
==== Front
Saudi J Gastroenterol
Saudi J Gastroenterol
SJG
Saudi J Gastroenterol
Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association
1319-3767
1998-4049
Wolters Kluwer - Medknow India

38752302
SJG-30-210
10.4103/sjg.sjg_50_24
Review Article
Eosinophilic esophagitis: Current concepts in diagnosis and management
Alsohaibani Fahad I. 1
Peedikayil Musthafa C. 1
Alzahrani Mohammed A. 2
Azzam Nahla A. 3
Almadi Majid A. 3
Dellon Evan S. 4
Al-Hussaini Abdulrahman A. 5
1 Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Department of Medicine, King Khalid University, Abha, Saudi Arabia
3 Division of Gastroenterology, Department of Medicine, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
4 Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, USA
5 Division of Pediatric Gastroenterology, Children’s Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Address for correspondence: Dr. Fahad I. Alsohaibani, Department of Medicine MBC # 46, King Faisal Specialist Hospital and Research Center, P.O BOX 3354. Riyadh 11211, Saudi Arabia. E-mail: alsohaibani@hotmail.com
Jul-Aug 2024
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03 2 2024
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Copyright: © 2024 Saudi Journal of Gastroenterology
2024
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Eosinophilic esophagitis is an antigen-mediated chronic inflammatory disorder that has risen in incidence and prevalence over the past 2 decades. The clinical presentation is variable and consists of mainly esophageal symptoms such as dysphagia, heartburn, food impaction, and vomiting. Current management relies on dietary elimination, proton-pump inhibitors, and topical corticosteroids with different response rates and relapses after treatment discontinuation. With a better understanding of the underlying pathophysiology, many molecules emerged recently as targeted treatment including dupilumab (IL4/IL13 blocker), as the first FDA-approved biological treatment, which has changed the management paradigm.

Eosinophilic esophagitis
dupilumab
dysphagia
food impaction
proton-pump inhibitor
swallowed steroids
==== Body
pmcINTRODUCTION

Eosinophilic esophagitis (EoE) is a chronic, progressive immune-mediated type 2 (T-helper cell) inflammatory condition, characterized clinically by symptoms related to esophageal dysfunction such as dysphagia and food impaction and histologically by predominant eosinophilic infiltrate of the esophageal mucosa, with subsequent development of fibrosis which could progress and affect the quality of life. EoE is a clinicopathological entity that has been an area of research for the past 20 years. Over the past 2 decades, emerging literature has improved the understanding of the epidemiology and pathogenesis of EoE, in turn leading to better diagnostic and therapeutic options.[123] In this article, we highlight the current diagnostic and treatment modalities for EoE.

EPIDEMIOLOGY

EoE was first reported in 1978 and then characterized as a clinicopathologic entity in 1993. Since 2000, the number of publications increased dramatically [Figure 1].[456] The incidence and prevalence of EoE have risen rapidly in the last 2 decades.[7891011] The pooled incidence rate of EoE in North America and Europe is 3.7/100,000 patient years (95% confidence interval (CI) 1.7–6.5) with an estimated overall pooled prevalence of 22.7/100,000 (95% CI: 12.4–36.0).[1213]

Figure 1 Number of publications of EoE between 1978 and 2022

The first report of EoE from Saudi Arabia was in 2009, and since then, several reports were published.[14151617181920] Local data on EoE showed epidemiological similarities to North America and Europe such as male predominance (80–100%), increasing incidence, and most patients having concomitant atopic diseases (60–90%). Interestingly, a study of 42 pediatric Saudi patients with dysphagia during the period from 1993 to 2002 found no cases of EoE.[21] The subsequent rise in EoE in the Saudi community since then may be related to the concurrent rise in the prevalence of other atopic diseases (such as asthma, atopic dermatitis, and rhinitis) (17–43%), which is comparable or even higher than that reported in other industrialized countries.[2223] The increase in EoE and atopic diseases in the Saudi community suggests that environmental factors drive this change in epidemiology, but the underlying reason remains speculative. Saudi Arabia has witnessed significant economic prosperity over the past 30 years and changes toward Western lifestyle, especially related to improved hygienic standards, dietary habits, and medical practices that might alter the gut microbiota such as overuse/misuse of antibiotics during early childhood, lack of breastfeeding, and increased rates of cesarean sections, all of which have been linked to the rise in EoE incidence.[242526]

PATHOGENESIS

EoE is a T-helper-mediated type-2 chronic inflammatory condition of the esophagus.[27] Although there is a genetic susceptibility associated with the disease, as manifested in monozygotic and dizygotic twin studies, it appears that environmental factors play a larger role.[272829] Nonetheless, several genes have been identified to be associated with EoE including TSLP, STAT6, EMSY, and CAPN14.[272930] The tight junctions between the epithelial cells of the esophageal mucosa are an important factor in maintaining the integrity of the barrier function, which limits the exposure to antigens and pathogens from the esophageal lumen [Figure 2]. Alterations in this barrier function expose immune cells to allergens and trigger an immune response that is responsible for the pathogenesis of EoE. Factors affecting barrier function include increased protease activity, decreased junctional proteins, increased cellular proliferation causing basal cell hyperplasia, and decreased differentiation of cells.

