Determination of Biopsy Yield That Optimally Detects Eosinophilic Gastritis and/or Duodenitis in a Randomized Trial of Lirentelimab

Abstract

Background & aims: Eosinophilic gastritis (EG) and eosinophilic duodenitis (EoD), characterized by chronic gastrointestinal (GI) symptoms and increased numbers or activation of eosinophils and mast cells in the GI tract, are likely underdiagnosed. We aimed to determine rates of EG and EoD and number of biopsies required to optimize detection using screening data from a randomized trial of lirentelimab (AK002), an antibody against siglec-8 that depletes eosinophils and inhibits mast cells. We also characterized endoscopic features and symptoms of EG and EoD.

Methods: Subjects with moderate-to-severe GI symptoms, assessed daily through a validated patient-reported outcome questionnaire, underwent endoscopy with a systematic gastric and duodenal biopsy protocol and histopathologic evaluation. EG diagnosis required presence of ≥30 eosinophils/high-power field (eos/hpf) in ≥5 hpfs and EoD required ≥30 eos/hpf in ≥3 hpfs. We analyzed diagnostic yields for EG and EoD and histologic, endoscopic, and clinical findings.

Results: Of 88 subjects meeting symptom criteria, 72 were found to have EG and/or EoD (EG/EoD), including patients with no prior diagnosis of EG/EoD. We found that GI eosinophilia was patchy and that examination of multiple biopsies was required for diagnosis-an average of only 2.6 per 8 gastric biopsies and 2.2 per 4 duodenal biopsies per subject met thresholds for EG/EoD. Evaluation of multiple nonoverlapping hpfs in each of 8 gastric and 4 duodenal biopsies was required to capture 100% of EG/EoD cases. Neither endoscopic findings nor symptom severity correlated with eosinophil counts.

Conclusions: In an analysis of patients with moderate-to-severe GI symptoms participating in a clinical trial of lirentelimab for EG/EoD, we found eosinophilia to be patchy in gastric and duodenal biopsies. Counting eosinophils in at least 8 gastric and 4 duodenal biopsies is required to identify patients with EG/EoD, so they can receive appropriate treatment. (ClinicalTrials.gov, Number: NCT03496571).

Keywords: EGID; Eosinophilic Enteritis; Histology; Immune Cell.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Biopsy and Histopathology Protocol and EG/EoD Diagnostic Criteria.

Criteria used for systematic biopsy collection, histopathologic examination, and diagnosis of EG/EoD.

Figure 2.. Number of Biopsies Required to Optimize Detection of EG/EoD.

(A, B) Cumulative percent of EG cases (A) and EoD cases(B) that would be captured by minimum number of biopsies out of a total of 8 gastric and 4 duodenal biopsies collected per subject. (C, D) Heatmaps showing the number of positive hpfs per biopsy collected during screening EGD for each EG/EoD subject. Vertical columns contain data for each subject with EG or EoD, horizontal rows contain data for each biopsy, and each cell contains the number of positive hpfs (those with ≥30 eos); cells are color-coded on a scale from green to red, with red indicating fewer positive hpfs. Diagnostic thresholds could be met with any combination of 5 hpfs in the stomach and/or any combination of 3 hpfs in the duodenum. (C) Heatmap of 45 subjects with EG, showing number of positive hpfs in each of 8 gastric biopsies (4 from corpus and 4 from antrum). (D) Heatmap of 62 subjects with EoD, showing number of positive hpfs in each of 4 duodenal biopsies. One patient in each analysis (C, D) did not meet the histologic threshold with the standard 8 gastric and 4 duodenal biopsies but did meet the threshold with collection of additional gastric and duodenal biopsies from areas of interest during screening EGD, as permitted per protocol.

Figure 2.. Number of Biopsies Required to Optimize Detection of EG/EoD.

