Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized histologically by a dense eosinophilia (>15 eosinophils [eos] per high-power field [HPF]) (1–3). Clinically, EoE can present with a variety of symptoms ranging from food refusal and emesis to dysphagia and food impactions (4). Significant effort has been invested during the last few years to decipher the pathogenesis and pathophysiology of EoE. The ultimate goal is to discover better treatment options or a cure for this condition.
At the time of writing the present article, the only therapies that have consistently demonstrated resolution or improvement in esophageal eosinophilia have been dietary restriction and steroids (5–11). Although elimination diets can be effective, some patients have difficulty adhering to a restricted diet (12). Systemic steroids have been shown to be effective; however, their adverse effects make them unsuitable for long-term maintenance therapy.
Topical steroids have become an attractive therapeutic option because they have proven efficacious at limiting esophageal inflammation while allowing patients to consume a less restricted diet. Topical steroids can improve quality of life (13) and decrease inflammation (9,10), while at the same time avoiding the adverse effects of systemic steroids.
Budesonide is typically mixed with Splenda to create a slurry (10); however, we have encountered many families who are weary of the use of artificial sweetener in high doses for their children. With this in mind, we compared the effectiveness of Neocate Nutra with Splenda as a mixing agent for budesonide. Neocate Nutra is a hypoallergenic food product designed for babies with food allergies. It is distributed as a powder that can then be prepared into a semisolid. Based on its ability to be mixed to a slurry consistency and its hypoallergenic properties, we hypothesized that it would be a comparable mixing agent to Splenda.
The present retrospective review was approved by the Boston Children's Hospital institutional review board. Patients were referred to the Eosinophilic Gastrointestinal Disease Clinic at Boston Children's Hospital for evaluation based on an earlier diagnosis of EoE. All of the patients included in the present report were diagnosed as having EoE based on endoscopic finding of >15 eosinophils/HPF on esophageal biopsies while on acid blockade based on consensus recommendations (14). On consultation, parents were given options for therapy, including dietary interventions (targeted or 6-food elimination diets) or topical steroid therapy. We offered the families who chose oral viscous budesonide (OVB) the choice of mixing the medication into slurry consistency with either Splenda that we explained as a standard of care or Neocate Nutra.
Patients were treated with a dose of budesonide determined by age. Patients <10 years of age received 1 mg (0.5 mg/2 mL Respules) and those >10 years of age received 2 mg/day. Medication was mixed into slurry consistency by adding either 10 packets of Splenda or 2.5 cm3 of Neocate Nutra per milligram of budesonide. Patients were instructed to avoid anything to eat or drink for 30 minutes after medication administration. No dietary or medication changes were made between time of therapy initiation and follow-up endoscopy.
Upper Gastrointestinal Endoscopy and Biopsies
A follow-up endoscopy was performed at least 10 weeks after the start of therapy by a pediatric gastroenterologist at Boston Children's Hospital. Biopsies were collected from distal, mid, and proximal esophagus. The highest number of eosinophils per high-power field in any of the biopsies was then taken and compared with pretreatment highest number of eosinophils per high-power field. Patients were grouped into nonresponders if the eosinophil count remained >15 eos/HPF, responders if <15 eos/HPF, and in remission if the eosinophil count was ≤6 eos/HPF. Because data were collected retrospectively and there was high variability among endoscopist documents, other markers of EoE were not assessed, including endoscopic score or additional histologic markers of esophagitis.
The group treated with budesonide mixed with Neocate Nutra was compared with the group treated with budesonide mixed with Splenda in their demographic and clinical characteristics. Demographic variables included race, age, and sex. Clinical variables included initial eosinophil count, proton pump inhibitor use, or concomitant dietary elimination. The comparisons were performed using the Wilcoxon test and the Fisher exact test for continuous and categorical covariates, respectively.
To compare treatments with Neocate Nutra and Splenda, we used logistic regression, with the outcome defined as successful response to treatment. A priori we defined treatment with Neocate Nutra to be noninferior to Splenda if the odds ratio (OR) of treatment success with Neocate Nutra as compared with Splenda was >0.67 with 95% confidence. The noninferiority margin of 0.67 on the OR scale corresponds to <10% noninferiority margin for the difference between the response rates between the treatments.
To account for possible confounding by choice of the mixing ingredient, we computed propensity score for the choice of treatment by Neocate Nutra, which was included in the logistic regression model. Because of the small size of the study, matching based on propensity score was not feasible, and we included propensity score as one of the covariates in the model. The propensity score was built based on the demographic variables (age, race, sex), clinical variables (pretreatment eosinophil count, proton pump inhibitor use, dietary restrictions of milk, egg, wheat, soy, and/or peanut, history of atopy, positive skin prick test), time to follow-up endoscopy, and date of diagnosis. Because of a statistically nonsignificant effect of the propensity score and a small number of unsuccessful treatments, propensity score was not included in the final model. The analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC).
