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. Author manuscript; available in PMC: 2026 Oct 15.
Published before final editing as: Clin Gastroenterol Hepatol. 2026 Oct 12:S1542-3565(26)00756-1. doi: 10.1016/j.cgh.2026.09.048

Diffuse esophageal eosinophilia is associated with increased endoscopic severity and topical steroid non-response in patients with eosinophilic esophagitis

Stefani Aleman 1, Alexandra A Weir 1, Sean S LaFata 1, Timothy S Gee 1, Angelica R Mirzoca 1, Arjun K Juneja 1, Hannah L Thel 1, Brenderia A Cameron 1, Justin McCallen 1, Christopher J Lee 1, Gustaf N Hendrick 1, Jose C Bermudez 1, Daniel Song 1, Walker D Redd 1, Trevor S Barlowe 1, Cary C Cotton 1, Craig C Reed 1, Evan S Dellon 1,2
PMCID: PMC13665495  NIHMSID: NIHMS2215531  PMID: 42863780

Abstract

Background and aims:

Variability of esophageal eosinophil distributions and its impact on disease presentation and treatment outcomes in eosinophilic esophagitis (EoE) is unclear. We aimed to determine whether isolated proximal or distal involvement differs from diffuse involvement in EoE presentation and treatment outcomes.

Methods:

This retrospective cohort study analyzed patients of all ages with newly diagnosed EoE from the UNC EoE Clinicopathologic database. Patients were classified as distal esophagus-only (≥15 eos/hpf), proximal-only (≥15 eos/hpf), and diffuse involvement (≥15 eos/hpf in both regions). Outcomes included histologic response (<15, ≤6, and <1 eos/hpf), global symptomatic response, and endoscopic response after treatment. Baseline characteristics and post-treatment response were compared between patients with localized and diffuse eosinophil involvement.

Results:

Of 888 cases of EoE, eosinophil counts were higher in the distal (54.8±44.7) versus proximal esophagus (44.0±40.1; p<0.001). Diffuse involvement (n=623; 70%) was associated with more inflammatory endoscopic findings and higher mean EREFS (4.0±1.8, p<0.001) compared to those with proximal (2.8±1.8) and distal involvement (2.7±1.6). Strictures and worse disease severity (Index of Severity for EoE) were also more frequent in diffuse disease. After topical corticosteroid treatment (n=395), patients with diffuse disease had reduced histologic response (at all thresholds) and endoscopic response compared to those with localized disease.

Conclusions:

EoE patients with diffuse esophageal eosinophilic involvement had greater baseline disease severity and decreased histologic and endoscopic treatment response to topical corticosteroids than those with localized disease. Diffuse disease involvement could be an important marker for risk stratification and therapeutic decision-making in EoE disease management.

Keywords: EoE, treatment, cohort study, outcomes, disease extent

Introduction

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease that is rapidly rising in incidence, prevalence, and associated health care costs.1, 2 Diagnosis requires both clinical symptoms and histological evidence of esophageal eosinophilic inflammation. Symptoms of esophageal dysfunction in adolescents and adults are most commonly dysphagia and food impaction, and in children are non-specific but can include poor growth, feeding dysfunction, abdominal pain, and vomiting.3 In addition, esophageal biopsies obtained during endoscopy must demonstrate at least 15 eosinophils per high-power field (eos/hpf) for diagnosis. Current guidelines recommend at least six biopsies be taken from a minimum of two esophageal levels to maximize diagnostic sensitivity given the patchy distribution of inflammation in EoE.4

Though quantification of esophageal eosinophil counts is critical for the diagnosis of EoE, the clinical significance of a single peak eosinophil count has recently been questioned.5 Eosinophil counts have generally not been shown to predict treatment response or correlate with disease severity. Notably, in the Index of Severity for EoE (I-SEE), an eosinophil count of >60 eos/hpf adds only 2 points to the total score, conferring a relatively low weight to this component.6 In addition, clinical trials of eosinophil-depleting drugs have demonstrated ongoing endoscopic and histologic disease activity despite biopsies showing no eosinophils remaining.7–9 It is unclear whether the extent of eosinophilic involvement throughout the esophagus may reflect diffuse inflammatory disease activity or have more utility than the peak eosinophil count; recent studies report conflicting associations with disease characteristics and prediction of treatment response.10–15

Given the variability in distribution of eosinophils in the esophagus and the unclear impact of this variability on disease activity and treatment response, we aimed to determine if isolated proximal or distal esophageal eosinophil involvement affects EoE presentation and treatment outcomes compared to diffuse esophageal involvement. We hypothesized based on clinical experience that those with more diffuse involvement would have more severe EoE disease features and would be less responsive to treatment.