Figure 2 EoE is a chronic inflammatory condition of the esophagus which is allergen-driven, and its manifestation varies with age and could be provoked by either ingested food allergens or inhaled locally deposited aeroallergens. Although there is a genetic predisposition, environmental factors appear to have a larger role. Impaired epithelial barrier function with increased proteas activity, decreased junctional proteins, increased cellular proliferation (basal cell hyperplasia), and decreased differentiation. There is also an immune dysregulation with an increase in eosinophils, basophils, mast cells, and Th2 lymphocytes and an increase in IL-4, IL-5, and IL-13. These factors, in addition to the enhanced expression of TGF-β, result in activation of fibroblasts in the lamina propria, collagen deposition, and tissue stiffness. CCL 26: encodes eotaxin-3, CD4: cluster of differentiation 4, IL: interleukin, TGF-β: transforming growth factor beta, Th2: T helper 2 cell, TSP1: thrombospondin-1, TSPAN12: tetraspanin 12. Created by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/) and the figure was adapted from Underwood et al.[31]

The subsequent antigen exposure provokes an inflammatory immune response, where antigen presenting cells result in activation into dendritic cells, which interact with T helper 2 (Th2) cells and Type 2 lymphoid innate cells and secretion of IL-4, which induces differentiation of Th2 cells, IL-5 and IL-13, and eotaxin-3. These in turn cause further immune activation and eosinophilic migration and infiltration. Dendritic cells also express epithelial-derived cytokines IL-25, IL-33, and TSLP, called alarmins, which also play a role in the immune response to antigen exposure.[32] These factors, in addition to the enhanced expression of TGF-β, result in activation of fibroblasts in the lamina propria, collagen deposition, tissue remodeling, and fibrosis in a subset of susceptible individuals.[3272930] The decreased expression of the membrane protein tetraspanin 12 (TSPAN12) in endothelial cells results in a chronic Th2-mediated inflammation, resulting in increased IL-13, which induces profibrotic mediators in fibroblast and resulting tissue remodeling and fibrosis. Although IgE and IgG4 antibodies derived from B-cells are increased in EoE, they do not appear to have a prominent role in the development of EoE.[33]

CLINICAL MANIFESTATIONS

Data from local studies are in line with the prior literature suggesting that EoE predominantly follows two distinct patterns of presentation that varies with age [Figure 3]. Young children with EoE tend to present with feeding difficulty, vomiting, regurgitation, and failure to thrive, whereas older children, adolescents, and adults are more likely to present with heartburn, dysphagia, and food impaction. Due to similar clinical presentations of gastroesophageal reflux disease (GERD) and EoE in young children, the distinction between these two entities can be difficult. Many young children receive conventional anti-GERD therapy, including proton-pump inhibitors (PPIs), prior to the diagnosis of EoE. In fact, some patients with EoE underwent fundoplication to treat severe GERD.[3435] This emphasizes the need for an esophageal biopsy when controlling GERD symptoms becomes difficult.

Figure 3 Clinical presentations of EoE according to the age

One of the main objectives of therapy is elimination of symptoms linked to esophageal dysfunction; nevertheless, assessing symptoms related to EoE can present some challenges. The validated metrics for patient-reported outcomes have lately been made accessible. Most issues in patients with EoE arise from coping strategies that ease food passage. Patients with EoE typically adopt coping strategies to make eating easier. These adaptive habits are denoted by the IMPACT acronym [Box 1]. Therefore, it is crucial to verify with the patients using the abovementioned questions that they are not lowering their symptoms by cutting out particular foods or developing adaptive eating habits.[36]

Box 1 The IMPACT acronym for taking a history when EoE is suspected

• Imbibe fluids with meals	
• Modifying food (cutting into small pieces)	
• Prolonged meal times	
• Avoidance of hard textured foods	
• Chewing excessively	
• Turning away pills	

The natural history of EoE is one of a chronic and, in many patients, progressive disease. For example, the predominance of the two patterns of symptoms in two different populations (young children versus older children and adults) suggests potential progression of untreated disease [Figure 4].[37383940] One possible explanation is that the esophagus in EoE passes through an “inflammatory phase” in infants and young children and a “fibrotic phase” in older children. The first is characterized by extensive eosinophilic inflammation that causes damage to the esophagus and its sphincter, resulting in reflux symptoms. As the disease progresses, in untreated cases, the esophagus proceeds into a “fibrotic phase”, characterized by subepithelial fibrosis and subsequent esophageal remodeling and thickening, that leads to esophageal lumen narrowing and subsequent dysphagia and food impaction, which is more frequently encountered among adults (25%) as compared to pediatric (6.3%) EoE patients.[384142] This model is supported by a number of studies showing higher rates of fibrostenosis with increasing symptom duration prior to diagnosis and by studies showing progression after diagnosis in untreated patients.[43444546474849] The high incidence of esophageal narrowing in pediatric case series from Saudi Arabia (13–28%) suggests that this progressive process may evolve rapidly in some children. An alternative explanation is that there are different phenotypes of EoE. The significant frequency of consanguinity (82%) among children with EoE, and esophageal narrowing in one of the local studies, might indicate that a subset of patients with EoE may have a genetic predisposition to stricture formation.[18]

Figure 4 Natural history of EoE if untreated

DIAGNOSIS

The diagnosis of EoE is a multifaceted process that involves the integration of clinical, endoscopic, histologic, and ancillary data. The initial step typically involves a comprehensive assessment of the patient’s medical history, including symptomatology, duration of symptoms, triggers for symptoms, concomitant atopic conditions, and responses to previous interventions.[5051] A meticulous notation of patient history is essential to differentiate EoE from other conditions with similar clinical presentations.[525354] The definitive diagnosis of EoE is based on histological confirmation through esophageal biopsies; however, laboratory and imaging tests serve as supportive tools to exclude other potential etiologies of esophageal eosinophilia, monitor disease activity, and guide therapeutic strategies.[55] Therefore, other potential causes of esophageal symptoms and esophageal eosinophilia should be excluded before making the diagnosis of EoE [Box 2].

