Introduction
Eosinophilic esophagitis (EoE) is a leading cause of dysphagia and food impaction
in young adults and a common cause of chronic esophagitis [1]. EoE is a clinicopathologic disorder defined both by symptoms and objective findings
of eosinophilia (> 15 eosinophils per high power field [hpf]) on esophageal biopsies
[2]. Current guidelines recommend that at least six esophageal biopsies be obtained
from two different locations in the esophagus, most typically the distal and proximal
halves [3]. As the number of biopsies reaches six or more, the diagnostic sensitivity for EoE
significantly improves [3]
[4]. Obtaining biopsies from different esophageal locations may also improve detection
of EoE given its patchy nature [5].
Many endoscopists have adopted the practice of routinely separating esophageal biopsies
into different jars based on their location (proximal vs. distal). This approach,
although more expensive and somewhat more time-consuming, has been theorized by physicians
to differentiate EoE from gastroesophageal reflux disease (GERD), with the assumption
that eosinophils will be more numerous in the distal esophagus in GERD and more diffuse
in EoE [3]
[6]. Some studies have supported this theory by showing significant proximal eosinophilia
in adults diagnosed with EoE compared with GERD [7], while others have not [8]
[9]. While acknowledging the associated additional costs and the added procedural time
and risks, the clinical benefits of separating pathology specimens into different
jars remain unclear. Updated guidelines in 2011 raised the question of whether the
distribution of inflammatory changes in EoE predicts response to proton pump inhibitor
(PPI) therapy [10]. The current study was designed to address several of these unanswered questions.
We hypothesized that biopsies from different locations could be important in assessing
the extent and degree of inflammation in the esophagus. Biopsies from different locations
could also help assess the degree of overlap with GERD. Finally, results of esophageal
biopsies from distal and more proximal sites could be used to predict treatment response.
The patchy nature of EoE may be a reflection of the extent of disease, while dense
eosinophilia limited to the distal third of the esophagus may represent a milder form
of EoE or an overlap with GERD that has better treatment response when compared with
diffuse disease. Therefore, our study aimed to compare patient demographics, symptoms,
clinical characteristics, and treatment outcomes of patients with limited EoE (Lim-EE)
vs. those with diffuse EoE extending to the proximal parts of the esophagus (Dif-EE).
Methods
Patient selection and study design
This study was a retrospective review of patients who underwent esophagogastroduodenoscopy
(EGD) with esophageal biopsies positive for eosinophils at Mayo Clinic in Jacksonville,
Florida, between December 2011 and December 2019. Only patients who had at least one
esophageal biopsy showing more than 15 eosinophils/hpf, obtained from both the distal
and proximal esophagus and separated into different pathology specimen jars, were
included. An average of 4 passes (2 biopsy pieces/pass) per patient were obtained.
EoE was defined as the presence of ≥ 15 eosinophils/hpf. Patients were subclassified
into distal (Lim-EE) and diffuse (Dif-EE) based on the extent of EoE. The Lim-EE group
was defined by localized eosinophilic involvement of the distal third of the esophagus
and lack of eosinophilia in the proximal esophagus. The Dif-EE group was defined by
esophageal eosinophilia in both the proximal and distal esophagus. We assessed treatment
outcomes based on histopathologic and clinicopathologic response (see below). A summary
of patient selection and study design is presented in [Fig. 1].
Fig. 1 Summary of the patient selection and study design. EGD, esophagogastroduodenoscopy;
HPF, high power field; EoE, eosinophilic esophagitis.
Indications and protocol for obtaining segmental esophageal biopsies
In our institution, we frequently perform segmental esophageal biopsies in patients
who present with dysphagia, patients who have incidental endoscopic findings concerning
for EoE, and patients who present for Barrett’s surveillance in order to rule out
dysplasia. Our protocol for obtaining segmental esophageal biopsies in patients with
dysphagia or those who have endoscopic findings suggesting EoE is to obtain at least
2 passes (2 biopsy pieces/pass) from the lower distal third as well as the upper and/or
middle third. Some endoscopists separate these into two jars, which was an inclusion
criterion in our study, while others place them all in one jar. For Barrett’s surveillance,
it is common in our practice to obtain biopsies from the distal as well as middle
thirds of the esophagus to rule out dysplasia. Indications for esophageal biopsies
are summarized in [Table 1].
