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Retrospective Comparison of Fluticasone Propionate and Oral Viscous Budesonide in Children With Eosinophilic Esophagitis

Fable, Jacqueline M.*; Fernandez, Marina; Goodine, Susan; Lerer, Trudy; Sayej, Wael N.†,§

Journal of Pediatric Gastroenterology and Nutrition: January 2018 - Volume 66 - Issue 1 - p 26–32
doi: 10.1097/MPG.0000000000001626
Original Articles: Gastroenterology
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Background: Eosinophilic esophagitis (EoE) is treated with dietary modification and/or pharmacologic management with swallowed topical steroids. Swallowed fluticasone propionate (FP) and oral viscous budesonide (OVB) have proven to be effective in resolving symptoms and reversing histologic changes in children and adults with EoE. There are minimal comparative studies between the 2 agents.

Objective: The aim of the study was to retrospectively compare endoscopic and histologic outcomes after FP versus OVB therapy in children with EoE in our center.

Methods: We performed a retrospective chart review of subjects diagnosed with EoE at a tertiary care center between 2010 and 2015. Inclusion criteria were FP or OVB therapy for ≥8 weeks along with pre- and post-treatment endoscopic evaluation. Demographic and clinical features and endoscopic and histologic assessment were recorded for comparative analysis. Histologic response was defined as <15 eos/hpf and remission as <5 eos/hpf.

Results: The study included 68 EoE patients (20 FP and 48 OVB) with a mean age of 10.6 ± 5.2 years (range 1–20 years); 81% were boys and 68% were Caucasian. No significant demographic or clinical differences were noted between the 2 study groups. Overall histologic response to topical steroids was seen in 44 of 68 (65%) patients. A significantly greater number of patients achieved histologic response with OVB (36/48, 75%) than with FP (8/20, 40%) (P = 0.0059). Mean pretreatment peak eos/hpf was 46 ± 19 in the FP group versus 45 ± 23 in the OVB group. Mean post-treatment peak eos/hpf was 20 ± 29 in the FP group versus 12 ± 16 in the OVB group (P = 0.002). There was also a significantly greater difference in the change of absolute eos/hpf from pre- to post-treatment in the OVB group (−33) versus FP (18) (P = 0.047). A greater number of OVB-treated patients without asthma had a histologic response compared to those with asthma (P = 0.031). The response to OVB was not affected by the delivery vehicle, namely sucralose (Splenda) versus Neocate Duocal.

Conclusions: Our data suggest that treatment with OVB leads to better endoscopic and histologic outcomes than FP. Adherence to treatment and history of asthma are major determining factors in the response to treatments. Using Neocate Duocal as the OVB delivery vehicle is just as effective as sucralose.

*Department of Pediatrics, University of Rochester Medical Center, Rochester, NY

Division of Digestive Diseases, Hepatology and Nutrition

Department of Research, Connecticut Children's Medical Center, Hartford

§Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT.

Address correspondence and reprint requests to Wael N. Sayej, MD, Division of Digestive Diseases, Hepatology and Nutrition, Connecticut Children's Medical Center, 282 Washington St, Hartford, CT 06106 (e-mail: wsayej@connecticutchildrens.org).

Received 11 September, 2016

Accepted 14 April, 2017

The study was supported by the Adopt a Friend Grant from the Connecticut Children's Medical Center Foundation and Connecticut Children's Medical Center Strategic Research Funds.

The authors report no conflicts of interest.

What Is Known

  • Oral topical steroid therapies with oral viscous budesonide or fluticasone propionate are effective treatment options for patients with eosinophilic esophagitis.
  • Sucralose (Splenda) is the delivery vehicle of choice for oral viscous budesonide.

What Is New

  • Oral viscous budesonide is more effective than inhaled fluticasone propionate in children with eosinophilic esophagitis.
  • The absence of asthma is a major determining factor in achieving response or remission.
  • Neocate Duocal is just as effective as Sucralose for oral viscous budesonide delivery to the esophageal mucosa.