Box 2 Differential diagnosis of EoE and esophageal eosinophilia

• Gastroesophageal reflux disease	
• Eosinophilic gastrointestinal diseases	
• Hypereosinophilic syndrome	
• Achalasia	
• Crohn disease	
• Celiac disease	
• Esophageal infections (fungal, viral)	
• Connective tissue and autoimmune disorders	
• Vasculitides	
• Dermatologic conditions (e.g., pemphigus)	
• Drug hypersensitivity	
• Pill induced esophagitis • Graft versus host disease	
	
• Marfan syndrome type 2	
• Hyperimmunoglobulin E syndrome	
	
• PTEN hamartoma tumour syndrome	
• Netherton syndrome	
	
• Severe atopy metabolic wasting syndrome	

Laboratory investigations

Blood Eosinophil Count: Although not specific to EoE, an elevated blood eosinophil count may suggest the presence of systemic allergic inflammation and contribute to the overall clinical understanding. Peripheral blood eosinophilia occurs in 40–60% of the cases; therefore, a normal blood eosinophil count does not rule out EoE.[55565758]

Genetic and Molecular Studies: Emerging studies have explored the genetic and molecular underpinnings of EoE to uncover the intricate mechanisms driving this condition. Genetic studies have identified several susceptibility loci associated with EoE, thereby clarifying the genetic predisposition to this disorder. Molecular analyses, such as gene expression profiling, offer insights into the complex pathways involved in EoE pathogenesis. Although these studies are still in their nascent stages, they hold a promise for enhancing our understanding of the disease and potentially guiding us toward personalized treatment approaches.[5657] However, these tests are not currently used in diagnostic algorithms for EoE.

Imaging and motility testing

Barium Swallow: Barium esophagram is a conventional radiographic technique used to evaluate esophageal anatomy and function. In patients with EoE, a barium swallow can reveal characteristic findings such as esophageal rings and strictures. These structural abnormalities, although nonspecific to EoE, can provide information regarding the extent of esophageal involvement and help differentiate EoE from other esophageal disorders such as GERD.[1958]

Esophageal High-resolution Manometry: High-resolution manometry can be used to evaluate esophageal motility and function. It can also provide insights into esophageal dysmotility; although not specific to EoE, it can be observed in some cases.[59] The most common findings are weak or failed peristalses, esophagogastric junction outflow obstruction (EGJOO), or hypertensive peristalses.[60] Dysmotility may contribute to symptoms such as dysphagia and chest pain. The integration of manometric data with other diagnostic criteria aids in the comprehensive evaluation of patients with suspected EoE,[52] though it is not generally used primarily in the evaluation of EoE.

Endoscopy

Endoscopic assessment provides essential information regarding mucosal changes, patterns of involvement, and responses to therapeutic interventions.[6162] Mucosal abnormalities indicative of EoE include edema (decreased vascularity), linear furrows, concentric rings, white exudates, and strictures or narrowing [Figure 5]. These visual findings, although not specific to EoE, increase the suspicion for EoE and provide important information required to differentiate EoE from other esophageal disorders. The presence and distribution of these features can vary, necessitating a thorough examination of the entire esophagus, and an optimal technique has been suggested.[63] Esophageal strictures are potential complications of EoE that can contribute to symptoms such as dysphagia and food impaction; therefore, endoscopic dilation of strictures can be performed to alleviate symptoms.[1864] This technique is safe in EoE, provided a cautious approach is used.[6566] Endoscopy also plays a crucial role in monitoring the efficacy of therapeutic interventions in patients with EoE. Repeat endoscopic evaluations after 3–4 months of treatment initiation allow clinicians to assess the response to therapies such as dietary modification and pharmacological treatments and perform endoscopic dilation if needed. Improvement in mucosal appearance, reduction in eosinophilic infiltration, and resolution of mucosal exudates are indicators of successful treatment.[6768]

Figure 5 Endoscopic findings in EoE: a: Esophageal rings persisting in a patient with EoE on treatment. b: exudates and edema. c: Exudates, rings, edema, furrows, and mild narrowing. d: Crepe-paper mucosa after passing the scope in a narrowed proximal esophagus

Endoscopic Reference Score

The Endoscopic Reference Score (EREFS) is a scoring system used to assess the severity of EoE. There are many EREFS scoring systems available, the most widely used is the modified EREFS [Figure 6]. It is based on five endoscopic findings: Edema, Rings, Exudates, Furrows, and Strictures.[6970] The EREFS was developed in 2013 by Hirano et al. and has been validated in multiple studies. It is a reliable and reproducible method for assessing the severity of EoE. The EREFS can be used to monitor disease activity over time and to assess the response to treatment.[697071]