Table 1
Demographics and clinical characteristics.
|
Lim-EE[1]
(n = 126)
|
Dif-EE[2]
(n = 353)
|
P value
|
|
Age, mean (SD), years
|
50.8 (16.2)
|
46.4 (15.3)
|
0.0073
|
|
Sex (male), n (%)
|
77 (61.1)
|
216 (61.2)
|
0.55
|
|
Race (white), n (%)
|
118 (93.7)
|
335 (94.9)
|
0.65
|
|
BMI, mean (SD), kg/m[2]
|
27.4 (5.30)
|
28.1 (9.77)
|
0.61
|
|
Indication for performing EGD with segmental biopsies, n (%)
|
|
|
57 (45.2)
|
202 (57.2)
|
0.02[3]
|
|
|
|
|
28 (22.2)
|
66 (18.7)
|
0.43
|
|
|
7 (5.6)
|
6 (1.7)
|
0.05
|
|
|
19 (15.1)
|
31 (8.8)
|
0.06
|
|
|
3 (2.4)
|
8 (2.3)
|
> 0.99
|
|
|
9 (7.1)
|
42 (11.9)
|
–
|
|
|
13 (10.3)
|
13 (3.7)
|
0.02[3]
|
|
History of asthma, n (%)
|
28 (22.2)
|
101 (28.6)
|
0.19
|
|
History of eczema, n (%)
|
12 (9.5)
|
26 (7.4)
|
0.46
|
|
History of seasonal allergies, n (%)
|
51 (40.5)
|
162 (45.9)
|
0.29
|
|
History of food impaction, n (%)
|
13 (10.3)
|
44 (12.5)
|
0.63
|
|
History of esophageal perforation, n (%)
|
0
|
4 (1.1)
|
0.58
|
|
Reflux esophagitis on EGD,[4] n (%)
|
29 (23.0)
|
52 (14.7)
|
0.04[3]
|
|
|
12 (9.5)
|
12 (3.4)
|
0.01[3]
|
|
|
9 (7.1)
|
24 (6.8)
|
> 0.99
|
|
|
4 (3.2)
|
10 (2.8)
|
0.77
|
|
|
4 (3.2)
|
6 (1.7)
|
0.29
|
|
PPI use before initial EGD/biopsy, n (%)
|
45 (35.7)
|
132 (37.4)
|
0.82
|
|
Esophageal dilation at time of biopsy, n (%)
|
30 (23.8)
|
84 (23.8)
|
> 0.99
|
|
Bravo[5] testing, n (%)
|
12
|
23
|
0.40
|
|
|
5 (41.7)
|
13 (56.5)
|
|
Ambulatory pH monitoring, n (%)
|
9
|
15
|
0.39
|
|
|
2 (22.2)
|
7 (46.7)
|
SD, standard deviation; BMI, body mass index; EGD, esophagogastroduodenoscopy; EoE,
eosinophilic esophagitis; GERD, gastroesophageal reflux disease; PPI, proton pump
inhibitor.
1 EoE limited to the distal esophagus.
2 EoE with diffuse involvement.
3 Statistically significant.
4 Los Angeles classification.
5 Bravo pH Monitoring System (Medtronic, Minneapolis, Minnesota, USA).
Demographics and clinical characteristics
Lim-EE and Dif-EE groups were compared based on patient demographics (age, sex, race,
body mass index), relevant clinical characteristics (history of asthma, eczema, seasonal
allergies), clinical presentation/indications, and findings on their initial diagnostic
EGD including reflux esophagitis graded using the Los Angeles (LA) classification
system, pertinent medications at the time of biopsies (e. g. PPI, steroids), relevant
clinical testing for GERD if available (Bravo [Medtronic, Minneapolis, Minnesota,
USA] and ambulatory pH monitoring test results), and disease complications such as
food impaction and esophageal perforation. To determine the number of patients who
were on PPI by the time of the initial or follow-up EGD, we manually checked the medication
list for each patient on the day of the EGD.
