CONTEXT:

Treatment of eosinophilic esophagitis (EoE) is focused on dietary, pharmacologic, and endoscopic therapy options. Within the pharmacologic alternatives, topical corticosteroids are the most used, and a large number of studies evaluating their effectiveness have been published, requiring a new summary of evidence.

OBJECTIVE:

To evaluate the histologic and clinical effectiveness of the use of corticosteroids in pediatric patients with a diagnosis of EoE.

DATA SOURCES:

Cochrane Central Register of Controlled Trials, Medline, Embase, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, Latin American and Caribbean Health Sciences Literature, and ClinicalTrials.gov (June 2019).

STUDY SELECTION:

We selected randomized controlled trials assessing corticosteroids versus a placebo or dietary treatment of EoE in children.

DATA EXTRACTION:

Methodologic quality of evidence was evaluated by using the Cochrane Collaboration’s risk of bias tool and the Grading of Recommendations Assessment, Development, and Evaluation system. The primary outcomes were clinical and histologic improvement.

RESULTS:

A total of 1655 studies were identified. Five studies were included (206 patients). Histologic response was 49.25% in the corticosteroids group and 4.16% in the placebo group (risk ratio 11.05 [confidence interval 3.8–32.15]; P < .0001). Symptomatic response was 33.6% in the corticosteroids group and 21.8% in the control group (risk ratio 1.62 [confidence interval 0.94–2.79]; P = .08). There were no major adverse effects.

LIMITATIONS:

Heterogeneity of the diagnosis of EoE.

CONCLUSIONS:

Our review revealed favorable results of corticosteroids versus placebo, mainly in histologic response. More studies are needed, by using validated clinical scores, to obtain more reliable results.

Eosinophilic esophagitis (EoE) is a chronic esophageal, immuno-antigen–mediated disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophilic infiltration, with a count of ≥15 eosinophils per high-power field (HPF).1  It is the second most prevalent cause of chronic esophagitis, after gastroesophageal reflux disease (GERD).2 

The incidence of EoE has increased and varies widely from 1 to 20 new cases per 100 000 inhabitants per year. The prevalence is currently estimated at 57 cases per 100 000 inhabitants,3  and it is more common in male patients than in female patients.2  The pathophysiology includes genetic and environmental factors, food antigens, and aeroallergens.4  The diagnosis also implies the elimination of other causes of esophageal eosinophilia, such as GERD.1  However, it has been recently recommended that the response to proton pump inhibitors (PPIs) should not be used as an exclusion criterion for diagnosis,5  but data on this topic are limited in children.2,6 

The symptoms of EoE vary with age (vomiting, eating disorders, and failure to thrive in infants and preschool-aged children; dysphagia, food impaction, and heartburn in older children and adolescents).7  It should be noted that a high percentage of patients may manifest respiratory symptoms, such as cough and sleep disorders.8  Patients with a diagnosis of EoE have a higher prevalence of rhinitis, asthma, and eczema than the general population.9 

The treatment of EoE includes dietary and pharmacologic measures and endoscopic therapies for complications. The 6-food elimination diet is the most frequently employed dietary therapy, which includes the exclusion of wheat, milk, egg, nuts, soy, fish, and shellfish.10  Topical corticosteroids are one of the most reported pharmacologic measures in the literature.11  Other therapies include the use of antihistamines, immunomodulators, and biological drugs, but the data are limited.2,5,12  The natural history of the disease without treatment could lead to food impaction, perforation, malnutrition, and esophageal stenosis in adults.4,13  In addition, EoE may have a profound effect on the quality of life, including sleeping difficulties, depression, and school problems.14,15 

The majority of pharmacologic and dietary interventions are focused on the reduction of eosinophilic infiltration of the esophagus. Corticosteroids decrease fibrosis16  and increase the interleukin 13 level, acting as an immunomodulator of the allergic response4  as well as in the eosinophil apoptosis pathway.17  Topical corticosteroids decrease esophageal infiltration by eosinophils, mast cells, and lymphocytes.18 

Thus, corticosteroids could be considered as a treatment pillar; they are widely available and there is evidence to support their use. However, some randomized controlled trials (RCTs) are less conclusive in symptomatic response, and in several new RCTs, researchers have tried to analyze the effectiveness of this therapy. This is why it is necessary to conduct a systematic review (SR) to summarize and update the evidence available to date. In this review, we summarize the available evidence of corticosteroids in EoE. Our objective is to assess the benefits and harms of corticosteroids versus a placebo or exclusion diets for EoE in children.

In this review, we followed the Cochrane guidelines for SRs and meta-analyses. We performed a review protocol (E.M.-O, I.M.-C, M.T.O.-L, L.V, J.C.G, unpublished observations).

We included all RCTs comparing corticosteroid forms with a placebo or with dietary interventions in pediatric populations (up to 18 years old) with a diagnosis of EoE. We defined EoE-like symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa as a count of at least 15 eosinophils per HPF in the biopsy specimen, whether the patient had received a PPI previously. We excluded all RCTs without a clear methodology, studies with poorly reported or unreported outcomes, and RCTs that include patients with gastrointestinal comorbidities.

If, during the selection of trials, we identified observational studies in which authors reported adverse events caused by, or associated with, corticosteroids, these were included to examine data on adverse events (harm) only.

The primary outcomes were clinical improvement or decrease in symptoms (vomiting, abdominal pain, dysphagia, and food impaction), including different scores (eg, dysphagia symptoms scores, the EoE Activity Index, the Mayo Dysphagia Questionnaire, the Pediatric EoE Symptom Scoring System, vomiting improvement, a clinical symptoms score [CSS], a symptom screening score, a symptom scoring tool [SST], and the Dysphagia Symptoms Questionnaire [DSQ]1924 ); histologic improvement (decrease in the number of eosinophils per HPF to <15 in endoscopy); all causes of mortality and morbidity related to EoE (food impaction, perforation, malnutrition, and esophageal stenosis); and health-related quality of life (determined exclusively by means of validated scales, classifications, and measurement systems, such as the Pediatric Quality of Life Inventory, Child Health Questionnaire, and DISABKIDS25 ).

The secondary outcomes were serious and nonserious adverse events (based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guidelines for Good Clinical Practice definition of a serious adverse event).26 

We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group (CUGPDG) Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, Embase (OvidSP), and Science Citation Index Expanded (Web of Science). No language or document-type restrictions were applied. Additional references were identified by manually searching the references of articles from the computerized databases. We searched online trial registries, such as ClinicalTrials.gov, the European Medicines Agency, the World Health Organization International Clinical Trial Registry Platform, and the US Food and Drug Administration, for ongoing or unpublished trials. In addition, online trial registries were searched, and experts in the field and pharmaceutical companies were contacted to inquire about additional trials. In the Supplemental Information, we show the search strategies and the time spans of the searches. The searches were conducted on June 20, 2019.

