Beyond the Eosinophil: Mastering the Complexities of EoE Diagnosis

Co-Chairs and Presenters, Margaret H. Collins, MD, AGAF, and Nirmala Gonsalves, MD, AGAF, FACG, discuss eosinophilic esophagitis in this CME/MOC/CC activity titled “Beyond the Eosinophil: Mastering the Complexities of EoE Diagnosis.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CC information, and to apply for credit, please visit us at https://bit.ly/3EvY7IJ. CME/MOC/CC credit will be available until August 26, 2026.

1. Beyond the Eosinophil

Mastering the Complexities of EoE Diagnosis

Margaret H. Collins, MD, AGAF
Professor of Pathology and Pediatrics (secondary)
University of Cincinnati College of Medicine
Director of Gl Pathology Research

Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio

Nirmala Gonsalves, MD, AGAF, FACG
Professor of Medicine

Division of Gastroenterology & Hepatology

Director

Eosinophilic Gastrointestinal Disorders Program

Gl Division Director of Faculty Development & Wellness
Northwestem University

The Feinberg School of Medicine

Chicago, Illinois

Go online to access full CME/MOC/CC information, including faculty disclosures,

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2. Our Goals for Today

Enhance your ability to identify key diagnostic criteria
for EoE

Strengthen your skills in recognizing histologic
changes beyond eosinophilic infiltration and the role of

histologic scoring systems

Provide guidance on fostering effective
communication between gastroenterologists and
pathologists to improve diagnostic accuracy in EoE

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3. Identifying and Diagnosing EoE
Recognizing Key Clinical
and Histopathologic Features

4. is and Symptoms Vary Among Ch

Differences in Symptom Presentation

Infants and Children ® Adolescents and Adults
Reflux-like symptoms. Dysphagia
Vomiting and nausea + Food impaction
Abdominal pain 6 + Substernal chest pain
Food refusal + Reflux-like symptoms
Failure to thrive (heartburn, regurgitation)

PeerVi
1. Jchnson DT et. Am J Manag Core. 2021 (ul 17) SS11-SS18 PeerView

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5. Adaptive Behaviors (IMPACT) Mask Symptoms‘

© IMBIBE fluids to facilitate passage of solid food
O MODIFY foods (cut into small pieces, puree foods)
@ PROLONG meal times

O AVOID harder-texture foods

© CHEW excessively

@ TURN away pills and tablets

1. Hirano, Fura GT. Gastoontrtgy. 2020, 158.40-851.2 Lee Ke a Front Post 20188113. PeerView

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6. Diag EoE Is Com

stic Delay

Time between symptom onset of EoE and diagnosis ranged from
1.

3.5 years in children and 3-8 years in adults!

Findings from a study of 705 patients with EoE from age 6 months
to 65 years?

+ This time gap increased as the patient age at diagnosis increased

+ Median time from symptom onset to diagnosis was ...
— 1 year in children <11 years of age
- 2 years in patients 11-17 years of age
- 4 years in adults

+ The presence of food allergy and atopic dermatitis was associated
with a more prompt diagnosis (and was also more common
in younger populations)

1. Shaheen NJ tal Di Esophagus. 2018318. 2. Chohade Met LY Ary Oi Inmuna Prot 20185:15341544. PeerView

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7. Early Diagnosis Is Important!*

Uncontrolled, EoE can lead to ...

Esophageal stricture

Of patients with severe diagnostic delay, 57% had food impactions and
52% had a stricture

Feeding dysfunction (especially relevant for children)
+ 14%-60% of patients with EoE have feeding dysfunction
21% of children with EoE and feeding disorders also had failure to thrive

tro, 2019:12:301-990, 2. Warners Metal. stroentorl 2018:113:896-844

Aer ROIS NAB LOA PeerView

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8. Updated EoE Diagnostic Algorithm’

ical presentation suggestive of EoE

Esophageal eosii

nophilia 215 eos/hpf

Evaluate the differential

diagnosis of EoE

Diagnosis of EoE

+ Symptoms of esophageal dysfunction
+ Modification and avoidance (IMPACT) behaviors
+ Feeding dysfunction

+ Concomitant atopic conditions

+ Family history of EOE/EGID

+ Assess EREFS

u; EGD with biopsy { À

Assess for ibrostenosis.
Obtain 26 biopsies from different esophageal
levels, targeted findings of EoE

+ GERD, pill esophagitis, drug hypersensitivity reactions,

non-EoE EGIDs, hypereosinophiic syndrome,
Crohn disease, achalasia, infectons,

connective issue or autoimmune disease, etc

1. Delon ES et al. Am J Gastroenterol. 2025:120-31-59.

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9. Endoscopic Findings

Rings

Exudates

1. Gonsalves N ot al. Garointost Endose. 2006.54:319-319,

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) © uo

Food
Impaction

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10. EoE Endoscopic Reference Score (EREFS)!