Eosinophilic esophagitis (EoE) is an emerging illness of the esophagus with both active and chronic inflammation that can lead to long-term sequelae of fibrosis and esophageal strictures. It is an allergy-associated disease, characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil infiltration into the esophageal epithelium (>15 eosinophils per high-power field [eos/hpf]). EoE has garnered increased attention since its recognition as a separate entity from reflux disease in 1993 (1,2), and often diagnosed before a child's sixth birthday. The incidence and prevalence of EoE have increased dramatically over the past 20 years. (3) In children incidence and prevalence are currently estimated to be 0.7 to 10 per 100,000 and 0.2 to 43 per 100,000 per person-year, respectively (3).

Patients with EoE typically present with feeding difficulties, failure to thrive, vomiting, pain and difficulty with swallowing, and food impactions in the esophagus (4). The goals of therapy are to resolve symptoms of esophageal dysfunction, prevent complications from long-standing EoE, and maintain histologic remission. Therapeutic options include dietary modifications and topical steroids (TS). Dietary management includes elemental diets (5,6), directed elimination diets (7–10), and a 6-food elimination diet (10–12). When followed, elimination diets can be highly effective; however, poor compliance is often an issue that prevents symptomatic and histologic resolution of EoE (13,14). If dietary restriction is not practical or adherence to food elimination is not effective, swallowed TS are used (fluticasone propionate [FP] or oral viscous budesonide [OVB]). In many centers, TS are the first-line treatment for EoE.

Both swallowed FP and OVB are proven to be effective in resolving symptoms and reversing histologic changes. Albert et al (15) retrospectively compared the efficacy of FP and OVB in 75 patients (age 2–64 years, mean 33 years) and showed an overall response rate of 51% and no difference in response to FP (48%) versusOVB (56%). No study has, however, yet compared the 2 treatment options, retrospectively or prospectively, in children with EoE. Fluticasone is puffed into the mouth by a metered-dose inhaler and then swallowed (16). This form of TS treatment has a number of benefits, including its ease of administration and limited systemic side-effect profile. Studies looking at FP use in children with EoE have reported significant improvement in both symptoms and histologic findings (17–20). Budesonide is another common steroid that has been used for treatment of EoE (21–24). Dellon et al (25) showed that viscous budesonide was superior to swallowed nebulized budesonide solution in terms of histologic improvement, although both therapies resulted in similar clinical improvement. Budesonide mixed in sucralose has been shown to be effective and safe in children with EoE (26). Early comparisons using sucralose (23,24) or Neocate Nutra (27) as delivery vehicles for viscous budesonide suggested similar efficacy in terms of histological and clinical improvement.

Our goals in the present study were to retrospectively compare treatment outcomes in children who received oral TS therapy at our center, identify any factors that influenced the success or failure of therapy, and determine whether an alternative delivery vehicle for budesonide, namely Neocate Duocal, was just as effective as sucralose in achieving histologic improvement.

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METHODS

We performed a retrospective chart review of patients with documented EoE, defined endoscopically as >15 eos/hpf on esophageal biopsies with normal gastric and duodenal biopsies, who were treated with OVB or FP at Connecticut Children's Medical Center (CCMC) between 2010 and 2015. The primary outcome measure was histological response, defined as a decrease in peak eosinophil count to <15 eos/hpf after a minimum of 8 to 12 weeks of therapy with FP or OVB. Patients were treated with FP or OVB with age-dependent dosing consistent with current recommendations (28,29). The secondary outcome was a comparison of the efficacy of OVB when using 2 different delivery vehicles (Duocal vs sucralose). The present study was approved by the institutional review board at CCMC, Hartford, CT (IRB 14-113).

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Patient Demographics and Clinical Data

The OVB- and FP-treated groups were compared in terms of their demographic, endoscopic, and histological characteristics. Demographic characteristics included age, sex, race, height, weight, and body mass index. Clinical characteristics included prior therapies (proton pump inhibitors [PPIs], H2 blockers), simultaneous dietary elimination (directed dietary elimination, dairy elimination, 6-food elimination diet), history of other atopic diseases (asthma, eczema, seasonal or environmental allergies, and allergic rhinitis), and history of medication and food allergies. Characteristics on initial endoscopic evaluation leading to TS therapy included normal appearance and the presence of furrows, rings, white specks/plaques, strictures, luminal narrowing, crepe-paper esophagus, or erosions. Histological characteristics included peak eos/hpf and basal layer hyperplasia.

