathologic alterations other than PEC may contribute to many of the symptoms associated with EoE.

T1
TABLE 1:
Some Eosinophilic Esophagitis Histology Scoring System Composite and Individual Feature Scores Correlate With PEESSv2 Scores

Eosinophilic Esophagitis Histology Remission Scores Correlate Significantly With Reduced Symptoms Scores

Histology remission was based on the overall level of histological abnormality such that the sum of the EoEHSS features could not exceed 3 for either grade or stage within a biopsy; in addition, grade and stage scores signified PEC ≤15/HPF. Forty-four of 46 subjects (14) had proximal and distal biopsies obtained at all endoscopies including additional endoscopies (see Supplemental Table 8, Supplemental Digital Content, https://links.lww.com/MPG/B770, for demographics). As expected given the definition of remission, the median PEC for those in remission (1 [0–3]/HPF) was significantly lower than the median for those not in remission (52.0 [27–87]/HPF, P < 0.0001). Also among these 44 subjects, 10 had biopsies with remission scores at any endoscopy, 26 subjects never achieved remission, and 8 had biopsies with both remission and nonremission scores. A total of 54 biopsies with PEC ≤15/HPF (most with PEC ≤6/HPF) were obtained from 21 subjects at 1 or more endoscopies. A total of 82 biopsies with PEC ≥15/HPF were obtained from 30 subjects at 1 or more endoscopies, including 7 subjects who had biopsies with PEC ≤15/HPF at a different endoscopy. Four subjects who had PEC ≤15/HPF did not achieve remission due to the persistence of pathologic alterations other than PEC ≥15/HPF. Being in histology remission was not associated with age at diagnosis or duration of disease.

Among the 42 subjects who had proximal and distal esophageal biopsies and a PEESSv2.0 questionnaire completed ≤30 days of endoscopy, total symptoms scores and scores for the dysphagia, pain, and GERD, but not nausea and vomiting, domains as measured by PEESSv2.0 were significantly reduced in biopsies having remission scores determined by the EoEHRS (Table 2). Generally, partial remission PEESSv2.0 values were intermediate between full remission and no remission EoEHRS values for most symptoms, suggesting that full histologic remission is associated with greater symptom reduction than is partial remission (Table 3). For pain scores, partial remission symptom scores were almost identical to no remission scores strongly suggesting that more global remission is required for pain abatement. Conversely, compared to no remission, partial remission scores for GERD were significantly reduced, suggesting that global remission may not be as necessary for GERD symptom relief (Supplemental Table 5, Supplemental Digital Content, https://links.lww.com/MPG/B770, shows possible clinical responses to remission scores).

T2
TABLE 2:
PEESSv2.0 scores (median [IQR]) in subjects with and without histology remission
T3
TABLE 3:
PEESSv2.0 scores (median [IQR]) in subjects with full remission (all their biopsies had Eosinophilic Esophagitis Histology Remission Score in remission scores) versus partial remission (one of two of their biopsies had Eosinophilic Esophagitis Histology Remission Score in remission score)

Additional analyses showed some types of therapies were associated with significant reductions in some EoEHSS features (Supplemental Table 6 and Supplemental Fig. 1, Supplemental Digital Content, https://links.lww.com/MPG/B770, scatter plots show symptoms/features relations by therapy) but this finding must be confirmed with larger studies. Also, symptoms scores and EoEHSS features scores are lower in biopsies with PEC <15/HPF compared to ≥15/HPF (Supplemental Tables 7 and 8, Supplemental Digital Content, https://links.lww.com/MPG/B770, respectively).

Eosinophilic Esophagitis Histology Remission Score Correlated With Reduced Biologic Measures of Disease Activity

In our prior work with PEESSv2.0, we found both genetic and histologic EoE biomarkers were associated with symptoms (14). For histologic studies we used 80 biopsies from 40 subjects (all white boys, age 6.5 [IQR 4.8–10.9] range 2.5–16.1 years). We now show that biopsies with EoEHRS had reduced CPA3 gene expression (P = 0.0022), and reduced tryptase gene expression (P = 0.0088) (Table 4). In addition, biopsies with histologic remission had reduced numbers of tryptase-positive cells (P = 0.0005), reduced numbers of chymase-positive cells (P = 0.028), and reduced eosinophil peroxidase total staining value (P = 0.013) (Table 4). These associations with reduced expressions of genetic and histologic biomarkers support the relevance of this histology remission score.

T4
TABLE 4:
Eosinophilic esophagitis biologic disease activity (median [IQR]) in subjects with and without histology remission

DISCUSSION

We report that the EoEHSS scores (composite and individual features) correlate, more strongly than PEC, with total symptoms scores, and dysphagia, GERD and pain domains scores, as measured by the validated PEESSv2.0 tool. The EoEHRS we identify is strongly associated with reduced markers of disease activity, and patients with biopsies showing EoEHRS have significantly lower symptoms scores.

