Table 4.

Outstanding questions and progress in the non-EoE EGID field

Question	Progress
How do we interpret eosinophil number in tissues that have eosinophils during homeostasis? How can we improve diagnosis for non-EoE EGID?	Consensus criteria are being established in a consensus process led by CEGIR.
Is the number of eosinophils a relevant parameter or, for instance, may localization of the eosinophilia or other histologic or molecular findings be more informative for disease assessment and outcomes and/or therapeutic endpoint assessment?	Histology Scoring Systems (HSS) that take into account a number of parameters in addition to eosinophils are being developed. Likewise, endoscopic scoring systems have been (e.g., EoG-EREFS) and are being developed. Molecular and cellular dissection of disease pathogenesis is developing a framework for disease biomarkers. Furthermore, patient-reported outcome (PRO) metrics are being developed and have been used in EoG/EoD clinical trials; their coimplementation with clinical care is a focus area.
Why do non-EoE EGID have lower prevalence than EoE? Are they underdiagnosed?	Prevalence studies are ongoing and have suggested that a combination of factors, including increased disease recognition and the allergy epidemic, are contributing to increased diagnosis of non-EoE EGID.
How do non-EoE EGIDs, IBS, DBGI (formerly FGID) relate? What does this mean for our understanding of non-EoE EGID?	A detailed analysis of eosinophil levels and type 2 immunity is currently underway; disease overlap may be present in some patients.
Why are some tissues affected and not others?	This is a cardinal question, and detailed studies of EoE suggest that tissue-specific, genetically defined pathways and susceptibility are involved.
Are there differences between resident and infiltrating eosinophils and their role in disease initiation, perpetuation, resolution, and/or recurrence?	Fundamental studies about eosinophil heterogeneity are revealing multiple populations of eosinophils, some with potential helpful properties (e.g., regulatory eosinophils). The role of eosinophil heterogeneity in EGID is an outstanding question.
Do the affected areas represent distinct diseases in a continuum or a spectrum?	Evidence is emerging that distinct tissue involvement in non-EoE EGID may represent a disease continuum, but this is a debated topic.
How do we separate functional dyspepsia, DBGI (e.g., IBS), and EGID?	In most clinical cases, a thorough histologic and pathologic evaluation will lead to the diagnosis of EGID. Moreover, clinicians with familiarity with non-EoE EGID clinical manifestation and appropriate medical workup are able to recognize and differentiate these diseases for clinical and research purposes. Detailed cellular, molecular, and neuro-immunologic characterization of these diseases will likely facilitate future diagnosis and patient phenotyping and endotyping.
What is the EoC disease course and does it differ from gastric and enteric EGID disease courses? What underlies EoC’s lower association with atopy relative to other non-EoE EGID?	Preliminary studies suggest a distinct etiology and disease course for EoC; more studies are needed.
What are appropriate endpoints to assess a treatment’s clinical benefit for each non-EoE EGID?	A series of broad outcome metrics spanning histologic, endoscopic, molecular, and clinical features are being developed. This is a focus area of CEGIR.
How can the development of approaches and assessments for “clinical benefit” for clinical trials and “meaningful benefit” for clinical practice be complementary?	Increasing dialogue between key stakeholders, including patients, researchers, and FDA and industry representatives, will be key in this regard.
What are appropriate endpoints to assess a treatment’s clinical benefit for each non-EoE EGID? How can non-invasive and QOL assessments be developed and/or validated for meaningful benefit for clinical practice?	A series of validated endpoints involving clinical, endoscopic, histologic, and molecular features are being developed and will likely prove to be valuable.