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Inclusion Criteria

We reviewed the charts of 279 active patients, ages 1 to 20, with EoE documented by endoscopic biopsy. Eighty-four patients who were treated with OVB or FP at CCMC between 2010 and 2015 were identified but only 68 were included in the present study. Sixteen patients were excluded due to insufficient data. Patients were required to have undergone upper endoscopy with biopsy both before treatment initiation and at least 8 to 12 weeks after treatment with FP or OVB. The choice of TS was determined based on patient preference, provider preference, history of failing a previous steroid regimen, or insurance coverage. A total of 65 of 68 patients received high-dose PPI therapy before starting the steroid therapy and only 3 of 68 were not treated with high-dose PPI therapy due to severity of symptoms and endoscopic findings. All patients received concomitant high-dose PPI therapy during treatment with the steroid therapy. Individuals with various comorbidities including inflammatory bowel disease, celiac disease, and Helicobacter pylori gastritis were excluded from the study.

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Treatment Protocols

At CCMC, children from 1 to 10 years are treated with fluticasone 110 μg/puff inhaler, 2 puffs twice per day. Children older than 11 years are treated with fluticasone 220 μg/puff inhaler, 2 puffs twice per day. Patients treated with FP, regardless of age, were instructed not to use a spacer.

The dosage of OVB in the present study was 0.5 mg BID (0.25 mg/2 mL or 0.5 mg/2 mL Respules) in children ages 1 to 10 years, and 1 mg BID (one 1 mg/2 mL Respule or two 0.5 mg/2 ml Respules) in children ages 11 to 20 years. Patients were instructed to prepare OVB by opening the liquid budesonide Respules and mixing the contents with 5 packets of sucralose (Splenda), then swallowing the mixture slowly over 5 to 10 minutes. This was done twice daily (total of 10 packets of sucralose per day). From 2012 to 2015, Neocate Duocal was used as a delivery vehicle due to long-term safety concerns about using 10 packets of sucralose per day. Patients were instructed to mix 1 tablespoon of Duocal with 1 or 2 Respules of budesonide and to swallow slowly over 5 to 10 minutes. A subset of patients, who were not willing to use the sucralose or Duocal, used other regimens (2 packets of Truvia, 2 packets of Stevia, 1 tablespoon of pasteurized maple syrup or honey). All patients treated with OVB or FP were instructed to abstain from eating or drinking for 30 minutes after medication administration, and to drink something after 30 minutes to rinse the medications.

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Outcomes

The primary outcome was histological response, defined as a decrease in peak eosinophil count to <15 eos/hpf after 8 to 12 weeks of therapy with FP or OVB. Complete remission was defined as <5 eos/hpf. Patients who continued to have >15 eos/hpf were considered to be treatment failures. Secondary outcomes included endoscopic visualization, presence of side effects from TS, and self-reported adherence or nonadherence (<50%) with TS. Endoscopic improvement was based on resolution of furrows, white specks or trachealization. We also compared histologic outcomes between the different OVB delivery vehicle subgroups (sucralose or Neocate Duocal).

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Statistical Analysis

Groups were compared using t tests for continuous variables and chi-square or exact tests for categorical variables. Subgroup analyses compared differences in histological outcomes between Sucralose and Neocate Duocal as the delivery vehicles for OVB and between patients with and without asthma.

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RESULTS

Demographic and Clinical Characteristics of Study Groups

Of the 279 patients ages 1 to 20 years who had EoE documented by endoscopic biopsy, 84 were treated with swallowed FP or OVB at CCMC between 2010 and 2015. Sixty-eight patients were included in the present study and 16 were excluded due to insufficient data. Patient characteristics and demographics are presented in Table 1. There were no significant differences with regard to demographic characteristics with the 1 exception of requiring secondary therapy. Patients who failed initial therapy and required a treatment course with a second steroid were more likely to have received FP as the initial treatment (P = 0.005). Three patients (6%) failed OVB and were switched to FP, whereas 7 (35%) patients switched from FP to OVB.