EDEMA (loss of vascular markings)
Grade 0: Distinct vascularity
Grade 1: Decreased

Grade 2: Absent

RINGS (trachealization)

Grade 0: None

Grade 1: Mild (ridges)

Grade 2: Moderate (distinct rings)
Grade 3: Severe (not pass scope)

EXUDATE (white plaques)

Grade 0: None

Grade 1: Mild (510% surface area)
Grade 2: Severe (>10% surface area)

FURROWS (vertical lines)
Grade 0: None

Grade 1: Mild

Grade 2: Severe (depth)

STRICTURE
Grade 0: Absent
Grade 1: Present

1. Hirano A etal Gut 2013:62.489496.

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GRADE 0

ERE

GRADE1 GRADE2

GRADE 3

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11. Increasing the Diagnostic Yield’?

At least 3 biopsies from the distal esophagus and
3 biopsies from the proximal esophagus should be taken

Targeting endoscopic lesions (eg, exudates)
increases the diagnostic yield

1. Gonsalves N etal. Gas
3 Hirano tet a

test Endosc. 2006:64:313-319;2. Shah A et a. Am J Gastroenterol, 2009:108:716-721

iby. 2018155601608. PeerView

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12. Case Scenari ohn, a 28-Year-Old Man

John reports increasing difficulty swallowing meat and bread
over the past 6 months. He often needs to drink water to help
food go down and has had two recent episodes of food

impaction requiring self-induced regurgitation.

+ Medical history: Seasonal allergic rhinitis; mild intermittent asthma
+ Medications: Occasional loratadine

+ Family history: Father with atopic dermatitis and younger sister with
celiac disease

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13. Case Scenari

john, a 28-Year-Old Man (Cont’d)

+ Physical exam: Unremarkable £ à
+ Upper endoscopy
the esophagus

— Longitudinal furrows and concentric rings in
— Mild narrowing noted in the mid-esophagus
— 3 biopsies obtained from proximal and
distal esophagus (6 total)
+ Pathology findings

— 25 eos/hpf in both proximal and distal
esophageal samples

Does this suggest EoE?

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14. Assessing Disease Severity: I-SEE Index

+ Measures symptom features and complications along with inflammatory and
fibrostenotic features on both endoscopic and histologic examination that can be
completed at routine visits to assess EoE severity using a point scale

7-14: Moderate

1. Delon ES etal. Gostonneroagy. 2022.163:0-78 PeerView

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15. Download the

Assessing Disease Severity: I-SEE Index! (Cont'd) Practice Aid!
Points 4Point 5 Points
Daly in soca coring =

Points per feature 4 Point
‘Symptoms and Complications
Symptoms Weekly
Complications =
Inflammatory Features
Endoscopy (edema,
furrows, andlor exudates) Localized
Histology 15.60 comp
Fibrostenotic Features.

Present but
Endoscopy (rings,

‘endoscope
strictures) an
Histology =

Food impaction with ER vist or
‘endoscopy
(pationt aged 218 y)

Ditfuse
>60 eosinph
Present, but requires dilation or a

‘snug fit when passing a standard
‘endoscope

BZH or LPF (or DECISEA if no LP)

+ Esophageal perforation
Food impaction wil ER vist. Malu wih body mass <Sh percentle or
pole, _ decreased growth trajectory
(patent 9900 <18Y) Persistent inflammation requiring elemental
formula, systemic cortcosterod, or
Hospializaton due EE immunomodulatory treatments

Cannot pass standard upper endoscope;
- repeated dilations (In an adult aged 218 y); or
‘any dilation (in a child aged <18 y)

1. Delon ES et al. Gastoontovlogy. 2022:163:50.78.

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16. Going Beyond Eosinophil Count
Understanding Histopathologic
Changes in EoE and

Their Clinical Implications

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17. Eosinophils Are Not the Entire Sto!

