Gastroenterology
Volume 139, Issue 2 , Pages 418-429.e1, August 2010

Oral Viscous Budesonide Is Effective in Children With Eosinophilic Esophagitis in a Randomized, Placebo-Controlled Trial

Departments of Pediatrics and Pathology, University of California, San Diego, La Jolla, California; and Rady Children's Hospital San Diego, San Diego, California

Received 28 December 2009; accepted 5 May 2010. published online 10 May 2010.

Article Outline

Background & Aims

Eosinophilic esophagitis (EoE) is caused by immunologic reactions to ingested/inhaled allergens. The diagnosis is considered if ≥15 eosinophils per high-powered field (eos/hpf) are detected in mucosal biopsies. Placebo-controlled studies have not been conducted to evaluate the safety and efficacy of oral viscous budesonide (OVB).

Methods

Children with EoE were randomly assigned to groups that were given OVB (n = 15) or placebo (n = 9). Patients <5 feet and ≥5 feet tall received 1 mg and 2 mg OVB daily, respectively. All patients received lansoprazole. Duration of treatment was 3 months, followed by repeat endoscopy and biopsies. Patients were classified as responders if their peak eosinophil counts were ≤6 eos/hpf, partial responders were 7–19 eos/hpf, and nonresponders were ≥20 eos/hpf. Baseline and post-treatment symptoms and endoscopic and histologic features were scored.

Results

Thirteen (86.7%) children given OVB (P < .0001) and none who received placebo (P = .3) were classified as responders. Mean pre-/post-treatment peak eosinophil counts were 66.7 and 4.8 eos/hpf, respectively, in the group given OVB (P < .0001); they were 83.9 and 65.6 eos/hpf, respectively, in the group given placebo (P = .3). In the group given OVB, there were significant reductions from baseline values in proximal (P = .002), mid (P = .0003), and distal (P = .001) esophageal eosinophilia. After OVB therapy, compared with baseline, the mean symptom (P = .0007), endoscopy (P = .0005), and histology scores improved (P = .0035) significantly.

Conclusions

OVB is an effective treatment of pan-esophageal disease in children with EoE. OVB improves symptoms and endoscopic and histologic features. Proton pump inhibitor single therapy did not significantly improve esophageal eosinophilia or symptoms of EoE.

Keywords: Topical Corticosteroids, Lansoprazole, Lamina Propria Fibrosis, Scoring Tools

Abbreviations used in this paper: ANCOVA, analysis of covariance, EHS, epithelial histology score, EoE, eosinophilic esophagitis, GERD, gastroesophageal reflux disease, hpf, high-powered field, LP, lamina propria, LPHS, lamina propria histology score, OVB, oral viscous budesonide, PPI, proton pump inhibitor, SST, symptom scoring tool, TGFβ1, transforming growth factor–β1

 

See related article, Chang JY et al, on page 669 in CGH.

Eosinophilic esophagitis (EoE) is a clinicopathologic disease characterized by esophageal eosinophilia and gastrointestinal symptoms. It most likely represents an immunologic reaction to ingested and inhaled allergens.1, 2, 3, 4, 5 Prevalence of EoE is increasing with rates now ranging from 6 to 30 cases per 100,000.6, 7, 8, 9 Although this may also represent increased physician-recognition, it is likely that the rise in prevalence is real and mirrors the recent increase in prevalence of atopic disorders, such as asthma.8, 10 The diagnosis of EoE is dependent upon finding ≥15 eosinophils per high power field (eos/hpf) in esophageal mucosal biopsies.11, 12 Symptoms of EoE often mimic gastroesophageal reflux disease (GERD), but are often refractory to acid-suppression therapy. Symptoms include regurgitation, vomiting, pain, anorexia, and dysphagia.10, 11 Although the optimal therapy for EoE is unclear, a major concern for untreated EoE is esophageal remodeling and development of strictures, which are reported in 16%–40% of adult patients.13, 14, 15 A likely prerequisite of esophageal remodeling is the presence of lamina propria (LP) fibrosis, as seen under light microscopy and measured by levels of transforming growth factor–β1 (TGFβ1) and phosphorylated Smad2/3.16, 17, 18 We recently reported that LP remodeling associated with EoE diminishes with topical corticosteroid therapy,16, 17 and that patients with specific polymorphisms in the TGFβ1-promotor gene may respond better to corticosteroid therapy.17

Treatment options for EoE are dietary restriction including those identified by skin testing,5 6-food elimination diet,19 and elemental formula.1, 20 Systemic corticosteroids21 are effective but are seldom warranted. Topical corticosteroids, such as fluticasone proprionate, administered through a metered-dose inhaler, and oral viscous budesonide suspension (OVB), can safely induce and maintain low esophageal eosinophil levels.22, 23, 24, 25, 26, 27, 28 We previously reported our retrospective experience of 20 children with EoE treated with OVB for 3–4 months.27 Eighty percent of these patients achieved the histologic study end point and also had significant improvement of their symptoms and endoscopic findings.27

In this report, we describe the results of the first placebo-controlled study using OVB for the treatment of EoE in children. Histologic, symptomatic, and endoscopic responses to OVB therapy are reported. In addition, esophageal biopsies containing LP were evaluated for vascular activation and TGFβ1.

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Materials and Methods 

This randomized, double-blinded, placebo-controlled study to determine the efficacy and safety of OVB was approved by Rady Children's Hospital, San Diego and University of California at San Diego Human Research Protection Program, and informed consent was obtained for each participant. A separate informed consent was obtained for genotyping. This study was conducted under Investigator Investigational New Drug Application #77,022.