TABLE 1

TABLE 1

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Response to Treatment

The overall response rate to TS therapy was 44 of 68 (65%). A significantly greater number of patients responded to OVB (36/48, 75%) compared with FP (8/20, 40%) (P = 0.0059, odds ratio 4.5, 95% confidence interval 1.1–2.5) (Fig. 1). Remission was achieved by a higher percentage of patients in the OVB group (26/48, 54%) than the FP group (7/20, 35%), but this was not statistically significant (P = 0.1). The prevalence of atopic disease (asthma, eczema, and environmental and seasonal allergies) and food allergies was similar in both groups (Table 1). Of the patients treated with OVB, those without asthma were more likely to have a histologic response than those with asthma (P = 0.031). This difference was not observed in the FP group. Lastly, most patients were treated with high-dose PPI therapy before starting steroid therapy except for 3 patients (2 in the FP group and 1 in the OVB group). We included them because of their disease severity based on symptoms and endoscopic findings and did not believe that they would respond to PPI therapy alone. They were treated with high-dose PPI therapy concomitantly with their steroid therapy. These 3 patients continue to be on steroid therapy.

FIGURE 1

FIGURE 1

Endoscopic findings are summarized in Table 2. Overall, there was a significant improvement or complete resolution of furrows and eosinophilic exudates after treatment with the TS (P = <0.0001). There was a more significant and robust resolution of characteristic endoscopic findings in the OVB group compared to the FP group, especially regarding the resolution of furrows (P = <0.0001 vs P = 0.1967, respectively).

TABLE 2

TABLE 2

Histologically, there was no significant difference in the pretreatment peak eosinophil count between the FP and OVB groups (P = 0.6427) (Fig. 2A). Post-treatment peak eosinophil counts were significantly lower in the OVB group (12 eos/hpf) compared to the FP group (30 eos/hpf) (P = 0.02) (Fig. 2B). In addition, although the peak eosinophil counts were significantly lower after treatment than before treatment in both groups (P = <0.0001 for OVB, P = 0.0265 for FP), the decrease in peak eos/hpf was significantly higher in the OVB group than in the FP group (Fig. 2C and D). Lastly, the change in absolute eosinophil counts from pre- to post-treatment was significantly greater in the OVB group (−33 eos/hpf) than in the FP group (−18 eos/hpf) (P = 0.047) (Fig. 2E).

FIGURE 2

FIGURE 2

Basal cell hyperplasia (BCH) was noted in all patients and is summarized in Table 3. Overall, there was a significant improvement in BCH, especially those with marked/severe BCH, from pre- (75%) to post- (21%) treatment, P = <0.0001. Pretreatment BCH was severe in 85% of patients who received FP and 71% of those who received OVB (P = 0.2285). Post-treatment BCH was severe in 30% of patients who received FP compared to 16% of those who received OVB (P = 0.6352). BCH was significantly improved from pre- (85%) to post- (30%) treatment in patients who received FP (P = 0.0003) and from pre- (71%) to post- (16%) treatment in patients who received OVB (P = <0.0001).

TABLE 3

TABLE 3

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Delivery Vehicle for OVB

A total of 11 (23%) patients mixed their budesonide with Duocal, 33 (69%) mixed it with sucralose, and 4 (8%) mixed it with other vehicles (truvia, stevia, maple syrup, or honey) (Fig. 3A). The type of delivery vehicle, namely sucralose, Duocal, or other, did not have a statistically significant impact on histologic response. The response rates for these 3 groups were 73%, 76%, and 50%, respectively, and remission rates were 55%, 58%, and 50%, respectively (Fig. 3B).

FIGURE 3

FIGURE 3

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Adherence to Therapy

Twelve of the 68 patients (18%) self-reported poor adherence and were less likely to achieve histologic response after treatment. Nonadherence was reported by 7 of 48 (15%) patients in the OVB group compared to 5 of 20 (25%) patients in the FP group (NS). Histologic response was achieved in 43 of 56 (77%) adherent patients compared to 1 of 12 (8%) nonadherent patients, (P = <0.001). Surprisingly, there was no difference in age between the adherent compared with nonadherent patients in both the OVB and FP groups.

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DISCUSSION

Treatment of EoE is limited, and continues to pose a challenge for physicians and patients. The choice of which swallowed TS to use is usually determined jointly by patients and their physicians. Since the recognition of EoE, there have been many published studies on TS, elemental diets, and dietary elimination regimens.

