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J Allergy Clin Immunol Pract. Author manuscript; available in PMC 2023 June 01.
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Published in final edited form as:

J Allergy Clin Immunol Pract. 2022 June ; 10(6): 1598–1605.e2. doi:10.1016/j.jaip.2022.02.037.

Benralizumab Completely Depletes Gastrointestinal Tissue

Eosinophils and Improves Symptoms in Eosinophilic
Gastrointestinal Disease
Fei Li Kuang, MD, PhDa,b,
Michelly Sampaio De Melo, MDc,d,
Michelle Makiya, MSb,
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Sheila Kumar, MDe,

Thomas Brownb,
Lauren Wetzlerb,
JeanAnne M. Ware, MSN, MPHb,
Paneez Khoury, MDb,
Margaret H. Collins, MDf,
Martha Quezado, MDc,d,
Stefania Pittaluga, MD, PhDc,d,
Amy D. Klion, MDb
aDivision of Allergy Immunology, Northwestern University Feinberg School of Medicine, Chicago,
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Ill
bHuman Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, Md
cLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National
Institutes of Health, Bethesda, Md
dHuman Eosinophil Section, LPD/National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, Md
eDigestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, Md
fDivisionof Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center,
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University of Cincinnati College of Medicine, Cincinnati, Ohio

Abstract

Corresponding author: Fei Li Kuang, MD, PhD, Northwestern University Feinberg School of Medicine, 240 East Huron St, M-307,
Chicago, IL 60611. feili.kuang@northwestern.edu.
Conflicts of interest: F. L. Kuang receives research support from AstraZeneca to conduct mechanistic studies in an ongoing phase 3
study of benralizumab treatment for hypereosinophilic syndromes. The rest of the authors declare that they have no relevant conflicts
of interest.
 Kuang et al. Page 2

BACKGROUND: Previous studies of targeted eosinophil biologics in eosinophilic esophagitis

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have yielded mixed results. Possible explanations include incomplete eosinophil depletion with
anticytokine (anti–IL-5) treatments and/or irreversible fibrotic tissue changes contributing to
symptomatology.

OBJECTIVE: To characterize the therapeutic effect of eosinophil depletion in patients with

hypereosinophilic syndrome with varied eosinophilic gastrointestinal (GI) disorders.

METHODS: Hematologic, histologic, endoscopic, and clinical symptoms for a subset (n = 7) of

hypereosinophilic syndrome patients with GI tissue eosinophilia enrolled in a phase 2 clinical trial
of benralizumab (anti–IL-5RA) were assessed before and after treatment (NCT02130882).

RESULTS: Blood and GI tissue eosinophils were completely depleted in all segments of the
GI tract, and all patients reported improved GI symptoms, in some cases as early as after the
first monthly dose. Some patients had recurrent symptomatic flares without recurrent peripheral
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or tissue eosinophilia, in most cases after prolonged symptomatic remission and in the setting of
liberalization of dietary restrictions and/or tapering of background therapy. Although eosinophil-
associated histologic changes improved in all segments, epithelial changes persisted in the
esophagus and stomach in patients with recurrent disease flares even after 1 year of treatment.
Serum tryptase and GI mast cells were generally unchanged with treatment, and increases were
not associated with disease flares. Serum levels of IL-4 and IL-5 increased with benralizumab
treatment (both P < .05).

CONCLUSIONS: Benralizumab treatment completely depleted blood and GI tissue eosinophilia

in patients with eosinophilic GI disorders, but clinical response, while encouraging, was
heterogeneous. Residual symptoms in some patients may reflect persistent epithelial changes in
the upper GI tract.
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Keywords
Hypereosinophilic syndrome; Eosinophilia; mAb; Eosinophilic esophagitis; Eosinophilic gastritis;
Eosinophilic colitis; Eosinophilic enteritis