Methods

Study design and patients

This retrospective cohort study included patients of all ages from the UNC EoE Clinicopathologic database through May 2024 who had an incident diagnosis of EoE according to contemporaneous guidelines.3, 16–18 The details of this database have been previously described.19–22 The study was approved by the UNC Institutional Review Board. In brief, all patients underwent a clinically indicated upper endoscopy, and the protocol at our center is to take four biopsy fragments from both the proximal and distal halves of the esophagus (eight total). EoE was diagnosed with a peak count of at least 15 eos/hpf (hpf = 0.24 mm2) in any biopsy, in the absence of competing causes of esophageal eosinophilia. Prevalent cases were excluded, and no included patients had been previously treated with a topical steroid or diet elimination. After identification of the incident EoE patient cohort, electronic medical records were reviewed to extract demographics, symptoms, concomitant atopic conditions (asthma, eczema, allergic rhinitis, and food allergies), endoscopic findings, and the overall peak eosinophil count from any location in the esophagus. Disease severity was measured with I-SEE, as previously described.6, 23

Distal and proximal esophageal eosinophil counts were recorded, and patients were categorized into three groups: distal-only (≥15 eos/hpf; considered localized disease), proximal-only (≥15 eos/hpf; considered localized disease), and diffuse involvement (≥15 eos/hpf in both regions). While mid-esophageal biopsies may be obtained at the provider’s discretion as a separate specimen, this is not a consistent practice at our center, and analyses were limited to biopsies from proximal and distal sites. Inclusion in the present analysis required patients to have data for both proximal and distal regions, and this group was our overall study cohort (n=888).

Treatments and outcomes

In addition to the baseline data recorded above, treatment data were also extracted. At our center, patients choose either pharmacologic or dietary treatment using a shared decision-making framework.24 Given the time span of this study and the requirement for proton pump inhibitor (PPI) non-response for EoE diagnosis in earlier years, we elected to focus on topical corticosteroid (tCS) use as well as food elimination diets (FED). For tCS, patients were treated with either swallowed fluticasone via an inhaler or aqueous budesonide mixed into a slurry. Doses ranged from 1 mg to 2 mg per day, depending on formulation, patient age and size, and provider preference.25 No patients were treated with the Food and Drug Administration (FDA)-approved budesonide oral suspension, as it was not available during the study time period.26 After 8–12 weeks of therapy, a repeat endoscopy with biopsies was performed. For FED, patients underwent either targeted or empiric elimination based on guidelines at the time of treatment selection and patient and provider preference.27 Repeat endoscopy with biopsy was performed after 6–8 weeks of food elimination. Our tCS subpopulation included 395 subjects, while our FED subpopulation included 235 subjects.

We assessed a range of outcomes for this study for patients with post-treatment endoscopy and biopsy data. Histologic response was defined as <15 eos/hpf post-treatment,28, 29 with additional assessment thresholds of ≤6, and <1 eos/hpf.30 Symptom response was determined using a global provider-reported assessment documented in the medical record, as validated patient-reported outcome measures are not routinely used at our center. This approach has been successfully used previously.22, 25, 31, 32 Endoscopic findings were evaluated using the EoE Endoscopy Reference Score (EREFS),33 which ranges from a score of 0–9 based on the most severe findings reported throughout the esophagus.34, 35 Edema was graded as 0–1, rings were 0–3, exudates and furrows were both 0–2, and strictures were 0–1, with stricture diameter (mm) recorded when available. For patients evaluated prior to the adoption of EREFS, the endoscopic severity score (ESS) was also used, in which the same five features were scored dichotomously (0–1), yielding a total score from 0–5.35 Additionally, we used an EREFS threshold of ≤2 to indicate endoscopic response for the subset of patients in whom EREFS was available.36, 37 For all patients, we assessed a provider-reported endoscopic improvement based on overall post-treatment endoscopic appearance compared to baseline.