Screening 

Patients were referred to the Eosinophilic Esophagitis Clinic at Rady Children's Hospital, San Diego by pediatric gastroenterologists and allergists. Patients had an established diagnosis of EoE, including, when necessary, a previous challenge with proton pump inhibitor (PPI) therapy with repeated endoscopy and biopsies to exclude GERD. At initial evaluation patients were offered alternative nonstudy therapeutic options. Individuals with esophageal peak eosinophil counts ≥20 eos/hpf were asked to participate by the study coordinator. Biopsies were obtained <2 months before study entry, and no changes in diet, asthma, or allergy therapy were allowed in the interim or during the study. Specific dietary restrictions are reported in Table 1. Baseline and post-treatment morning cortisol levels (normal range, 7–25 ug/dL) were measured to estimate adrenal suppression using an Automated Chemiluminescent Immunoenzymatic Assay System (BeckmanCoulter, Brea, CA).

Table 1. Patient Data
Patient no.Age (y)SexRace/ethnicityHeight, ftAtopyAllergy, +RAST/SPTDietary restrictionsPrevious PPILong-term therapyAdverse events
Oral viscous budesonide + PPI group
33MaleNon-Hisp white<5As, EcNo—YesNo—
46MaleHispanic white<5ARYes—NoNo—
515FemaleNon-Hisp white≥5EcNoMYesNoEmesis (wk 1)
98MaleNon-Hisp white<5As, AR, EcYes—YesAlbuterol—
127MaleNon-Hisp Afr Am<5NoYes—NoAbilify—
1313MaleNon-Hisp white≥5As, AR, EcNo—NoZyrtec—
165MaleNon-Hisp white<5NoNoMNoNo—
201MaleHispanic white<5NoNoNYesNoOral candida
215FemaleNon-Hisp white<5NoNo—NoNo—
2210MaleHispanic white<5ARYesN/S/FYesZyrtecTransient headache
254FemaleHispanic white<5AsNoM/E/beefYesSingular, Flovent—
2613MaleNon-Hisp white≥5ARYes—NoNo—
283MaleHispanic white<5As, ARNo—YesClaritin, pulmonary nebulizer—
297MaleNon-Hisp white<5ARNo—NoNo—
3217MaleHispanic white≥5ARYes—YesFlovent—
Placebo + PPI group
26MaleNon-Hisp white≥5ARNo—YesNo—
610FemaleNon-Hisp Asian<5ARNoAppleYesNo—
142MaleNon-Hisp Indian<5AR, EcYesW/E/S/N/peasYesNoEczema worse
178MaleNon-Hisp white<5NoYesGlutenYesSulfasalazineChest infection
1916MaleNon-Hisp white≥5AsYes—NoNoMild abdominal pain
243MaleHispanic white<5AsYes—NoZantacTransient headache
2710MaleNon-Hisp white<5As, ARYes—NoNo—
3012MaleNon-Hisp white<5NoNo—YesNo—
312MaleHispanic white<5AsNo—YesAlbuterolTransient diarrhea
Withdrawal from studyReason
115MaleNon-Hisp white≥5As, ARYes—NFloventSucralose issue (wk 1)
715MaleNon-Hisp white≥5EcYesWNFloventSteroids for asthma
815MaleNon-Hisp white≥5AR, EcYes—NNoPoor compliance
1010MaleNon-Hisp white<5ARNo—YAlbuterolRash (wk 1)
116MaleHispanic white<5As, AR, EcYes—NSingular, AlbuterolSteroids for asthma
155MaleNon-Hisp white<5AsYesM/W/E/NNNoSucralose issue (wk 1)
235FemaleNon-Hisp white<5NoYesW/NYZyrtec, NasonexLost to follow-up

NOTE. Atopic patients had asthma (As), eczema (Ec), and allergic rhinitis (AR). Patients were deemed food or aeroallergen-sensitized/allergic if radioallergosorbent testing (RAST) or skin-prick testing (SPT) was positive. Patients <5-feet tall received 1 mg OVB and those ≥5 feet received 2 mg. Patient no. 18 was randomized (OVB group) and collected the drug, but was treated with steroids for asthma and did not take the study drug. Patient nos. 25, 28, and 32 had received intermittent topical steroid therapy for asthma before, but not during the study. Dietary restrictions before baseline biopsies were maintained during the study and are shown.

E, eggs; F, fish; M, milk; N, nuts; S, soy; W, wheat.

Randomization and Treatment 

OVB is a viscous liquid consisting of budesonide nebulizer suspension (Pulmicort respules; AstraZeneca, London, UK) mixed with sucralose (Splenda; McNeil Nutritions, Fort Washington, PA). Using a validated computer-based random number generator (Proc Plan in SAS version 9.1; SAS Institute, Inc, Cary, NY), subjects were randomized 2:1 into OVB and placebo groups, respectively. Both groups received lansoprazole solutabs (Prevacid; TAP Pharmaceuticals, Deerfield, IL). Subjects <5-feet tall received OVB 1 mg and those ≥5-feet tall received OVB 2 mg. Subjects younger than 10 years old received lansoprazole 15 mg twice daily and those 10 years or older received lansoprazole 30 mg twice daily. Treatment lasted 3 months. Physicians, pathologists, study coordinators, statisticians, and patients were blinded to treatment during the study.