Comparing histopathologic treatment response
This analysis involved patients who had a follow-up EGD with biopsies following their
initial EGD. Response to treatment was defined as the presence of < 15 eosinophils/hpf
on both proximal and distal esophageal biopsies. The follow-up period was calculated
as the time between initial and repeat endoscopies. We reviewed and collected treatment
data at the time of both endoscopies including medical therapy (type and dose), food
elimination diets, and esophageal dilations.
Comparing clinicopathologic treatment response
Patients included in this analysis were followed in one of two ways: they either underwent
repeat EGD with biopsies or were followed clinically based on their symptoms. A positive
treatment response was defined as physician-documented symptomatic improvement on
follow-up or a histopathologic improvement (< 15 eosinophils/hpf) at the time of follow-up
EGD. Symptomatic improvement was defined as resolution of the presenting symptom documented
in physicians’ notes. The follow-up period was calculated as the time between the
initial EGD and repeat endoscopy or date of the clinical follow-up visit.
Statistical analysis
Continuous variables were summarized with the sample median and range. Categorical
variables were summarized with number and percentage of patients. Comparisons between
groups were made using a Wilcoxon rank sum test or Fisher’s exact test. Univariate
and multivariable logistic regression models were used to identify predictors for
treatment response. All tests were two-sided with alpha level set at 0.05 for statistical
significance. Statistical analyses were performed using JMP, Version 14.1.0 (SAS Institute
Inc., Cary, North Carolina, USA, 1989–2019).
Institutional Review Board approval was obtained. Patients were not compensated in
any form for participating in the study.
Results
Patient demographics and clinical characteristic
We initially included 508 patients who had an EGD with biopsies that showed > 15 eosinophils/hpf
between December 2011 and December 2019; however, we eventually excluded 29 patients
who did not have segmental biopsies (i. e. biopsies were not taken from two separate
locations in the esophagus and were not placed in different jars). Patients were grouped
based on the location of esophageal eosinophilia. A total of 126 patients had Lim-EE
and 353 had Dif-EE. A summary of patient demographics and clinical characteristic
is shown in [Table 1].
When compared with patients with Dif-EE, those with Lim-EE were older (mean 50.8 [SD
16.2] vs. 46.4 [SD 15.3] years; P = 0.007) and had a higher incidence of endoscopically identified reflux esophagitis
(23.0 % vs. 14.7 %; P = 0.04), especially LA grade A esophagitis (9.5 % vs. 3.4 %; P = 0.01). Patients with Lim-EE were more likely to present with iron deficiency anemia
(5.6 % vs. 1.7 %; P = 0.05), dyspepsia (15.1 % vs. 8.8 %; P = 0.06), or as part of a Barrett’s surveillance program (10.3 % vs. 3.7 %; P = 0.02). In contrast, patients with Dif-EE presented more frequently with dysphagia
vs. patients with Lim-EE (57.2 % vs. 45.2 %; P = 0.02). Only a small number of patients had Bravo testing and pH monitoring, with
no statistically significant differences between the two groups.
Treatment outcomes
We compared the clinicopathologic treatment response of 78 patients with Lim-EE and
257 patients with Dif-EE. These were the subset of patients who underwent repeat EGD
or had a follow-up clinic visit following their initial EGD. There were no differences
in demographics or clinical characteristics between the two groups (Supplemental Table 1s). Both groups had similar treatment data (PPI use, dose and type, steroid use and
type, elimination diet), as shown in [Table 2].