Statistical analysis

Characteristics of the study population were summarized with descriptive statistics. Baseline characteristics and post-treatment outcomes were compared among patients with distal versus proximal versus diffuse eosinophilic involvement using one-way ANOVA for continuous variables and chi-square test for categorical variables. Pre- and post-treatment outcomes within groups were compared using a paired t-test for continuous variables and McNemar’s test for categorical variables. Treatment data for tCS and FED were analyzed separately. Given that the division into three study groups yielded some groups with a small sample size (especially for patients with proximal-only disease), we performed a secondary analysis comparing localized (proximal- or distal-only) versus diffuse esophageal involvement. Logistic regression was used to adjust for potential confounders in the association between baseline disease features and localized (proximal- or distal-only) versus diffuse esophageal involvement. Last, logistic regression was also used to adjust for potential confounders in the association between histologic response to tCS treatment and localized versus diffuse involvement.

Results

Patient characteristics and association with eosinophil distributions

We identified 888 newly diagnosed patients with EoE who met study inclusion criteria. Of these, 194 (22%) had distal only eosinophilia, 71 (8%) had proximal only eosinophilia, and 623 (70%) had diffuse eosinophilia in both proximal and distal locations. Overall, across all patient biopsy samples, mean eosinophil counts were higher in distal samples (54.8±44.7) compared to proximal samples (44.0±40.1; p<0.001).

Demographics, body mass index (BMI), atopic conditions, and family history of EoE or other eosinophilic gastrointestinal disease were similarly distributed across patients with localized and diffuse esophageal involvement; only younger age was associated with diffuse involvement (Table 1). Symptom duration and individual types of symptoms prior to EoE diagnosis were also similar across groups. However, patients with diffuse involvement had a higher mean EREFS (4.0±1.8, p<0.001) compared to those with proximal (2.8±1.8) or distal involvement (2.7±1.6), reflecting both greater inflammatory and fibrostenotic features. For example, exudates were more frequently reported in those with diffuse involvement (61%), compared to those with proximal (43%) or distal involvement (36%; p<0.001), as were rings (58% diffuse vs 49% proximal vs 43% distal; p=0.001) (Table 1). Stricture prevalence did not vary between groups, but among patients requiring dilation, stricture diameter was smaller in diffuse involvement (11.6±3.2 mm) compared to those with proximal (12.7±3.4mm) or distal (13.1±3.8mm; p=0.04). Overall disease severity, as measured by total I-SEE, was higher in diffuse involvement by both total score (p=0.006) and severity categories (p=0.001), with diffuse involvement having more frequent moderate-to-severe disease (Table 1). Results were similar on the secondary analysis assessing localized (proximal- or distal-only) versus diffuse esophageal involvement (Supplementary Table 1).

Table 1.

Baseline characteristics of newly diagnosed patient with EoE as stratified by extent of esophageal eosinophil distribution