Using appropriate precautions, budesonide suspension (0.5 mg/2 mL) or the same volume of placebo (sterile water) was placed by the investigational pharmacist into sealed light-protective vials. Formal stability analysis on budesonide suspension had confirmed the drug to be stable for at least 3 months in the vials. Subjects received a study number that was affixed to each vial of drug/placebo, which was dispensed monthly. Only the pharmacist had access to the randomization code. Immediately before ingestion, preferably at bedtime, the contents of each vial was mixed with Splenda (ten 1-g packets to 1 mg budesonide to create approximately 8 mL volume). Patients did not eat or drink for 30 minutes after drug ingestion.

Patients were withdrawn from the study if they were noncompliant with therapy (<50% drug) or if they required systemic corticosteroid therapy for reasons including acute asthma. Compliance was determined every month by unopened vial count. During the study, collected data were stored in a locked cabinet. One month after study completion, the database was “locked” and the randomization code revealed.

Outcomes Measures 

The primary outcome measure was improvement of esophageal eosinophilia. The response to therapy was determined by comparing baseline and final treatment peak counts/hpf under light microscopy (×400). Patients were categorized into responders (0–6 eos/hpf), partial responders (7–19 eos/hpf), and nonresponders (≥20 eos/hpf) based on final treatment biopsy results. Secondary outcome measurements included response of symptoms and endoscopic and histologic features to treatment. These were ascertained using previously reported, but as yet nonvalidated tools29, 30, 31 (see Table 2).

Table 2. Scoring Tools for Endoscopy, Histology, and Symptoms Taken From Previous Reports29, 30, 31
Eosinophilic esophagitis tool and categoriesScore in each esophageal level proximal, mid, distalMaximum score per level/symptomMaximum total score
Endoscopy scoring tool
Mucosal pallor/reduced vasculature
0 = Absent

1 pt = present

3 pts15 pts
Linear furrows/mucosal thickening
White plaques
Concentric rings/stricture
Friability/“tissue-paper” mucosa
Histology scoring tools
Epithelial histology score
Peak eosinophil count
0 = 0 Eos/hpf

1 pt = 1–10 Eos/hpf

2 pts = 1–20 Eos/hpf

3 pts = 21–40 Eos/hpf

4 pts = 41–60 Eos/hpf

5 pts = >61 Eos/hpf

12 ptsCalculated as a mean of all 3 levels. Therefore maximum is 12 pts
Basal zone hyperplasia
0 = <20% of epithelial thickness

1 pt = 21%–50%

2 pts = 51%–75%

3 pts = >75%

Dilated intercellular spaces
0 = Absent

1 = Present

Epithelial desquamation
0 = Absent

1 = Present

Eosinophil clusters/abscesses
0 = Absent

1 = Present

Degranulated eosinophils.
0 = Absent

1 = Present

Lamina propria histology score
Peak eosinophil count
0 = 0 Eos/hpf

1 pt = 1–5 Eos/hpf

2 pts = 6–20 Eos/hpf

3 pts = >2 0 Eos/hpf

6 ptsCalculated as a mean of all three levels. Therefore maximum is 6 pts
Lamina propria fibrosis
0 = Absent

1 pt = Mild

2 pts = Moderate

3 pts = Severe

Including fibroblast and collagen bundles
Symptom scoring tool
Heartburn/regurgitation
0 = Absent

1 pt = Mild symptoms that are intermittent and do not interrupt daily activities.

2 pts = Severe symptoms that occurred every day and/or interrupted daily activities.

2 pts14 pts
Abdominal pain
Nausea/vomiting
Anorexia/early satiety
Dysphagia
Symptom induced nocturnal wakening
Gastrointestinal bleeding

NOTE. For the symptom score, subjects requiring urgent hospital attention for esophageal food impaction or gastrointestinal bleeding within the previous 2 months received 2 points.

Eos, eosinophil; pts, points.

Upper gastrointestinal endoscopy and endoscopy scoring tool 

Repeat endoscopy was undertaken using the Olympus P160 endoscope (by RD) at 3 months of treatment. Mucosal biopsies were taken from the distal (2–3 cm above the gastroesophageal junction), proximal (2–3 cm below the cricopharyngeus muscle), and mid (midway between distal and proximal) esophageal levels. Gastric and duodenal biopsies were also obtained. An endoscopy scoring tool, previously used to differentiate the endoscopic features of EoE from GERD,29 was modified for this study. The endoscopy score was determined by RD, who performed >80% of baseline esophagogastroduodenoscopies and all follow-up procedures. The other baseline endoscopy scores were determined using endoscopy reports and photographs. The maximum endoscopy score was 15.

Patient monitoring and symptom scoring tool (SST) 

The SST, devised originally for children with acid-peptic disorders, is used regularly in our clinic.27, 30, 31 The SST has been used to differentiate between EoE, GERD, and patients with other atopic and nonatopic disorders.29 Physical examination and symptom questionnaire completion occurred at monthly clinic visits. In addition, the subjects/guardians were contacted every week and the SST was recorded (maximum 14 points). Baseline symptom scores were estimated from the questionnaires and from physician-dictated clinical records taken within 1 month of study enrollment. There was no baseline criterion for minimum SST severity. Final symptom scores were calculated from the mean of the symptom scores recorded during the last month of treatment.

Biopsies and histology scoring tool 

Proximal, mid, and distal esophageal biopsies, taken before and after treatment, were processed routinely and evaluated using light microscopy (×400) by a pediatric pathologist (RN). Before entering the study, all baseline biopsies were reviewed again by a blinded observer (RN). Two biopsies per level yielded between 15 and 20 evaluable hpfs. A histology scoring tool was used to score features within the epithelium and LP separately,29 because the latter was not present in each biopsy. When LP was present, features of fibrosis, including the presence of fibroblasts, thickness of collagen bundles, and collagen accumulation, were evaluated16 (Table 2).