Study Selection

Two independent reviewers (I.M.-C and E.M.-O) selected the titles according to inclusion and exclusion criteria. In case of disagreement, a third reviewer (J.C.G) resolved the differences. The review was performed according to the Cochrane regulations in the CUGPDG, and the data analysis were performed by using RevMan 5.

Data Extraction

Two authors (E.M.-O. and I.M.-C.) independently completed the data extraction form on the included studies and retrieved the following data: general information (title, journal, year, publication status, and trial design), sample size (number of participants meeting the criteria and total number screened), baseline characteristics (baseline diagnosis, age, sex, race, disease severity, and concurrent medications used), severity of EoE (different scores included; already described), all causes of mortality and morbidity, and adverse events (serious and nonserious). J.C.G. arbitrated in the event of disagreements in data extraction.

Assessment of Risk of Bias in Included Studies

We followed the recommendations of the CUGPDG to assess the risk of bias of the included trials. The different domains of bias were evaluated separately. The domains evaluated were allocation sequence generation, allocation concealment, blinding of participants and personnel, blinded outcome assessment, incomplete result data, selective outcome reporting, for-profit bias, and other detected bias. A general evaluation summary was made later by classifying the trials as high, uncertain, or low risk of bias. Two independent reviewers (I.M.-C. and E.M.-O.) assessed the risk of bias of the included trials, and a third author (J.C.G.) served as the arbitrator.

Measures of Treatment Effect

For dichotomous outcomes, we planned to calculate the risk ratio (RR) with 95% confidence interval (CI). For continuous outcomes, we planned to calculate the mean difference with 95% CI if the same scale was used in all studies to report health-related quality of life and standardized mean difference with the 95% CI if different scales were used in the studies to report health-related quality of life.

Because only one trial was found post hoc, we decided to use Fisher’s exact test for dichotomous outcomes and Student’s t test for continuous outcomes.

Dealing With Missing Data

Whenever possible, the original investigators were contacted for missing data. The trial data were analyzed by using the intention-to-treat principle.

Assessment of Heterogeneity

Heterogeneity was identified by visual inspection of the forest plots by using a standard χ2 test and a significance level of α = .1 and by considering the low power of such tests. The χ2 test was used for heterogeneity to detect between-trial heterogeneity. In addition, the degree of heterogeneity observed in the results was specifically examined with the I2 statistic,27  in which I2 values of ≥75% indicate a substantial level of heterogeneity.28 

Assessment of Reporting Biases

We planned to assess reporting biases with funnel plots of the relative risk estimates from the individual trials (plotted on a logarithmic scale) against trial size or precision (variance) or the estimators.

Data Synthesis

This SR was conducted according to the recommendations stated in the Cochrane Handbook for Systematic Reviews of Interventions.29  The statistical software Review Manager 5, provided by Cochrane, was used to analyze data and produce summary estimates of the treatment effect,30  and results of dichotomic outcomes were presented as odds ratio (OR) or RR, both with 95% CI.

Subgroup Analysis and Investigation of Heterogeneity

We planned to perform the following subgroup analyses of trials at low risk of bias compared with trials at high risk of bias: type of corticosteroids (different routes of administration, different doses, and different type of corticosteroids), types of diets, use of PPI, and clinical improvement related with histologic response and symptomatic response.

The heterogeneity of the studies was determined by using the Cochran Q test or the I2 statistic. On the basis of the results, a fixed-effect estimator was chosen when a study was homogeneous and a random effect model was chosen when a study was heterogeneous.

Summary of Findings Tables

We created a summary of findings table to present and provide information about quality of evidence and magnitude of effects of the interventions and to summarize data on outcomes using GRADEpro on histologic and symptomatic response. The certainty of a body of evidence considers within-trial risk of bias, indirectness of the evidence (population, intervention, control, and outcomes), unexplained inconsistency (heterogeneity) of results (including problems with subgroup analyses), imprecision of results, and risk of publication bias. The levels of evidence were defined as high, moderate, low, or very low.31 

Results of the Search

We identified 1655 records in the initial search; 573 were removed because they were duplicates, leaving a total of 1082 records. After reviewing the title or abstract, 1067 studies were excluded. We identified a total of 15 records; 6 of them were excluded for not meeting our inclusion criteria,12,3236  3 were excluded because data were published in a more recent study,3739  and 1 was excluded because the authors did not report complete information for analysis (Fig 1).40  The reasons for exclusion are listed in Table 1.

FIGURE 1

Study flow diagram. Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. For more information, visit www.prisma-statement.org.

FIGURE 1

Study flow diagram. Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. For more information, visit www.prisma-statement.org.