Between June 2008 and June 2013, 46 children were treated with OVB mixed with Splenda, and 14 were treated with OVB mixed with Neocate Nutra at the Boston Children's Hospital Eosinophilic Gastrointestinal Disease program. The 2 groups were not significantly different in their demographic or clinical characteristics (Table 1).
Peak Esophageal Eosinophil Count Per High Powered Field
A total of 13 of the 14 patients (92.9%) who were treated with OVB compounded with Neocate Nutra demonstrated histologic response defined by <15 peak eos/HPF. Nine of the 14 (64%) patients achieved remission defined as ≤6 peak eos/HPF. Mean pretreatment and posttreatment peak eosinophil counts were 62 eos/HPF (range 20–120 eos/HPF) and 9 eos/HPF (range 0–100 eos/HPF), respectively. Of the 46 patients treated with OVB compounded with Splenda, 30 patients (65%) achieved histologic response and 23 patients (50%) achieved remission. Mean pretreatment and posttreatment peak eosinophil counts for the Splenda group were 59.5 eos/HPF (range 20–180 eos/HPF) and 25.5 eos/HPF (range 0–200 eos/HPF), respectively (Fig. 1). The variance in timing between prescopes and postscopes in the Splenda group was 10 weeks to 20 months and in the Nutra group was 10 weeks to 6 months.
The OR of success with Neocate Nutra as compared with Splenda was 6.93 (95% CI 0.83–57.91, P = 0.0728). Because 0.83 > 0.67, we conclude noninferiority of Neocate Nutra. None of the other covariates had a statistically significant (at P = 0.05) association with the treatment success. To account for possible confounding by choice of the mixing ingredient, we computed propensity score for the choice of treatment by Neocate Nutra, which was included in the logistic regression model. Because of a statistically nonsignificant effect of the propensity score (P = 0.6713) and a small number of unsuccessful treatments in the Neocate Nutra group (n = 1), propensity score was not included in the final model.
In the present study, we demonstrated that budesonide mixed with Neocate Nutra to make a viscous slurry is a promising therapeutic treatment option for children with EoE. We showed that it is at least as effective as the present standard, budesonide mixed with Splenda.
Faubion et al first described the use of topical steroids to control eosinophilic esophageal inflammation in 1998 (11). The first randomized, double-blind, placebo-controlled study comparing fluticasone with placebo demonstrated 55% remission in treatment group versus 9% in placebo (9). Recently a different topical steroid, budesonide mixed into a viscous slurry, has been shown to be efficacious, with a response rate of 87% (10). To achieve the desired viscosity for the budesonide preparation, Dohil et al used Splenda at a dose of 10 packets per milligram of budesonide (0.5 mg/2 mL Respules).
In our experience, parents are often reluctant to have their children consume such large amounts of Splenda. Splenda is composed of the organochlorine sweetener sucralose and the fillers maltodextrin and glucose. It is generally considered to be a safe product, but a toxicology study in rodents suggested that Splenda can increase levels of cytochrome CYP3A4 and CYP2D (15). The same study suggested that high doses of Splenda increase the fecal pH, cause mild depletion of goblet cells, and decrease colonic colonization of anaerobes, bifidobacteria, lactobacilli, Bacteroides, and Clostridia. These findings have been disputed (16,17), and at this point, there is no clear evidence that Splenda exerts any harmful effects on humans.
We acknowledge that there are several limitations to our study. It is a retrospective study, so we were unable to validate our patients’ compliance with their medication. That may explain why our Splenda cohort achieved a lower response rate than published in the original controlled trial. Additionally, because it was a retrospective study, the interval between endoscopies was not uniform among patients, which may have affected the degree of mucosal healing. Because our study was retrospective and endoscopies were performed by different providers, we did not collect data on gross endoscopic findings and instead chose to focus only on eosinophil count as our outcome measure. Symptom scores were not consistently collected, so we chose to study histologic instead of clinical response of our therapy options.
In summary, we believe our study offers an alternative innovative and palatable mixing agent to create a viscous budesonide slurry. Neocate Nutra can be an effective substitute for families who are concerned about the use of the standard recipe with Splenda. Our study demonstrates noninferiority to Splenda and a promising 93% response rate to OVB mixed with Neocate Nutra. We acknowledge that our study sample is small and prospective studies are needed to determine whether it is a superior mixing agent.
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