INTRODUCTION
Eosinophilic gastrointestinal disease (EGID) is defined by the presence of gastrointestinal
(GI) symptoms accompanied by excess tissue eosinophils in single or multiple parts
of the GI tract and can present with or without significant blood eosinophilia.1,2 The
most common GI segment involved is the esophagus (eosinophilic esophagitis [EoE])
followed by the stomach (eosinophilic gastritis [EG]), small bowel (when with gastric
involvement, eosinophilic gastroenteritis [EGE], or by itself, eosinophilic enteritis [EE]), and
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colon (eosinophilic colitis). Unlike EoE, EG, EGE, EE, and eosinophilic colitis are often
accompanied by blood eosinophilia3 that can rise to the level of hypereosinophilia (blood
eosinophilia ≥1500 cells/μL).4,5 Current therapeutic options for non-EoE EGIDs include
topical and systemic corticosteroids and/or empiric food elimination diets. These treatments
are associated with side effects, affect quality of life, and have variable efficacy. Disease
remission is typically defined by a combination of endoscopic evaluation with reduction in
GI tissue eosinophils and symptomatic improvement.

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After promising early results,6 randomized placebo-controlled clinical trials using

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IL-5 antibodies (ie, mepolizumab and reslizumab) to treat patients with EoE have
been disappointing, with persistence of clinical symptoms despite decreased GI tissue
eosinophilia by approximately 50% in those who were treated in most studies.7–9 One
suggested explanation was that persistent symptoms, such as dysphagia in EoE, may
represent fibrosis or structural changes that would not be impacted by removal of
inflammatory cells, such as eosinophils. An alternate proposed explanation was that
symptoms reflected incomplete eosinophil tissue depletion.

Benralizumab is an afucosylated antibody directed against the alpha chain of the IL-5
cytokine receptor (IL-5RA), which is highly expressed on eosinophils and their precursors,
and to a lesser degree on basophils and mast cells. Benralizumab is Food and Drug
Administration–approved as add-on treatment for moderate to severe eosinophilic asthma
and dramatically depletes both peripheral blood and tissue eosinophils. A phase 2
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clinical trial of benralizumab (30 mg subcutaneously monthly) in PDGFRA-negative

hypereosinophilic syndrome (HES) demonstrated a complete hematologic response in 17
of 19 subjects with undetectable absolute eosinophil counts (AECs) in most cases.10 Seven
of the 20 subjects in the study had HES with GI symptoms and documented GI eosinophilia
that met criteria for EGID. All 7 experienced symptomatic improvement on benralizumab,
and repeat endoscopic evaluation with tissue biopsy after 3 to 6 months of benralizumab
therapy revealed complete depletion of tissue eosinophils in all segments of the GI tract.
This study aimed to describe the hematologic, histologic, and symptom findings after 1 year
of benralizumab therapy in these 7 patients.

METHODS
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Twenty symptomatic, treatment-refractory PDGFRA-negative patients with HES and an

AEC of greater than or equal to 1000 cells/μL despite treatment were recruited and enrolled
on a clinical trial of benralizumab (NCT0213088210). The clinical trial consisted of 12
weeks of placebo versus benralizumab 30 mg subcutaneously given every 4 weeks, followed
by open-label benralizumab 30 mg subcutaneously given every 4 weeks for up to 48 weeks.
Responders were eligible to continue benralizumab on an open-label extension. All study
participants were coenrolled on a natural history protocol to study patients with eosinophilia
(NCT00001406). Both studies were approved by the National Institute of Allergy and
Infectious Diseases Institutional Review Board at the National Institutes of Health. All
subjects signed informed consent.

Seven of the 20 subjects enrolled on the original trial (subjects #6, #7, #11, #13, #14,
#15, and #16) met criteria for EGID, defined as GI symptoms and historical evidence of
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GI tissue eosinophilia (≥15 eosinophils/HPF) in esophageal biopsies for EoE, greater than
or equal to 30 eosinophils/HPF in stomach/duodenum biopsies for EG/EGE, and more
than 60 eosinophils/HPF in colon biopsies for eosinophilic colitis. Because this was not a
trial focused on eosino-philic GI disease but on HES in general, patients were not block
randomized for GI disease, which resulted in uneven numbers randomized to placebo (n =
2) or drug (n = 5) during the first section of the trial. Endoscopy and tissue biopsies were
performed at baseline and at week 24 (after 3 or 6 doses of the drug). All 7 subjects had

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upper endoscopies with biopsies of every GI segment. Five of the 7 subjects also underwent
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lower GI endoscopic evalua-tion (colonoscopy), with tissue biopsy of every GI segment in