Table 2
Treatment data for patients included in the clinicopathologic response analysis.
|
Lim-EE[1]
(n = 78)
|
Dif-EE[2]
(n = 257)
|
P value
|
|
Lim-EE[1]
(n = 78)
|
Dif-EE[2]
(n = 257)
|
P value
|
|
Elimination diet before initial EGD/biopsy, n (%)
|
0
|
5 (1.9)
|
0.59
|
Elimination diet after initial EGD/biopsy, n (%)
|
10 (12.8)
|
44 (17.1)
|
0.38
|
|
PPI use before initial EGD/biopsy, n (%)
|
30 (38.5)
|
101 (39.3)
|
0.37
|
PPI use after initial EGD/biopsy, n (%)
|
68 (87.2)
|
214 (83.3)
|
0.37
|
|
|
10 (33.3)
|
34 (33.7)
|
0.57
|
|
44 (64.7)
|
149 (69.6)
|
0.64
|
|
|
33.8 (11.6)
|
32.0 (10.9)
|
0.46
|
|
55.1 (20.3)
|
56.3 (22.6)
|
0.68
|
|
PPI type, n
|
|
PPI type, n
|
|
|
|
33
|
117
|
|
35
|
117
|
|
|
8
|
27
|
|
8
|
21
|
|
|
20
|
45
|
|
20
|
45
|
|
|
0
|
2
|
|
0
|
2
|
|
|
4
|
20
|
|
4
|
20
|
|
|
1
|
1
|
|
1
|
2
|
|
Steroid use before initial EGD/biopsy
|
5 (6.4)
|
13 (5.1)
|
0.57
|
Steroid use after initial EGD/biopsy
|
10 (12.8)
|
55 (21.4)
|
0.14
|
|
|
3
|
9
|
Fluticasone
|
9
|
41
|
|
|
2
|
4
|
Budesonide
|
1
|
14
|
EGD, esophagogastroduodenoscopy; PPI, proton pump inhibitor; BID, twice daily; SD,
standard deviation.
1 Eosinophilic esophagitis (EoE) limited to the distal esophagus
2 EoE with diffuse involvement.
Over 60 % of patients (61.5 %) with Lim-EE (n = 48 /78) responded to treatment based
on repeated biopsy or documented clinical improvement, compared with 44.8 % (n = 115/257)
in the Dif-EE group (P = 0.009) at a mean follow-up of 14.4 (SD 16.5) and 15.0 (SD 1.1) months (P = 0.81), respectively ([Fig. 2]). Based on improvement in clinical symptoms alone, 76.7 % of patients with Lim-EE
(n = 23 /30) responded to treatment compared with 51.1 % (n = 46 /90) in the Dif-EE
group (P = 0.02).
Fig. 2 Response to treatment. a Observed esophagitis during repeat esophagogastroduodenoscopy. b Repeat biopsy results. c Repeat biopsy or clinical symptoms. EGD, esophagogastroduodenoscopy; EoE, eosinophilic
esophagitis. *Statistically significant.
We compared treatment response of 48 patients with Lim-EE and 167 patients with Dif-EE
exclusively based on histopathology results of repeated esophageal biopsies. Indications
for repeated EGD with biopsies are outlined in Supplementary Table 2s. Lim-EE patients were older (52.8 [SD 14.8] vs. 47.7 [SD 14.9]; P = 0.036) and had a higher incidence of endoscopically identified esophagitis on the
initial EGD (27.1 % vs. 12.0 %; P = 0.02), particularly grade D esophagitis (8.3 % vs. 1.8 %; P = 0.046) compared with Dif-EE (Supplemental Table 2s). Both groups received similar treatments including PPI dose and type, steroids dose
and type, esophageal dilation, and elimination diet trial, as shown in [Table 3]. They also had similar follow-up time for repeated biopsies (12.5 [SD 16.8] and
14.1 [SD 18.2] months, respectively; P = 0.63).