Figure 6 EREFS endoscopic grading system for EoE[72] (Wolters Kluwer Health, Inc. Permission Licence Number 5720730303645)

Endoluminal Functional Lumen Imaging Probe (EndoFLIP)

EndoFLIP is a minimally invasive technique that uses high-resolution impedance planimetry to measure the distensibility of the esophagus [Figure 7]. It is a new technology that is still being evaluated for its use in EoE, but it has the potential to be a valuable tool for assessing the severity of disease and monitoring the response to treatment.[7374] It is performed during an upper endoscopy. A small catheter is passed through the endoscope and positioned in the distal esophagus where a small balloon is inflated to measure the pressure required to distend the esophagus and calculate the distensibility index (DI).[75] Studies have shown that patients with EoE have lower DIs than healthy controls. Studies have shown that DI improves after treatment with topical steroids, suggesting that EndoFLIP can be used to assess the efficacy of therapy.[76]

Figure 7 Physiomechanical model of EoE. FLIP panometry outputs from six patients (A-F) with EoE are displayed reflecting the physiomechanical states of EoE. In A–C, esophageal distensibility is normal (noted by normal diameters of the esophageal body). In A, a normal contractile response involving repetitive antegrade contractions (RACs) is triggered, whereas B is weak with some evidence of contractions (BCR/IDCR with low bag pressures). C is nonreactive without triggering of contractility and can be achalasia-like (ALP) if the EGJ-DI >3.0 and Weak-GERD-like if EGJ-DI is >3.0. In D–F, fibrostenotic obstruction is reflected by reduced distensibilty (low diameters/reduced compliance) of the esophageal body and EGJ. In D, there is evidence of RACs with a rate of 6 and this pattern is associated with higher pressures than normal and a low EGJ-DI mechanical obstruction. Panel E shows reactive-spastic contractility patterns and is associated with spastic-like responses (IDCR/SRCR) and no evidence of RACs. The pressures in this pattern are usually well above 80 mmHg. F is nonreactive with absent contractile response, and the pressure is usually high, but does not have severe fluctuations like D and E (Image courtesy of Professor John E. Pandolfino, Chicago, IL, USA)

Histopathology

Histopathological evaluation is the gold standard of EoE diagnosis, providing definitive evidence of eosinophilic inflammation within the esophageal mucosa. The presence of eosinophils in the esophageal mucosa is a hallmark feature of EoE, and a comprehensive understanding of the histological changes aids accurate diagnosis and differentiation from other esophageal disorders.[62] The consensus diagnostic threshold is the identification of ≥15 eosinophils per high-power field (eos/hpf) in at least one esophageal biopsy specimen.[77] Eosinophilic infiltration can involve deeper layers, including into the lamina propria, muscularis mucosa, subepithelium, and muscularis propria.[7879] This infiltration pattern distinguishes EoE from other esophageal disorders and underscores its distinct pathophysiology.[53]

Eosinophils within the esophagus can be distributed sporadically, with areas presenting with focal eosinophilic infiltration. This irregular distribution emphasizes the importance of obtaining a minimum of six biopsy samples from multiple levels of the esophagus during endoscopy, as a single negative biopsy does not rule out EoE because of sampling error.[518081] Other histological features can provide supporting evidence for EoE diagnosis, which include microabscess formation, eosinophil degranulation, superficial layering of eosinophils, basal zone hyperplasia, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis.[77] These changes contribute to the characterization of the overall histological characteristics of EoE and in conjunction with clinical and endoscopic findings aid in its differentiation from other conditions such as GERD.[62]

The British Society of Gastroenterology recommends withdrawal of PPI for at least 3 weeks before endoscopy to improve diagnostic accuracy and avoid the need for a repeat procedure. It also recommends that six biopsies should be taken from at least two different sites in the esophagus, with a combination of targeted biopsies from visible areas of mucosal surface abnormality (e.g., furrows) and nontargeted biopsies among the six biopsies in order to maximize the chances of making an EoE diagnosis.[82]

TREATMENT

Therapeutic goals in treatment of EoE are to induce clinical, endoscopic, and histologic remission; to improve quality of life; and to prevent complications. From a patient’s perspective, the most important outcome is improvement of the symptoms and quality of life. From a physician’s point of view, improving histologic and endoscopic inflammation with medications or diet is a main treatment goal, which should translate to improved symptoms. Unfortunately, only modest concordance exists between symptoms and histology.[83] Several treatment outcomes now have validated instruments and are available for use in both research and clinical settings.[83848586] The treatment of EoE can be categorized into three classes (3 Ds), Diet, Drugs, and Dilation. A treatment algorithm is illustrated in [Figure 8].