TGFβ1 and TGFβ1 promotor genotype 

LP remodeling is associated with increased TGFβ1-positive and pSmad2/3-positive eosinophils and also increased expression of TGFβ1 signaling transcription factor in the subepithelial space.16, 17, 18 After staining of biopsies containing LP with TGFβ1 and pSmad2/3 primary antibody (Santa Cruz Biochemicals, Santa Cruz, CA) positive stained cells were enumerated in 3–5 hpf at ×400 magnification.16 Mean value was calculated and expressed as TGFβ1-positive and pSmad2/3-positive cells/hpf.

A polymorphism (TT genotype) of the C-509T promoter region of TGFβ1 has been associated with increased TGFβ1 levels and also more severe airways obstruction in asthmatics.32 Patient's DNA was isolated from peripheral blood, and the C-509T SNP of the TGFβ1 promoter was analyzed. The TGFβ1 promoter genotype was assessed using forward (5′-GGGGACAGTAAAATGTATGGG-3′) and reverse (5′-GTCACCAGAGA- AAGAGGAC-3′) TGFβ1 promoter primers, followed by digestion with DdeI to yield 242, 189, and 53 base-pair products analyzed by gel electrophoresis.17 The frequency of the CC, CT, and TT alleles in the study group was evaluated and correlated, when possible, with the severity of LP fibrosis and the response to OVB therapy.

Statistical Analysis 

The a priori power of the primary end-point analysis was estimated using Fisher's exact test with .05, two-tailed significance level. Assuming a histologic response rate of 80% in the OVB group and 20% in the placebo group, there was 85% power to detect a significant between-group difference with sample sizes of 20 and 10, respectively.

All statistical analyses were conducted using SAS Version 9.1 (SAS Institute, Inc). Inferential statistical testing was performed with 2-tailed tests at the .05 significance level. Efficacy analyses for histology, endoscopy, and symptom score variables were conducted on the modified intent-to-treat analysis set, which was defined as all subjects who received at least 1 dose of study drug and completed both pre- and post-treatment biopsy assessments.

Hypothesis tests for the primary efficacy end point (ie, the percentage of histologic responders) were analyzed using Fisher exact test. Discrete secondary efficacy variables, including the percentage of subjects with ≥50% reduction in the clinical symptom score from baseline at each week, and the percentage of subjects with complete histologic resolution and complete resolution of symptoms were also analyzed using Fisher exact test. Change from baseline in maximum peak eosinophil count, total endoscopy score, and absolute and percent change from baseline in clinical symptom score were analyzed using an analysis of covariance (ANCOVA) model with a main effect for treatment and the baseline score as a covariate. For those instances in which deviations may have occurred from the statistical assumptions underlying the ANCOVA model (eg, non-normality or heterogeneity of variance), a sensitivity analysis was also performed, and consisted of ranking the scores/counts across the 2 treatment groups, and then performing an ANCOVA on the ranked data.33 The resulting P values from this nonparametric analysis are identified and provided alongside the ANCOVA P values, where applicable.

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Results 

Between February 2008 and July 2009, thirty-one patients with EoE were randomized; 24 completed the study and were included in the final analysis. Of these 24 subjects, 15 received OVB and PPI and 9 received placebo and PPI. One patient with a prior diagnosis of EoE had symptoms, pan-esophageal furrowing, and exudates on endoscopy, but a peak eosinophil count of 15 eos/hpf (patient no. 30) was also enrolled. There were 20 male and 4 female patients (mean age, 7.8 years; range, 1–17 years; median, 7 years). Eighteen children had asthma, eczema, and/or allergic rhinitis; 11 had food/aeroallergen allergy with positive skin and/or radioallergosorbent testing. There was no significant difference between the OVB and the placebo groups for race/ethnicity, age, presence of atopy or food/aeroallergen sensitization, previous use of PPIs, height, and weight (before or after treatment) (see Table 1).

Final analysis was not possible in 7 patients who withdrew from the study without repeat endoscopy. Reasons for withdrawal included not wanting to take Splenda, acute asthma requiring systemic corticosteroids, noncompliance with therapy, and adverse event (transient rash attributed to lansoprazole; patient no. 10). No serious adverse events were reported in 24 study-completers. One patient (no. 20) developed oral candida, which responded to nystatin. Esophageal candida was not found at follow-up esophagogastroduodenoscopy in any of the subjects.

There was no significant difference between pre-/post-treatment mean morning cortisol levels, which were 12.7 ug/dL (range, 4.1–21) and 9.1 ug/dL (range, 4.4–16), respectively, for the OVB group and 10.1 ug/dL (range, 5.8–14) and 10.4 ug/dL (range, 5.3–16), respectively, for the placebo group (P = .31).

Primary Outcomes 

Peak esophageal eosinophil count 

OVB and PPI therapy significantly reduced the mean peak eosinophil count from baseline when compared with placebo and PPI (P = .0001; nonparametric test P = .0003). This reduction in peak eosinophil count in the OVB group, compared with placebo, was significant at all esophageal levels, including proximal (.0024), mid (P ≤ .0001), and distal (P = .0001). Peak eosinophil count responses to study drug are shown in Figure 1. All gastric and duodenal biopsies were normal. Mean compliance with study treatment for both groups group was 80% (see Table 3, Table 4).