Distal eosinophils only (n = 194) Proximal eosinophils only (n = 71) Diffuse eosinophils (n = 623) p
Age at diagnosis (mean yrs ± SD) 30.5 ± 20.5 29.0 ± 48.3 26.7 ± 17.6 0.03
 Children <18 years (n, %) 72 (37) 27 (38) 250 (40) 0.74
Male (n, %) 125 (64) 43 (61) 413 (66) 0.60
White (n, %) 162 (86) 67 (94) 523 (86) 0.12
BMI (mean kg/m2 ± SD) 24.1 ± 7.2 24.9 ± 8.3 24.2 ± 7.0 0.78
Any atopic condition (n, %) 124 (64) 50 (70) 393 (63) 0.51
 Allergic rhinitis 86 (44) 37 (52) 285 (46) 0.53
 Asthma 54 (28) 20 (28) 171 (28) 0.99
 Eczema 29 (15) 17 (24) 126 (20) 0.16
 Food allergy 66 (34) 27 (39) 208 (34) 0.71
Family history of EoE or EGID* 10 (6) 3 (5) 22 (4) 0.61
Symptom length prior to diagnosis (mean years ± SD) 7.5 ± 9.4 5.6 ± 6.5 6.6 ± 7.8 0.24
Symptoms (n, %)
 Dysphagia 157 (81) 55 (77) 517 (83) 0.46
 Food impaction 65 (34) 29 (41) 225 (36) 0.54
 Heartburn 70 (36) 29 (41) 208 (33) 0.40
 Chest pain 22 (11) 12 (17) 71 (11) 0.39
 Abdominal pain 36 (19) 17 (24) 97 (16) 0.16
 Nausea 18 (9) 12 (17) 60 (10) 0.14
 Vomiting 39 (20) 27 (38) 184 (30) 0.006
 Failure to thrive 10 (5) 4 (6) 36 (6) 0.95
Endoscopic findings (n, %)
 Exudates 69 (36) 30 (43) 377 (61) < 0.001
 Rings 83 (43) 35 (49) 360 (58) 0.001
 Edema 88 (45) 30 (42) 415 (67) < 0.001
 Furrows 135 (70) 53 (75) 548 (88) < 0.001
 Stricture 63 (32) 21 (30) 184 (30) 0.75
 Narrowing 25 (13) 12 (17) 124 (20) 0.08
 Crepe-paper mucosa 5 (3) 5 (7) 22 (4) 0.22
 Dilation 60 (31) 23 (32) 195 (31) 0.97
  Stricture diameter (mean mm ± SD) 13.1 ± 3.8 12.7 ± 3.4 11.6 ± 3.2 0.04
 Total EREFS (mean ± SD)** 2.7 ± 1.6 2.8 ± 1.8 4.0 ± 1.8 < 0.001
 Total ESS (mean ± SD)** 2.3 ± 1.4 2.4 ± 1.5 3.0 ± 1.3 < 0.001
Peak eosinophil count (mean eos/hpf ± SD) 51.9 ± 40.7 38. 5 ± 24.9 76.6 ± 47.6 < 0.001
 Distal counts 51.8 ± 40.7 5.6 ± 4.6 64.2 ± 44.4 < 0.001
 Proximal counts 4.4 ± 4.4 38. 0 ± 24.9 57.0 ± 39.4 < 0.001
I-SEE total score (mean ± SD) 7.8 ± 5.7 8.1 ± 5.2 9.3 ± 6.4 0.006
I-SEE categories (n, %) 0.001
 Mild 112 (58) 35 (49) 259 (42)
 Moderate 57 (30) 29 (41) 277 (45)
 Severe 24 (12) 7 (10) 86 (14)
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*

data available for n=172, 62, 547

**

EREFS data available for n=135, 48, 451; ESS = endoscopic severity score, for which all data available

On logistic regression, we found that younger age, presence of exudates, rings, edema, furrows, and more severe disease by I-SEE were independently associated with diffuse eosinophilic involvement compared to localized involvement.

Treatment outcomes

There were 395 patients in our cohort who were treated with topical steroids and had a follow-up endoscopy with biopsy. There were no significant differences in the specific tCS or dose prescribed (Table 2). Patients with diffuse disease were less likely to achieve a histological response at the <15 eos/hpf threshold (51%) compared to those with proximal (70%) or distal (67%; p=0.01) involvement; results were similar for the ≤6 eos/hpf (p=0.002) and <1 eos/hpf (p<0.001) thresholds (Figure 1). Post-treatment EREFS was highest for those with diffuse involvement (2.5 ± 2.0 vs 1.8 ± 1.7 proximal vs 1.5 ± 1.6 distal; p<0.0001), and an endoscopic response of EREFS ≤2 was also less likely with diffuse involvement (58%) compared to proximal (70%) or distal (81%) (p=0.004). However, global symptom response was not different between groups (Table 2; Figure 1). Results were similar on the secondary analysis assessing localized (proximal- or distal-only) versus diffuse esophageal involvement (Supplementary Table 2). The association between diffuse disease and reduced odds of achieving histological remission (<15 eos/hpf) to tCS remained significant after adjusting for other predictors of response including BMI, esophageal dilation at baseline, age at diagnosis, race, insurance status, baseline endoscopic severity, and baseline disease severity (I-SEE) (adjusted odds ratio 0.47; 95% confidence interval: 0.26–0.86; Table 3).22, 32, 38–40

Table 2.