Figure 8 Treatment algorithm in patients with EoE

Diet

Food elimination diets (FEDs) are an important therapeutic option for classically defined EoE, given that food antigens cause EoE in many patients. Diet elimination is commonly used aiming to identify and remove specific foods that trigger inflammation.[86] There are three main approaches: elemental formula, targeted (allergy test-based) elimination, and empiric elimination. The data on efficacy of elemental diets for treatment of EoE are mainly derived from observational studies with an overall histologic response (defined as <15 eos/hpf) of approximately 94%.[87] One meta-analysis assessed the effect of elemental diet in achieving histological remission, and its effectiveness reached up to 91%.[84] In contrast, single-arm studies reported that 50% of subjects on a skin testing-guided elimination diet failed to achieve histologic remission, and these diets have fallen out of favor.[37888990] Instead, empiric elimination diets where the most common food triggers are removed are more commonly used. These can range from one-food elimination diets (1-FED), where only animal milk is removed, to six-food elimination diets (6-FED) where dairy, wheat, egg, soy, nuts, and seafood are removed. A multicenter, randomized, open-label trial that assigned participants to either the 1-FED or the 6-FED for 6 weeks found that 34% of participants on 6-FED and 40% of participants on 1-FED achieved remission. Thus, 1-FED and 6-FED were equally effective at treating EoE. Interestingly, 50% of them did not respond to 1-FED achieved remission after treatment with 6-FED, while >80% of the nonresponders to 6-FED achieved remission with topical steroids.[91] These data suggest it may be reasonable to start with less restrictive diets and then “step-up” to more restrictive diets for nonresponders who are motivated to continue with the diet approach.[92]

Regardless of which diet is chosen, the initial elimination phase typically lasts for 6 to 8 weeks, during which patients must strictly avoid the suspected trigger foods. Then, endoscopy and biopsy are performed to assess for response. If there is remission, that indicates response to diet, and then a reintroduction phase can be started. Here, the eliminated foods are reintroduced one at a time, with follow-up endoscopies after 6–8 weeks after each food. If there is recurrent inflammation, then that food is a trigger and is best avoided in the long term; if there is no recurrent inflammation, then the food is safe and can be continued. Then the next food is reintroduced. Working with a dietician is very important for food elimination diets, but there are also published resources to help providers and patients move through this process.[88] Long-term adherence with diet can be challenging.[89] This can be due to high cost of elemental formulas used in pediatric patients, social isolation created by diet restrictions, long-term adherence issues, and the potential need for repeated endoscopic biopsies during the food reintroduction phase.[93] Of note, one study reported that patients with EoE refractory to PPI monotherapy or FED monotherapy can successfully achieve histologic remission and symptom benefits when combination therapy of PPI and FED was used, but there are limited data available on the long-term effectiveness of this approach.[94]

Proton-pump inhibitors

Due to its safety profile, ease of administration, and good response rates, PPIs have been considered as a first-line pharmacologic treatment for EoE.[87959697] PPIs are thought to influence the integrity of the barrier function and might explain the positive effect PPIs could have on EoE patients and suppressing gastric acid, which, when reflux is present, also impairs the esophageal barrier function.[27] European and International consensus recommendations have recently removed the PPI trial from the diagnostic criteria of EoE.[5597] The American Gastroenterological Association and the Joint Task Force on Allergy Immunology Practice Parameters (AGA/JTF) suggest using PPI over no treatment.[87] It is also necessary to realize that because GERD and EoE may coexist, some patients may need to be treated with both a PPI and different anti-inflammatory treatments (e.g., dietary elimination or topical corticosteroids) in order to optimally treat both conditions, though there are few data on combination therapy.[87] The observed improvement in histology and clinical status may be due to PPI therapy’s anti-inflammatory effects, which inhibit the Th2-allergic pathway, rather than acid suppression alone. Similar to topical corticosteroids, PPIs suppress the expression of cytokines (eotaxin-3/Th2-cytokine).[95]

In a systematic review, PPI showed no significant efficacy for achieving histologic remission when given twice daily compared with once-daily dosages (55.9% vs 49.7%; P = 0.96) and the overall efficacy rates in inducing histologic remission were nonsignificant in the presence of abnormal pH monitoring (65.4%), compared with those patients showing normal esophageal acid exposure time (49.3%).[98] However, the European guidelines recommends a dose of 20–40 mg of omeprazole or equivalent, twice daily, for 8 weeks.[9598] Both retrospective and prospective studies reported histological remission after an 8-week course of treatment with PPI, with rates of remission varying from 33% to 50%, depending on the histologic cutoff used to define remission (<5–7 eosinophils/hpf or <15 eosinophils/hpf). In addition, symptom improvement is common with PPI therapy despite persistent eosinophilic infiltration,[959899100] therefore it is important to assess response with endoscopy and biopsy and not just symptoms.

Some data are available that evaluate long-term effects after a PPI response is achieved. A multicenter study included 75 patients who responded to PPI treatment over a mean follow-up period of 26 months; 73% maintained remission following a decrease in the PPI dosage, while 14% regained response with an increase in dose.[101] A retrospective cohort study of newly diagnosed adults with EoE, who had initial histologic response to PPI-only therapy, found at 3.6 ± 2.9 years follow-up time that 60% and 64% maintained histologic and symptom responses, respectively; younger age and dilation prior to PPI treatment were the only factors associated with long-term loss of PPI response.[102] In responders, the lowest effective PPI dose should be used for maintenance.[8795]