Table 3
Treatment at the time of initial and repeat esophagogastroduodenoscopy.
|
Initial EGD
|
P value
|
|
Repeat/follow-up EGD
|
P value
|
|
Lim-EE[1]
(n = 48)
|
Dif-EE[2]
(n = 167)
|
Lim-EE[1]
(n = 48)
|
Dif-EE[2]
(n = 167)
|
|
Elimination diet before initial EGD/biopsy, n (%)
|
0
|
11 (6.6)
|
0.13
|
Elimination diet after initial EGD/biopsy, n (%)
|
3 (6.3)
|
21 (12.6)
|
0.30
|
|
Dilation performed at time of initial EGD, n (%)
|
15 (31.3)
|
41 (24.6)
|
0.36
|
Dilation performed at follow-up EGD, n (%)
|
16 (33.3)
|
42 (25.1)
|
0.27
|
|
|
5
|
12
|
|
2
|
15
|
|
|
2
|
7
|
|
2
|
10
|
|
|
8
|
22
|
|
12
|
17
|
|
PPI use before EGD/biopsy, n (%)
|
18 (37.5)
|
58 (34.7)
|
0.41
|
PPI use after initial EGD/biopsy, n (%)
|
39 (81.3)
|
128 (76.7)
|
0.56
|
|
|
13 (72.2)
|
36 (62.1)
|
0.77
|
|
27 (69.2)
|
95 (74.2)
|
0.54
|
|
|
55.2 (22.6)
|
50.1 (23.3)
|
0.34
|
|
56.9 (20.4)
|
56.6 (22.9)
|
0.71
|
|
PPI type, n
|
0.60
|
PPI type, n
|
0.31
|
|
|
6
|
22
|
|
19
|
68
|
|
|
2
|
13
|
|
5
|
17
|
|
|
5
|
10
|
|
12
|
28
|
|
|
1
|
2
|
|
0
|
1
|
|
|
3
|
10
|
|
2
|
14
|
|
|
1
|
1
|
|
1
|
0
|
|
Steroid use before EGD/biopsy, n (%)
|
4 (8.3)
|
16 (9.6)
|
> 0.99
|
Steroid after initial EGD/biopsy, n (%)
|
5 (10.4)
|
29 (17.4)
|
> 0.99
|
|
|
0
|
1
|
|
4
|
21
|
|
|
4
|
9
|
|
1
|
8
|
|
|
0
|
7
|
|
0
|
0
|
EGD, esophagogastroduodenoscopy; TTS, through the scope; PPI, proton pump inhibitor;
BID, twice daily; SD, standard deviation.
1 Eosinophilic esophagitis (EoE) limited to the distal esophagus.
2 EoE with diffuse involvement.
Assessing outcomes, Lim EE patients had a 22.9 % reduction in reflux esophagitis observed
at follow-up EGD (P = 0.002) compared with 4.8 % in the Dif-EE group (P = 0.06). Histopathologic response was achieved in 52.5 % of patients in the Lim-EE
group and 39.7 % in the Dif-EE group (P = 0.15). Results are illustrated in [Fig. 2].
After adjusting for age and sex, the extent of esophageal involvement in EoE (Lim-EE
vs. Dif-EE) predicted clinicopathologic treatment response with an adjusted odds ratio
(aOR) of 1.89 (95 % confidence interval [CI] 1.13–3.20; P = 0.02) and clinical response with an aOR of 3.12 (95 %CI 1.22–8.02; P = 0.02). However, extent of esophageal involvement did not predict histologic response,
with an aOR of 1.40 (95 %CI 1.40–0.31; P = 0.31).
We repeated our analysis to include patients with esophageal symptoms only (dysphagia,
chest pain, dyspepsia, food impaction, and heartburn) and observed similar outcomes.
Clinical improvement was documented in 60.5 % (46 /76) of the Lim-EE group compared
with 44.8 % (108/241) in the Dif-EE group (P = 0.02), while histologic response was observed in 51.2 % (21 /41) in the Lim-EE
group compared with 41.2 % (63/153) in the Dif-EE group (P = 0.29).
For the clinicopathologic response, the number of patients who were on PPIs before
the initial EGD was 30 /78 (38.5 %) with Lim-EE and 101 /257 (39.3 %) with Dif-EE.
