Digestive Diseases and Sciences

, Volume 57, Issue 5, pp 1413–1419 | Cite as

Transient PPI Responsive Esophageal Eosinophilia May Be a Clinical Sub-phenotype of Pediatric Eosinophilic Esophagitis

  • Ranjan DohilEmail author
  • Robert O. Newbury
  • Seema Aceves
Case Report



Eosinophilic esophagitis (EoE) and gastroesophageal reflux (GERD) both cause esophageal eosinophilia. Reports show that esophageal eosinophilia meeting criteria for EoE may respond to acid suppression mono-therapy. Consensus guidelines have termed this entity “PPI-responsive esophageal eosinophilia” (PPIRee) and recommend a trial with proton-pump inhibitors (PPIs) prior to a definitive EoE diagnosis. The mechanisms of PPIRee and whether this represents a sub-phenotype of GERD, a sub-phenotype of EoE, or its own distinct entity remain unclear.


A database search revealed children who had an initial histologic response to PPI monotherapy but had recurrence of esophageal eosinophilia and symptoms despite continued PPI therapy. In order to understand the patterns of esophageal inflammatory cells during PPI therapy we performed quantitative immunohistochemistry for mast cells, CD1a positive antigen presenting cells, and CD45RO memory T cells.


Four pediatric patients (mean age 9.5 years) had a mean peak eosinophil count of 52 eos/hpf which initially resolved completely during PPI mono-therapy. However, despite continued PPI therapy, endoscopic abnormalities and pan-esophageal eosinophilia recurred (mean peak eosinophil count of 64 eos/hpf). There was no seasonal variation or lack of PPI adherence that explained the return of eosinopihlia. Similar to eosinophilia, mastocytosis and CD45RO cells were transiently decreased during PPI therapy.


PPIs appear to be capable of transiently resolving multiple inflammatory cell subsets including eosinophils, mast cells, and CD45RO cells. Our data suggest that patients with PPIRee should have continued monitoring for EoE during PPI monotherapy. The numbers of patients in whom PPIRee is a transient phenomenon and whether PPIRee represents a sub-phenotype of EoE in children merits further investigation.


Proton-pump inhibitors Mast cells CD45RO cells 



The authors would like to thank Kevin Alford for his contributions in the laboratory and also Dr.’s Ikuo Hirano and Glen Furuta for their comments. Support was provided by a grant from The Hearst Foundation.