  • View full-size image.
  • Figure 1. 

    Individual pre- and post-treatment peak eosinophil (Eos) counts following 3 months' treatment with OVB and PPI (n = 15) and placebo plus PPI (n = 9). HPF, high-powered field; Tx, treatment.

Table 3. Individual Patient Data Are Shown for Subjects in the Oral Viscous Budesonide and Placebo Groups Both Before and After Treatment
Patient no.ResponseCompliance (%)Peak eosinophil count (hpf)Symptom score (max. 14 pts)Endoscopy score (max. 15 pts)Epithelial histology score (12 pts)LP histology score (6 pts)Morning cortisol (umol/dL)
PrePostPrePostaPrePostPrePostPrePostPrePost
Oral viscous budesonide + PPI
3Responder10027046404.304 —4.4
4Responder984504270904 —7
5Responder83125442424.32.7 158
9Responder901246306610.51.34 7.69.8
12Responder64252906050.7617.14.7
13Responder67324209570.7 —5.4
16Responder93744130091.33.301610
20Responder7566460009.30.7 128.4
21Responder6885021607.70 149.2
22Responder751103313060.3 178.6
25Responder83110340507.31 1316
26Partial714817315171.34 108.6
28Responder7820063001.50 0.34.19.9
29Responder906000070404 2114
32Nonresponder67472520772.751 1412
Mean86.7%80.166.64.83.51.24.61.56.31.03.80.412.79.1
Placebo + PPI
2Nonresponder100105100569910.39.33 7.15.3
6Partial8275743524.51.5 1012
14Nonresponder906711812998.79.1458.96.8
17Nonresponder82753520948.75.3 1114
19Nonresponder7298130627711.311 128.4
24Nonresponder629082309188.74 1416
27Nonresponder819028216694.3 5.86
30Nonresponder90154202763.75.7331315
31Nonresponder651404811958.7662.59.3—
Mean0%80.483.965.62.71.87.75.48.16.84.03.510.110.4

aRepresents a mean of the symptom scores measured during the last month of treatment (ie, at weeks 9–12).

Table 4. Mean Values for Peak Eosinophil Counts, Endoscopy, Symptoms, and Histology Scores
Category according to feature or esophageal levelOVB + PPI change from baseline within group, mean (SD/median)Placebo + PPI change from baseline within group, mean (SD/median)Change from baseline OVB group superior to placebo group
PrePostPrePost
Eosinophil count
Total (all levels)66.7(36.4/60)4.8(7.0/3)83.9(33.7/90)65.6(43.3/48)
P<.0001aP=.30P=.0001a
Proximal esophagus28.1(27/20.5)1.1(1.5/0)44(32.7/30)43.3(40.9/35)
P=.0024aP=.96P=.0024a
Mid esophagus46.4(34.5/36)2.9(6.1/1)79.6(36.9/87)62(46.2/48)
P=.0003aP=.56P=<.0001a
Distal esophagus48.9(37.6/43.5)4.1(7.3/1)60.3(28/58)46.9(31.9/34)
P=.001aP=.34P=.0001a
Endoscopy score
Total (maximum 15)4.6(2.8/5)1.5(2.5/0)7.8(1.6/9)5.4(2.8/6)
P=.0005aP=.04aP=.041a
Pallor/reduced vascular2(1.3/3)0.67(1.1/0)2.9(0.3/3)2.2(1.2/3)
P=.002aP=.11P=.025a
Furrows/thickening1.67(1.2/2)0.6(1.1/0)2.9(0.3/3)2(1.2/3)
P=.007aP=.052P=.076
Plaques0.9(1.0/1)0.07(0.3/0)1.67(1.4/2)1(1.5/0)
P=.004aP=.26P=.07
Concentric rings/stricture0(0/0)0.07(0.3/0)0.2(0.4/0)0(0/0)
P=.33P=.33P=.49
Friability/tissue paper0(0/0)0.07(0.3/0)0.1(0.3/0)0.1(0.3/0)
P=.33P=.35P=.48
Symptom score
Total (maximum 14)3.5(2.3/3)1.2(1.87/0.7)2.67(2/2)1.85(1.8/1.8)
P=.0007aP=.22P=.031a
Heartburn/regurgitation0.79(0.8/1)0.23(0.45/0)0.33(0.5/0)0.32(0.4/0.3)
P=.008aP=.89P=.033a
Abdominal pain0.8(0.8/1)0.39(0.6/0.3)0.56(0.7/0)0.3(0.4/0)
P=.10P=.28P=.87
Nausea/vomiting0.73(0.8/1)0.07(0.2/0)0.67(0.7/1)0.2(0.3/0)
P=.004aP=.065P=.11
Anorexia/early satiety0.33(0.7/0)0.28(0.56/0)0.33(0.7/0)0.32(0.7/0)
P=.66P=.85P=.76
Dysphagia0.73(0.8/1)0.18(0.5/0)0.67(0.9/0)0.3(0.5/0)
P=.017aP=.20P=.46
Nocturnal wakening0.2(0.6/0)0.05(0.1/0)0.1(0.3/0)0.37(0.3/0.5)
P=.34P=.047aP=.001a
GI bleeding0(0/0)0(0/0)0(0/0)0(0/0)
P=.33P=.33P=.48
Epithelial histology score6.3(2.6/7)1(1.3/0.7)8.1(2.5/8.7)6.8(3.0/6)P=.0035a
P=<.0001aP=.11
LP histology score3.8(1.4/4.0)0.4(0.5/0.3)4.0(1.2/4.0)3.5(01.3/3)b
bb
Cortisol levels12.7(5.0/13.0)9.1(3.2/8.6)10.1(2.9/9.3)10.4(4.3/10.2)P=.31
P=.09P=.80

NOTE. Mean morning cortisol levels are shown in umol/dL. Baseline and post-treatment comparisons are made both within the groups and between the OVB and placebo groups.