Treatment response to topical steroids as stratified by extent of esophageal eosinophil distribution

Distal only (n = 81) Proximal only (n = 30) Diffuse (n = 284) p
Type of steroid used (n, %) 0.94
 Fluticasone 21 (26) 7 (23) 80 (28)
 Budesonide 60 (74) 23 (77) 204 (72)
Mean steroid dose (mcg ± SD) 1754 ± 779 1839 ± 754 1749 ± 699 0.81
Post-treatment peak eosinophil count (mean eos/hpf ± SD) 17.7 ± 33.1 17.8 ± 29.9 27.4 ± 39.4 0.07
 p value vs baseline < 0.001 0.01 < 0.001
Histologic response (n, %)
 <15 eos/hpf 54 (67) 21 (70) 146 (51) 0.01
 ≤6 eos/hpf 49 (60) 20 (67) 121 (43) 0.002
 <1 eos/hpf 35 (43) 16 (53) 70 (25) < 0.001
Global symptom response (n, %)* 30 (81) 8 (73) 86 (73) 0.60
Post-treatment endoscopic findings (n, %)
 Normal 15 (19) 10 (33) 46 (16) 0.07
 Exudates 10 (13) 5 (19) 96 (35) < 0.001
 Rings 33 (41) 12 (43) 135 (49) 0.43
 Edema 17 (21) 6 (22) 110 (40) 0.003
 Furrows 29 (36) 13 (48) 166 (60) 0.001
 Stricture 30 (37) 8 (29) 97 (35) 0.72
 Narrowing 7 (9) 7 (29) 59 (21) 0.02
 Crepe-paper mucosa 0 (0) 0 (0) 3 (1) 0.56
 Dilation 28 (35) 8 (30) 91 (33) 0.89
  Stricture diameter (mean mm ± SD) 14.8 ± 3.2 13.1 ± 3.5 14.0 ± 2.6 0.29
 Candida 7 (9) 3 (12) 19 (7) 0.64
Endoscopic response (n, %) 65 (80) 24 (80) 184 (65) 0.02
Post-treatment endoscopic severity (mean scores ± SD)
 EREFS** 1.5 ± 1.6 1.8 ± 1.7 2.5 ± 2.0 < 0.001
  p value vs baseline < 0.001 0.01 < 0.001
 ESS 1.5 ± 1.3 1.6 ± 1.6 2.2 ± 1.5 < 0.001
  p value vs baseline < 0.001 0.002 < 0.001
 EREFS response of ≤2** 47 (81) 12 (70) 122 (58) 0.004
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*

available for n=37, 11, and 118

**

available for n=58, 17, and 211

Figure 1.

Figure 1.

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Treatment response thresholds to topical steroids stratified by as stratified by extent of esophageal eosinophil distribution.

Table 3:

Relationship between lower histologic response to topical corticosteroids and diffuse disease after adjusting for other predictors of response

Odds ratio Lower 95% confidence interval Upper 95% confidence interval
Histologic response (diffuse vs local) 0.47 0.26 0.84
BMI (1 point increase) 0.91 0.87 0.95
Dilation at baseline 0.68 0.38 1.23
Age at diagnosis (1 year increase) 1.03 1.01 1.05
Race (non-white) 0.63 0.29 1.36
Health insurance 3.94 1.75 8.85
Endoscopic severity (1 point increase in ESS) 0.82 0.66 1.00
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Given the time course of this study and changes in diagnostic guidelines related to PPI use,3 we performed a subanalysis for histologic response (15 eos/hpf) to tCS stratified by those diagnosed prior to 2018 (PPI failure required) and those diagnosed 2018 forward (no PPI trial needed). We found there were no overall differences in the histologic response rates to tCS based on timing: 55% (150/272) of patients pre-2018 had histologic response (<15 eos/hpf) and 58% (71/123) of the 2018-forward group had histologic response (p=0.63). The overall population trends also generally held, with lower histologic rates for diffuse disease compared to localized disease, for pre-2018 (52% vs 63%; p=0.10) and 2018-forward (51% vs 82%; p=0.003).

