Diagnosis of eosinophilic esophagitis (EoE), per consensus recommendations, requires clinical symptoms, more than15 eosinophils/high-power microscopic field, and a failed proton pump inhibitor (PPI) trial. However, 30% to 50% of patients with esophageal eosinophilia respond to PPI monotherapy despite their EoE-like clinical features. This new clinical entity, referred to as PPI-responsive esophageal eosinophilia (PPI-REE), poses a diagnostic dilemma. Using the recently validated “EoE diagnostic panel” comprising 94 EoE-associated genes, Wen et al (p 187
) comparatively characterized the molecular signatures of PPI-REE and EoE. Their novel findings demonstrate that untreated PPI-REE has an allergic/TH
2 signature that largely overlaps with the EoE transcriptome. Moreover, PPI monotherapy alone was sufficient to normalize PPI-REE's EoE-like signature, including mast cell genes and markers of impaired barrier function. The authors propose that a cluster of genes might predict whether a patient with esophageal eosinophilia will respond to a PPI, which could alter current clinical paradigms and practice. With its striking EoE-like allergic/TH
2 cause, PPI-REE should be re-evaluated as an allergic subentity of EoE, with antiallergic treatment considered in addition to PPIs. These interesting and transformative findings call for future genome-wide comparison and large-scale validation of the predictive genes of PPI responsiveness identified by the authors.