GI, gastrointestinal; SD, standard deviation.

aStatistically significant.

bInadequate number of LP samples for formal statistical analysis.

OVB group 

Thirteen of 15 patients (86.7%) who received OVB were responders (P < .0001), 1 was a partial responder (patient no. 26), and 1 was a nonresponder (patient no. 32). Mean pre- and post-treatment peak eosinophil counts for the OVB group were 66.7 eos/hpf (range, 22–125 eos/hpf) and 4.8 eos/hpf (range, 0–25 eos/hpf), respectively. When biopsies, taken pre-/post-treatment from the same levels, were compared there was a significant reduction in peak eosinophil counts in the proximal (P = .002), mid (P = .0003), and distal (P = .001) esophagus, respectively. Peak eosinophil count was 0–1 eos/hpf in biopsies from the distal, mid, and proximal esophagus in 8, 10, and 11 subjects, respectively. The peak count was ≤6 eos/hpf from distal in 13, mid in 14, and proximal in 14. OVB was, therefore, effective in reducing pan-esophageal eosinophilia. All patients <5-feet tall (n = 11; mean age, 6.3 years; range, 2–10 years) responded to therapy. Of the 4 patients ≥5-feet tall (mean, 15.1 years; range, 13–17 years), 2 responded, 1 was a partial responder (patient no. 26), 1 was a nonresponder (patient no. 32). Patient nos. 26 and 32 returned 30% of the OVB vials unopened.

Placebo group 

None of the 9 patients (0%) who received placebo was responder. Mean pre-/post-treatment peak eosinophil counts for the group was 83.9 eos/hpf (range, 15–140 eos/hpf) and 65.6 eos/hpf (range 7–130 eos/hpf) (P = .3), respectively. When biopsies, taken pre-/post-treatment from the same levels, were compared there was no significant reduction in peak eosinophil counts in the proximal (P = .96), mid (P = .56), and distal (P = .34) esophagus. Therefore, placebo and PPI therapy did not significantly reduce eosinophilia at any esophageal level. One patient (no. 6) was a partial responder (post-treatment peak eosinophil count was 7 eos/hpf with basal zone hyperplasia in esophageal biopsies). After study completion, subject no. 6 commenced open-label OVB therapy, and eosinophils and basal zone hyperplasia were absent in repeat biopsies.

Secondary Outcomes 

Upper gastrointestinal endoscopy score 

The EST was used to measure the endoscopy score. The mean total endoscopy score fell significantly following OVB compared with the placebo group (P = .041; nonparametric test P = .0418) (see Table 3, Table 4).

OVB group 

There was a significant improvement in the mean endoscopy score from 4.6 (range, 0–9) before and 1.5 (range, 0–7) after treatment (P = .0005). In 9 of the 15 patients the endoscopy score normalized after treatment. None of the group had an esophageal stricture.

Placebo group 

Although, the mean endoscopy score improved from 7.8 (range, 4–9) before to 5.4 (range, 1–9) (P = .041) after treatment, none of the endoscopy scores completely normalized. One patient (no. 19) had an esophageal stricture.

Symptom score 

The most commonly reported symptoms were dysphagia, vomiting, regurgitation, and abdominal pain. The mean total symptom score decreased significantly from baseline after OVB compared with the placebo group (P = .031; nonparametric test P = .0458). When the mean symptom scores, taken from all patients within the group and averaged for months 1, 2, and 3 were compared with baseline, the mean scores improved significantly in the OVB group but not in the placebo group (see Figure 2).

  • View full-size image.
  • Figure 2. 

    Mean symptom scores during months 1, 2, and 3 of the study for patients in the OVB and placebo groups. Comparing changes from baseline, the mean symptom score improved significantly in the OVB group during months 1, 2, and 3, but not in the placebo group.

OVB group 

The mean symptom score improved from 3.5 (range, 0–10) at baseline to 1.2 (range, 0–7) after treatment (P = .0007). By study week 3, there was a significant change in mean symptom score compared with baseline (P < .05). Symptom categories that significantly improved compared with baseline were heartburn/regurgitation (P = .008), nausea/vomiting (P = .004), and dysphagia (P = .017). Seven patients had a post-treatment symptom score of 0.

Placebo group 

The mean symptom score was 2.7 (range, 1–6) before and 1.8 (range, 0–7) after treatment (P = .22). None of the symptom categories showed significant improvement from baseline. Placebo and PPI did not significantly improve symptoms in most patients. Only 2 patients had a post-treatment symptom score of 0.

Epithelial and LP histology scores (EHS and LPHS) 

The EHS was measured in all patients, and the LPHS was measured in 13 and 6 subjects before and after treatment, respectively. There was an improvement in EHS (P = .0035) and LPHS over baseline in the OVB group when compared with the placebo group.

OVB group 

The decrease in mean EHS from baseline (from 6.3 to 1.0) after treatment was significant (P < .0001). Paired (from the same subject) pre- and post-treatment biopsy samples containing LP were available for 2 patients in the OVB group. There was a decrease in mean LPHS from baseline of 3.8 to 0.4. These results suggest that both LP eosinophilia and fibrosis improves with OVB (see Table 3 and Figure 3).