4 subjects and random biopsy in 1 subject. Three patients had an additional endoscopy with
biopsies performed after 1 year. Biopsies were reviewed and scored by National Institutes of
Health pathol-ogists using both standard of care and research protocols (M.H. Collins, MD,
unpublished data). Mast cells were enumerated in 5 HPF using tryptase immuno-staining
(clone AA1; Dako). GI tissue lymphocytes were qualita-tively evaluated using CD3 (Clone
2GV6; Roche), CD4 (Clone SP35; Roche), CD8 (Clone SP57; Roche), and CD20 (clone
L26; Roche) immunostaining using an automated staining system (Benchmark ULTRA,
Roche) according to the manufacturer instructions.

Serum total IgE and tryptase levels were measured as part of the parent clinical trial. Serum
cytokines (IL-4, IL-5, IL-13, IFN-γ, and IL-17A) were evaluated by multiplex analysis
(Millipore) following manufacturer’s instructions. Statistical analyses of mast cell counts
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and serum cytokine, tryptase, and total IgE levels were performed using nonparametric
matched-pairs signed rank test (Wilcoxon).

RESULTS
The clinical characteristics of the 7 subjects with HES with significant GI symptoms and
biopsy-proven GI tissue eosino-philia are provided in Table I. The subjects ranged in age
from 23 to 53 years (median age, 35 years) and were predominantly (5 of 7) female. Six
of the 7 subjects had more than 1 affected GI segment, and symptoms tended to correspond
with the segments demonstrating GI eosinophilia on biopsy. Most (5 of 7) subjects were on
medical and/or dietary therapies for their disease at clinical trial entry and had previously
failed multiple therapies, including other experimental therapies. Despite treatment, these
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patients continued to experience debilitating GI symptoms (indicated in bold in Table

I) and had significant blood eosinophilia with AECs exceeding 1000 cells/μL, meeting
the inclusion criteria for the trial. Comorbid atopic disorders were common: 3 of 7 had
significant IgE-mediated food allergies and 5 of 7 carried a diagnosis of asthma.

Five of the 7 subjects with HES with eosinophilic GI manifestations were randomized
to drug for the first 12 weeks, and 2 were randomized to placebo; the latter 2 subjects
received benralizumab as part of the open-label protocol after 12 weeks. Peripheral blood
eosinophilia dramatically decreased in all 7 subjects within 1 day of receiving the active
drug (Figure 1, A) and remained suppressed throughout the remainder of the 48-week trial
(Figure 1, B) with 1 exception (subject #6).

All 7 subjects reported clinical improvement, but the timing and degree of improvement
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varied by individual. Some subjects reported improved GI symptoms as early as after 1 or 2

doses of the active drug, whereas others did not report improvement until after 4 or 5 doses
(see Table E1 in this article’s Online Repository at www.jaci-inpractice.org). By week 48, 4
of 7 subjects had either tapered medical therapy and/or expanded their diet or altered their
food consumption patterns (Table II). Although subject 6 reported clinical improvement
and was able to taper off hydroxyurea by 1 week after her first dose and slowly reduce
her prednisone to 5 mg, she unfortunately relapsed at week 32 with return of eosinophilia

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and symptoms (Figure 1, B). By week 48, she had resumed prednisone 15 mg daily (Table
II). As previously reported,10 the loss of efficacy in this subject was not due to antidrug
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antibodies.

Endoscopic evaluation and biopsies were performed at baseline and at week 24 (after receipt
of 3 or 6 monthly doses of benralizumab). Endoscopic findings in the esophagus and
stomach (n = 7) were mildly improved at week 24 as compared with baseline (see Table E2
in this article’s Online Repository at www.jaci-inpractice.org). The duodenum (n = 6) and
colon (n = 5) had normal endoscopic appearances in all subjects studied at baseline and at
week 24. On histological examination, tissue eosinophils were completely depleted in all GI
segments examined at week 24 (Figure 210). Eosinophil granule protein staining at week 24
confirmed the absence of tissue eosinophils in all cases examined.10

The effect of eosinophil depletion on concomitant medical/dietary therapies or food