Until recently, there has never been a retrospective or prospective comparison of response to the 2 most commonly used TS, FP, and budesonide. Albert et al (15) recently reported on a retrospective comparison of 75 patients (children and adults, ages 2–64 years, median 33 years) who received fluticasone or budesonide. The response rate was 51% overall, and did not differ significantly between the 2 groups (48% in the FP group and 56% in the OVB group). In previous studies, retrospective and prospective, the response rate to budesonide was reported to be 80% to 87% (23,26). Response rates to fluticasone have been reported to be approximately 40% to 62% (17,30,31). The present study, although retrospective, is the first to compare treatment response to FP versus OVB in children. Our overall response rate was 65%. The response rate was 75% in the OVB group versus 40% in the FP group (P = 0.0059), consistent with the published literature. The remission rates were 54% and 35% in the OVB and FP groups, respectively. In comparison with the study of Albert et al, we demonstrated a higher response rate and a significant difference in response between the FP and OVB groups.

Endoscopically, there was significant improvement and/or resolution in visual findings (furrows, white specks, or trachealization) after treatment with FP and OVB, but these results were more robust in the OVB group compared to the FP group. Histologically, OVB was superior to FP in achieving higher response and remission rates, lower post-treatment peak eosinophil counts, and greater reduction in absolute eosinophil counts. There was significant improvement in BCH in both groups from pre- to post-treatment. It is likely that the higher response and remission rates with OVB are due to better surface contact of the viscous solution (OVB) with the esophageal mucosa compared to the swallowed inhalant (FP). It is also possible that patients were not swallowing the FP properly.

Both medications have been shown to be safe, with similar side-effect profiles. Although Harel et al (32) showed, in a retrospective study, that OVB led to suboptimal adrenocorticotropic hormone stimulation test results in 6 of 14 (43%) patients, Philla et al (33) recently showed that swallowed oral TS therapy with OVB or FP did not suppress adrenal function. In our study, we did not have any data on the effects of these steroids on the adrenal axis. Only 2 patients on FP developed thrush and 1 developed candida esophagitis, whereas only 1 patient on OVB developed thrush.

With regard to the delivery vehicle, the safety of long-term sucralose use is of concern. In the present study, we showed that Duocal was just as effective as sucralose. Although Duocal does not contain any protein, it is not considered to be a hypoallergenic supplement. In addition, it contains cornstarch and coconut oil, which makes it contraindicated in patients with allergies to corn and coconut. Neocate Nutra, a hypoallergenic supplement, has been shown to be just as effective as sucralose (27). There may be cost and insurance coverage issues associated with Nutra, however, and Duocal, pasteurized honey, or maple syrup may be excellent alternatives for patients placed on OVB.

There are many strengths to our study. This is the first study in pediatrics to retrospectively compare the 2 most commonly used EoE therapies, FP and OVB. For all 68 patients included in the study, histologic and endoscopic data were completely available and documented.

The major limitation with our study is that it uses a retrospective cohort design to compare 2 different treatment options. Because of this, selection bias is likely. Specifically, patients could have been prescribed fluticasone compared to budesonide due to provider preference, a history of treatment success or failure, patient preference, insurance issues, or other reasons that could affect our measured response rates. Similarly, the dose of steroids prescribed is lower than current practices, and compliance was not measured and could be difficult to definitively discern from the medical records. Butz et al (34) and Gupta et al (35) showed that higher doses of FP and oral budesonide suspensions were more effective in 2014. Most of our patients included in the present study were treated with standard of care that was based on the 2011 EoE consensus recommendations for children and adults (36). In addition, there were 10 patients that were included in the study that were not steroid naïve. We included those patients in the study to show that failing 1 steroid regimen is not an indication that they will fail the other. Lastly, 3 patients were not treated with PPI therapy before starting steroid therapy and were included in the study. These 3 patients continue to be on steroid therapy and PPI therapy, yet, continue to have persistent inflammation. Two patients have asthma and 1 patient has noncompliance issues.

In summary, OVB may be a more effective treatment choice than swallowed FP in children with EoE. It leads to better histologic and endoscopic response and remission. In addition, of patients we could confirm to be noncompliant, this was a major contributing factor in failure to achieve response or remission. The absence of asthma is a significant indicator for achieving response. Lastly, Duocal is just as effective as sucralose as a delivery vehicle for budesonide.

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Keywords:

Duocal; eosinophilic esophagitis; oral viscous budesonide; Splenda; sucralose; swallowed fluticasone propionate

© 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,