+ Histopathology scoring systems facilitate comprehensive consistent biopsy evaluations that track changes
such as the impact of therapeutic agents on tissue, and may reveal aspects of the disease under study

+ For EoE, the EoEHSS was developed to quantify eight key EoE features, only one of which is the severity
and extent of eosinophilic infiltration

— Eosinophil inflammation (derived from peak eosinophil count)
— Basal zone hyperplasia

- Eosinophil abscesses

— Eosinophil surface layering

— Dilated intercellular spaces

— Surface epithelial alteration

— Dyskeratotic epithelial cells

— Lamina propria fibrosis

1. Cling MH ot a. Dis Esophogus. 2017:20:8 PeerView

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18. Eosinophilic Esophagitis Histology Scoring System

HSS scores evaluate severity (grade) and extent (stage) of pathology’

0 is normal, 3 is worst

The EoE HSS is responsive!3

The EoE HSS is reliable (aka reproducible)!9,10

1. Colins MH et al. Dis Esophagus. 2017:20:-8,2. Coline Meta. Am J Surg Pathol. 2019:43:1601-1509,
120:168:111-122, 4, Delon ES at al Cin Gastroantera! Hepatol. 2021.19:473-483

pins
mr Ml Atom Par DORADO 10 Vin MOL Pe [6.9 2022002000 PeerView
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19. EoEHSS Inflammatory and Architectural Components

Inflammatory components:
black arrows, white asterisk

Architectural components:
bar, black arrowheads, black
asterisks, thin black arrows,

bottom right photo

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1. Colins MH et al. Dis Esophagus. 2017:30:1-8

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20. EoEHSS Significance

Master regulator of EoE pathology!

Basal zone hyperplasia Persistent symptoms?+

Reduced impedance*

Dilated intercellular spaces Increased antigen passage®

Surface epithelial alteration + Predict lamina propria fibrosis?-8
dyskeratotic epithelial cells https://Is2021.shinyapps.io/pre_Ipf

Furrows + eosinophil inflammation +
eosinophil abscess + basal zone hyperplasia + Predict active EoE?
dilated intercellular spaces

1 Rockman Mata Y Ary Cn Immunol 20191421023. 2 Baton S tal Am J Gaxonntr! 2020118224258
3 Wholan KA ot al. in Gastroontera! Hepatol 2020 18:1475-1482. 4. Wenzel AA el. Pediatr Gastoantaval Nutr. 2022:74:031.034.

3 kata DA tl Cin Gesca put 2015131242124, 6. Monta EV tal Alment Pharmacol Tor 201748427405.

7. Hremain G ot a. Cin Gostroenteroi Mopatol 2021:19:1814-1823, 8. Hiromath G et a. AmJ Gastroontoro! 2022:117-272-279, PeerView

9. Hiremath Gota. Gastrointest Endosc. 2020;91:788-796.

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21. Gastrointestinal Mucosa Is One of Several Layers

Epithelium lines the luminal
surface of the esophageal wall,
and is associated with lamina
propria

Muscularis mucosa (white bar)
separates mucosa from
submucosa

Most of the wall thickness is
composed of muscularis propria
(black bar)

4. Cling MH ta. Pedi Dov Patho. 202225:124-439. PeerView

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22. Improving Multidisciplinary
Collaboration Between
Gastroenterologists and Pathologists

23. Collaboration Matters in EoE

EoE is a clinicopathologic diagnosis
Accurate diagnosis requires both symptom assessment
and histopathologic confirmation (215 eos/hpf)!3

Clinical-pathologic mismatch is common
Patients may present with typical EoE symptoms but have borderline
or patchy eosinophilia—or vice versa

Close communication improves accuracy
+ Pathologists need clinical context: age, symptoms, location of biopsies
+ Gastroenterologists need detailed histologic feedback beyond eosinophil counts

Takeaway: When clinicians and pathologists engage in bidirectional dialogue,
they can avoid over- or underdiagnosis of EoE and guide appropriate treatment decisions

1. elon etl. Gestoontrtny. 2018 15:1022- 108.010, 2,Lucendo AI el Utd Eur Gostoonta!d20175:395-958. 3. Den ES. Dg ov. 0raszaess. Peer View

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24. opsy Protocols and Histopathologic Review

+ Standardize biopsy collection + Encourage detailed pathology reporting

— Obtain at least 6 biopsies from both — Ask for commentary on at least:
roximal and distal esophagus!
p phag > Basal zone hyperplasia
— Label location-specific samples to aid

interpretation of eosinophil distribution > Dilated intercellular spaces
+ Include clinical indication and > ln ane (surface
suspicion on pathology requisition
à La ay req dyskeratotic epithelial cells if
— “Rule out EoE” is helpful—but adding lamina propria is absent or
details like “solid food dysphagia x 6 uninterpretable)
months, history of atopy” strengthens .
interpretive accuracy + Use structured templates or synoptic

reports when possible to standardize
terminology across cases

1. Shah At Am Gastroenterol, 2008,104:716-721 PeerView

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25. Case Scenario: Matt, a 7-Year-Old Boy