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TABLE 1

Reasons for Exclusion

Study, yReason for Exclusion
Andreae et al,12  2016 This study was conducted in the pediatric population, and the authors evaluated clinical and histologic improvement with the use of fluticasone in different schemes. However, there was no comparison with a placebo, and the study was not randomized. The option of each therapy was conducted by participants and their families. 
Oliva et al,32  2019 In this study, the clinical, endoscopic, and histologic efficacy of a 12-wk maintenance therapy of viscous oral budesonide was evaluated in patients younger than 18 y old. However, the study was not randomized, and there was no comparison with a placebo. 
Collins et al,37  2011 This study delivers results already reported in the study by Gupta et al.41  
Dellon et al,38  2015 In this study, the authors aim to determine if BOS is superior to a placebo in reducing symptoms of dysphagia and eosinophil count in adolescents and adults with EoE. The results they report are included in the study by Dellon et al,42  so this study was excluded. 
Dellon et al,36  2019 In this study, the authors only reported AEs of the population included in the study by Dellon et al.42  
Gupta et al,39  2011 In this study, the authors evaluated the efficacy and safety of BOS in different doses compared with a placebo. It is a randomized study; however, its results are the beginning of a larger and more updated study already reported within the studies included in this review.41  
Hirano et al,33  2017 This study was randomized, double-blind, and placebo controlled, and the authors evaluated safety and histologic improvement with the use of fluticasone in 2 regimens compared with a placebo. However, of a total N of 24 patients, 9 were adolescents and the rest were adults. Results were reported without subgroup analysis, so this study was excluded. 
Oliva et al,40  2018 In this study, the authors wanted to evaluate the efficacy and safety of topical corticosteroids versus diet; however, no results are reported yet. 
Schaefer et al,35  2008 In this study, the authors made a comparison between oral prednisone and topical fluticasone in the treatment of EoE, evaluating clinical and histologic responses. It was a randomized study in the pediatric population; however, no comparison was made with a placebo or diet, so it was excluded. 
Straumann et al,34  2011 This study was randomized and placebo controlled. The authors evaluated clinical and histologic response of corticosteroid use. The adult population and adolescents were included as part of the inclusion criteria; however, in the report of results, there was only a patient of 16 y, so no subgroup analysis was performed. Therefore, this study was excluded. 
Study, yReason for Exclusion
Andreae et al,12  2016 This study was conducted in the pediatric population, and the authors evaluated clinical and histologic improvement with the use of fluticasone in different schemes. However, there was no comparison with a placebo, and the study was not randomized. The option of each therapy was conducted by participants and their families. 
Oliva et al,32  2019 In this study, the clinical, endoscopic, and histologic efficacy of a 12-wk maintenance therapy of viscous oral budesonide was evaluated in patients younger than 18 y old. However, the study was not randomized, and there was no comparison with a placebo. 
Collins et al,37  2011 This study delivers results already reported in the study by Gupta et al.41  
Dellon et al,38  2015 In this study, the authors aim to determine if BOS is superior to a placebo in reducing symptoms of dysphagia and eosinophil count in adolescents and adults with EoE. The results they report are included in the study by Dellon et al,42  so this study was excluded. 
Dellon et al,36  2019 In this study, the authors only reported AEs of the population included in the study by Dellon et al.42  
Gupta et al,39  2011 In this study, the authors evaluated the efficacy and safety of BOS in different doses compared with a placebo. It is a randomized study; however, its results are the beginning of a larger and more updated study already reported within the studies included in this review.41  
Hirano et al,33  2017 This study was randomized, double-blind, and placebo controlled, and the authors evaluated safety and histologic improvement with the use of fluticasone in 2 regimens compared with a placebo. However, of a total N of 24 patients, 9 were adolescents and the rest were adults. Results were reported without subgroup analysis, so this study was excluded. 
Oliva et al,40  2018 In this study, the authors wanted to evaluate the efficacy and safety of topical corticosteroids versus diet; however, no results are reported yet. 
Schaefer et al,35  2008 In this study, the authors made a comparison between oral prednisone and topical fluticasone in the treatment of EoE, evaluating clinical and histologic responses. It was a randomized study in the pediatric population; however, no comparison was made with a placebo or diet, so it was excluded. 
Straumann et al,34  2011 This study was randomized and placebo controlled. The authors evaluated clinical and histologic response of corticosteroid use. The adult population and adolescents were included as part of the inclusion criteria; however, in the report of results, there was only a patient of 16 y, so no subgroup analysis was performed. Therefore, this study was excluded. 

Overall, 5 studies were included24,4144  for quantitative synthesis (meta-analysis), and 1 quasi-randomized pediatric study was included for report of harm only.36 

Included Studies

The characteristics of each included study are described in Table 2.