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avoidance patterns was heterogeneous (Table II). At baseline, 2 subjects (#7 and #15)
carefully arranged their mealtimes to avoid having GI symptoms during critical parts of
their work day, but with eosinophil depletion, they were able to eat more freely. Two other
subjects (#13 and #14) were able to reintroduce specific foods back into their diet. One
subject (#14) became intolerant of a food (shrimp) that they had tolerated at the beginning
of the trial. Four subjects (#7, #11, #14, and #16) reported partial return of symptoms
or episodic worsening of symptoms at approximately 1 year, typically in the context of
tapering off medications or food reintroduction. One subject continued to have episodic
flares of disease, albeit improved over baseline, without change in diet or medication (#16).
Peripheral blood eosinophil count remained suppressed (AEC = 0) at 1 year in all 6 subjects
with EGID who remained on benralizumab therapy.
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Endoscopic evaluation was repeated at 1 year in 3 subjects (#7, #11, and #16). In all 3 cases,
tissue eosinophils remained undetectable (Figure 2, C).

To determine whether continued symptoms were the result of other effector cells, additional
immunohistochemical evaluation of biopsy specimens was performed. Tryptase staining
demonstrated that mast cell numbers (reported as the average number in ≥5 HPF) were
not significantly different at baseline and 24 weeks in the group overall (Figure 3, A).
Individual subjects demonstrated either an increase or a decrease in GI tissue mast cell
counts, but the direction did not correlate with the presence of symptoms. Moreover, serum
tryptase levels (a measure of total mast cell burden) were measured at baseline and every
3 months thereafter and were unchanged throughout the course of the trial (Figure 3,
B). Immunohistochemical stains for T and B lymphocytes in GI tissue demonstrated the
presence of both cell types at baseline, with CD3+ T cells being predominant. There was no
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qualitative change after treatment with benralizumab (data not shown).

Baseline, week 24, and week 52 tissue biopsies were reviewed in detail using both
published and unpublished scoring mechanisms that highlight changes related to both
eosinophils and epithelial cells (Collins et al11 and M.H. Collins, MD, unpublished data).
In biopsies from subjects who had recurrent flares, tissue epithelial features such as
spongiosis and basal zone hy-perplasia improved in grade and stage but persisted in the

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esophagus. Furthermore, reactive epithelial changes in the stomach persisted or worsened

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despite depletion of eosinophils (Figure 2). Interestingly, all subjects with primary colonic
involvement experienced disease remission without recurrent flares, with colonic mucosa
depleted of eosinophils but otherwise normal in appearance at week 24 (Figure 4).

Murine and limited human studies suggest that eosinophils play an immunoregulatory role
in maintaining homeostasis in the GI tract through their effects on TH2 cells (reviewed
in Klion et al12). To determine whether eosinophil depletion resulted in disruption of
this putative immunoregulatory role leading to symptom recurrence in patients with GI
involvement treated with benralizumab, serum TH2 cytokines (IL-4, IL-5, IL-13) as well
as IFN-γ and IL-17A were measured at baseline and 48 weeks. Serum IL-4 and IL-5
levels, but not IL-13, IFN-γ, or IL-17A, were significantly increased at 48 weeks (geometric
mean IL-4: 2.95 vs 35.61 pg/mL, P = .047, and IL-5: 6.38 vs 110.5 pg/mL, P = .0156,
paired Wilcoxon rank; see Figure E3, B, in this article’s Online Repository at www.jaci-
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inpractice.org). Total IgE levels were also examined and, in all but 1 subject (#14), remained
stable throughout the course of the trial (Figure E3, A).