Corticosteroids

Swallowed topical corticosteroids (STCs) are an option in the treatment of EoE, and their efficacy has been confirmed in a series of studies. It is not advised to use systemic steroids in EoE according to the multiple guidelines,[559697103] given that both pediatric and adult EoE patients can effectively induce histological remission with topical corticosteroids. Long-term topical steroid is useful in maintaining remission in patients who respond well to STC. The corticosteroids exert their activity through a complex mechanism based on their anti-inflammatory and antiallergic effects on esophageal tissue.[104] One major issue with corticosteroid use is how the medication is delivered to the esophagus to allow for optimal exposure to the esophageal mucosa for an extended period. However, the lack of standardization of these drugs is a serious concern because the variety of mixing agents used are not specifically made for esophageal delivery, and irregularities in medication preparation and correct administration can result in variability in effectiveness. The three main formulations of STC are orally dispersible steroid tablets, oral viscous budesonide (OVB), and fluticasone propionate (FP) multidose inhaler (MDI). Numerous trials on both adults and children have demonstrated the efficacy of STC therapy in treating EoE and OVB and MDI was found to be similar, so either is a suitable treatment for EoE.[58105106107108109110111112113114] Some predictors of steroid response have also been reported, and those who require esophageal dilation or who have severe narrowing of the esophagus may be less likely to respond.[115116]

The AGA/JTF recommends STC over oral glucocorticosteroids for patients with EoE.[97] According to the British Society of Gastroenterology, using STC in maintenance therapy lowers the chance of recurrent food bolus impaction.[82] When treating EoE, STCs are useful in inducing clinical and histological remission, however, after stopping STC, there is a significant increase in clinical and histological relapse.[117118119] Therefore, maintenance therapy has been suggested after a clinical assessment.[114] Both pediatric and adult EoE patients can effectively induce histological remission with topical corticosteroids. When used to treat EoE, STCs appear to have a good safety profile as no significant side effects have been noted. A 10% chance of developing esophageal candidiasis is possible.[97]

Various meta-analyses showed the superiority of budesonide viscous, budesonide suspension, and fluticasone over placebo.[120] In the short term, STC was more effective at inducing clinical, endoscopic, and histological response than placebo.[113121122] In a systematic review and network meta-analysis of randomized placebo-controlled studies, swallowed fluticasone and budesonide were found equal in inducing clinical and histological response.[121] A network meta-analysis shows that swallowed viscous budesonide was the most effective pharmacologic therapy for EoE among the reported pharmacologic treatments.[123] Another network meta-analysis found that the optimal treatment for adult patients with EoE was 1 mg of swallowed budesonide orodispersible taken twice daily, whereas swallowed fluticasone was the ideal treatment for pediatric patients.[124] The summary of RCTs for the treatment of EoE with different STC is shown in Table 1.[125]

Table 1 Summary of randomized controlled trials that treated EoE by STC

Reference	Patients (n)	Mean age	STC	Comparator	Formulation	Dosage/day	Duration (weeks)	Histological remission (%) in treatment/comparator	Symptoms improved in STC/comparator	
Dellon et al.[126]	25	34.4	Budesonide	Budesonide (spray, swallowed)	Suspension	Suspension and spray: 1 mg b.i.d	8	64/27	Yes/no	
Straumann et al.[127]	36	36	Budesonide	Placebo	Suspension	1 mg b.i.d	2	72/11	Yes/yes	
Dohil et al.[128]	32	7.8	Budesonide	Placebo	Suspension	1-2 mg OD (body weight adapted)	12	87/0	Yes/yes	
Hirano et al.[129]	322	N/A	Budesonide	Placebo	Oral suspension	2 mg b.i.d	12	53/1	Yes/yes	
Gupta et al.[130]	81	9.1	Budesonide	Placebo	Suspension	0.35-2.8 mg OD (age adapted)	12	Low-dose: 24; Mediumdose: 53; High-dose: 94; Placebo: 6	Yes/no	
Miehlke et al.[131]	76	39.7	Budesonide	Placebo	Orodispersible tablet, suspension	Orodispersible tablet: 1 mg b.i.d or 2 mg b.i.d; Suspension: 2 mg b.i.d	2	Orodispersible tablet: 100/95; Suspension: 95; Placebo: 0	Yes/no	
Dellon et al.[132]	93	21.5	Budesonide	Placebo	Suspension	2 mg b.i.d	12	39/3	Yes/yes	
Lucendo et al.[133]	88	37	Budesonide	Placebo	Orodispersible tablet	1 mg b.i.d	6	93/0	Yes/yes	
Dellon et al.[112]	111	36/39	Budesonide	Placebo	Budesonide: oral viscous; Fluticasone: spray (swallowed)	Budesonide 1 mg b.i.d; Fluticasone 880 µg b.i.d	8	71/64	Yes/no	
Butz et al.[111]	24	12.6	Fluticasone	Placebo	Spray (swallowed)	880 µg b.i.d	12	65/0	No/no	
Moawad et al.[99]	42	38	Fluticasone	Esomeprazole	Spray (swallowed)	Fluticasone 440 µg b.i.d, esomeprazole 40 mg OD	8	24/18	No/no	
Hirano et al.[134]	24	N/A	Fluticasone	Placebo	Orally disintegrating tablet	1.5 mg b.i.d or 3 mg OD	8	N/A	Yes/yes	
Dellon et al.[108]	103	N/A	Fluticasone	Placebo	Orally disintegrating tablet	3 mg b.i.d or 1×3 mg OD or 1.5 mg b.i.d or 1.5 mg OD	12	2×3 mg: 80; 1×3 mg: 66.7; 2×1.5 mg: 86.4; 1×1.5 mg: 47.6; Placebo: 0	Yes/N/A	
Konikoff et al.[105]	36	96	Fluticasone	Placebo	Spray (swallowed)	440 mcg b.i.d	12	50/9	N/A	
Peterson et al.[100]	30	34.6	Fluticasone	Esomeprazole	Spray (swallowed)	Fluticasone 440 µg b.i.d; esomeprazole 40 mg OD	8	15/33	Yes/yes	
Schaefer et al.[135]	80	7.2	Fluticasone	Prednisone	Spray (swallowed)	Fluticasone 440-880 µg b.i.d; prednisone: 1 mg/kg/dose b.i.d; maximum 30 mg b.i.d	4	94/94	Yes/no	
Alexander et al.[110]	42	37.5	Fluticasone	Placebo	Spray (swallowed)	880 µg b.i.d	6	62/0	Yes/no	

