2015-09-11 20:46:51 UTC

PPI-Responsive Esophageal Eosinophilia: What Is It?

Sept. 9, 2015

Some 30 to 50 percent of patients with symptomatic esophageal eosinophilia respond to PPI therapy.

John Pandolfino

Stuart Jon Spechler, MD

Esophageal Diseases Center, Department of Medicine, VA North Texas Healthcare System, and the University of Texas Southwestern Medical Center, Dallas, Texas

This article originally appeared in the August/September 2015 issue of AGA Perspectives.

Eosinophilic esophagitis (EoE) is an immune-mediated disease manifested clinically by symptoms of dysphagia, heartburn and chest pain, and histologically by esophageal eosinophilia. Gastroesophageal reflux disease (GERD) can cause similar symptoms and histological abnormalities and, occasionally, it can be difficult to distinguish EoE from GERD. Before the recent recognition of a condition called “proton pump inhibitor responsive esophageal eosinophilia” (PPI-REE), we physicians thought we could make that distinction with a trial of PPI therapy.

PPIs became available for clinical use in the U.S. in 1989, and clinicians rapidly appreciated that these potent inhibitors of gastric acid secretion were remarkably effective for treating GERD. The first case series describing EoE as a unique, clinicopathologic syndrome distinct from GERD was published in 1993. Reports soon followed of similar patients with esophageal symptoms and eosinophilia who did not respond to PPIs, but who did respond to elemental diets and steroids. To characterize patients with this new esophageal disorder, early EoE investigators deemed it necessary to exclude GERD as the cause of esophageal eosinophilia, and a trial of PPIs seemed to be the most logical and convenient means to accomplish that goal.

Initially our rationale for a PPI trial seemed sound — since gastric acid inhibition was the only important effect of PPIs — then only an acid-peptic disorder like GERD could respond to them. In 2007, a consensus report from the AGA Institute defined EoE as a primary clinicopathologic disorder characterized by esophageal symptoms, esophageal biopsies showing ≥15 eosinophils per high-power field, and the absence of pathologic GERD as evidenced by normal esophageal pH monitoring or lack of response to PPIs. This definition implied that EoE and GERD were mutually exclusive disorders that could be distinguished by a trial of PPI therapy.

But the PPI waters surrounding EoE were already muddied by the time that consensus report was published. In 2006, a report from Children’s Hospital in Boston described three patients with esophageal symptoms and dense eosinophilia that resolved with PPI therapy, a finding initially construed as evidence that large numbers of eosinophils could be seen in peptic esophagitis. Later, in 2007, my colleagues and I published a report contending that the interaction between GERD and EoE might be complex, that the notion of establishing a clear distinction between the two disorders was too simplistic and that a favorable response to PPI therapy should not preclude a diagnosis of EoE.1

Subsequent studies showed that some patients with typical EoE symptoms and esophageal eosinophilia, but no evidence of GERD by endoscopy or esophageal pH monitoring, nevertheless responded clinically and histologically to PPIs. This condition, which we now call PPI-REE, is not rare. Some 30 to 50 percent of patients with symptomatic esophageal eosinophilia respond to PPI therapy. A number of studies have now shown that the clinical, endoscopic, histologic and esophageal gene expression features of PPI-REE and EoE are virtually identical, and multivariate analyses have not identified any feature that can distinguish PPI-REE from EoE.2


We generally do not define diseases by their response to a single medication.


There are at least two possible explanations for PPI-REE:

1. Despite normal endoscopic and pH monitoring studies, PPI-REE patients have GERD-induced esophageal eosinophilia that responds to PPIs.

2. PPI-REE patients have EoE that responds to anti-inflammatory effects of PPIs that are independent of their effects on gastric acid secretion. Drs. Edaire Cheng and Xi Zhang, from our laboratory in Dallas, have published data supporting the latter explanation.

EoE is an allergic disorder with manifestations mediated by allergic (Th2) cytokines such as IL-4 and IL-13. It is thought that eosinophils accumulate in the esophagus of EoE patients because Th2 cytokines stimulate the esophagus to secrete eotaxin-3, a potent eosinophil chemoattractant. Using cultures of esophageal squamous cells from EoE patients, Drs. Cheng and Zhang have shown that omeprazole, in concentrations readily achieved in blood with conventional dosing, blocks Th2 cytokine-stimulated eotaxin-3 secretion.3

By blocking esophageal production of this eosinophil chemoattractant, PPIs might decrease esophageal eosinophils and symptoms in EoE patients. This anti-inflammatory effect of PPIs is entirely independent of any effect on gastric acid secretion. However, it is also possible that subclinical acid reflux contributes to EoE pathogenesis and, by preventing that acid reflux, the antisecretory effects of PPIs also might benefit EoE patients. In either case, the notion that a positive response to PPIs precludes a diagnosis of EoE seems contrived and untenable.

We generally do not define diseases by their response to a single medication. For example, we do not consider mesalamine-responsive colitis a fundamentally different disease than ulcerative colitis that does not respond to mesalamine. Why do we do this for EoE when every clinical, histological and laboratory feature studied to date suggests that EoE and PPI-REE are the same disease? In my opinion, the major reason that investigators have created an arbitrary distinction between these conditions is the persistent notion that gastric acid inhibition is the only possible therapeutic effect of PPIs. This notion is so firmly entrenched in our collective medical psyche that we are reluctant to accept the premise that PPIs can do anything in the esophagus other than treat GERD. For now, a trial of PPIs for patients with symptomatic esophageal eosinophilia makes sense if for no other reason than it often works; 30 to 50 percent of patients get better, regardless of what we choose to call the condition. 

Dr. Spechler serves as a consultant for Takeda Pharmaceuticals and Interpace Diagnostics

References

1.Spechler SJ, Genta RM, Souza RF. Thoughts on the complex relationship between gastroesophageal reflux disease and eosinophilic esophagitis. Am J Gastroenterol 2007; 102:1301-6.

2.Dellon ES, Speck O, Woodward K, Gebhart JH, Madanick RD, Levinson S, Fritchie KJ, Woosley JT, Shaheen NJ. Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. Am J Gastroenterol 2013; 108:1854-60.

3. PDellon ES, Speck O, Woodward K, Gebhart JH, Madanick RD, Levinson S, Fritchie KJ, Woosley JT, Shaheen NJ. Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. Am J Gastroenterol 2013; 108:1854-60.

4. Franciosa M, Triadafilopoulos G, Mashimo H. Stretta Radiofrequency Treatment for GERD: A Safe and Effective Modality. Gastroenterol Res Pract 2013;2013:783815.

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