DISCUSSION
In patients with HES with GI involvement, benralizumab depleted blood eosinophils within
1 day and GI tissue eosinophils at the first time point examined (24 weeks). Although
eosinophil depletion persisted through 1 year of treatment, with associated improvement
in symptoms in all patients, the degree of symptomatic improvement and the time it took
for this to occur were variable. Potential explanations for this variability include (1) a lag
between eosinophil depletion and normalization of the mucosa and (2) involvement of other
cells, such as epithelial cells or mast cells, in the pathogenesis of symptoms.
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Published studies in adults and children with EoE have described persistence of basal
zone hyperplasia and spongiosis despite reduction of tissue eosinophilia and improvement
of symptoms with either dietary or corticosteroid treatment.13,14 In the present study,
associated epithelial changes were demonstrated in both affected esophageal and stomach
biopsies despite undetectable tissue eosinophils, even after 1 year of treatment. More
importantly, these findings were accompanied by persistence of symptoms. The finding
that epithelial changes persist in the stomach despite complete eosinophil depletion has not
been previously reported. In contrast, there were few to absent epithelial changes associated
with colonic eosinophilia in the biopsies of symptomatic subjects at baseline, similar to what
has been recently reported in larger studies,15 and the colonic histology normalized with
eosinophil depletion, paralleling the complete clinical response experienced by the subjects.
These data suggest important differences between the pathogenesis of EGIDs in the different
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GI segments.

There is increasing interest in understanding the role of mast cells in EGIDs. In our
study, GI tissue mast cells were enumerated. Their levels were unaffected by anti–IL-5RA
(benralizumab) treatment and were similar between subjects who did and did not have
persistent symptoms and histological changes. Consistent with these findings, serum tryptase
levels were unchanged over the course of the study. This lack of evidence for mast cell

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involvement differs from published data in pediatric EoE, where increased tissue mast cells
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were associated with abnormal endoscopic findings consistent with EoE and continued
symptoms despite histologically inactive disease, defined as tissue eosinophils less than
15 cells/HPF,16 but is consistent with reported data in the stomach and duodenum. In a
recent study of patients comparing patients with EG/EGE (n = 52) to patients without
EGID who underwent endoscopy and biopsy for upper GI symptoms (n = 123), mast cells
were measured in the stomach and duodenum. Peak mast cell numbers were significantly
increased in the EG/EGE cohort in the stomach (44.2 ± 19.6 compared with 21.9 ± 8.2
cells/HPF) and duodenum (47.5 ±14.8 compared with 28.1 ± 9.3 cells/HPF).17 Although
mast cell numbers were correlated with eosinophil number in the tissues of patients with
EG/EGE, there was no correlation between GI symptoms and higher mast cell counts in
either cohort, suggesting that mast cell counts alone are not determinative of symptoms.17 A
recent phase 2 study of the anti–Siglec-8 mAb lirentelimab, which depletes eosinophils and
reduces mast cell activation,18,19 demonstrated tissue eosinophil depletion and improvement
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of symptoms in patients with EG; symptom scores were reduced by more than 30% in
only 27of 43 patients.20 Whether these 27 patients had higher levels of tissue mast cells or
increased mast cell activation was not addressed.

Finally, serum cytokine data in the present study provided little evidence for a major effect
of benralizumab and eosinophil depletion on the global cytokine milieu. Of the cytokines
measured, only IL-4 and IL-5 were significantly changed over the course of the study.
Increases in serum IL-5 have been previously reported in benralizumab trials in asthma21
and may reflect the loss of the main consumer of this cytokine, the eosinophil. An increase
in serum IL-4 may explain the increases in total IgE in some patients, especially subject #14,
because it is a driver of B-cell isotype switching. The significance of this observation is yet
to be determined, however, because it was not universal among the subjects with recurrent or
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persistent symptoms.

Dietary therapies through specific food avoidance are one of the mainstays of therapies for
EGIDs of the upper tract (eg, EoE and EG) but they carry significant burden and impact
on quality of life. One hope of both clinicians and patients is that newer therapies could
allow reintroduction of specific foods previously avoided. If the eosinophil is the sole or
primary effector cell in EGID, one might expect that complete elimination of this cell with
benralizumab should allow one to reintroduce specific foods previously avoided to reduce
eosinophilic inflammation. Larger, carefully designed studies and validated biomarkers
for food triggers will be needed to address this mechanistically and clinically important
question. Finally, the eosinophil is suggested to be important in metabolism, host defense,
and malignancy. Although this study is small, the lack of deleterious effects noted in
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our hypereosinophilic subjects depleted of eosinophils suggests that this cell type may
either play a limited role in the above-mentioned processes and/or alternate compensatory
pathways exist.

Limitations of the present study include the small number of subjects and the lack of
validated symptom scores in subjects with GI symptoms, because the original study was not
designed to focus on eosinophilic GI disease and symptom scoring tools were not available
when the phase 2 clinical study was initiated. The strengths of the current retrospective study

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include the length of follow-up and the breadth as well as detailed analyses of individual
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subject clinical and laboratory data.