(A, B) Cumulative percent of EG cases (A) and EoD cases(B) that would be captured by minimum number of biopsies out of a total of 8 gastric and 4 duodenal biopsies collected per subject. (C, D) Heatmaps showing the number of positive hpfs per biopsy collected during screening EGD for each EG/EoD subject. Vertical columns contain data for each subject with EG or EoD, horizontal rows contain data for each biopsy, and each cell contains the number of positive hpfs (those with ≥30 eos); cells are color-coded on a scale from green to red, with red indicating fewer positive hpfs. Diagnostic thresholds could be met with any combination of 5 hpfs in the stomach and/or any combination of 3 hpfs in the duodenum. (C) Heatmap of 45 subjects with EG, showing number of positive hpfs in each of 8 gastric biopsies (4 from corpus and 4 from antrum). (D) Heatmap of 62 subjects with EoD, showing number of positive hpfs in each of 4 duodenal biopsies. One patient in each analysis (C, D) did not meet the histologic threshold with the standard 8 gastric and 4 duodenal biopsies but did meet the threshold with collection of additional gastric and duodenal biopsies from areas of interest during screening EGD, as permitted per protocol.

Figure 2.. Number of Biopsies Required to Optimize Detection of EG/EoD.

(A, B) Cumulative percent of EG cases (A) and EoD cases(B) that would be captured by minimum number of biopsies out of a total of 8 gastric and 4 duodenal biopsies collected per subject. (C, D) Heatmaps showing the number of positive hpfs per biopsy collected during screening EGD for each EG/EoD subject. Vertical columns contain data for each subject with EG or EoD, horizontal rows contain data for each biopsy, and each cell contains the number of positive hpfs (those with ≥30 eos); cells are color-coded on a scale from green to red, with red indicating fewer positive hpfs. Diagnostic thresholds could be met with any combination of 5 hpfs in the stomach and/or any combination of 3 hpfs in the duodenum. (C) Heatmap of 45 subjects with EG, showing number of positive hpfs in each of 8 gastric biopsies (4 from corpus and 4 from antrum). (D) Heatmap of 62 subjects with EoD, showing number of positive hpfs in each of 4 duodenal biopsies. One patient in each analysis (C, D) did not meet the histologic threshold with the standard 8 gastric and 4 duodenal biopsies but did meet the threshold with collection of additional gastric and duodenal biopsies from areas of interest during screening EGD, as permitted per protocol.

Figure 2.. Number of Biopsies Required to Optimize Detection of EG/EoD.

(A, B) Cumulative percent of EG cases (A) and EoD cases(B) that would be captured by minimum number of biopsies out of a total of 8 gastric and 4 duodenal biopsies collected per subject. (C, D) Heatmaps showing the number of positive hpfs per biopsy collected during screening EGD for each EG/EoD subject. Vertical columns contain data for each subject with EG or EoD, horizontal rows contain data for each biopsy, and each cell contains the number of positive hpfs (those with ≥30 eos); cells are color-coded on a scale from green to red, with red indicating fewer positive hpfs. Diagnostic thresholds could be met with any combination of 5 hpfs in the stomach and/or any combination of 3 hpfs in the duodenum. (C) Heatmap of 45 subjects with EG, showing number of positive hpfs in each of 8 gastric biopsies (4 from corpus and 4 from antrum). (D) Heatmap of 62 subjects with EoD, showing number of positive hpfs in each of 4 duodenal biopsies. One patient in each analysis (C, D) did not meet the histologic threshold with the standard 8 gastric and 4 duodenal biopsies but did meet the threshold with collection of additional gastric and duodenal biopsies from areas of interest during screening EGD, as permitted per protocol.

Figure 3.. Histologic Features.

(A) High-power (20X) images of EG/EoD specimens showing patchiness of eosinophils in different biopsies from the same subject (left) and among different hpfs from the same biopsy (right). (B) Peak number of gastric (left) and duodenal (right) eos/hpf in subjects with EG and EoD. Green dotted line indicates median peak eos/hpf. (C) Peak gastric (left) and duodenal (right) mast cell (MC) counts in subjects who met histologic criteria for EG/EoD. The histologic criteria for elevated MCs is ≥30 MCs/hpf (above gray area)(, –34); green dotted line indicates median peak MCs/hpf in patients with EG/EoD.