TABLE 2

Characteristics of the Included Studies

Study, yDesignPopulation Age; SettingDiagnosisInterventionHistologic Response CriteriaSymptomatic Response CriteriaAdjuvantsResults
Konikoff et al,44  2006 RCT, multicentric 3–18 y; CCHMC and Rady Children’s Hospital-San Diego >24 eosinophils per HPF in at least 1 biopsy specimen Swallowed FP 880 μg divided twice daily for 3 mo (n = 21); placebo (n = 15) <1 eosinophil per HPF in at least 1 biopsy specimen Presence of clinical symptoms PPI use during study was registered (38% in intervention group and 33% in placebo group) FP had histologic response in 10 of 21 patients (47%) in intervention group and 1 of 15 (6.6%) in control group; FP only improves vomiting 
Dohil et al,24  2010 RCT, 1 center 1–18 y; Rady Children’s Hospital-San Diego >20 eosinophils per HPF OVB 1 mg in patients <5 ft tall and 2 mg in patients >5 ft tall for 3 mo (n = 15); placebo (n = 9) Responders: 0–6 eosinophils per HPF; partial responders: 7–19 eosinophils per HPF; nonresponders: >20 eosinophils per HPF SST score = 0 (SST used to analyze heartburn or regurgitation, abdominal pain, nausea or vomiting, anorexia or early satiety, dysphagia) PPI when necessary to rule out GERD; lansoprazole in both groups; specific dietary restrictions without changes Histologic response in 13 of 15 patients in intervention group and 0 of 9 patients in control group; symptomatic response in 7 of 20 patients in intervention group and 2 of 11 patients in control group 
Butz et al,43  2014 RCT, multicentric 3–30 y (we analyzed patients <18 y); CCHMC, University of Utah, Children’s Hospital Colorado, Children’s Hospital of Philadelphia >24 eosinophils per HPF in at least 1 biopsy specimen Fluticasone 1760 μg twice daily (n = 28); placebo (n = 14) <1 eosinophil per HPF in proximal and distal esophageal biopsy specimens Presence of clinical symptoms with a semivalidated symptom score PPI for at least 2 mo or having a negative result on pH probe Histologic response in 12 of 18 patients (67%) in intervention group and 0 of 11 patients (0%) in control group; symptomatic response in 7 of 22 patients for vomiting, 4 of 22 patients for dysphagia, and 5 of 22 patients for food impaction; only vomiting reached statistical significance 
Gupta et al, 41 2015 RCT 2–18 y; Riley Hospital for Children at Indiana University Health >20 eosinophils per HPF in 2 esophageal biopsy specimens; CSS > 3 in EoE OVB 2 mg twice daily for 12 wk (n = 53); arms: low dose (n = 21), medium dose (n = 20), high dose (n = 20); placebo (n = 18) <6 eosinophils per HPF in all biopsy specimens EoE CSS = 0 at the end of the treatment (adapted symptom score used to analyze heartburn, abdominal pain, nocturnal awakening with symptoms, nausea and regurgitation, anorexia or early satiety, dysphagia or food impaction) PPI was registered; did not use response PPI as an exclusion criterion Histologic response in 23 of 53 patients in intervention group and 0 of 18 patients in control group; Symptomatic response in 12 of 53 patients in intervention group and 6 of 18 patients in control group 
Dellon et al,42  2017 RCT, multicentric 11–40 y; 25 centers throughout United States >15 eosinophils per HPF, at least 4 d with dysphagia in previous 2 wk OVB 2 mg twice daily for 12 wk (n = 18); placebo (n = 17) <6 eosinophils per HPF DSQ score = 0 and No. patients with 30% and 50% reduction in DSQ score Included only patients without histologic improvement after 8 wk of high doses of PPIs Histologic response in 8 of 18 patients in intervention group and 1 of 17 patients in control group; symptomatic response information was not available in patients <18 y after contact with SHIRE industry 
Study, yDesignPopulation Age; SettingDiagnosisInterventionHistologic Response CriteriaSymptomatic Response CriteriaAdjuvantsResults
Konikoff et al,44  2006 RCT, multicentric 3–18 y; CCHMC and Rady Children’s Hospital-San Diego >24 eosinophils per HPF in at least 1 biopsy specimen Swallowed FP 880 μg divided twice daily for 3 mo (n = 21); placebo (n = 15) <1 eosinophil per HPF in at least 1 biopsy specimen Presence of clinical symptoms PPI use during study was registered (38% in intervention group and 33% in placebo group) FP had histologic response in 10 of 21 patients (47%) in intervention group and 1 of 15 (6.6%) in control group; FP only improves vomiting 
Dohil et al,24  2010 RCT, 1 center 1–18 y; Rady Children’s Hospital-San Diego >20 eosinophils per HPF OVB 1 mg in patients <5 ft tall and 2 mg in patients >5 ft tall for 3 mo (n = 15); placebo (n = 9) Responders: 0–6 eosinophils per HPF; partial responders: 7–19 eosinophils per HPF; nonresponders: >20 eosinophils per HPF SST score = 0 (SST used to analyze heartburn or regurgitation, abdominal pain, nausea or vomiting, anorexia or early satiety, dysphagia) PPI when necessary to rule out GERD; lansoprazole in both groups; specific dietary restrictions without changes Histologic response in 13 of 15 patients in intervention group and 0 of 9 patients in control group; symptomatic response in 7 of 20 patients in intervention group and 2 of 11 patients in control group 
Butz et al,43  2014 RCT, multicentric 3–30 y (we analyzed patients <18 y); CCHMC, University of Utah, Children’s Hospital Colorado, Children’s Hospital of Philadelphia >24 eosinophils per HPF in at least 1 biopsy specimen Fluticasone 1760 μg twice daily (n = 28); placebo (n = 14) <1 eosinophil per HPF in proximal and distal esophageal biopsy specimens Presence of clinical symptoms with a semivalidated symptom score PPI for at least 2 mo or having a negative result on pH probe Histologic response in 12 of 18 patients (67%) in intervention group and 0 of 11 patients (0%) in control group; symptomatic response in 7 of 22 patients for vomiting, 4 of 22 patients for dysphagia, and 5 of 22 patients for food impaction; only vomiting reached statistical significance 
Gupta et al, 41 2015 RCT 2–18 y; Riley Hospital for Children at Indiana University Health >20 eosinophils per HPF in 2 esophageal biopsy specimens; CSS > 3 in EoE OVB 2 mg twice daily for 12 wk (n = 53); arms: low dose (n = 21), medium dose (n = 20), high dose (n = 20); placebo (n = 18) <6 eosinophils per HPF in all biopsy specimens EoE CSS = 0 at the end of the treatment (adapted symptom score used to analyze heartburn, abdominal pain, nocturnal awakening with symptoms, nausea and regurgitation, anorexia or early satiety, dysphagia or food impaction) PPI was registered; did not use response PPI as an exclusion criterion Histologic response in 23 of 53 patients in intervention group and 0 of 18 patients in control group; Symptomatic response in 12 of 53 patients in intervention group and 6 of 18 patients in control group 
Dellon et al,42  2017 RCT, multicentric 11–40 y; 25 centers throughout United States >15 eosinophils per HPF, at least 4 d with dysphagia in previous 2 wk OVB 2 mg twice daily for 12 wk (n = 18); placebo (n = 17) <6 eosinophils per HPF DSQ score = 0 and No. patients with 30% and 50% reduction in DSQ score Included only patients without histologic improvement after 8 wk of high doses of PPIs Histologic response in 8 of 18 patients in intervention group and 1 of 17 patients in control group; symptomatic response information was not available in patients <18 y after contact with SHIRE industry 

CCHMC, Cincinnati Children’s Hospital Medical Center; FP, fluticasone propionate; OVB, oral viscous budesonide.

A total of 5 RCTs that fulfilled the inclusion criteria were found. One study42  included adult and pediatric populations, so the authors were contacted to obtain the data of the patients <18 years old. The total number of patients recruited for the meta-analysis was 206.

Two studies were conducted in a single hospital medical center,41  and 3 were multicentric.4244  More details are presented in Table 2.

All the included RCTs involved children with an endoscopic diagnosis of EoE, and a minimum of 15 eosinophils per HPF in the esophageal biopsy specimen was accepted as an inclusion criterion.

Previous use of PPIs was variable between the studies. More details about this are presented in Table 2.

Some patients included in the RCTs had an exclusion diet; however, the studies did not provide sufficient information to perform subgroup analyses. Butz et al43  reported that all included patients completed 3 months of an elimination diet or refuted the diet without specifying how many patients refuted or what type of diet they had. During the study, patients were only instructed to keep the diet unchanged. Konikoff et al44  performed a food allergen prick test before starting the study. If an allergen was identified, it was excluded from the diet, and if the patient responded, he or she was not selected for the study. If the patient rejected the diet or had no response to exclusion, the diet was included in the study. Dohil et al24  only described in both groups (corticosteroids and placebo) whether the participants made any type of diet exclusion. Gupta et al41  only mentioned that if there were dietary measures, they were not modified during the study. Dellon et al42  did not refer to diets.

Two studies used fluticasone,43,44  and 3 studies used budesonide. All studies used different doses of corticosteroids and different time periods. The details of the interventions performed are described in Table 2.

In all studies, the authors considered histologic and symptomatic improvement as primary or secondary outcomes. The histologic response criteria were variable between studies. The response criteria of each study are detailed in Table 2. Regarding clinical improvement, Konikoff et al44  evaluated vomiting. Gupta et al41  considered symptomatic response using a >50% reduction in the CSS (not validated, based on a physician’s evaluation of the frequency of symptoms in the last 2 weeks); clinical resolution was considered with a CSS of 0. Butz et al43  evaluated change in the symptom screening score (semivalidated score that included questions of frequency and severity) at the beginning of the study and at 3 and 6 months. Dohil et al24  evaluated the response in symptoms using SST on the basis of average scores. Dellon et al42  used as a primary outcome change in the DSQ score.

Additionally, a randomized open-label clinical study was found in which the effects of corticosteroids on the growth of patients diagnosed with EoE were analyzed.36 

The risk of bias was assessed in each of the included studies (Table 3). Additionally, a summary was made of each element of risk of bias, presented as a percentage in all included studies (Figs 2 and 3).