In summary, our data contribute to the emerging body of data that suggest that there
may be differences in presentation, pathogenesis, and treatment responses depending on
the segment of GI involvement in EGIDs.3,22,23 Notably, despite the small numbers,
subjects with primary colonic involvement report substantial improvement in symptoms
after benralizumab treatment. In aggregate, most subjects experienced improvement in
symptoms, providing further evidence that eosinophils are important drivers of disease
pathogenesis in EGID.

CONCLUSIONS
Targeted eosinophil treatment with benralizumab depleted tissue eosinophils below the
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level of detection in patients with HES with GI tissue involvement. Although eosinophil
depletion was associated with significant symptomatic improvement, diversity in clinical and
histologic responses between patients over time and in different GI segments suggests that
factors other than eosinophils likely play a role in disease pathogenesis in at least some
settings. Clinical trials in larger cohorts of patients with EGID with single and multiple
GI segment involvement using therapies that target eosinophils alone (NCT04543409,
NCT03473977, NCT03656380) or in conjunction with other cell types (NCT04322604)
are needed to address these issues.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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Acknowledgments
This work was supported in part by the Division of Intramural Research at the National Institute of Allergy and
Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases. The content of this
publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor
does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Abbreviations used
AEC absolute eosinophil count

EG eosinophilic gastritis

EGE eosinophilic gastroenteritis

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EGID eosinophilic gastrointestinal disease

EoE eosinophilic esophagitis

HES hypereosinophilic syndrome

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What is already known about this topic?

Reduction or normalization of gastrointestinal (GI) tissue eosinophilia with diet or
corticosteroid therapy is associated with clinical remission in patients with eosinophilic
GI disease.

What does this article add to our knowledge?

Although benralizumab dramatically depletes GI tissue eosinophils and improves
symptoms in treatment-refractory patients with hypereosinophilic syndrome and GI
eosinophilia, clinical response over time is heterogeneous and may depend on the GI
segment affected.

How does this study impact current management guidelines?

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Benralizumab may be useful for the treatment of patients with hypereosinophilic

syndrome and GI eosinophilia that is refractory to standard therapy. Larger studies are
needed to confirm these findings.
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FIGURE 1.
AECs in the 7 subjects with eosinophilic GI disease in (A) the week after receiving their first
dose of benralizumab and (B) over the 48 weeks of the trial. For those randomized to drug
(solid symbols), Figure 1, A, depicts the first week of the clinical trial. For those randomized
to placebo (open symbols), Figure 1, A, depicts the first week in the open-label phase (week
12).
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FIGURE 2.
Histological features (hematoxylin and eosin) of gastric biopsies at baseline and week
24 at 200×. (A) Subject 16 at baseline with increased eosinophils in the lamina propria
and glandular epithelium, and epithelial changes with marked (>5 HPF) increased
nuclear:cytoplasmic ratio. (B) Subject 16 at week 24 with persistent epithelial changes
consisting of marked (>5 HPF) increased nuclear:cytoplasmic ratio and reduced mucin
despite resolution of tissue eosinophils. (C) Subject 16 at 1 year with persistent epithelial
changes. (D) Subject 14 at baseline with increased eosinophils in the lamina propria and
glandular epithelium, and mild/moderate epithelial changes (≤5 HPF) consisting of reduced
mucin and increased nuclear:cytoplasmic ratio. (E) Subject 14 at week 24 with persistent
epithelial changes with reduced mucin and increased nuclear:cytoplasmic ratio found in
more than 5 HPF despite resolution of tissue eosinophils. Black arrows, eosinophils; blue
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arrows, areas of increased nuclear:cytoplasmic ratio and reduced mucin; inset (black box,
400×).
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FIGURE 3.
(A) MC numbers in tissue at baseline and after 3 to 6 doses of benralizumab treatment.
Tryptase-positive MCs were enumerated in an average of 5 HPF per sample. (B) Serum
tryptase levels over the 48 weeks for each subject. Benra, Benralizumab; BL, baseline; MC,
mast cell.
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FIGURE 4.
Histological features (hematoxylin and eosin) of colonic biopsies at baseline and week 24
at 200×. (A) Subject 13 at baseline with increased eosinophils in the lamina propria and
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glandular epithelium. (B) Subject 13 at week 24 with resolution of tissue eosinophilia.