  1. 1.
    Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133:1342–1363.PubMedCrossRefGoogle Scholar
  2. 2.
    Winter HS, Madara JL, Stafford RJ, Grand RJ, Quinlan JE, Goldman H. Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology. 1982;83:818–823.PubMedGoogle Scholar
  3. 3.
    Noel RJ, Tipnis NA. Eosinophilic esophagitis—a mimic of GERD. Int J Pediatr Otorhinolaryngol. 2006;70:1147–1153.PubMedCrossRefGoogle Scholar
  4. 4.
    Aceves S, Newbury R, Dohil R, Schwimmer J, Bastian J. Distinguishing eosinophilic esophagitis in pediatric patients: clinical, endoscopic, and histologic features of an emerging disorder. J Clin Gastroenterol. 2007;41:252–256.PubMedCrossRefGoogle Scholar
  5. 5.
    Dellon ES, Gibbs WB, Fritchie KJ, et al. Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2009;7:1305–1313.PubMedCrossRefGoogle Scholar
  6. 6.
    Spechler SJ, Genta RM, Souza RF. Thoughts on the complex relationship between gastroesophageal reflux disease and eosinophilic esophagitis. Am J Gastroenterol. 2007;102:1301–1306.PubMedCrossRefGoogle Scholar
  7. 7.
    Steiner SJ, Gupta SK, Croffie JM, Fitzgerald JF. Correlation between number of eosinophils and reflux index on same day esophageal biopsy and 24 hour esophageal pH monitoring. Am J Gastroenterol. 2004;99:801–805.PubMedCrossRefGoogle Scholar
  8. 8.
    Ngo P, Furuta GT, Antonioli DA, Fox VL. Eosinophils in the esophagus—peptic or allergic eosinophilic esophagitis? Case series of three patients with esophageal eosinophilia. Am J Gastroenterol. 2006;101:1666–1670.PubMedCrossRefGoogle Scholar
  9. 9.
    Spergel JM, Brown-Whitehorn TF, Beausoleil JL, et al. 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr. 2009;48:30–36.PubMedCrossRefGoogle Scholar
  10. 10.
    Dranove JE, Horn DS, Davis MA, Kernek KM, Gupta SK. Predictors of response to proton pump inhibitor therapy among children with significant esophageal eosinophilia. J Pediatr. 2009;154:96–100.PubMedCrossRefGoogle Scholar
  11. 11.
    Sayej WN, Patel R, Baker RD, Tron E, Baker SS. Treatment with high-dose proton pump inhibitors helps distinguish eosinophilic esophagitis from noneosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2009;49:393–399.PubMedCrossRefGoogle Scholar
  12. 12.
    Molina-Infante J, Ferrando-Lamana L, Ripoll C, et al. Esophageal eosinophilic infiltration responds to proton pump inhibition in most adults. Clin Gastroenterol Hepatol. 2011;9:110–117.PubMedCrossRefGoogle Scholar
  13. 13.
    Peterson KA, Thomas KL, Hilden K, Emerson LL, Wills JC, Fang JC. Comparison of esomeprazole to aerosolized, swallowed fluticasone for eosinophilic esophagitis. Dig Dis Sci. 2010;55:1313–1319.PubMedCrossRefGoogle Scholar
  14. 14.
    Dellon ES, Chen X, Miller CR, et al. Tryptase staining of mast cells may differentiate eosinophilic esophagitis from gastroesophageal reflux disease. Am J Gastroenterol. 2011;106:264–271.PubMedCrossRefGoogle Scholar
  15. 15.
    Aceves SS, Chen D, Newbury RO, Dohil R, Bastian JF, Broide DH. Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-beta1, and increase esophageal smooth muscle contraction. J Allergy Clin Immunol. 2010;126:1198–1204.PubMedCrossRefGoogle Scholar
  16. 16.
    Aceves SS, Newbury RO, Dohil MA, Bastian JF, Dohil R. A symptom scoring tool for identifying pediatric patients with eosinophilic esophagitis and correlating symptoms with inflammation. Ann Allergy Asthma Immunol. 2009;103:401–406.PubMedCrossRefGoogle Scholar
  17. 17.
    Ngo P, Furuta G, Burks W. The pathobiology of eosinophilic gastroenteritis of childhood: is it really the eosinophil, allergic mediated, or something else? Curr Gastroenterol Rep. 2004;6:436–440.PubMedCrossRefGoogle Scholar
  18. 18.
    Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, Burks AW, Chehade M, Collins MH, Dellon ES, Dohil R, Falk GW, Gonsalves N, Gupta SK, Katzka DA, Lucendo AJ, Markowitz JE, Noel RJ, Odze RD, Putnam PE, Richter JE, Romero Y, Ruchelli E, Sampson HA, Schoepfer A, Shaheen NJ, Sicherer SH, Spechler S, Spergel JM, Straumann A, Wershil BK, Rothenberg ME, Aceves SS. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128(1):3–20.e6.Google Scholar