TABLE 3

Risk of Bias in Each of the Included Studies

StudyRandom Sequence Generation (Selection Bias)Allocation Concealment (Selection Bias)Blinding of Participants and Personnel (Performance Bias)Blinding of Outcome Assessment (Detection Bias)Incomplete Outcome Data (Attrition Bias)Selective Reporting (Reporting Bias)Other Bias
Konikoff et al44  Low risk; quote: “A clinical research coordinator dispensed metered dose inhalers containing active drugs or placebo to each patient according to a computer-generated randomization list. No blocking or stratification schemes were used.” Low risk; all participants were blinded to the treatment allocation for the duration of the study (except the study statisticians, but they had no contact with the participants). Low risk; quote: “All participants and study staff (with the exception of the previous clinical research coordinator) were blinded to the treatment allocation for the duration of the study. Only the study statisticians had access to the data not blinded, but not they had contact with the participants.” Low risk; appropriate results (histologic remission) and primary and secondary outcomes were reported. High risk; quote: “One patient was excluded from the FP group after initiation, because this patient did not meet the inclusion criteria for the diagnosis of EoE. Four patients withdrew from the placebo group: 3 due to increased symptoms and one due to non-compliance. These 5 patients were excluded from the analysis, because they had no follow-up esophageal biopsy samples on which to base their response to treatment.” Low risk; primary and secondary outcomes were reported. At least 24 eosinophils per field were used as a diagnostic criterion, which could have caused selection bias, including patients with more serious illness. 
Dohil et al24  Low risk; quote: “Using a computer-validated random number generator (SAS Process Plan version 9.1; SAS Institute, Inc, Cary, NC), subjects were randomized 2:1 in OVB and placebo groups, respectively.” Unclear risk; quote: “Only the pharmacist had access to the randomization code.” Low risk; quote: “Doctors, pathologists, study coordinators, statisticians, and patients were blinded to treatment during the study.” Low risk; appropriate results (histologic remission) and all results were reported. High risk; quote: “The final analysis was not possible in 7 patients who withdrew from the study without repeating endoscopy. Reasons for withdrawal included acute asthma requiring systemic corticosteroids, non-compliance with therapy and adverse events (transient rash attributed to lansoprazole; patient No. 10). ” Low risk; all results were reported, including AEs. Quote: “No serious adverse events were reported in 24 people who completed the study. One patient (No. 20) developed oral candidiasis, which responded to nystatin. No esophageal candidiasis was found in follow-up esophagogastroduodenoscopy in any case.” At least 20 eosinophils per field were used as a diagnostic criterion, which could have caused selection bias. In addition, PPI response was used as an exclusion criterion when necessary without specification of this criterion. 
Butz et al43  Low risk; quote: “Randomization was performed by members of the CCHMC research pharmacy. The randomization scheme was generated using the Randomization.com website (available: http://www.randomization.com). Participants were assigned to a single treatment using a random permutated block method.” Unclear risk; quote: “The assignment sequence was known only to the CCHMC pharmacist, and the site pharmacist was aware of individual assignments only after enrolment/assignment.” Unclear risk; quote: “To keep the blind, only 1 staff member, in addition to the pharmacy staff, was not blind. This individual was not blind to the individual randomization of the participants after the first 3 months to stratify each participant during the next 3 months.” Low risk; quote: “After all the participants completed the study and the database was finalized, the team members were blinded for the data analysis.” Low risk; quote: “Five participants withdrew from the FP group during phases 1 and 2 due to prohibited medications, 2 due to the loss of the follow-up evaluation and 1 due to an adverse event (seizure of absence that was considered little likely to be related to FP). A participant from the placebo group was lost in the follow-up evaluation during phase 1.” Unclear risk: All results, including AEs, are reported. However, the reason for considering only 26 studies in the intermediate analysis is unclear. Quote: “An intermediate analysis was added to the study after the start. The intermediate analysis was performed using the 3-month remission status for 26 participants (60% of the sample size).” This study used at least 24 eosinophils per field as a criterion, which could cause selection bias when choosing patients with more severe disease. In addition, it included patients who completed 3 mo of an elimination diet but also those without diet. 
Gupta et al41  Unclear risk: it is mentioned that the study is randomized, but the method of randomization is not explained. Quote: “Subjects were randomized to 1 of 4 treatment groups…(placebo, low dose BOS, medium dose BOS or high dose BOS) in a 1:1:1:1 ratio; randomization was stratified by group of age (2–9 and 10–18 years).” High risk: not mentioned; the authors say that both the placebo and the active formulation had similar presentation, but they do not explain who really were blind from the selection. Unclear risk: it is clear to patients, but it is not clear to staff. Quote: “Placebo was a viscous liquid similar in appearance and taste to the active medication of the study, a proprietary formulation containing budesonide. The subjects received placebo and/or active study medication twice a day for 12 weeks.” The authors also refer to the pathologist as a blind participant. Unclear risk: it is clear for endoscopic evaluation, but it is not clear for a symptom score. Quote: “The histological response was based on the review of esophageal biopsies by the same central pathologist who was blinded to the treatment group of the subject. The score is based on a physician’s evaluation of the frequency and disruption of multiple symptoms within 6 categories.” Low risk; quote: “The complete analysis set, defined as all subjects who received at least 1 dose of the study drug and had biopsies after the start of at least 2 esophageal levels and a CSS EoE after the start, was used to determine the response to treatment; this included subjects who completed and did not complete the treatment period (that is, they received ≥77 days of study medication).” Low risk: all results were reported, including AEs. At least 20 eosinophils per field were used as a diagnostic criterion, which could have caused selection bias. 
Dellon et al42  Low risk: the randomization program was generated by SynteractHCR, Inc, and its accuracy was verified by using strict quality control procedures. Unclear risk: quote: “The allocation of treatment was not blinded in the situation in which non-blinding was absolutely necessary for the management of patient safety or for purposes of regulatory reports to the FDA.” Low risk: quote: “Participants researchers, sponsor, study site staff, and central pathologist were blinded to patient treatment, until after all patients had completed the treatment period and database stay locked.” Low risk: appropriate results (histologic remission) and all results were reported. Unclear risk: 5 patients dropped out, 2 in the budesonide arm (1 because of an AE and 1 because of lack of compliance) and 3 in the placebo arm (1 for lack of efficacy, 1 for lack of compliance, and 1 because of pregnancy). Therefore, 87 were included in the result analysis set (49 in BOS arm and 38 in placebo arm). Low risk: all results were reported, including AEs. This study used established diagnostic criteria. 