There were 235 patients who were treated with FED and had post-treatment endoscopy with biopsy, the majority of whom were treated with empiric elimination, though there was heterogeneity in diet treatment modalities. However, there were no differences in histologic response (<15 eos/hpf) for those with diffuse involvement (37%) compared to localized (proximal-only or distal-only) involvement (44%; p=0.32). There were also no differences in symptom responses between these groups, but endoscopic findings persisted in the diffuse group with lower endoscopic response (EREFS ≤2) for the diffuse group (48%) compared to the localized group (75%; p=0.001) (Supplementary Table 3).

Discussion

Quantification of esophageal eosinophilia is central to diagnosis of EoE and, along with symptoms and endoscopic finding, informs understanding treatment response.4, 30 However, eosinophilic infiltration is patchy,41, 42 and the clinical implications of diffuse versus localized esophageal involvement on disease presentation or outcomes remains unclear. In this retrospective cohort study of nearly 900 incident EoE patients, diffuse involvement was associated with more severe endoscopic findings (EREFS) and higher overall disease severity (I-SEE), despite similar demographics, concomitant atopic conditions, and symptoms across groups. Diffuse disease was also associated with significantly reduced histologic and endoscopic responses to tCS treatment, whereas symptom response was similar. In contrast, the extent of eosinophilic involvement did not impact histologic outcomes of dietary elimination. These data suggest that the extent of eosinophilic involvement, rather than independent peak eosinophil counts, may provide clinically relevant information regarding disease severity and predict tCS treatment response.

Results to date from prior studies examining the extent of eosinophilic involvement in the esophagus have reported inconsistent findings. For example, a prospective cohort study from Collins and colleagues in a multicenter consortium did not demonstrate differences in symptom burden or quality of life between uni- and multiregional disease,10 and post-hoc analyses by Godat and colleagues of a randomized clinical trial with budesonide orodispersible tablets also did not show differences in histological response across extent of disease involvement.12 One potential explanation is that patients in our cohort were using off-label tCS formulations whereas patients in the clinical trial were using an esophageal-specific formulation. Off-label formulations may not coat the esophagus as uniformly as esophageal-specific formulations due to inconsistent patient preparation (mixing technique and viscosity), variable dosing, and suboptimal adherence to the esophageal mucosa. This non-uniform coating could lead to inadequate drug delivery across all affected regions, which could be problematic in diffuse disease where complete esophageal coverage is needed for remission, though we acknowledge that our distal only group had better tCS response than the diffuse group, which might not be expected if distal drug delivery was an issue. In contrast, a multisite retrospective cohort study from Sorg and colleagues evaluating similar therapies (PPI, tCS, and FED) with a comparable prevalence of diffuse disease involvement (64%) found lower rates of endoscopic fibrotic remission in diffuse disease, but no significant association in overall treatment response (potentially due to limited sample size).15 Additional studies have associated localized disease with improved treatment response. Hartnett and colleagues also found that distal-predominant disease was associated with PPI response while Heil and colleagues observed in the Swiss EoE cohort that proximal only disease, though infrequent (which we also observed), was associated with better treatment resonse.13, 14 Our findings, supported by the large sample size, suggests that EoE patients with diffuse histologic involvement of the esophagus represent a more treatment-refractory phenotype.

Our findings also add to a growing body of evidence identifying clinical predictors of treatment response to topical corticosteroids. Previous studies have shown baseline dilation,38, 43 narrow-caliber esophagus,19 older age,39 higher BMI,32 higher disease severity (I-SEE)22, and higher social vulnerability44 are associated with reduced histologic response to tCS. Incorporating diffuse eosinophilic involvement to this existing set of predictors reinforces a consistent pattern linking treatment resistance to disease severity, fibrostenosis, and extent of esophageal involvement. Although these factors are not yet sufficient to guide clinical decision-making, it is still important information to have in discussions with individual patients. These factors, when coupled with emerging molecular predictors,45–47 may ultimately support personalized treatment decisions related to tCS. An important caveat is that these prior data are largely derived from off-label rather than esophageal-specific formulations which may mitigate some of these clinical and disease-related factors.12

