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Strategies for Medical Management of Pediatric Eosinophilic Esophagitis

Chawla, Neha*; Deshmukh, Mangesh†,‡; Sharma, Ajay*,§; Patole, Sanjay||,¶

Journal of Pediatric Gastroenterology and Nutrition: December 2016 - Volume 63 - Issue 6 - p e152–e157
doi: 10.1097/MPG.0000000000001298
Original Articles: Gastroenterology
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Objective: Eosinophilic esophagitis (EoE) is associated with significant morbidity in children. Strategies for optimizing its outcomes are hence essential. We aimed to review the strategies for medical management of EoE in children.

Methods: We conducted a systematic review of randomized controlled trials (RCTs) of medical interventions in children with EoE, using the Cochrane methodology. Databases including PubMed, EMBASE, CINAHL, Cochrane Central Library, and Google scholar were searched up to March 2016. Primary outcomes included histological (peak eosinophil count) and symptomatic remission. Secondary outcomes were improvement in endoscopic and other histological parameters and adverse effects.

Results: A total of 5 RCTs (N = 448) with low to unclear risk of bias were included. The interventions included topical oral steroids, swallowed enteral steroids and anti- interleukin (IL)5 agent. Pooling of data from all trials was not possible owing to significant heterogeneity in interventions. Meta-analysis of data (N = 141) from 3 RCTs (oral viscous budesonide: 2, fluticasone: 1) showed significant histological remission in the intervention versus control group participants (risk difference: 10.32 [95% confidence interval: 3.04, 35.03]; P = 0.0002), level of evidence—low. Compared with anti-IL5 agent, the trials assessing steroids reported high rates of clinical remission. Clinical remission did not correlate with histological improvement in any trial. Except for systemic corticosteroids, there were no significant adverse effects related to other interventions.

Conclusions: Limited low-quality evidence exists on the effects of various interventions in children with EoE. The beneficial effects of swallowed steroid need to be confirmed in large well-designed RCTs.

*Department of Paediatrics, St John of God Hospital, Midland

Department of Neonatal Paediatrics, Fiona Stanley Hospital

Department of Neonatology, St John of God Subiaco Hospital

§Department of Paediatric Gastroenterology, Princess Margaret Hospital

||Centre for Neonatal Research and Education, University of Western Australia

Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women, Perth, Western Australia, Australia.

Address correspondence and reprint requests to Dr Ajay Sharma, FRACP, Department of Paediatric Gastroenterology, Princess Margaret Hospital, Perth, WA 6008, Australia (e-mail: paedneurogi@gmail.com).

Received 15 April, 2016

Accepted 3 June, 2016

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org).

This research project received no grant from any funding agency in the public, commercial or not-for-profit sectors.

All authors declare that the work submitted has not been published previously, that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere including electronically in the same form, in English or in any other language, without the written consent of the copyright holder.

All authors declare that there is no competing interest involved.

The authors report no conflicts of interest.

What Is Known

  • Eosinophilic esophagitis is a major cause of upper gastrointestinal morbidity in children.
  • For the last 2 decades eosinophilic esophagitis has been increasingly reported from various parts of the world.
  • Various treatment strategies are used to manage eosinophilic esophagitis.

What Is New

  • This is the first systematic review of randomized controlled trials of various interventions for eosinophilic esophagitis in children.
  • Current evidence of the effects of various interventions in children with eosinophilic esophagitis is limited, and of low quality.
  • Large definitive trials are needed to confirm if oral swallowed steroids are effective in achieving histological and clinical remission.

Eosinophilic esophagitis (EoE) is defined as “a chronic, immune or antigen-mediated, esophageal disease characterized clinically by symptoms related to esophageal dysfunction, and histologically by eosinophil-predominant inflammation” (1). For the past 2 decades, EoE has been increasingly reported from various parts of the world, especially from the developed nations, possibly because of increased frequency and diagnosis of the disease (2). The estimated incidence is 1.3 to 12.8/100,000 children and adults in the United States and Europe (3). Serial audits by Cherian et al (4) indicate a rapid increase in the prevalence of EoE from 0.05 to 0.89/10,000 children in Western Australia.

EoE is a major cause of upper gastrointestinal morbidity with symptoms related to esophageal dysfunction. The youngest children present with vomiting, poor appetite, and poor growth, whereas the older children complain of abdominal pain (1,5). The long-term complications of EoE include fibrosis, stricture formation, and food impaction (6–9). The management of EoE requires a multidisciplinary team. The annual health care cost of EoE has been estimated to be as high as $1.4 billion in the United States (10).