  • View full-size image.
  • Figure 3. 

    (A) Pretreatment distal esophageal mucosal biopsy. Above left, showing several intraepithelial eosinophils, basal zone hyperplasia, and intercellular edema (H&E ×200). Above right, lamina propria with fibrosis and eosinophilic inflammation (H&E ×400). (B) Post-treatment with OVB, distal esophageal biopsy from the same patient. Above left, unremarkable epithelium (H&E ×100). Above right shows lamina propria with no evidence of fibrosis or eosinophilic inflammation (H&E ×400). (C) Esophageal mucosal biopsies (×400 light microscopy) stained for profibrotic mediators showing LP in a responder patient. Upper images show transforming growth factor–β1 (TGFβ1)-positive (brown) cells and lower images show phosphorylated Smad2/3-positive (red) cells pre- and post-treatment with OVB.

Placebo group 

The change in mean EHS (from 8.1 to 6.8; P = .11) from baseline was not significant. Paired pre- and post-treatment biopsy samples containing LP were available for 3 patients in the placebo group. There was a decrease in mean LPHS from baseline of 4.0 to 3.5.

TGFβ1 and TGFβ1 promotor genotype 

TGFβ1 promotor C-509T SNP was evaluated in 11 patients in the OVB group. TGFβ1 and pSmad2/3 staining were evaluated in biopsies with LP (11 biopsies from 8 patients; 7 pre, 4 post), including 3 with paired pre/post (1 OVB, 2 placebo group) biopsies.

Genotype 

Of the 9 OVB responders who were evaluable for genotyping, 7 had the genotype CC/CT (2 CC, 5 CT), the partial responder was CC, and the nonresponder was TT. One patient in the placebo group was TT genotype and had an esophageal stricture; 1 placebo patient was CC and subsequently responded to open-label OVB. The remaining genotyped placebo patients (n = 6) were CT.

TGFβ1 

Quantitative immunohistochemistry of biopsies demonstrated that OVB reduced the numbers of TGFβ1- and pSmad2/3-positive cells in the lamina propria (Figure 3C). Prior to therapy, OVB and placebo patients had similar numbers of TGFβ1- (106 vs 78) and pSmad2/3- (73 vs 105) positive cells. In contrast to OVB-treated patients, patients on placebo continued to have elevated numbers of TGFβ1- (OVB: 29, placebo: 131) and pSmad2/3-positive cells (OVB: 58, placebo:108). In this limited number of patients, OVB decreased the fibrosis score from 2.5 to 0 following treatment; placebo treatment did not (mean, 2.3 before and 2.5 after therapy). Both TGFβ1- (r = 0.89, P = .002) and pSmad2/3- (r = 0.65, P = .03) positive cells correlated with the severity of fibrosis.

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Discussion 

OVB is a thick liquid that is intended to coat the full length of the esophagus and therefore treat pan-esophageal eosinophilia.27 In a previous retrospective study of OVB in children, the primary histologic end point (≤7 eos/hpf) was achieved in 80% of patients.27 In our present study, which is the first randomized, double-blind, placebo-controlled study using OVB, the histologic end point of ≤6 eos/hpf was achieved in 87% of children with EoE. In addition, patients receiving OVB had a significant improvement in symptom score, endoscopy score, EHS, and LPHS. A recent placebo-controlled study using fluticasone, administered through a metered-dose inhaler, showed that 50% of patients responded to therapy, compared with 9% in the placebo group (P = .047); however, when the same histologic end point as used in our study (≤6 eos/hpf) was applied, a statistically significant difference between fluticasone and placebo groups was not achieved.28 The patients that did respond to fluticasone were younger (ie, mean age 5.9 years for responders vs 11.3 years for nonresponders), shorter (ie, mean height of 118.3 cm for responders and 146.2 cm for nonresponders), and nonallergic patients.28 Response to fluticasone was particularly poor in the distal esophagus compared with OVB (mean distal eosinophil counts were 82.2 eos/hpf before and 45.7 eos/hpf after fluticasone, compared with 48.9 eos/hpf before and 4.1 eos/hpf after OVB therapy). In our study, we show that OVB is an effective therapy for pan-esophageal disease with 87% of OVB post-treatment patients having ≤6 eos/hpf in the distal esophageal biopsies and 100% having ≤6 eos/hpf in proximal esophageal biopsies. All patients <5-feet tall (mean age, 6.3 years; mean height, 119.4 cm; range, 81.7–175.2 cm) receiving OVB responded to therapy. Of the 4 patients ≥5-feet tall (mean age, 15.1 years), 2 responded (mean, height 169.1 cm), 1 patient failed, and another had a partial response to OVB (mean height of partial and nonresponder, 173.2 cm). The nonresponder failed to respond only in the distal esophagus (before OVB treatment his eosinophil counts in proximal, mid, and distal biopsies were 31, 35, and 48 eos/hpf, respectively, and after treatment were 0, 1, and 17 eos/hpf, respectively), suggesting that in this tall child adequate amounts of drug may not have reached the distal esophagus. Clearly, some of the taller patients do respond to therapy and it is unlikely that height alone determines response to therapy with OVB, as other factors such as drug compliance will play a role. Nine (60%) of the 15 patients in the OVB group had negative food/aeroallergen skin prick/radioallergosorbent testing, and all (100%) of these patients responded to therapy. Of the 6 who tested positive and received OVB, 4 responded, 1 was a partial responder, and the other a nonresponder. The nonresponder and partial responder were older, taller, male allergic children (15 and 17 years) who returned 30% of the study drug vials unopened.