Dupilumab

Dupilumab is a human monoclonal IgG4 antibody that binds to the IL-4Rα subunit to suppress interleukin-13 (IL-13) and interleukin-4 (IL-4) signaling. In May 2022, the FDA approved dupilumab for use in adult and pediatric subjects ≥12 years of age with EoE,[136] with approvals following in multiple other locations globally. The approval was based on the results of a phase 3 randomized, double-blind, multicenter, placebo-controlled trial in two parts (A and B), with outcomes assessed after 24 weeks of treatment. Eligible patients who completed part A or part B could continue the trial in part C and received dupilumab at a weekly or every 2 weeks dose of 300 mg for an additional 28 weeks. In part A, histologic remission (defined as ≤6 eos/hpf) occurred in 60% of patients who received 300 mg subcutaneously weekly dupilumab and in 5% who received placebo (P < 0.01). In part B, histologic remission occurred in 59% with weekly dupilumab, 60% with dupilumab every 2 weeks, and 6% with placebo (P < 0.01). The DSQ scores improved with weekly dupilumab as compared with placebo (P < 0.01) but not with dupilumab every 2 weeks; therefore, approval was for weekly dosing. In January 2024, FDA approved dupilumab for the treatment of pediatric patients aged 1 to 11 years, weighing at least 15 kg, with EoE. The approval was based on Phase 3 EoE KIDS trial showing a greater proportion of children taking dupilumab achieved histological remission compared to placebo.

The most common adverse event that occurred during the treatment period was injection-site reactions. No deaths were reported; however, serious adverse events occurred in 7 patients who received weekly dupilumab, 1 who received dupilumab every 2 weeks, and 1 who received placebo.[125] Other adverse events reported from clinical trials in non-EoE conditions in adults include cutaneous herpesvirus infections, conjunctivitis, local injection site reactions (up to 18%), and facial erythema. In children, skin infections, conjunctivitis, upper respiratory tract infections, and worsening of atopic dermatitis have been reported. Blood hypereosinophilia has been cited as another possible side effect.[136137138139140141] Dupilumab is generally considered as a second-line therapy for patients who have not responded to first-line therapies including PPI, STC, or dietary elimination and for patients who have developed side effects or are at high risk for steroid-related complications and require steroid-sparing alternatives.[142] Another additional consideration for dupilumab includes patients who have comorbid atopic diseases such as asthma or atopic dermatitis.

Emerging and novel therapies

Given the increase in knowledge of EoE pathophysiology, many new therapeutic targets have been identified, a number of which are under study. The effectiveness of mepolizumab, a fully humanized anti − IL-5 monoclonal antibody, failed to meet the primary goal of reducing dysphagia symptoms, though it did improve eosinophil counts and endoscopic severity.[143144145] Reslizumab, a neutralizing antibody against IL-5, was investigated for its effects in children and adolescents suffering from eosinophilic esophagitis. It also did not affect the clinical activity score, but it did lower the intraepithelial esophageal eosinophil counts in children and adolescents.[146] Benralizumab, an eosinophil-depleting antibody that causes antibody-dependent cellular cytotoxicity (by activating the IL5 receptor alpha subunit), was tested in a multicenter randomized trial, and though it had high histologic response rates (>80%) compared to placebo, it failed to improve symptoms or endoscopic findings of EoE, suggesting that the eosinophil alone is not driving disease pathogenesis and may be too specific of a treatment target.[147]

A recombinant humanized monoclonal antibody against IL13, cendakimab (previously called RPC4046), interferes with the ability of IL-13 to bind to IL13RA1 and IL13RA2 receptor subunits and resulted in improvement of histologic and endoscopic characteristics of EoE and was tolerated well in a phase 2 study.[148149] The phase 3 study is ongoing.

The anti-IgE antibody omalizumab was not effective for EoE treatment, suggesting that EoE in adults is an IgG4-associated rather than IgE-induced allergy.[150] Infliximab, an anti-TNF antibody, did not demonstrate any therapeutic effects in open-label trials.[151] Esophageal eosinophilia was not reduced in pediatric patients by cromolyn when added to a viscous solution.[152] A study on montelukast reported that 40% experienced remission but was not different from the placebo group.[153] Two case reports of patients with concurrent inflammatory bowel disease and EoE, whose treatment produced a clinical and histological response, indicate vedolizumab possible significance in the management of EoE. Two case series on eosinophilic gastroenteritis have further established its antieosinophil properties.[154155] Recently, results of phase 2 trials of an S1P receptor modulator and of an immunomodulatory chaperone protein were promising, and these agents may be studied in the figure.[156157] Summary of some of the expermintal therapies used for EoE is provided in Table 2.