The goal of treatment is to reduce inflammation and improve symptoms in the short term, and prevent long-term complications (eg, fibrosis, stricture). Dietary therapy and/or topical steroids are common components of the treatment for EoE. Various dietary interventions have been used in treatment of patients with EoE. The common options include empiric elimination diet, targeted elimination diet, and elemental diet. The most effective dietary option is the removal of all foods because it ensures the elimination of causative foods (11). The common topical steroids for treating EoE patients are swallowed fluticasone and budesonide. Recurrence of symptoms after stopping steroids, however, occurs in majority of patients because the food antigens causing these symptoms have not been eliminated (11). Optimization of therapeutic strategies to improve the outcomes of EoE in children is important considering the significant health burden and suffering associated with this condition. We therefore aimed to review the strategies for the management of EoE in children.

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METHODS

We conducted a systematic review (SR) of randomized controlled trials (RCTs) of medical interventions in children with EoE using the Cochrane methodology (12). Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were used for reporting (13).

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Eligibility Criteria

Types of Studies

RCTs and quasi-RCTs were eligible for inclusion in the review. Non-RCTs, reviews, and commentaries were excluded, but read to identify other potential studies.

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Participants

Children younger than 18 years’ age with EoE.

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Inclusion Criteria

Studies evaluating any intervention (eg., corticosteroids, protein pump inhibitors [PPI] at any dose, by any route) for EoE, and reporting clinical and histological outcomes were included.

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Exclusion Criteria

Non-RCTs, review articles without original data on children with EoE, and those that provided duplicate information (ie, repeated abstracts presented at different conferences or abstracts published later as a full report) were excluded.

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Type of Interventions

Any medical intervention (eg, corticosteroids, anti-interleukin [IL]5, PPI including dietary therapy) versus control.

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Primary Outcomes

First, histological remission (histological responders) defined a peak eosinophil count of <6/high-power field (HPF) (×400) in the proximal and distal esophagus after therapy. Second, symptomatic improvement defined as >50% reduction of symptoms including heartburn, abdominal pain, nausea, regurgitation or vomiting, dysphagia, foreign body/food impaction, and weight loss.

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Secondary Outcomes

First, improvement in endoscopic parameters including findings of linear furrows, white exudates, and rings in EoE. The other histological parameters included basal zone hyperplasia, elongation of vascular papillae, eosinophilic degranulation, microabscess, and subepithelial fibrosis. Second, adverse effects secondary to intervention.

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Search Strategy

Reviewer (N.C. and A.S.) conducted the literature search independently. We searched the Cochrane Central Register (CENTRAL), PubMed, and EMBASE databases and Google scholar for studies reported from the earliest available online year of indexing until March 2015 using the keywords/MeSH terms {Eosinophilic Esophagitis OR Eosinophilic Oesophagitis} AND {Treatment OR Management OR Intervention} AND Children OR Pediatrics. We restricted our search to publication type “Randomized controlled Trial,” “Controlled Trial,” or “Clinical Trial.” References of the obtained studies were reviewed to identify additional studies. Search strategy is summarized in Fig. 1.

FIGURE 1

FIGURE 1

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Study Selection

Reviewers A.S. and N.C. identified potentially eligible studies and read the abstracts of the citations obtained from the initial broad search independently. Full-text articles of these studies were obtained and assessed independently by reviewers A.S. and N.C. for eligibility using the predefined eligibility criteria. Differences in opinion were resolved by group discussion among all reviewers to reach consensus. Multiple publications of the same study were excluded to avoid duplication of data.

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Data Extraction

Reviewer NC, MD independently completed a pre-specified data extraction form for all included studies. For dichotomous outcomes, the number of patients with the event and the number of patients analyzed in each treatment group of each study were entered into the form. For continuous outcomes, the mean and standard deviations (SD) were entered. Disagreements were resolved by group discussion until consensus was reached.

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Assessment of Risk of Bias

We used the Cochrane “Risk of Bias Assessment Tool” to assess the methodological quality of the included trials (14). For each trial, information was sought regarding the method of randomization, allocation concealment, blinding of participants and outcome assessors, completeness of follow-up, selective reporting, and other biases. The studies were assigned as of high, low, or unclear ROB. Reviewers N.C. and M.D. assessed each study independently. Disagreements were resolved by discussion.

