Eosinophilic esophagitis (EoE) is an emerging disease in the field of pediatric gastroenterology. While evidence of this condition has been present since the 1960s, characterization of the disease did not occur until 1993 [1]. Kelly et al. [2] were the first to show that an elemental diet was effective in treating esophageal eosinophilia that was unresponsive to anti-reflux therapy. At the most basic level, EoE is characterized by the abnormal presence of eosinophils in the squamous epithelium of the esophagus. The diagnosis of EoE requires a combination of both clinical and pathologic findings, including the following: symptoms related to esophageal dysfunction, the presence of eosinophils on esophageal mucosal biopsy (≥15 eosinophils per high-power field), isolated eosinophilia in the esophagus, and the absence of any secondary causes [3]. Since the recognition of EoE in the 1990s, our understanding of this condition has improved but many questions remain unanswered, including the exact pathophysiology, characteristic histological findings, therapeutic endpoints, as well as biomarkers and molecular signatures that can aid in diagnosis [34].

Increased interest in more specific treatment guidelines has spurred research into the efficacy of current recommendations. Treatment options for this condition currently include medical therapies such as high-dose proton pump inhibitors (PPIs) [567], topical corticosteroids [89101112], and elimination diets such as elemental [13], empiric [14151617], and specific or directed elimination diets [15161819]. End points for treatment of EoE include improvements in both clinical symptoms as well as evidence of histologic response [316182021]. Treatment of EoE frequently requires a combination of both dietary and medical therapy. Two common dietary interventions include the dairy-free diet (DFD) [19] and the costly six-food elimination diet (SFED) [22]. The efficacies of these interventions were first demonstrated in 2006 and 2012, respectively, and they have shown continued success since their introduction [16182021]. Milk has been identified as the most common food trigger, followed by wheat [20]. Recent research has demonstrated the efficacy of additional diets such as the 4-food elimination diet, which has the advantage of covering major allergens while at the same time being less restrictive than SFED [16]. Given the multiple treatment strategies available, it has been difficult to validate a specific treatment protocol. Nowhere is this more apparent than in selecting a dietary elimination protocol for a patient, since in addition to nutrition, the clinician must consider patient lifestyle, adherence to therapy, and caregiver resources [322].

In this retrospective study, we aimed to evaluate treatment responses to DFD and SFED as initial therapies. We also sought to identify factors that may contribute to the success or failure of treatment, and specifically analyzed the following: treatment duration, age, sex, concurrent medical therapy, and objective findings on endoscopy and histology prior to and after therapy.

We conducted a retrospective study of patients who had been treated for EoE (n=345). Retrospective and prospective data were entered into a Microsoft Access database by a single individual in the department of pediatric gastroenterology at Connecticut Children's Medical Center, Hartford, CT, USA. This database was approved by the institutional review board at Connecticut Children's Medical Center (IRB#: 15-046-CCMC). This database included demographic information, therapies (both dietary and medical), patient-reported compliance, endoscopy results, histology/biopsy results, and laboratory results. A single user abstracted the data elements listed below into an Excel spreadsheet. Potential confounders in this study included compliance and ancillary therapies such as medications. Patients were treated by various providers in our practice, and dietary therapies were determined based on both provider and patient preferences.

In this retrospective study, we sought to evaluate the efficacy of DFD and SFED as first-line therapies for the treatment of EoE in our practice. This was not intended to be a head-to-head comparison but rather a comparison of first line options. Treatment with DFD and SFED as first-line therapies resulted in responses in 57% and 52% of children, respectively. These response rates were not surprising given the results of previous studies. In a retrospective study, Kagalwalla et al. [19] showed that the response to DFD was 65% when used as the initial therapy for EoE treatment. In a second retrospective study, this same group found that 75% of patients responded to SFED [18]. In a meta-regression analysis, Cotton et al. [23] showed an overall response rate of 69% to SFED (95% prediction limits 31.9–91.4%).

While multiple therapies have been shown to be effective for EoE, optimal treatment protocols remain elusive due to the need to tailor treatment to individual patients. We anticipated that patients with longer intervals between endoscopies would have increased response rates due to decreased antigen loads. However, as noted above, there was no significant difference between treatment groups with regards to treatment duration; patients treated <10 weeks had the highest response rate, but this finding was not statistically significant. Given this finding, decisions on the duration of therapy prior to repeat endoscopy should be based on a combination of factors, including patient adherence and the complexity of dietary therapy. We suspect that the longer the endoscopy interval, the more likely it is that the patient will become non-adherent, as seen in those who underwent repeat endoscopy after very long intervals (>6 months) and were eventually excluded. Most studies on dietary management of EoE performed endoscopies at intervals of 6–8 weeks. The consensus statements from 2007 and 2011 recommended treatment of 6–12 weeks (depending on the treatment) between endoscopies [324]. The 2018 AGREE conference was not clear nor specific with regards to the duration between endoscopies [3]. Our practice is to do endoscopies at intervals of 8–12 weeks to minimize the number of endoscopies and anesthesia done in a short period of time.

