Letter to the Editor: Beyond current therapies - any more promising strategies for refractory non-esophageal eosinophilic gastrointestinal diseases?

Abstract

We read with interest the multicenter study by Lee et al on non-esophageal eosinophilic gastrointestinal diseases. Although most patients responded well to conventional therapies, high relapse rates highlight the limitations of these treatments. To address this, we suggest that endoscopic ultrasound be considered in clinical practice for selected patients with suspected deeper-layer involvement, obstructive symptoms, unexplained ascites, severe disease, or discordance between symptom severity and mucosal biopsy findings. Furthermore, fecal microbiota transplantation and leukapheresis warrant further investigation as potential novel therapeutic strategies. As current evidence is largely limited to case reports and indirect disease models, these approaches require additional mechanistic and preclinical studies to evaluate their efficacy and safety. Individualized regimens should also be considered to optimize outcomes in this challenging disease.

Key Words: Non-EOE eosinophilic gastrointestinal diseases; Endoscopic ultrasound; Fecal microbiota transplantation; Leukapheresis; Eosinophilic gastrointestinal diseases

Core Tip: This letter comments on a multicenter study of non-esophageal eosinophilic gastrointestinal diseases. High relapse rates after initial response to conventional therapies highlight the need for improved treatment strategies. We suggest the use of endoscopic ultrasound in selected patients with suspected deeper-layer involvement or atypical presentations. Additionally, fecal microbiota transplantation and leukapheresis are suggested as exploratory approaches that warrant further investigation. Given that current evidence is limited to case reports and indirect disease models, additional mechanistic and preclinical studies are urgently needed to evaluate their efficacy and safety and formulate optimal individualized regimens for this disease.

TO THE EDITOR

Eosinophilic gastrointestinal diseases (EGIDs) are chronic, immune-mediated disorders characterized by gastrointestinal symptoms and pathological eosinophilic tissue infiltration, after exclusion of secondary etiologies[1]. According to the latest international consensus, EGIDs can be classified into two main phenotypes: Eosinophilic esophagitis (EoE) and non-EoE EGIDs[2]. In Asia, non-EoE EGIDs are more common, with an estimated incidence and prevalence of 3.07 per 100000 person-years and 17.23 per 100000 population, respectively, in 2022[3]. However, compared with EoE, non-EoE EGIDs have been less studied, with no widely accepted evidence-based guidelines currently available for their diagnosis or treatment.

At present, conventional treatments for non-EoE EGIDs mainly include empiric elimination diets, corticosteroids, and, more recently, biologic agents[4]. However, long-term disease control remains suboptimal in some patients. We read with interest the retrospective study by Lee et al[5] entitled “Presentation and treatment of eosinophilic gastroenteritis in Busan and Gyeongnam, Korea: A multicenter study”. In this context, Lee et al[5] systematically reviewed 73 Korean patients with non-EoE EGIDs and found that although most patients initially responded to treatment, the relapse rate in the enterocolitis subgroup was as high as 43.3%. These findings underscore the need for optimized disease stratification and exploration of additional therapeutic approaches.

ACCURATE CLASSIFICATION OF NON-EOE EGIDS REMAINS CHALLENGING

Conventional endoscopic biopsies primarily obtain mucosal samples and may miss involvement of muscular or serosal layers. Clinically, the mucosal subtype typically presents with abdominal pain and diarrhea, the muscular subtype presents with obstructive symptoms (e.g., nausea, vomiting, and bloating), and the serosal subtype presents with eosinophilic ascites[6]. Endoscopic ultrasound (EUS) enables visualization of the full thickness of the gastrointestinal wall and, when indicated, facilitates targeted tissue acquisition from deeper layers[7], thereby potentially reducing the risk of missed diagnoses and treatment delays. However, direct evidence supporting the use of routine EUS for improving diagnostic yield, changing management, predicting relapse, or improving clinical outcomes in non-EoE EGIDs is currently lacking. For current practice, we propose considering EUS for patients with suspected muscular or serosal layer involvement, obstructive symptoms, unexplained ascites, severe disease, or discordance between symptom severity and mucosal biopsy findings to support diagnostic evaluation and inform management decisions. Whether EUS-based phenotyping can predict prognosis or guide more aggressive treatment in high-risk patients remains to be tested in prospective studies. Therefore, although the accessibility and operator-dependent variability of EUS may limit its widespread implementation in some settings, we suggest that EUS be considered a promising area for future investigation.