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Data Synthesis

Meta-analysis was planned using Review Manager 5.3 (Cochrane Collaboration, Nordic Cochrane Centre) if pooling of data was possible and justified according to the “intention-to-treat” principle. We used a random-effects model for meta-analysis assuming heterogeneity. Categorical measure of effect size was expressed as risk difference (Mantel-Haenszel method) and mean difference (inverse variance method) was used for continuous measures. Statistical heterogeneity was assessed using the χ2 test, I2 statistic, and by visual inspection of the Forest plot (overlap of confidence intervals). A narrative synthesis was planned if meta-analysis was not possible because of significant heterogeneity in included studies and/or nonavailability of the outcome measures in the desired form.

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Assessment of Publication Bias

The risk of publication bias was to be assessed by a funnel plot (15).

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Summary of Findings Table

The key information concerning the quality of evidence, the magnitudes of effect of the intervention, and the sum of available data on the main outcomes are presented in the “Summary of findings table” as per the GRADE guidelines (16).

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RESULTS

The literature search retrieved 483 potential relevant citations (Supplemental Digital Content 1, Fig. 1, http://links.lww.com/MPG/A717). After carefully reviewing the abstracts, 415 (including 12 duplicate studies) were excluded. A total of 45 studies were excluded due to nonfulfillment of the inclusion criteria. Furthermore, 17 non-RCTs were excluded. These studies comprised PPI-1, anti-IL therapy-1, elimination diet-5, and steroid ± diet therapy-10. We excluded one RCT by Assa’ad et al (17) investigating efficacy of different doses of IL5 agent mepolizumab due to lack of placebo arm. Finally, only 5 RCTs (N = 448) were included in the review (18–22). These 5 trials assessed different interventions including swallowed steroids {oral viscous budesonide (OVB): 2, fluticasone: 1} (18,21,22), anti-IL5 agent (reslizumab) (20), and oral prednisolone (18). Their characteristics are described in Supplemental Digital Content 2, Table 1, http://links.lww.com/MPG/A718. The ROB in these studies was low to unclear (Supplemental Digital Content 3, Fig. 2, http://links.lww.com/MPG/A719).

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Details of Included Randomized Controlled Trials

  1. Schaefer 2008 (18): This open-label RCT evaluated systemic versus topical corticosteroid therapy. Children were randomized to receive oral prednisolone or swallowed fluticasone for 4 weeks, followed by an 8-week weaning protocol. The results showed effectiveness of oral and swallowed steroid therapy in achieving initial histological and clinical improvement but with high rate of relapse and need for maintenance therapy. Significant systemic adverse effects were noted in the oral prednisolone group but not with swallowed fluticasone.
  2. Dohil 2010 (19): This was randomized double-blind placebo-controlled trial. Patients were randomized to receive OVB or placebo for 3 months. Significant histological remission and improvement in symptoms and endoscopy scores was reported in patients receiving OVB.
  3. Spergel 2012 (20): This double-blind RCT evaluated the effect of different doses of an antibody to IL5 (reslizumab: 1, 2, 3 mg/kg) at weeks 0, 4, 8, and patients who received reslizumab showed statistically significant reduction in esophageal eosinophil counts. This was, however, not accompanied by a significant difference in clinical symptoms and quality of life between the reslizumab versus placebo group.
  4. Gupta 2015 (21): This was randomized, double-blind, placebo-controlled trial assessing low-, medium-, or high-dose OVB versus placebo treatment for 12 weeks. High- and medium-dose OVB treatment resulted in significant histological remission. Patients in both the OVB and placebo group, however, reported clinical improvement.
  5. Konikoff 2006 (22): This was a randomized double-blind placebo-controlled trial evaluating the efficacy of swallowed fluticasone versus placebo administered for 3 months. Patients who received swallowed fluticasone showed significant high rates of histological remission compared with those receiving placebo. Swallowed fluticasone had more pronounced effect in the proximal esophagus in younger children with no allergy.
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Primary Outcome