Figure 3.. Histologic Features.

(A) High-power (20X) images of EG/EoD specimens showing patchiness of eosinophils in different biopsies from the same subject (left) and among different hpfs from the same biopsy (right). (B) Peak number of gastric (left) and duodenal (right) eos/hpf in subjects with EG and EoD. Green dotted line indicates median peak eos/hpf. (C) Peak gastric (left) and duodenal (right) mast cell (MC) counts in subjects who met histologic criteria for EG/EoD. The histologic criteria for elevated MCs is ≥30 MCs/hpf (above gray area)(, –34); green dotted line indicates median peak MCs/hpf in patients with EG/EoD.

Figure 3.. Histologic Features.

(A) High-power (20X) images of EG/EoD specimens showing patchiness of eosinophils in different biopsies from the same subject (left) and among different hpfs from the same biopsy (right). (B) Peak number of gastric (left) and duodenal (right) eos/hpf in subjects with EG and EoD. Green dotted line indicates median peak eos/hpf. (C) Peak gastric (left) and duodenal (right) mast cell (MC) counts in subjects who met histologic criteria for EG/EoD. The histologic criteria for elevated MCs is ≥30 MCs/hpf (above gray area)(, –34); green dotted line indicates median peak MCs/hpf in patients with EG/EoD.

Figure 4.. Endoscopic Appearance.

(A) Percent of EG subjects with each EG-REFS score (0= normal and 1=mild). (B) Percent of subjects with each EG-REFS. (C) Percent of subjects with endoscopic abnormalities (EG-REFS >0) in any area of stomach. (D) Box and whisker plot (Tukey method) of subjects with (blue) and without (gray) histologic EG. No EG indicates subjects who did not meet histologic criteria for EG or EoD (n=15) or who met histologic criteria for only EoD (n=26). One subject from the EG group and 2 from the No EG group were not assessed by EG-REFS at screening and are not included in analysis. P value calculated by 2-sample t test.

Figure 4.. Endoscopic Appearance.

(A) Percent of EG subjects with each EG-REFS score (0= normal and 1=mild). (B) Percent of subjects with each EG-REFS. (C) Percent of subjects with endoscopic abnormalities (EG-REFS >0) in any area of stomach. (D) Box and whisker plot (Tukey method) of subjects with (blue) and without (gray) histologic EG. No EG indicates subjects who did not meet histologic criteria for EG or EoD (n=15) or who met histologic criteria for only EoD (n=26). One subject from the EG group and 2 from the No EG group were not assessed by EG-REFS at screening and are not included in analysis. P value calculated by 2-sample t test.

Figure 4.. Endoscopic Appearance.

(A) Percent of EG subjects with each EG-REFS score (0= normal and 1=mild). (B) Percent of subjects with each EG-REFS. (C) Percent of subjects with endoscopic abnormalities (EG-REFS >0) in any area of stomach. (D) Box and whisker plot (Tukey method) of subjects with (blue) and without (gray) histologic EG. No EG indicates subjects who did not meet histologic criteria for EG or EoD (n=15) or who met histologic criteria for only EoD (n=26). One subject from the EG group and 2 from the No EG group were not assessed by EG-REFS at screening and are not included in analysis. P value calculated by 2-sample t test.

Figure 4.. Endoscopic Appearance.

(A) Percent of EG subjects with each EG-REFS score (0= normal and 1=mild). (B) Percent of subjects with each EG-REFS. (C) Percent of subjects with endoscopic abnormalities (EG-REFS >0) in any area of stomach. (D) Box and whisker plot (Tukey method) of subjects with (blue) and without (gray) histologic EG. No EG indicates subjects who did not meet histologic criteria for EG or EoD (n=15) or who met histologic criteria for only EoD (n=26). One subject from the EG group and 2 from the No EG group were not assessed by EG-REFS at screening and are not included in analysis. P value calculated by 2-sample t test.