StudyRandom Sequence Generation (Selection Bias)Allocation Concealment (Selection Bias)Blinding of Participants and Personnel (Performance Bias)Blinding of Outcome Assessment (Detection Bias)Incomplete Outcome Data (Attrition Bias)Selective Reporting (Reporting Bias)Other Bias
Konikoff et al44  Low risk; quote: “A clinical research coordinator dispensed metered dose inhalers containing active drugs or placebo to each patient according to a computer-generated randomization list. No blocking or stratification schemes were used.” Low risk; all participants were blinded to the treatment allocation for the duration of the study (except the study statisticians, but they had no contact with the participants). Low risk; quote: “All participants and study staff (with the exception of the previous clinical research coordinator) were blinded to the treatment allocation for the duration of the study. Only the study statisticians had access to the data not blinded, but not they had contact with the participants.” Low risk; appropriate results (histologic remission) and primary and secondary outcomes were reported. High risk; quote: “One patient was excluded from the FP group after initiation, because this patient did not meet the inclusion criteria for the diagnosis of EoE. Four patients withdrew from the placebo group: 3 due to increased symptoms and one due to non-compliance. These 5 patients were excluded from the analysis, because they had no follow-up esophageal biopsy samples on which to base their response to treatment.” Low risk; primary and secondary outcomes were reported. At least 24 eosinophils per field were used as a diagnostic criterion, which could have caused selection bias, including patients with more serious illness. 
Dohil et al24  Low risk; quote: “Using a computer-validated random number generator (SAS Process Plan version 9.1; SAS Institute, Inc, Cary, NC), subjects were randomized 2:1 in OVB and placebo groups, respectively.” Unclear risk; quote: “Only the pharmacist had access to the randomization code.” Low risk; quote: “Doctors, pathologists, study coordinators, statisticians, and patients were blinded to treatment during the study.” Low risk; appropriate results (histologic remission) and all results were reported. High risk; quote: “The final analysis was not possible in 7 patients who withdrew from the study without repeating endoscopy. Reasons for withdrawal included acute asthma requiring systemic corticosteroids, non-compliance with therapy and adverse events (transient rash attributed to lansoprazole; patient No. 10). ” Low risk; all results were reported, including AEs. Quote: “No serious adverse events were reported in 24 people who completed the study. One patient (No. 20) developed oral candidiasis, which responded to nystatin. No esophageal candidiasis was found in follow-up esophagogastroduodenoscopy in any case.” At least 20 eosinophils per field were used as a diagnostic criterion, which could have caused selection bias. In addition, PPI response was used as an exclusion criterion when necessary without specification of this criterion. 
Butz et al43  Low risk; quote: “Randomization was performed by members of the CCHMC research pharmacy. The randomization scheme was generated using the Randomization.com website (available: http://www.randomization.com). Participants were assigned to a single treatment using a random permutated block method.” Unclear risk; quote: “The assignment sequence was known only to the CCHMC pharmacist, and the site pharmacist was aware of individual assignments only after enrolment/assignment.” Unclear risk; quote: “To keep the blind, only 1 staff member, in addition to the pharmacy staff, was not blind. This individual was not blind to the individual randomization of the participants after the first 3 months to stratify each participant during the next 3 months.” Low risk; quote: “After all the participants completed the study and the database was finalized, the team members were blinded for the data analysis.” Low risk; quote: “Five participants withdrew from the FP group during phases 1 and 2 due to prohibited medications, 2 due to the loss of the follow-up evaluation and 1 due to an adverse event (seizure of absence that was considered little likely to be related to FP). A participant from the placebo group was lost in the follow-up evaluation during phase 1.” Unclear risk: All results, including AEs, are reported. However, the reason for considering only 26 studies in the intermediate analysis is unclear. Quote: “An intermediate analysis was added to the study after the start. The intermediate analysis was performed using the 3-month remission status for 26 participants (60% of the sample size).” This study used at least 24 eosinophils per field as a criterion, which could cause selection bias when choosing patients with more severe disease. In addition, it included patients who completed 3 mo of an elimination diet but also those without diet. 
Gupta et al41  Unclear risk: it is mentioned that the study is randomized, but the method of randomization is not explained. Quote: “Subjects were randomized to 1 of 4 treatment groups…(placebo, low dose BOS, medium dose BOS or high dose BOS) in a 1:1:1:1 ratio; randomization was stratified by group of age (2–9 and 10–18 years).” High risk: not mentioned; the authors say that both the placebo and the active formulation had similar presentation, but they do not explain who really were blind from the selection. Unclear risk: it is clear to patients, but it is not clear to staff. Quote: “Placebo was a viscous liquid similar in appearance and taste to the active medication of the study, a proprietary formulation containing budesonide. The subjects received placebo and/or active study medication twice a day for 12 weeks.” The authors also refer to the pathologist as a blind participant. Unclear risk: it is clear for endoscopic evaluation, but it is not clear for a symptom score. Quote: “The histological response was based on the review of esophageal biopsies by the same central pathologist who was blinded to the treatment group of the subject. The score is based on a physician’s evaluation of the frequency and disruption of multiple symptoms within 6 categories.” Low risk; quote: “The complete analysis set, defined as all subjects who received at least 1 dose of the study drug and had biopsies after the start of at least 2 esophageal levels and a CSS EoE after the start, was used to determine the response to treatment; this included subjects who completed and did not complete the treatment period (that is, they received ≥77 days of study medication).” Low risk: all results were reported, including AEs. At least 20 eosinophils per field were used as a diagnostic criterion, which could have caused selection bias. 
Dellon et al42  Low risk: the randomization program was generated by SynteractHCR, Inc, and its accuracy was verified by using strict quality control procedures. Unclear risk: quote: “The allocation of treatment was not blinded in the situation in which non-blinding was absolutely necessary for the management of patient safety or for purposes of regulatory reports to the FDA.” Low risk: quote: “Participants researchers, sponsor, study site staff, and central pathologist were blinded to patient treatment, until after all patients had completed the treatment period and database stay locked.” Low risk: appropriate results (histologic remission) and all results were reported. Unclear risk: 5 patients dropped out, 2 in the budesonide arm (1 because of an AE and 1 because of lack of compliance) and 3 in the placebo arm (1 for lack of efficacy, 1 for lack of compliance, and 1 because of pregnancy). Therefore, 87 were included in the result analysis set (49 in BOS arm and 38 in placebo arm). Low risk: all results were reported, including AEs. This study used established diagnostic criteria. 