  1. Histological remission: All 5 trials reported this outcome (18–22). Individual trials assessing the efficacy of swallowed steroid showed significant histological remission from baseline after the treatment (18,21,22). The pooled estimate of 3 RCTs (2 OVB, 1 swallowed fluticasone) (N = 141) showed significant benefit in histological remission (risk difference: 10.32 [3.04, 35.03]; I2 = 0, χ2 = 0.29, P = 0.0002) (Fig. 1). Trial assessing anti-IL5 agent did not report significant histological remission from baseline (20). Spergel et al (20) reported significant improvement in eosinophil counts after reslizumab therapy but most patients did not reach remission (eosinophil count <5 HPF). The author raised the possibility that the dose of reslizumab may have been inadequate. The study by Schaefer et al (18) evaluating efficacy of oral prednisolone versus swallowed fluticasone reported high rate of histological remission in both groups (prednisolone: 81% vs oral fluticasone: 50%). The oral prednisolone group showed significant improvement compared with swallowed fluticasone between weeks 0 and 4 (P = 0.0440).
  2. Symptomatic improvement: All 5 trials reported this outcome (18–22). There was significant variation in the assessment of this outcome as different scoring systems were used to evaluate the symptoms of EoE. The trials reporting effects of swallowed steroids (OVB and swallowed fluticasone) showed some improvement in symptoms (18,21,22). Dohil et al (19) reported significant improvement in mean symptom score after OVB versus placebo (P = 0.031; nonparametric test P = 0.0458). Gupta et al (21) reported significant symptomatic improvement with OVB but the perceived clinical improvement did not correlate with histological remission as children in placebo arm also reported symptomatic relief without significant changes in eosinophil count. Konikoff et al (22) reported significant improvement in vomiting with swallowed fluticasone (67% pretreatment vs 27% posttreatment; P = 0.04). Other symptoms (eg, abdominal pain, dysphagia) did not show significant improvement. Authors noted significant correlation of symptomatic relief (vomiting) with histological remission.

The trial evaluating anti-IL5 agent did not report significant symptomatic relief after treatment (20). Spergel et al (20) reported improvement in most patients regardless of the treatment group allocation. A total of 56.4%, 63.2%, 64.9%, and 71.9% of patients in the 1, 2, 3 mg/kg reslizumab and placebo group, respectively, had a physician's EoE global assessment score of “none” or “mild.” Schaefer et al (18) reported high rate of symptomatic recovery from baseline (oral prednisolone: 100%, oral fluticasone: 97%) after 4 weeks of therapy. Meta-analysis was not possible considering the heterogeneity of tools (scoring systems) for assessing symptomatic outcomes in these studies.

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Secondary Outcomes

Endoscopic and Other Histological Parameters

Two RCTs that individually assessed OVB and swallowed fluticasone (19,22) reported improvement in endoscopic and histological parameter after the treatment. Schaefer et al (18) (oral prednisolone and swallowed fluticasone) reported improvement in histological parameters but did not assess endoscopic parameters. Meta-analysis was not possible due to heterogeneity of the intervention and outcome assessment.

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Adverse Effects

The common adverse effects included oral candidiasis, mild elevation of blood pressure, and issues related to intravenous access. The trials evaluating oral steroids reported systemic adverse effects as a result of prolonged therapy (18). None of the included trials reported intervention related serious adverse effects such as upper gastrointestinal bleeding or perforation, and none reported on long-term adverse effects. During the study period trials involving swallowed steroids (OVB, fluticasone) reported sporadic cases of oral and esophageal candidiasis (Dohil: 1/15, Gupta: 2/60, Konikoff: 1/21, and Schafer: 6/ 40) in the treatment arm, which resolved after oral Nystatin therapy (18,19,21,22). No data were, however, available about long- term use of these medications in these studies. These trials also reported mild elevation of blood pressure, which resolved without treatment. Studies involving oral prednisolone versus swallowed fluticasone (18) showed significant systemic adverse effect such as hyperphagia, weight gain, and/or cushingoid features in 40% of patients on oral prednisolone but none with swallowed fluticasone. Authors also reported high relapse rate (45%–50% after 20–24 weeks of treatment) and need for maintenance therapy (18). The trial evaluating reslizumab reported adverse effects such as headache, cough, nasal congestion, and upper respiratory tract infection in the intervention group (20).

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Publication Bias

We did not assess for publication bias, as the number of studies was small (23).

Grading of evidence and summary of findings (Supplemental Digital Content 4, Table 2, http://links.lww.com/MPG/A720): The grading of evidence was possible only for the studies involving swallowed steroids, as we were able to pool the data for histological remission. The evidence was considered low in view of the small sample size, heterogeneity of intervention and doses, and high ROB in some of the included studies (16).