The number of patients who were on PPIs after the initial EGD (until the follow-up
date) was 68 /78 (87.2 %) with Lim-EoE and 214/257 (83.3 %) with Dif-EE, as shown
in [Table 2]. For histologic response, the number of patients who were on PPI before the initial
EGD was 18/48 (37.5 %) with Lim-EE and 58/167 (34.7 %) with Dif-EE. The number of
patients who were on PPIs after the initial EGD (until follow-up EGD) was 39/48 (81.3 %)
with Lim-EE and 128/167 (76.7 %) with Dif-EE.
We performed a subanalysis of the clinicopathologic response after excluding patients
who where on PPIs or steroids at the time of biopsy during their initial EGD. The
total number of patients excluded was 131 patients, leaving 48 patients in the Lim-EE
group and 156 in the Dif-EE group to be included in this analysis. A total of 28/48
patients (58.3 %) with Lim-EE and 68/156 (43.6 %) with Dif-EE had clinicopathologic
response to treatment (P = 0.06). For histologic response, the total number of patients excluded from this
analysis was 76 patients. After analysis, 41/109 patients (37.6 %) with Dif-EE responded
histologically to treatment compared with 14/30 (46.7 %) with Lim-EE (P = 0.52).
Discussion
EoE is an inflammatory disorder characterized by patches of eosinophilic mucosal infiltration
involving single or multiple locations of the esophagus [11]. Current guidelines call for multiple biopsies from the proximal and distal esophagus
to increase the sensitivity of the endoscopy [4]. Separating biopsies into different jars is a common practice by endoscopists; however,
as this approach may result in significant monetary expense to the patient, is time-consuming,
and confers some added risk, a better understanding of its clinical utility is warranted.
Updated consensus statements have questioned the clinical value of defining the extent
of EoE disease and the ability of this measure to predict treatment response [3]
[10]
[12]. In the current study, we found potential benefits of segmental biopsies; specifically,
the extent of esophageal involvement may predict treatment response, as patients with
EoE limited to the distal esophagus had a better clinicopathologic response compared
with those with diffuse EoE.
Defining EoE and its correlation with GERD has been an area of active scientific inquiry
over the past decade [13]. Early studies suggested a strong overlap between the two disease states [14]
[15]. Subsequent investigations led to a change in classification, such that these two
disorders were thought to be distinctly separate based on response to PPI therapy
[12]
[16]. Therefore, the current notion is that EoE and GERD share a mutually complex relationship
and may indeed coexist. Although uncommon, EoE may cause reflux due to decreased esophageal
compliance or alterations to normal esophageal motility, whereas GERD may disrupt
the epithelial barrier integrity allowing antigen exposure and the eventual development
of eosinophilia [17].
In our study, we hypothesized that patients with eosinophilia limited to the distal
esophagus represent a population with GERD or mild EoE. A prior prospective study
by Frazzoni et al. concluded that reflux plays a role in the pathogenesis of EoE,
particularly in PPI-responsive cases [13]. In our cohort, Lim-EE patients were older, had a higher incidence of endoscopically
identified reflux esophagitis, and presented with dyspepsia or as part of a Barrett’s
surveillance program; patients with Dif-EE had a higher incidence of dysphagia. We
hypothesized that dysphagia is more common in Dif-EE due to the diffuse nature or
changes in compliance and/or motility as this entity likely represents patients with
EoE, compared with limited distal disease, which may be more compliant and have normal
motility and likely corresponds to GERD or mild EoE.
Managing and evaluating treatment outcomes in EoE may be challenging due to the discordance
between symptoms and histology [18]. The ultimate goal of treating EoE is to eliminate both patient symptoms as well
as the eosinophilia ( ≥ 15 eosinophils/hpf in biopsies). Treatment options may be
delivered as monotherapy or combination of PPI therapy, topical steroids, elimination
diet, and esophageal dilation [19]. In 2016, a meta-analysis that combined adult and pediatric patients reported PPI-induced
clinical and histologic remission in 60.8 % and 50.5 % of the patients, respectively
[20]. A follow-up study showed a 33 % sustained clinical remission and histologic remission
with < 15 eosinophils/hpf on PPI therapy alone [21]. In addition, Lucendo et al. reported 58 % complete remission (clinical and histologic)
with oral budesonide tablets (1 mg twice daily) compared with placebo [22].