Chief complaint
Chronic abdominal pain, poor appetite,

and episodes of gagging while eating

+ Duration of symptoms: 9 months
+ Parents report:

— Meals take an unusually long time
— Matt prefers soft or pureed foods
— He complains of “food getting stuck”

+ Medical history: Mild atopic dermatitis
and allergic rhinitis

+ Growth chart: Below 10th percentile for weight

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26. Case Scena

Matt, a 7-Year-Old Boy

.

Allergy testing: Positive for dust mites
and tree pollen

Lab work: No anemia, normal eosinophil count
in blood

Pediatric Gl referral: Clinical suspicion for EoE
Endoscopy findings

— Mild rings in the mid-esophagus

— No exudates

- Biopsies taken from proximal, mid,
and distal esophagus

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27. Case Scenario: Matt, a 7-Year-Old Boy—Pa
(Initial Read)

+ Eosinophil count: Ranges from 10-14 eos/hpf
+ Comment: “Mild increase in eosinophils, findings not definitive for EoE”

How should the gastroenterologist respond to the pathologist’s report?

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28. Case Sce Matt, a 7-Year-Old Boy

+ The gastroenterologist should: + Pathologist re-reviews
- Share detailed symptom history - Focal areas with >15 eos/hpf
- Confirm biopsy sites — Basal zone hyperplasia >50%
— Request review for additional — Dilated intercellular spaces
histologic features present
> Basal zone hyperplasia — Eosinophilic micro-abscess seen

in one section

> Dilated intercellular spaces

pe

Final diagnosis: EoE

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29. Targeted Agents and
the Future of EoE Management

30. EoE Suggested Approach to Management Algorithm:

Updated Guidelines!

EoE diagnosis

Treat inflammation and assess for

‘Anti-inflamm
treatment

elimination
eatment

‚Empiric elimination®

Fibr

Stenosis

reassessment pre
Nonresponse Goal diameter
of 16-18 mm
Dilation®
Dupilumabs Change or modify
u prior treatments"
n > Maintenance therapy and long-term monitoring
Nonresponse

histologic features inclucing quantified gosinophi count on esophageal biopsy. Patente receiving duplumab general should be PPI nonresponders o inolerant to

PI; consider eat use of duplumab if moderate to severe asthma or eczema is present and ater elevant subspecalistconsutation © Could include changing

‘medicaton, dose, or formation, moving to a more restive dit, or considering a cinica tal. PeerView

1 Dolon ES etal. Am J Gastroonforal.2025;120 31-50.

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31. Histopathologic Activity
Improvement of esophageal
eosinophilic inflammation
(<15 eos/hpf)

1. Delon ES ot al. Am J Gastroonora.2025.120:31.80

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Complete Nonresponse

Complete
Response

Improvement in inflammatory
features as quantified by
EREFS; goal for strictures is
to dilate to 16-18 mm

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32. reatment

Histopathologic insi:

diagnosis but

+ May help differentiate eosinophilic inflammation from chronic remodeling

+ Marked BZH, dilated intercellular spaces, or subepithelial fibrosis may
suggest a more refractory phenotype

+ These patients may benefit from targeted therapy earlier in the treatment
algorithm, and histopathologic evidence of persistent disease may help
support clinical justification for insurance coverage

+ May enhance shared decision-making with patients (eg, explain rationale for
targeted treatment, reinforce need for long-term treatment adherence, etc.)

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33. + Eosinophil count alone may not reflect disease activity or burden
— Other histologic changes contribute to symptoms and chronicity

+ Scoring systems such as the EoEHSS enable structured assessment of multiple histologic
domains

— Includes BZH, dilated intercellular spaces, lamina propria fibrosis, and more
+ BZH and dilated intercellular spaces are markers of epithelial injury and barrier dysfunction
— May persist even when eosinophil counts improve

+ Fibrotic changes (eg, lamina propria fibrosis) suggest chronic disease and may predict
stricture formation

+ Effective collaboration between gastroenterologists and pathologists can facilitate accurate
diagnosis of EoE and guide appropriate treatment decisions

+ Beyond diagnosis, histopathologic findings may help inform therapeutic strategies
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