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DISCUSSION

The results of our SR indicate that oral corticosteroids, swallowed steroids (OVB and fluticasone), were effective in achieving histological and clinical remission in children with EOE. Although oral prednisone therapy was associated with significant clinical and histological remission, there was high rate of relapse after stopping the treatment and significant systemic adverse effects. It is important to note that the trials evaluating swallowed steroids showed comparable histological and clinical benefits but reported significantly less adverse effects. Trials assessing OVB showed that medium- and high-dose treatment resulted in significant panesophageal reduction in epithelial eosinophilia, which correlated with symptomatic and endoscopic improvement (21). The most common adverse effect of swallowed steroids was oral candidiasis. There are, however, no studies to compare its incidence with short- or long-term use in children or adults. Alexander et al (24) have reported the incidence of oropharyngeal or esophageal candidiasis (mostly asymptomatic) as ∼15% with use of swallowed steroids. No other serious drug-related adverse effects were observed in short term. These studies, however, did not assess relapse rates and long-term adverse effects. It is possible that long-term adverse effects similar to those associated with systemic steroids may be evident after prolong use of swallowed steroids particularly when started in childhood. Overall, the current evidence supports the use of swallowed over systemic corticosteroids in the management of EoE in children.

The trials involving anti-IL5 agents is based on the hypothesis that IL5 plays an important role in esophageal accumulation of eosinophils in children with EoE, and blocking IL5 will lead to histological and clinical improvement (20). These trials reported improvement in esophageal eosinophilia, micro abscess, and eosinophilic aggregation but limited effect on basal zone hyperplasia, increased papillary length, and clinical symptoms. The relapse rate was high with this therapy. Failure to achieve complete remission in majority of the patients raises the possibility that other factors in addition to IL5, contribute to the pathogenesis of EoE. Response to therapy did not vary with the anti-IL5 doses used in the included studies. It is, however, possible that doses higher than those used in these studies may be required for histological and clinical remission (17,20). No long-term follow-up was available in the included anti-IL5 study.

The role of PPIs and elimination diets needs to be discussed as they are an integral part of the management of EoE (25–29). A subgroup of patients with typical EoE symptoms, but no GERD, have been reported to show a clinicopathologial response to PPI therapy (30,31). They are labeled as PPI responsive esophageal eosinophilia (PPI-REE). Patients with EoE may have esophageal hypersensitivity to acid-induced pain. Suppressing gastric acid secretion with PPIs may provide symptomatic relief for these patients (32). PPIs have been also reported to have anti-inflammatory effects (33), and to downregulate allergic TH2 inflammation in PPI-REE patients (34). Based on current evidence, the role of PPI as a maintenance therapy in proven EoE patients, however, seems to be controversial.

Observational studies have shown that elimination diets can be effective in symptomatic and histological improvement in patients with EoE but as yet there are no RCTs in this field (26–29). Various forms of dietary restriction have been reported to be useful in the management of EoE (29). A recent SR and meta-analysis of non-RCTs in children and adults showed high rates of histological remission (peak eosinophil counts to <15/HPF) with various forms of elimination diets (34). The overall effectiveness of elemental diet in inducing histological remission was 90.8% (95% confidence interval [CI], 84.7%–95.5%); 13 Studies (N = 429: 411 children; 18 adults). The effectiveness of six-food elimination diet (SFED) was 72% (95% CI, 66%–78%); 7 studies (N = 197: 75 children; 122 adults). Targeted elimination diet showed an overall effectiveness of 45% (95% CI, 35%–56%); 14 studies (N = 626: 594 children; 32 adults) in achieving histological remission. It was concluded that dietary strategies should be considered as the first-line therapy in children and adults with EoE (35). Compliance to such dietary restrictions is, however, a major challenge in children. Moreover, identification of food responsible for EoE is also difficult. Nutrient deficiency during long-term elimination diet is another significant concern.

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CONCLUSIONS

To our knowledge this is the first SR of RCTs on this important issue in children. The strength of our review relates to its comprehensive nature and robust methodology. The limitations include small sample size (5 RCTs, N = 448), high ROB bias in some of the included trials, heterogeneous interventions that did not allow pooling of data from all trials, varying follow-up periods, and inadequate assessment of long-term adverse effect and relapse rates. Large definitive RCTs assessing the efficacy of dietary treatment (with or without concomitant use of corticosteroids) and swallowed steroid therapy are hence warranted. It is important that such trials should assess the risk of relapse and long-term adverse effects associated with swallowed steroids in addition to clinical and histological remission. The factorial RCT design is best suited to evaluate the safety and efficacy of both steroids and dietary interventions in children with EoE.

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Keywords:

children; eosinophilic esophagitis; intervention; review; systematic

Supplemental Digital Content

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© 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,