CCHMC, Cincinnati Children’s Hospital Medical Center; FDA, US Food and Drug Administration; FP, fluticasone propionate; OVB, oral viscous budesonide.

FIGURE 2

Risk of bias graph: review authors’ judgements about feach risk of bias item presented as percentages across all included studies.

FIGURE 2

Risk of bias graph: review authors’ judgements about feach risk of bias item presented as percentages across all included studies.

Close modal
FIGURE 3

Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

FIGURE 3

Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

Close modal

The results are detailed in Figs 411.

FIGURE 4

Corticosteroids versus placebo: histologic response. df, degree of freedom; M-H, Mantel-Haenszel.

FIGURE 4

Corticosteroids versus placebo: histologic response. df, degree of freedom; M-H, Mantel-Haenszel.

Close modal
FIGURE 5

Corticosteroids versus placebo: symptomatic response. df, degree of freedom; M-H, Mantel-Haenszel.

FIGURE 5

Corticosteroids versus placebo: symptomatic response. df, degree of freedom; M-H, Mantel-Haenszel.

Close modal
FIGURE 6

Budesonide versus placebo: histologic response. df, degree of freedom; M-H, Mantel-Haenszel.

FIGURE 6

Budesonide versus placebo: histologic response. df, degree of freedom; M-H, Mantel-Haenszel.

Close modal
FIGURE 7

Budesonide versus placebo: symptomatic response. df, degree of freedom; M-H, Mantel-Haenszel.

FIGURE 7

Budesonide versus placebo: symptomatic response. df, degree of freedom; M-H, Mantel-Haenszel.

Close modal
FIGURE 8

Fluticasone versus placebo: histologic response. df, degree of freedom; M-H, Mantel-Haenszel.

FIGURE 8

Fluticasone versus placebo: histologic response. df, degree of freedom; M-H, Mantel-Haenszel.

Close modal
FIGURE 9

Fluticasone versus placebo: symptomatic response (dysphagia). M-H, Mantel-Haenszel.

FIGURE 9

Fluticasone versus placebo: symptomatic response (dysphagia). M-H, Mantel-Haenszel.

Close modal
FIGURE 10

Fluticasone versus placebo: symptomatic response (food impaction). M-H, Mantel-Haenszel.

FIGURE 10

Fluticasone versus placebo: symptomatic response (food impaction). M-H, Mantel-Haenszel.

Close modal
FIGURE 11

Fluticasone versus placebo: symptomatic response (vomiting). df, degree of freedom; M-H, Mantel-Haenszel.

FIGURE 11

Fluticasone versus placebo: symptomatic response (vomiting). df, degree of freedom; M-H, Mantel-Haenszel.

Close modal

Symptomatic Response

Symptomatic response was 33.6% in the corticosteroids group (39 of 116) and 21.8% in the control group (12 of 55) (RR 1.62; CI 0.94–2.79).

In the subgroup analysis, by type of corticosteroid, 2 studies were identified that compared budesonide against a placebo.24,41  In the first study,24  the most frequent symptoms were dysphagia, vomiting, abdominal pain, and regurgitation. In the intervention group, the CSS decreased from 3.5 to 1.2 after treatment, and in the placebo group, the decrease was from 2.7 to 1.8. The main decrease was in the symptoms of intestinal regurgitation and intestinal bleeding; however, the symptoms of dysphagia, vomiting, and abdominal pain had no significant difference between the 2 groups. Of 20 patients, 7 (35%) showed symptomatic improvement in the intervention group (score of clinical symptoms: 0), compared with 2 of 11 patients in the placebo group (18.18%). In one study,41  6 of 18 (33.3%) patients had a symptomatic response to the placebo, whereas in the intervention group, 12 of 53 (22.6%) patients had a symptomatic response.

The analysis was performed with a total of 102 patients; 19 of 73 (26%) had a symptomatic response in the intervention group, compared with 8 of 29 (27.5%) in the control group (RR 0.98 [CI 0.37–2.64]; P = .97), and this result had no statistical significance.

In 2 studies totaling 69 patients, fluticasone response versus a placebo in children was analyzed.43,44  Of those patients, 20 of 43 (46.5%) in the intervention group had a symptomatic response when vomiting was analyzed, compared with 4 of 26 (15.38%) in the control group, and this result was statistically significant (RR 3.21 [CI 1.24–8.27]; P = .02). In only 1 study43  were other symptoms, such as dysphagia and food impaction, reported: 4 of 22 patients (18.18%) in the fluticasone group and 4 of 11 (36.3%) patients in the control group reported decreased dysphagia (RR 0.5 [CI 0.15–1.63]; P = .25), whereas 5 of 22 patients (22.7%) in the fluticasone group and 1 of 11 patients (9%) in the control group reported a decrease in food impaction (RR 2.5 [CI 0.33–18.87]; P = .37); however, neither result reached statistical significance.

Histologic Response

Histologic response was 49.25% (66 of 134) in the corticosteroids group and 4.16% (3 of 72) in the placebo group (RR 11.05 [CI 3.8–32.15]; P < .0001).

Overall, 3 trials were identified in which budesonide was compared with a placebo. A total of 130 patients were included in the analysis. Forty-four of 86 patients (51%) had a histologic response in the intervention group, and 1 of 44 patients (2.27%) had a histologic response in the control group (RR 12.75 [CI 3.08–52.85]; P = .0005).

In 2 RCTs totaling 65 patients, fluticasone was compared with a placebo.43,44  Twenty-two of 39 patients (56%) had a histologic response in the intervention group, compared with 1 of 26 patients (3.8%) in the control group (RR 10.14 [CI 2.06–49.676]; P = .004). Both therapies had statistically significant results.

FIGURE 12

Corticosteroids compared with placebo for EoE in children: GRADE evidence profile and summary of findings table. a The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

FIGURE 12

Corticosteroids compared with placebo for EoE in children: GRADE evidence profile and summary of findings table. a The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

Close modal

Adverse Effects

Dohil et al24  reported 1 patient (5%) who developed oral candidiasis that responded to nystatin. There were no differences between mean morning cortisol levels before and after treatment. Konikoff et al44 reported that 1 patient (4.7%) in the fluticasone propionate group developed esophageal candidiasis. Gupta et al41  found that pyrexia and cough were the most common adverse effects (AEs) in the treatment group. A severe AE occurred in a subject of the high-dose budesonide oral suspension (BOS) group, but it was evaluated as not related to the study medication. Two (3.3%) subjects treated with BOS experienced oropharyngeal or esophageal candidiasis. The average cortisol values were within the reference ranges for each treatment group at all evaluation points, except 1 patient from the low-dose BOS group who had a cortisol value below the reference range. Small dose-related increases in systolic and diastolic blood pressure were also reported in the BOS groups. In the study by Butz et al,43  1 participant (4.5%) reported oral thrush at the 3-month study visit, which spontaneously resolved. Instances of decreased cortisol levels were reported as AEs, but the decreased cortisol level events between the fluticasone propionate and placebo groups were not significant. Dellon et al42  reported a serious AE in the BOS group related to an episode of food poisoning; thus, it was not considered to be related to the study medication. A second AE in the BOS group, which was considered to be related to the study drug, led to withdrawal due to chest pain, dyspnea, nausea, and vomiting. Rhinopharyngitis, upper respiratory tract infection, and oropharyngeal pain were the most frequently reported AEs in both groups. There was a case of esophageal candidiasis and oral candidiasis in the BOS group. There were no notable differences between the groups in cortisol levels or growth characteristics for patients aged <18 years.

