Eosinophilic Esophagitis Without Abundant Eosinophils? The Expanding Spectrum of a Disease That Is Difficult to Define

In 2007, the American Gastroenterological Association (AGA) provided a systematic review and consensus recommendations for the diagnosis and treatment of eosinophilic esophagitis (EoE) [1]. At that time, EoE was defined as a distinct clinical and pathologic entity characterized by the presence of clinical symptoms of esophageal dysfunction, an absence of gastroesophageal reflux disease (GERD) by either lack of response to proton pump inhibitor (PPI) therapy or normal pH monitoring values of the distal esophagus, and documentation of C15 eosinophils per high power field (Eos/HPF) in mucosal biopsies of the esophagus. Since its original description in children, EoE is now recognized as a disorder of adults as well. EoE is believed to represent an immune mediated disease for a variety reasons, but primarily because of its known association with other hypersensitivity or allergic disorders, the beneficial effect to steroid therapy in many patients, and by an abundance of studies that have shown an association with T-helper 2 mediated immunity via the action of eotaxin-3 and cytokines IL-13 and IL-5 [2–4]. Although EoE likely represents an allergic disorder, ultimately, the underlying initiating and perpetuating pathogenetic mechanisms remain unknown, which is partly the reason why it is difficult to establish definitive clinical and pathologic diagnostic criteria. In fact, the number of patients diagnosed with EoE is steadily increasing, and although this may be partly due to increasing awareness of this entity among clinicians, unfortunately, due to the lack of standardized diagnostic criteria prior to 2007, interpretation and comparison of data from prior studies (pre 2007) is difficult. There is a growing body of data, mainly related to the pathology, pathogenesis, natural history, and effect of certain forms of treatment, to suggest that the diagnostic criteria put forth in 2007 for EoE was in need of revision. For instance, there is evidence to suggest that there is a potential pathogenetic (or synergistic) relationship between EoE and GERD, as exemplified by the recent identification of patients who have overlapping clinical and pathologic features. Several studies have shown that eosinophil counts in patients with GERD may reach, or even exceed, the levels often associated with EoE [5–8]. Conversely, it is now being increasingly recognized that some patients with clinical and endoscopic features of EoE, but without GERD, contain lower than the normal threshold numbers of peak Eos/HPF in their esophageal biopsies. Also interesting is the recent identification of a subgroup of patients with esophageal eosinophilia and with clinical/endoscopic symptoms of EoE who respond positively to PPI therapy, termed ‘‘PPI-responsive EoE.’’ For instance, Ngo et al. described three patients with dysphagia and food impaction and [20 Eos/HPF in their esophageal biopsies who, following treatment with PPI, became clinically asymptomatic, achieved normal endoscopic findings, and normal, or near normal, intraepithelial eosinophil counts [9]. A recent prospective study by Molina-Infante et al. [8] of 35 patients with C15 Eos/HPF also provided evidence that a subgroup of patients with EoE may respond to PPI therapy. This and other clinical and pathologic data suggest that there may be a pathogenetic link between EoE and GERD, and that the original criteria used to diagnose EoE was in need of revision. As a result, the 2011 updated consensus recommendations for EoE in children and adults has altered the definition of EoE as ‘‘a disorder that represents a L. A. Doyle R. D. Odze (&) Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA e-mail: rodze@partners.org