In addition to conventional therapies, several underexplored strategies may warrant further investigation. Fecal microbiota transplantation (FMT) in combination with corticosteroids has been described in a single case report, resulting in successful remission of severe non-EoE EGIDs[8]. However, the extent to which FMT contributed independently to the observed remission remains uncertain, as concomitant corticosteroid therapy precludes a clear attribution of the therapeutic effect. Beyond this isolated report, evidence directly supporting FMT in non-EoE EGIDs is lacking, and the relevant evidence is therefore obtained indirectly. Benitez et al[9] have demonstrated that both children and adults with EoE exhibit esophageal dysbiosis, characterized by an increased abundance of Haemophilus and a decreased abundance of Firmicutes compared with healthy controls. Although the pathogenesis of non-EoE EGIDs remains incompletely understood, the current view is that non-EoE EGIDs are closely linked to Th2-mediated allergic responses (such as interleukin-4, interleukin-5, and interleukin-13)[10], similar to EoE. FMT has already shown therapeutic promise in a variety of Th2-associated allergic diseases, such as atopic dermatitis, asthma, and food allergies. Its primary mechanism of action involves restoring healthy gut microbiota and their metabolites, thereby repairing the intestinal barrier and regulating systemic immune balance[11-13]. While these observations are intriguing, they cannot be directly extrapolated to non-EoE EGIDs without dedicated investigation. Several practical challenges must also be addressed before FMT can be reasonably considered for this population, including the lack of standardized donor screening and preparation protocols to minimize infection risk, the need for regulatory frameworks that balance patient safety with treatment access, and the uncertain durability of any potential clinical response in the absence of long-term follow-up data[14]. We advocate foundational studies to clarify whether gut microbial dysbiosis plays a causal role in disease pathogenesis or merely represents an epiphenomenon of inflammation, and to establish whether microbiota-targeted interventions can meaningfully modify disease course.

ANOTHER EXPLORATORY CONCEPT IS LEUKAPHERESIS

Approximately 80% of patients with non-EoE EGIDs present with marked peripheral eosinophilia[15], and eosinophil counts may correlate with disease severity and multi-organ involvement[16]. Because eosinophil-mediated tissue injury is considered a key pathogenic mechanism[6], temporary reduction in circulating eosinophils may alleviate symptoms in selected patients with marked eosinophilia. Leukapheresis has already been used in the treatment of hypereosinophilic syndrome[17], producing transient reductions in eosinophil counts. However, this approach should be regarded as a potential adjunct for acute symptom control rather than a maintenance strategy, and its role in non-EoE EGIDs has not been established. Therefore, we propose that further evaluation should be conducted in pilot trials with well-defined endpoints to assess its efficacy, safety, and clinical relevance.

To clarify how each strategy can be applied, we propose matching them to different patient subgroups. In patients with suspected deeper-layer involvement, obstructive symptoms, unexplained ascites, or discordance between symptom severity and mucosal biopsy findings, we suggest EUS as a diagnostic adjunct to clarify the depth of infiltration. In contrast, FMT may serve as a potential adjunct therapy for patients with dysbiosis-associated or treatment-refractory disease. Given its transient effect, leukapheresis is best reserved for carefully selected patients with severe peripheral eosinophilia and severe symptoms, potentially functioning as a rescue intervention for acute symptom control rather than as maintenance therapy. Importantly, none of these approaches should be viewed as a replacement for established treatments, including empiric elimination diets, corticosteroids, and biologic agents. All the diagnostic and therapeutic strategies mentioned above require systematic evaluation in prospective studies before clinical application can be considered. Currently, biologics and other established therapies remain the mainstay of management for non-EoE EGIDs.

CONCLUSION

In conclusion, we propose that EUS-guided disease stratification, FMT, and leukapheresis represent promising adjunctive diagnostic and therapeutic strategies that warrant further investigation in non-EoE EGIDs. However, current evidence remains limited, and further validation through mechanistic studies, prospective observational cohorts, and carefully designed pilot trials is needed to assess their feasibility and safety. By integrating precise disease stratification with well-validated therapeutic strategies and tailoring treatment according to infiltration depth, peripheral eosinophil count, and prior treatment response, we hope to move toward more individualized management.