Finally, a study that was only used to report growth effects36  revealed an annual growth rate of 5.9 cm on average, with an SD of 7.8, for the group that used the placebo in the first stage and swallowed budesonide in the second stage and an annual growth rate of 3.6 cm on average, with an SD of 5.0, for the group that swallowed budesonide in both stages (patients <18 years of age).

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evaluation of this study revealed a moderate certainty of the evidence for all the main outcomes (Fig 12), so a favorable result of corticosteroids could be concluded. The risk of bias was low to moderate (Fig 4).

Corticosteroids are the treatment of choice for histologic response; however, the different clinical studies have been less clear in revealing symptomatic response. In this review, we only included the pediatric population to analyze this group and its behavior regarding the symptomatic response.

Our study revealed that corticosteroids have a statistically significant histologic response; however, this was not replicated in the symptomatic outcome. These results are similar to those reported in an SR in 201645 in which complete histologic remission in children with EoE was reported (OR 14.83; 95% CI 3.18–69.19). In that review, the authors also reported clinical improvement but without statistical significance (OR 3.54; 95% CI 0.89–14.09). One possible explanation for the differences in histologic and symptomatic response is the fact that the studies used different criteria to consider symptomatic response; some of them (the budesonide RCT) used CSSs, and others (the fluticasone RCT) analyzed for each symptom. There are many scores to assess clinical response in the literature; among them is the activity index of EoE, created in the adult population, which focuses on the symptom dysphagia. There is also the Mayo Dysphagia Questionnaire, a validated scoring system originally created for esophageal stenosis.46  Nevertheless, there is no consensus on what score to use for the evaluation of these patients, so the different scores used in the included studies were included.

One of the main limitations of this work is the heterogeneity of the diagnosis of EoE, with up to a minimum of 24 eosinophils per HPF considered. This could determine the exclusion of patients of lower severity in the studies, which would influence selection bias. In a review in 2018 an eosinophil count of >15 eosinophils per HPF was determined as a diagnostic criterion.46  However, although this threshold is already determined, this level is somewhat arbitrary, and the lack of a standardized diameter for the larger field in microscopes could lead to variations in the determination of eosinophil density.46 

On the other hand, the inclusion of the use of PPIs before diagnosis was not used uniformly in the studies, being used only in some cases and without information on the clinical response of these patients compared with those who did not use PPIs. In the latter case, the inclusion of patients with more serious illness who did not respond to any previous therapy could be determined. However, this point is in question. The latest guidelines indicate that up to 50% of patients who meet all the criteria of EoE would respond to PPIs; as such eliminating it as an exclusion criterion could be considered.5,6  Regarding the use of PPIs as first-line medical treatment, although we did not find RCTs of PPIs versus corticosteroids, we consider that patients should not receive a PPI as the only treatment until new evidence reveals the opposite.

Another limitation of the study was the wide variability in the exclusion diet criteria in the participants. One study was only limited to describe whether participants used some type of exclusion diet,24  whereas another excluded those patients who responded to the food exclusion diet after an allergen was identified in a prick test.44 However, some studies also included those patients who refuted the diet43,44  without being able to verify whether they responded to the exclusion of some foods. In another study,42  diet was not mentioned. This situation could have caused a patient selection bias, in which patients of lower severity, who could have responded only to dietary measures, were selected. In addition, the included studies used different treatment regimens in dose, frequency, and time. This is another limitation of our study.

In addition, it is important to mention that only 1 study compared systemic versus topical corticosteroids in children. This open-label study revealed similar results in clinical symptoms, but the systemic corticosteroids were better than topical corticosteroids in histologic improvement. However, patients in the first group had significantly more AEs. Considering all the evidence available to date, we suggest that topical corticosteroids be the first option in children with EoE.35 

Finally, although the selection of studies was rigorous and the pediatric population was reduced, the trials were at low-moderate risk of bias, and the sample sizes allowed for estimating of risks with adequate precision in symptomatic response. When we analyzed the histologic response, we noticed less precision in the sample; however, the evidence revealed a clear effect in favor of the corticosteroid group, so we consider that the sample is representative. However, more RCTs in pediatric population in this topic are needed.

Our review revealed favorable results for the use of corticosteroid versus placebo interventions, mainly in histologic response.

The GRADE evaluation of this study revealed a moderate certainty of the evidence for all the main outcomes, so a favorable result of corticosteroids could be concluded. The risk of bias was low to moderate, so the results should be interpreted with caution. However, considering all of the above, we can recommend the use of corticosteroids in patients with EoE because the benefit of their use would outweigh the risks.

More studies in pediatric population are needed, ideally with clinical evaluation by using validated and standardized scores, to obtain more reliable results.

Drs Munoz-Osores and Maldonado-Campos conceptualized and designed the study, analyzed data, drafted the manuscript, and reviewed and revised the manuscript; Ms Olivares-Labbe conceptualized and designed the study, conducted the literature search, and reviewed and revised the manuscript; Dr Villarroel designed the data collection instruments, analyzed data, and reviewed and revised the manuscript; Dr Gana conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

     
  • AE

    adverse effect

  •  
  • BOS

    budesonide oral suspension

  •  
  • CENTRAL

    Cochrane Central Register of Controlled Trials

  •  
  • CI

    confidence interval

  •  
  • CSS

    clinical symptoms score

  •  
  • CUGPDG

    Cochrane Upper Gastrointestinal and Pancreatic Diseases Group

  •  
  • DSQ

    Dysphagia Symptoms Questionnaire

  •  
  • EoE

    eosinophilic esophagitis

  •  
  • GERD

    gastroesophageal reflux disease

  •  
  • GRADE

    Grading of Recommendations Assessment, Development, and Evaluation

  •  
  • HPF

    high-power field

  •  
  • OR

    odds ratio

  •  
  • PPI

    proton pump inhibitor

  •  
  • RCT

    randomized controlled trial

  •  
  • RR

    risk ratio

  •  
  • SR

    systematic review

  •  
  • SST

    symptom scoring tool

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

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