This study has several limitations. As a single-center study at an academic center, generalizability may be limited. However, this is mitigated with the focus on incident cases (rather than complex referral patients) as well as the largest sample size yet to examine this question. Additionally, the retrospective study design precluded the use of validated patient-reported outcomes, which may contribute to the discordance between symptom and endoscopic or histologic outcomes. Although validated endoscopic metrics (EREFS) were used with response thresholds that are becoming accepted in the field, the EoE Histological Scoring System (HSS) was not available to more deeply explore histologic severity as it is not routinely used in clinical practice at our center and key non-eosinophil findings (e.g., basal zone hyperplasia, dilated intercellular spaces, lamina propria fibrosis) are inconsistently reported. There was also substantial heterogeneity of diet elimination strategies in the FED group. Though the majority were treated with empiric elimination, the types of foods were not standardized and were based on clinician and patient preference, and other strategies were also used (allergy test-directed/targeted; elemental). The numbers within these subgroups were also small and subgroup analyses were not possible. Therefore, conclusions in this FED subset should be interpreted with caution. A more global question could relate to whether the extent of histologic involvement could be subject to sampling error. This is unlikely given the consistent practice at our center of obtaining eight biopsies (four distal and four proximal) and would be expected to attenuate the observed associations. Finally, biopsies only assess the mucosal distribution, and we do not have a method of assessing extent of involvement for deeper esophageal layers such as the subepithelial or muscularis propria. Our study also cannot determine whether diffuse involvement represents a distinct biological phenotype or simply a marker of greater inflammatory burden. Therefore, future studies could potentially combine biopsy data with a measure such as the functional lumen imaging probe, which provides transmural disease assessment, and also incorporate molecular profiling, longitudinal assessment, and external validation to distinguish between these possibilities.

In conclusion, in this large retrospective cohort study, newly diagnosed EoE patients with diffuse esophageal eosinophilic involvement had greater baseline endoscopic (EREFS) and overall (I-SEE) disease severity compared to those with disease localized to either the distal-only or proximal-only esophagus. Moreover, diffuse involvement was also associated with reduced histological and endoscopic response to tCS, and this persisted after adjusting for potential confounders and other predictors of response. These findings suggest that diffuse esophageal involvement in EoE could be a clinically relevant marker of disease severity and treatment response that may warrant more aggressive management to achieve histological and endoscopic remission, particularly if our results are confirmed. Disease extent could also be considered when discussing treatment options and expected outcomes with patients.

Supplementary Material

Supplementary Material

Grant support/funding:

This study was supported in part by T32 DK007634 and NIH T35 DK007386

Disclosures:

Dr. Dellon reports research funding from: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Celldex, Dr. Falk Pharma, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Phathom, Regeneron, Revolo, Sanofi, Shire/Takeda, Uniquity; consulting fees from: Abbvie, Adare/Ellodi, Alfasigma, ALK, Allakos, Amgen, Anaptysbio, Apogee, Apollo, Aqilion, Arena/Pfizer, AstraZeneca, Bethanamist, Biocryst, Bryn, Calypso, Celgene/Receptos/BMS, Celldex, Cyted, Domain, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GI Reviewers, GSK, Holoclara, Invea, Knightpoint, LucidDx, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Roivant, Sanofi, Shire/Takeda, Target RWE, Third Harmonic Bio, Upstream Bio; and educational grants from: Allakos, Aqilion, Holoclara, Invea.

Dr. Reed reports consulting fees from AstraZeneca and GI Reviewers. None of the other authors have disclosures.

Data availability statement:

The data that support the findings of this study may be available on request to the corresponding author and with appropriate approvals in place. The data are not publicly available due to privacy or ethical restrictions.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material
NIHMS2215531-supplement-Supplementary_Material.pdf (200.1KB, pdf)

Data Availability Statement

The data that support the findings of this study may be available on request to the corresponding author and with appropriate approvals in place. The data are not publicly available due to privacy or ethical restrictions.

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