Table 2 Biological treatments for EoE

Name of therapy	Mechanism of action	Phase 1	Phase 2	Phase 3	Approved	Clinical trial details	
Dupilumab	Anti IL4/13					Approved in EU, USA and other countries for age ≥12	
Dupilumab	Anti-IL4/13					Approved in 2024 by FDA for children aged 1-11	
Cendakimab	Anti-IL13					Primary completion date Decemeber 2023	
Dectrekumab (QAX576)	Anti-IL13					Discontinued for EoE	
Tezepelumab	Anti-TSLP					Anticipated completion in 2026 Age 12-80	
IRL201104	mTB chaperonin 60.1 peptide					Completed October 2022 Age 18-75	
Barzolvolimab	Anti-KIT					Anticipated completion date 2025 Age ≥18	
Mepolizumab	Anti-IL5					Discontinued for EoE	
Reslizumab	Anti-IL5						
Benralizumab	Anti-IL5Rα						
Lirentelimab	Anti-Siglec-8						
Omalizumab	Anti-IgE						

Dilation

Esophageal strictures can occur as a complication of long-standing untreated esophageal inflammation in EoE patients.[55] Symptomatic improvement was reported in 87% of patients who underwent esophageal dilation; however, there is no significant histologic improvement in eosinophilia with dilation.[63158] Because of that, dilation should always be paired with anti-inflammatory treatments to address the underlying disease activity. Esophageal dilation with through-the-scope pneumatic balloons and Maloney or Savary bougies are the most commonly used, and all techniques can be used safely. A meta-analysis of 27 studies (2873 patients) who experienced dysphagia or reported food impactions, showed clinical improvement (95%) with a mean diameter after dilation of 16.1 mm. Adverse events reported were perforation (0.38%) and hemorrhage (0.05%), but there were no deaths.[159] The most common adverse event reported was chest discomfort or pain, which rarely required hospitalization. From a practical standpoint, dilation is usually started with a smaller diameter bougie or balloon and then progressed slowly to larger sizes with dilation sessions every 4–12 weeks, depending on stricture severity, targeting an esophageal diameter of 16 to 18 mm in adults.[18160] Most of the strictures required an average 2 to 5 sessions, yet some patients required maintenance dilation every 2 years.[159] The use of PPI in combination with scheduled dilations might reduce the need of frequent dilation.[161] Based on expert opinion, it is recommended that esophageal dilation should be considered in patients with fibrostenotic strictures, at the time of diagnosis in patients with dysphagia/food impaction and persistent esophageal strictures, after other measures have failed, and in patients with persistent dysphagia in the presence of endoscopic and histological remission with medical or dietary therapy.[60162]

LONG-TERM OUTCOMES AND COMPLICATIONS

The long-term outcomes of EoE are not completely understood, but EoE is likely a progressive disease, and therefore, early recognition and intervention is required to prevent persistent inflammation from causing remodeling, fibrosis, and stricture formation. It is exceedingly rare for a child to “grow out of” EoE or for EoE to resolve spontaneously. In general, the goal of all treatment modalities is to control patient symptoms, improve endoscopic appearance, and achieve histological remission.[163] Furthermore, therapeutic interventions could influence the natural history of the disease and reduction in the long-term complications, including food bolus impaction and stricture formation, and the need for esophageal dilatation.[120136164165166167]

Adherence to a regular annual EoE monitoring program by assessing clinical, endoscopic, and histological disease activity, regardless of symptoms, resulted in fewer stricture formations and earlier detection of histological relapse.[168] Also, a scoring system to assess EoE severity (Index of Severity for Eosinophilic Esophagitis (I-SEE)) has been developed and scores for mild, moderate, and severe disease have been proposed.[169] This may be helpful in the clinical setting to monitor treatment response, as severity can decrease with successful treatment.[170171] In the future, I-SEE may be able to guidele treatment and monitoring based on severity, but more data are required before this could be implemented.

CONCLUSION

Eosinophilic esophagitis is a chronic, progressive, immune-mediated disorder that is increasing in incidence and prevalence. The disease usually presents with vomiting and failure to thrive during childhood or dysphagia and food impaction in adults. Diagnosis is based on symptoms of esophageal dysfunction and esophageal eosinophilia (≥15 eos/hpf) in the absence of competing causes of eosinophilia. Therapeutic modalities for EoE are rapidly being developed. Current therapeutic options include PPI, topical corticosteroids, elimination diets, and new drugs such as biologics and small molecules that help in alleviating the symptoms and inducing histologic remission. Because EoE is chronic, treatment needs to be long-term, as the symptoms of recurrent disease activity is nearly universal after discontinuing treatments. Early recognition and initiation of appropriate treatment is crucial as disease progression to fibrosis and strictures is possible. In addition to assessing symptoms, all patients should be followed up with endoscopy and repeated biopsy for histopathological assessment.

Financial support and sponsorship

Nil.

Conflicts of interest

Evan S. Dellon, MD MPH

Research funding: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda

Consultant: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio

Educational grant: Allakos, Aqilion, Holoclara, Invea.

The other authors reported no conflicts of interest related to this work.
==== Refs
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