In our study, we assessed treatment outcomes based on either histologic response alone
or histologic and/or clinical response. Both Lim-EE and Dif-EE patients were treated
similarly with about 80 % of both groups receiving PPI therapy after their initial
EGD. This may simply reflect the common clinical practice of treating EoE patients
with a “step-up” approach that starts with PPI therapy followed by steroids. The Lim-EE
group had a 22.9 % reduction in esophagitis at follow-up EGD (P = 0.002) compared with 4.8 % in the Dif-EE group (P = 0.06). We realize that reported esophagitis may have been secondary to EoE, although
unlikely, or reflux, but given the lack of pH monitoring data, it was not possible
to make such a distinction. However, in both scenarios, better mucosal healing and
response to treatment in Lim-EE compared with Dif-EE may be considered. Furthermore,
61.5 % of patients with Lim-EE achieved clinicopathologic response compared with 44.8 %
in the Dif-EE group (P = 0.009) at a similar follow-up period of about a year. Given the significant age
difference between the groups, we performed a multivariate analysis adjusting for
age and sex. In support of our hypothesis, disease extent predicted clinicopathologic
response to treatment with an aOR of 1.89 (95 %CI 1.13–3.20; P = 0.02). To better characterize the observed effect, we performed a subanalysis of
treatment response based on improvement in clinical symptoms only and histopathologic
response only. Clinically, 76.7 % of patients with Lim-EE (n = 23 /30) responded to
treatment compared with 51.1 % (n = 46 /90) in the Dif-EE group (P = 0.02). Numerical analysis of the histopathologic response to treatment showed a
nonsignificant statistical difference in favor of the Lim-EE group (52.5 % vs. 39.7 %;
P = 0.15). After adjusting for age and sex, the extent of EoE predicted treatment response
based on clinical improvement with an aOR of 3.12 (95 %CI 1.22–8.02; P = 0.02); however, it did not predict histologic response, with an aOR of 1.40 (95 %CI
1.40–0.31; P = 0.31). We repeated our analysis to include patients with esophageal symptoms only
(dysphagia, chest pain, dyspepsia, food impaction, and heart burn) resulting in similar
outcomes. Clinical improvement was documented in 60.5 % (46 /76) of the Lim-EE group
compared with 44.8 % (108/241) in the Dif-EE group (P = 0.02), while histologic response was observed in 51.2 % (21/41) with Lim-EE compared
with 41.2 % (63/153) with the Dif-EE (P = 0.29). Our data suggest that our reported clinicopathologic improvement is primarily
driven by clinical improvement. Histopathologic remission is often harder to achieve
and requires a longer period of follow-up, which may also explain the observed results.
Most of our physicians recommend a follow-up EGD a few months following therapy for
patients who have an elevated esophageal eosinophil count. However, some patients
did not comply with our recommendation for a repeat EGD and others did not comply
with the timing of a repeat EGD. This could lead to an inevitable selection bias and
also explain the lack of statistical significance observed in the histologic outcomes.
Patients who remain symptomatic are more likely to attend their repeat EGD compared
with those who respond to treatment. Therefore, we may be selectively analyzing a
refractory EoE group in our histologic analysis. However, this bias should resolve
by analyzing the clinical response as shown in our clinical and clinicopathologic
outcomes analyses and results. It is also important to note that the analyzed response
to treatment is a combined analysis of available treatments shown in [Table 3], including elimination diet, PPI, and steroids. Given that the majority of patients
were treated with PPIs, the observed response to treatment is likely related to PPI
therapy. Unfortunately, we were not able to perform subanalyses based on treatment
methods because of the small number of patients in each category, which prevents statistical
significance from being determined. With regard to the change in treatments between
the initial and follow-up EGD, this is likely explained by the treatment protocol
we use for EoE. Our protocol recommends that after a diagnosis of EoE is made, the
first step should be PPI therapy and possibly consideration for elimination diet.
