Eosinophilic esophagitis (EE) is a worldwide chronic immune/antigen-driven inflammation of the esophagus manifested mainly with dysphagia and food impaction and characterized by elevated levels of eosinophils in the histopathological examination of an esophageal biopsy [1]. The clinical features of EE may differ with age; failure to thrive and food rejection are reported in young children, vomiting and food regurgitation occur in older children, while heartburn, food impaction, and dysphagia can be presented in adults [2]. EE is associated with other atopic conditions such as eczema, allergic rhinitis, and asthma [3, 4]. EE is more common in males, and can affect all ages [3]. Based on the consensus guidelines for the diagnosis of EE, a recent study conducted between 2011 and 2016 reported an incidence rate of 24 EE cases per 100,000 children per year, whereas the 5-year prevalence rate was 118 cases per 100,000 children [5]. More recently, another large cross-sectional study showed increasing incidence rates in the past 15 years, in both adults and children [6].

Unfortunately, the exact etiology of EE has not yet been clearly understood; however, most research studies support immune-mediated reactions [4]. Food allergens are considered substantial immunity triggers in the pathophysiology of EE, and the most commonly identified food allergens are dairy, soy, eggs, wheat, peanuts/treenuts, and fish/seafood. The six food elimination diet (SFED) approach relies on eliminating these specific food allergens [7, 8]. Moreover, environmental allergens have also been involved in the incidence of EE [9], and this has been emphasized by a large, recently conducted cohort study [10, 11]. A recently updated worldwide consensus diagnostic criteria for EE states that EE should be diagnosed when there are symptoms of esophageal dysfunction beside at least 15 eosinophils per high-power field (eos/hpf) on esophageal biopsy and after a thorough assessment of other non-EE disorders that could potentially be attributed to esophageal eosinophilia [12]. Proton pump inhibitors (PPIs), which are commonly used to diagnose EE by ruling out gastroesophageal reflux disease (GERD) [2], are, according to this updated evidence, better classified as a treatment of esophageal eosinophilia that may be due to EE rather than as a diagnostic criterion for EE [12]. The biopsy can detect eosinophils in the superficial epithelium, and more than 15 or 20 eos/hpf is confirmative [13]; recent guidelines report that 15 eos/hpf is the cut-off point of EE diagnosis [12]. Various endoscopic scoring systems are being developed as endoscopic outcome measures to identify individuals with EE and to follow their response to treatment; the Endoscopic Reference Score (EREFS) is a validated system used for initial diagnosis and treatment follow-up of EE [14]. Esophageal diseases, especially EE, can be assessed by the means of patient-related outcome (PRO) and clinician-reported outcome (ClinRO) measures. PRO incorporates various measures of symptom severity, functioning (disability), health status, health-specific quality of life, ‘general’ quality of life, and general health perceptions [15, 16]. Various PRO instruments have been developed and validated for the assessment of EE—especially clinical response to treatment, including the Eosinophilic Esophagitis Activity Index (EEsAI) and Dysphagia Symptom Questionnaire (DSQ). Several factors are incorporated in the EEsAI tool that assess dysphagia, behavioral adaptation to dysphagia, and pain with swallowing [17], while the DSQ has been shown to be content valid and is currently being further evaluated in a number of trials [16].

The current approaches to the management of EE comprise dietary elimination, endoscopy, and corticosteroids [18]. Although specific food elimination may be safe and efficacious, patient compliance is an issue [2]. While both approaches (pharmacological and food elimination diet) seem promising in managing EE, a recent meta-analysis concluded that both approaches have the same magnitude of histologic and symptomatic response [19]; however, the effectiveness of food elimination should be tempered by the absence of a randomized study and the potential challenges of adherence to such diets [20, 21]. It has also been reported that a food elimination diet is expensive, not palatable, and associated with marked weight loss, and thus results in high rates of dropout and non-compliance [22]. In 2002, a study revealed the ability of skin prick testing and patch testing to identify potential causative foods that might attribute to the pathogenesis of EE [23]. Later, it was reported that dietary management can benefit EE patients without the need for skin tests [24]. More recently, the use of skin-patch testing in food-related allergic disease per se has been questioned, and it was reported that such tests—disliked by both patients and clinicians—should not be used in EE [25]. In some cases, it may be necessary to remove the impacted food and dilate the esophagus via endoscopy; however, this carries the risk of perforation [3]. Thus, medical treatment with PPIs, which are effective remedies with few risks and low costs, should be considered first. Also, corticosteroids, specifically budesonide and fluticasone, which can inhibit maturation and activation of eosinophils through suppression of the release of their stimulating cytokines, have been proven effective in managing EE [26]. A network meta-analysis in 2016 deduced no statistically significant difference between PPIs and corticosteroids; however, their inferences were limited by the risk of bias and the small number of study participants [27]. In the same year, a meta-analysis of randomized controlled trials (RCTs) reported corticosteroids as having a promising role in histological remission of EE, but not a comparable role in relieving the clinical complaints [28]. However, there are contradictory results from recent RCTs, in which budesonide induced improvement of clinical symptoms as well as significant histological remission [29, 30]. Moreover, the previous systematic reviews and meta-analysis [27, 28] did not include non-randomized studies and only pooled the RCTs as a well-designed study, whereas it has been recommended that these studies not be excluded from meta-analysis [31]. Therefore, we aimed to conduct an updated large-scale systematic review and meta-analysis of randomized and non-randomized studies to assess the efficacy and safety of budesonide in the treatment of EE in both adults and children.