Eosinophilic Esophagitis Histology Remission Score Correlates With Reduced Biomarker Expression

An unmet need in EoE clinical care and research is determining therapeutic endpoints for children and adults (7,8). Virtually all studies define histology remission based on a single pathologic feature, eosinophil density (7,8). We suggest a histology remission score suitable for clinical care and research that evaluates pathology in addition to eosinophil density. Our EoEHRS requires PEC <15/HPF, and observed grade and stage scores that do not exceed 3. The recommendation is based on the extensive personal experience of 1 pathologist that may be unique and uncorroborated, but may also be valid and valuable, especially considering the significant relationships with reduced symptoms scores and biomarker levels.

Mast cells may be important markers of EoE disease activity (17,18). We show that remission biopsies have significantly reduced CPA3 and tryptase gene expression, and reduced tryptase-positive and chymase-positive cells. The validity of the definition of histology remission recommended herein is supported by significant reductions in mast cell biomarkers in biopsies meeting these remission criteria.

Eosinophilic Esophagitis Histology Scoring System Scores Correlate With Symptoms

Several single- and multi-institutional randomized clinical trials reported reduced eosinophil inflammation in esophageal biopsies following therapy for EoE, but not all reported corresponding improvements in clinical symptoms (12,19–25). These data strongly suggest that a single aspect of esophageal biopsy pathology, eosinophil density, is not sufficient to explain EoE symptoms.

Herein we report that among all subjects in this study, we found moderate correlations between both composite and individual EoEHSS feature scores and 3 of 4 PEESS v2.0 domains. Notably, many correlations occurred with the pain domain. Pain is an often persistent understudied EoE symptom (26), and abdominal pain was reported by 47.8% of subjects in this study (14). Pain is not related exclusively to PEC because pediatric EoE patients with PEC <15/HPF reported pain as frequently as those with PEC ≥15/HPF (27). These data suggest that to alleviate pain reducing PEC is insufficient, but improving the pathology features measured by the EoEHSS may be beneficial.

The EoEHSS is used to score biopsies of the Consortium of Eosinophilic Gastrointestinal Researchers (CEGIR, www.rdcrn.org/cegir), a part of the Rare Disease Clinical Research Network (28). An observational CEGIR study of pediatric subjects found that EoEHSS composite scores correlated moderately with PEESSv2.0 scores (individual features correlations with symptoms were not studied) in proximal, but not distal, esophageal biopsies (15); in this study correlations with symptoms in both proximal and distal biopsies were found. In the CEGIR study there were correlations with GERD and nausea/vomiting PEESSv2.0 domains, whereas herein we report moderate correlations with mean scores, dysphagia, GERD, and pain domains scores. Additional studies examining the relationship between EoEHSS scores and symptoms scores using validated instruments in various populations are required to further explore the relationships of EoEHSS with symptoms. Important implications of each study are that pathologic features other than PEC may be important in symptom generation, and those features should be evaluated before and after therapy, and symptoms are influenced by both the severity of the pathologic changes (grade) and the amount of tissue affected (stage). The CEGIR study did not uncover moderate correlations between histology and symptoms in biopsies from the distal esophagus, but such correlations were found in this study and we believe continuing to biopsy more than 1 site in the esophagus is prudent, especially considering the greater symptom reduction generally associated with full compared to partial remission.

We previously scored eosinophil peroxidase deposition in the biopsies reported in this study, and found significant correlations between those scores in distal esophageal biopsies and the PEESSv2.0 dysphagia domain (14,16). The current data were obtained using routine hematoxylin and eosin (H&E) stains, not immunohistochemical stains that add to cost and turn-around time. The H&E-based analyses showed significant correlations in proximal and distal biopsies for EoEHSS scores with dysphagia PEESSv2.0 domain scores, and also mean and pain scores. Thus, the EoEHSS features more broadly correlate with symptoms than eosinophil granule deposition.

Study Limitations

Although this study comprises a small number of subjects, it also comprises a substantial number of biopsies from a well-characterized cohort of pediatric patients with EoE. We performed many comparisons and thus the possibility exists that some of those significant correlations occurred by chance. Nevertheless, stronger correlations for EoEHSS features with symptoms compared to PEC may be clinically meaningful, and deserve attention and continued exploration.

CONCLUSIONS

We documented that EoEHSS composite and individual features correlated moderately with PEESS v2.0 mean scores, and dysphagia, GERD, and pain domains scores, whereas PEC correlated less strongly with those scores. We propose a score for histology remission that includes evaluation of features in addition to PEC and correlates with significant biomarkers reduction and symptom reduction. These data may potentially guide clinical care in a more directed and personalized manner, and could be suitable as endpoints for randomized clinical trials.

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Keywords:

Eosinophilic Esophagitis Histology Remission Score; Eosinophilic Esophagitis Histology Scoring System; eosinophilic esophagitis pain; pathology; pediatric; scale

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