Additionally, and surprisingly, response rates in the treatment groups did not differ with respect to age. We hypothesized that since parents would be more likely to manage younger patients' diets, these patients might have better compliance and thus, higher response rates. In fact, there was no significant difference between age groups, but surprisingly, older patients had numerically higher response rates. Additionally, older patients were more likely to be started on DFD rather than SFED (p=0.0070). This is generally done to minimize the difficulties that teenagers may face with dietary restrictions and to improve compliance.

The majority of patients (85%) underwent concomitant PPI therapy with the dietary elimination. Patients treated with both DFD and PPI therapy fared better than those who did not receive PPI therapy (p=0.0177). This was confirmed with bivariate logistic regression analysis (Table 5). There was no difference in the SFED group with respect to concomitant PPI therapy. PPIs have been shown to significantly inhibit IL-4–stimulated eotaxin-3 expression in EoE esophageal cells and to block STAT6 binding to the eotaxin-3 promoter [25]. Additionally, PPIs might have eosinophil-reducing effects independent of their influence on acid reflux, and response to PPIs might not distinguish EoE from gastroesophageal reflux disease [26]. Therefore, it is not surprising that patients who underwent an elimination diet with concomitant PPI therapy responded more favorably.

Since an association between atopic diseases and EoE has previously been demonstrated [272829], we compared treatment outcomes between those with and without evidence of atopic disease. There was no significant association, either in the overall sample or in treatment subgroups (Table 4). While atopy is helpful in the diagnosis of EoE, it does not appear to be applicable as a predictor of treatment response.

Significant improvement of gross endoscopic appearance was noted in the overall sample as well as in treatment subgroups (Table 2). It would have been optimal to compare these results with associated symptomatology, but the database did not include sufficient data on symptoms.

This study has several strengths. It reflects the comprehensive nature of real-life practice at a single major children's healthcare facility. The sample size is one of the largest in any pediatric or adult studies. While treatment approaches vary from practice to practice, we report on a single department experience where clinical decisions were similar among the providers. Retrospective and prospective data input was performed by a single individual, which decreased variability in reported patient profiles. Furthermore, an advantage of the database is that the same information was available for all patients.

A major exclusion criterion for this study was compliance with dietary therapy; while the database provided evidence on many occasions, these were restricted to subjective observations and patient admittance. As in any study, compliance is difficult to measure. In multiple instances, issues with compliance did not become apparent until the follow-up endoscopy, which voided the usefulness of the follow-up biopsy.

One of the weaknesses of this study was the lack of uniformity in treatment courses between patients. Despite having limited therapeutic options for EoE, general pediatric and adult practices across the country vary in their treatment approaches. On secondary analysis of our data it was noted that a significant number of patients (52%) started on DFD and a PPI had no prior PPI exposure. This makes it difficult to interpret response rates as this subset of patients were exposed to two recognized forms of treatment for EoE simultaneously. However, we would like to highlight the fact that none of our patients received what is considered to be high dose PPI therapy before or during treatment with dietary therapy. Standardized dosing was also difficult to identify as patients were noted to be on multiple formulations of PPI (i.e. omeprazole, lansoprazole) which have variable dosing based on age and weight. Lastly, our database did not include actual dosing of PPI therapy. Given this, PPI administration in these cases should be viewed as an adjunctive therapy vs dual therapy.

A major area of future research is the development of stepwise treatment protocols. Developing and validating a step-up treatment approach to EoE, in contrast to the commonly used top-down methods, would be a valuable tool for practitioners. We believe that starting with a dairy free diet as first line therapy, with or without PPI, is warranted. This should be followed by a 4- or 6-food elimination diet or oral topical steroids. Optimization of such a protocol could lead to decreased time to remission along with potential decreases in endoscopic procedures. These diets should be tried in addition to directed elimination diets based on allergy testing in patients with multiple food allergies. In these patients, it is not unreasonable to proceed with SFED or even more restrictive diets such as a hypoallergenic diet or an elemental diet if necessary. Further prospective studies are warranted to identify the most effective treatment approach.

DFD is an effective initial therapy for EoE and should be attempted before more extensive and costly elimination diets [22]. This has the advantage of eliminating one of the most common offending agents in EoE while remaining minimally restrictive. High-dose PPI therapy remains an important treatment option for EoE, however, adverse effects with long term use of PPI's has raised concerns. Concomitant use of PPIs with dietary therapy is also advised until a repeat endoscopy is performed. We believe that this warrants further studies and a prospective trial to evaluate a step-up approach to treating EoE in children and adults.