If the patient is taking once-daily PPI, the next step is to consider up-titrating
to twice daily. Steroids are usually utilized in refractory cases. Therefore, more
patients were on PPIs and twice-daily dosing by the time they underwent repeat endoscopies
compared with the initial EGD. At the time of follow-up EGD, we would expect the number
of patients prescribed steroids to be higher if they were refractory to twice-daily
PPIs. In addition, it remains uncertain whether the EoE response to PPI is due to
its anti-inflammatory mechanisms, such as decreasing eotaxin-3 expression, or its
anti-secretory activity from coexistent GERD [23]. A recent study by Sawada et al. focused on the extent of eosinophilia and PPI responsiveness.
The authors reported that the prevalence of PPI responders was significantly higher
in the limited group compared with the diffuse group (100 % vs. 63 %; P = 0.01), which supports our hypothesis [24]. It is important to note that both the Sawada et al. study and the current study
are similar, but not identical. The definition of disease extent was different; Sawada
et al. defined limited disease as an endoscopic lesion confined to one-third of the
esophagus (upper, middle, or lower), whereas in the current study Lim-EE was defined
as distal disease. In addition, Sawada et al. defined Lim-EE and Dif-EE endoscopically
whereas our study defined EoE histologically.
Our study is not free of limitations. First, we grouped patients based on the extent
of eosinophilia seen on the initial EGD, but some patients had already been treated
with a PPI before being seen at our referral center, which may have led to mosaic
grouping. In order to address this, we performed a subanalysis of the clinicopathologic
response after excluding patients who were on PPI or steroids at the time of biopsy
during their initial EGD. A total of 28/48 patients (58.3 %) with Lim-EE and 68/156
(43.6 %) with Dif-EE had clinicopathologic response to treatment (P = 0.06). This borderline significance is likely reflective of the inadequate sample
size and power loss after excluding 40 % of the original cohort. This trend would
likely be more significant with a larger cohort. Second, the majority of our patients
did not undergo pH monitoring studies, which limited our ability to distinguish between
GERD-esophagitis and EoE-esophagitis; therefore, we defined GERD on the basis of its
known clinical features. Third, our sample size did not allow us to substratify patients
or assess the outcomes based on different treatment regimens. We were also unable
to track treatment changes during the follow-up period that could have influenced
the observed outcomes. In addition, our evaluation of clinical responses was based
on physicians’ documentation in the medical records rather than a validated questionnaire.
Finally, the limited follow-up and the retrospective nature of the study may have
introduced other potential biases.
Despite these limitations, we believe that our study provides valuable information
that addresses a gap in the scientific literature and which also adds value to clinical
practice. We propose an added benefit of separating proximal and distal samples into
different jars to determine the extent of disease. Although the use of separate jars
increases overall cost, the information obtained provides valuable clinical information
with regard to differences in expected response to various treatments. Prior studies
have postulated a potential overlap between GERD and EoE, and our study now provides
clinical data in support of this concept [6]. Therefore, in symptomatic patients with limited EoE who fail to respond to conventional
PPI therapy, upscaling of treatment following the algorithm of EoE should be considered.
Prospective studies are needed to confirm our observations, and in particular to address
the potential correlation between the location of typical endoscopic findings of EoE
and the histology-based EoE phenotype (limited vs. diffuse). It may also be of interest
to investigate the clinical significance of esophageal eosinophilia limited to the
proximal part of the esophagus.
In conclusion, our study suggests that biopsies from multiple esophageal locations
may help stratify treatment outcomes in patients with EoE. Patients with EoE limited
to the distal esophagus responded better to PPI therapy than those with diffuse esophageal
involvement. This may represent a population of patients with GERD or milder EoE disease.
Those with diffuse involvement may represent a group less likely to respond to therapy.