  19. 19.
    Shah A, Kagalwalla AF, Gonsalves N, Melin-Aldana H, Li BU, Hirano I. Histopathologic variability in children with eosinophilic esophagitis. Am J Gastroenterol. 2009;104:716–721.PubMedCrossRefGoogle Scholar
  20. 20.
    Remedios M, Campbell C, Jones DM, Kerlin P. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointest Endosc. 2006;63:3–12.PubMedCrossRefGoogle Scholar
  21. 21.
    Tobey NA, Hosseini SS, Argote CM, Dobrucali AM, Awayda MS, Orlando RC. Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium. Am J Gastroenterol. 2004;99:13–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Kottyan LC, Collier AR, Cao KH, et al. Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner. Blood. 2009;114:2774–2782.PubMedCrossRefGoogle Scholar
  23. 23.
    Korsapati H, Babaei A, Bhargava V, Dohil R, Quin A, Mittal RK. Dysfunction of the longitudinal muscles of the oesophagus in eosinophilic oesophagitis. Gut. 2009;58:1056–1062.PubMedCrossRefGoogle Scholar
  24. 24.
    Nurko S, Rosen R. Esophageal dysmotility in patients who have eosinophilic esophagitis. Gastrointest Endosc Clin N Am. 2008;18:73–89.PubMedCrossRefGoogle Scholar
  25. 25.
    Kwiatek MA, Hirano I, Kahrilas PJ, Rothe J, Luger D, Pandolfino JE. Mechanical properties of the esophagus in eosinophilic esophagitis. Gastroenterology. 2011;140:82–90.PubMedCrossRefGoogle Scholar
  26. 26.
    Roman S, Hirano I, Kwiatek MA, Gonsalves N, Chen J, Kahrilas PJ, Pandolfino JE. Manometric features of eosinophilic esophagitis in esophageal pressure topography. Neurogastroenterol Motil. 2011;23:208–214.Google Scholar
  27. 27.
    Roman S, Lin Z, Kwiatek MA, Pandolfino JE, Kahrilas PJ. Weak peristalsis in esophageal pressure topography: classification and association with dysphagia. Am J Gastroenterol. 2010;106:349–356.PubMedCrossRefGoogle Scholar
  28. 28.
    Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. Dig Dis Sci. 2009;54:2312–2317.PubMedCrossRefGoogle Scholar
  29. 29.
    Mishra A, Hogan SP, Brandt EB, Rothenberg ME. An etiological role for aeroallergens and eosinophils in experimental esophagitis. J Clin Invest. 2001;107:83–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Almansa C, Krishna M, Buchner AM, et al. Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults. Am J Gastroenterol. 2009;104:828–833.PubMedCrossRefGoogle Scholar
  31. 31.
    Wang FY, Gupta SK, Fitzgerald JF. Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children? J Clin Gastroenterol. 2007;41:451–453.PubMedCrossRefGoogle Scholar
  32. 32.
    Fogg MI, Ruchelli E, Spergel JM. Pollen and eosinophilic esophagitis. J Allergy Clin Immunol. 2003;112:796–797.PubMedCrossRefGoogle Scholar
  33. 33.
    Biswas K, Bandyopadhyay U, Chattopadhyay I, Varadaraj A, Ali E, Banerjee RK. A novel antioxidant and antiapoptotic role of omeprazole to block gastric ulcer through scavenging of hydroxyl radical. J Biol Chem. 2003;278:10993–11001.PubMedCrossRefGoogle Scholar
  34. 34.
    Aceves SS, Newbury RO, Chen D, et al. Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy. 2010;65:109–116.PubMedCrossRefGoogle Scholar
  35. 35.
    Dohil R, Newbury R, Fox L, Bastian J, Aceves S. Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology. 2010;139:418–429.PubMedCrossRefGoogle Scholar
  36. 36.
    Saffari H, Clayton F, Fang JC, et al. Patchy eosinophil infiltration in an eosinophilic esophagectomy with implications for clinical biopsy ascertainment of EoE patients. Gastroenterology. 2011;5:S238.Google Scholar
  37. 37.
    Komazawa Y, Adachi K, Mihara T, et al. Tolerance to famotidine and ranitidine treatment after 14 days of administration in healthy subjects without Helicobacter pylori infection. J Gastroenterol Hepatol. 2003;18:678–682.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ranjan Dohil
    • 1
    • 2
    Email author
  • Robert O. Newbury
    • 1
    • 2
  • Seema Aceves
    • 1
    • 2
  1. 1.Departments of Pediatrics and PathologyUniversity of California, San DiegoLa JollaUSA
  2. 2.Rady’s Children’s HospitalSan DiegoUSA

Personalised recommendations