The threshold esophageal eosinophil count required for the diagnosis of EoE is not clearly established, although peak levels from ≥15 to ≥24 eos/hpf are used.10, 11, 12, 16, 27, 28, 29, 34, 35, 36 Some would stipulate that a trial of PPI therapy is mandatory before the diagnosis of EoE is made, as GERD may also cause esophageal eosinophilia. This statement was initially predicated on findings in only 3 patients.36 However, in most cases of GERD, esophageal eosinophilia is uncommon and relatively mild. In a recent retrospective study of patients with esophageal eosinophilia, patients with ≥20 eos/hpf, including those with abnormal 24-hour pH studies, were shown to respond poorly to PPI therapy.29 In our own study, none of the study patients receiving placebo plus PPI actually reached the end point of the study. Although 1 patient did, however, come close, with peak counts falling from 75 to 7 eos/hpf, it was only after poststudy treatment with OVB that the esophageal eosinophilia and basal zone hyperplasia disappeared completely. Compared with baseline, the placebo group in our study did not show a significant reduction in peak eosinophil count at any esophageal level, or significant improvement in EHS and LPHS (see Table 3). This would suggest that treating all patients routinely with PPI therapy before establishing a diagnosis of EoE may not be indicated and will in most patients only prolong the eosinophilic inflammation and associated symptoms.

Although, symptoms and endoscopic features do not always correlate with esophageal eosinophilia,10, 27 we have, in this study, used previously published tools29 to monitor the symptomatic, endoscopic, and histologic response to therapy. Patients in the OVB group had a significant improvement in mean symptom score compared both to baseline (P = .0007) and also to the change in symptom score seen in the placebo group (P = .031). Symptoms of nausea/vomiting, heartburn/regurgitation, and dysphagia significantly improved with OVB. The mean total endoscopy score significantly improved in the OVB-treated patients when compared with baseline (P = .0005) and also to placebo (P = .041). The EHS and the LPHS improved notably with OVB therapy, but not with placebo. This finding in the LP tissue was particularly important because it supports our recently reported observations that responders to OVB have a reduction in LP remodeling as measured by decreased profibrotic factors TGFβ1 and pSmad2/3.17 Immunologic staining confirmed that TGFβ1- and pSmad2/3-positive cells decrease significantly in LP after OVB, but not with placebo; however, the small numbers of patients with paired pre/post-LP were not amenable to statistical analysis. TGFβ1-and its signaling pathway pSmad2/3 are important mediators of fibrosis.16, 18 The number of TGFβ1- and pSmad2/3-positive cells correlated strongly with the severity of LP fibrosis. Our findings would suggest that reduction in esophageal eosinophilia induced by topical corticosteroids may be associated with reduced LP fibrosis and possibly remodeling.

Genetic polymorphisms (CC, CT, TT) at 509 in the TGFβ1 promoter region may be associated with increased TGFβ1 levels and also more severe airway obstruction in asthmatics.32 In a recent report, EoE patients with the CC genotype all responded to OVB and also had fewer LP TGFβ1-positive cells.16, 17 It was postulated that the CC genotype is a less fibrotic, more steroid-responsive form of EoE than the CT or TT genotype. In our present study 11 of 15 patients who received OVB were genotyped. Three were CC with 2 responders and 1 was a partial responder. One patient in the placebo group was CC and later responded to open-label OVB therapy. Although the numbers in this study are very small and larger studies are indicated, the findings are consistent with our previous observation that most CC patients are responsive to topical budesonide therapy, while CT and TT patients have a variable response to topical corticosteroid therapy.

OVB is an effective treatment of pan-esophageal eosinophilia in patients with EoE, and reduction in eosinophil count (to ≤6 eos/hpf) correlates well with symptomatic and endoscopic improvement. Although patients with negative food/aeroallergen skin prick/radioallergosorbent testing appear to respond better, patients testing positive do also respond and should also be considered for OVB therapy. In our small group of patients, subepithelial fibrosis was seen to improve with OVB therapy. Whether or not this has implications for preventing future stricture formation is not known, but merits further evaluation. Although 3 months of therapy with OVB is short and does not allow for an evaluation of long-term outcomes and the influence on the natural history of EoE, data from this study does support the need for a proprietary OVB medication specifically for the treatment of EoE.

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Acknowledgments 

The authors are indebted to Dr Janice Lookabaugh, independent consultant, for her help with the statistical analysis and to Diana Chen for technical assistance. Dr Seema Aceves would like to acknowledge Dr David Broide for his continued support.

Clinicaltrial.gov identifier number is NCT00638456.

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Supplementary material 

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References 

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 This article has an accompanying continuing medical education activity on page e17. Learning Objective: Upon completion of this activity, successful participants will be able to demonstrate an increase in their level of knowledge of the histologic and clinical features of eosinophilic esophagitis and will be able to determine which patients with EoE are more likely to respond to topical steroid therapy.

 Conflicts of interest The authors disclose the following: The University of California, San Diego has a financial interest in Meritage Pharma, the company sponsoring this research. Drs Dohil, Bastian, and Aceves and the University of California may financially benefit from this interest if the company is successful in developing and marketing its own product that is related to this research. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. The remaining authors disclose no conflicts.

 Funding Support was provided by a grant from Meritage Pharma, San Diego, CA.

PII: S0016-5085(10)00669-4

doi:10.1053/j.gastro.2010.05.001

Gastroenterology
Volume 139, Issue 2 , Pages 418-429.e1, August 2010

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