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TABLE I.

Baseline clinical characteristics of patients

GI tissue eosinophilia*
Kuang et al.

No. Age (y), sex GI symptoms (active, historic) E G D C Comorbid atopic disease Therapies (active, historic)

6† 48 F − + − + Asthma P, HU, IFN

Diarrhea (3× daily)
Abdominal pain Dysphagia
7 35 M Bloating + + + − Asthma, FA (crab, almond; P, topical budesonide, FV, hydroxychloroquine,
Constipation avoids shellfish and nuts), sirolimus‡
Abdominal pain (daily, with monthly exacerbation) allergic rhinitis
Diarrhea, weight loss, dysphagia, odynophagia, nausea, early
satiety
11 53 M Abdominal pain Diarrhea (3× /wk) dysphagia + + + − Asthma P, topical budesonide
early satiety, weight loss
13 37 F Diarrhea (5–7× daily) − + + + P, Elemental diet, enterocort, cromolyn
Nausea (daily)
Pill dysphagia
Abdominal pain
14 23 F Abdominal pain/cramping (daily) + + + − Asthma, FA (wheat, Elemental diet, dietary therapy, topical
Diarrhea (multiple times a day) suspected dairy) budesonide, cromolyn, FV, sirolimus‡
Dysphagia

15† 35 F − − − + P, FV, IFN

Diarrhea
Abdominal pain
Intermittent dysphagia
16 33 F + + − − Asthma, AR, FA (shrimp) P, IFN, FV, cromolyn, topical budesonide,
Nausea (constant, weekly worsening) sirolimus,‡ dietary therapy
Dysphagia (daily)

Budesonide, Budesonide slurry; C, colon; D, duodenum; E, esophageal; F, female; FA, food allergy; FV, swallowed flovent (fluticasone); G, gastric; HU, hydroxyurea; P, prednisone.

Historic symptoms and therapies as well as active GI symptoms and therapies at trial enrollment (bolded) are listed.

J Allergy Clin Immunol Pract. Author manuscript; available in PMC 2023 June 01.
*
Tissue eosinophilia meeting criteria as described in methods.
†
Subjects with lymphoid HES whose disease also included GI manifestations. Remaining subjects had HES single-organ overlap (EGID).
‡
Sirolimus given under phase I clinical trial.
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TABLE II.

Benralizumab allowed some subjects to reduce medical therapies for EGID and liberalize dietary restrictions

No. BL Tx Diet at BL Week 48 Tx Diet at week 48

Kuang et al.

6* P 10 mg daily, HU 1 g daily Unrestricted P 15 mg Unrestricted

Budesonide 6 mg, FV 440 twice a No attempt to reintroduce foods; eats more

7
Budesonide 9 mg FV 440 twice a day Avoids: chicken and beef plus FA foods day freely
11 Budesonide 3 mg Unrestricted None Unrestricted
Avoids: carrots, peas, apple, mango, banana, watermelon, Reintroduced most foods
13 None None
kiwi, strawberry, turkey, direct egg, corn, wheat, oats Avoids: wheat and mango
Consumes only shrimp, potato, fruit (apple, pear, lemon, Reintroduced fish, poultry, tomato, carrots.
14 FV 220 2p twice a day FV 220 2p twice a day
banana), vegetables (broccoli, lettuce) Unable to tolerate avocado and shrimp

15* None Unrestricted, but planned mealtimes to avoid symptoms None Eats unrestricted diet freely

Avoids: corn, rice, most meats, shrimp, shellfish, and pure

16 FV 220 2p twice a day FV 220 2p twice a day No attempts to reintroduce foods
egg

Budesonide, Budesonide slurry; P, prednisone; FA, food allergy; FV, swallowed fluticasone; HU, hydroxyurea; Tx, treatment.
*
Subjects with lymphoid HES and GI involvement. Remaining subjects were HES single-organ overlap (EGID). Subject #6 relapsed at week 32 and taken off benralizumab.

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