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Review

Proton Pump Inhibitor Therapy for Eosinophilic Esophagitis: History, Mechanisms, Efficacy, and Future Directions

ORCID Icon, , , ORCID Icon, , & show all
Pages 281-302 | Published online: 26 Feb 2022

References

  • Dellon ES, Liacouras CA, Molina-Infante J, et al. Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference. Gastroenterology. 2018;155:1022–1033 e10. doi:10.1053/j.gastro.2018.07.009
  • Mougey EB, Nguyen V, Gutierrez-Junquera C, et al. STAT6 variants associate with relapse of eosinophilic esophagitis in patients receiving long-term proton pump inhibitor therapy. Clin Gastroenterol Hepatol. 2020;19:2046–2053.e2. doi:10.1016/j.cgh.2020.08.020
  • Mougey EB, Williams A, Coyne AJK, et al. CYP2C19 and STAT6 variants influence the outcome of proton pump inhibitor therapy in pediatric eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2019;69:581–587. doi:10.1097/MPG.0000000000002480
  • Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med. 2015;373:1640–1648. doi:10.1056/NEJMra1502863
  • Navarro P, Arias A, Arias-Gonzalez L, et al. Systematic review with meta-analysis: the growing incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies. Aliment Pharmacol Ther. 2019;49:1116–1125. doi:10.1111/apt.15231
  • O’Shea KM, Aceves SS, Dellon ES, et al. Pathophysiology of Eosinophilic Esophagitis. Gastroenterology. 2018;154:333–345. doi:10.1053/j.gastro.2017.06.065
  • Hirano I, Chan ES, Rank MA, et al. AGA institute and the joint task force on allergy-immunology practice parameters clinical guidelines for the management of eosinophilic esophagitis. Gastroenterology. 2020;158:1776–1786. doi:10.1053/j.gastro.2020.02.038
  • 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. doi:10.1053/j.gastro.2007.08.017
  • Muir AB, Merves J, Liacouras CA. Role of endoscopy in diagnosis and management of pediatric eosinophilic esophagitis. Gastrointest Endosc Clin N Am. 2016;26:187–200. doi:10.1016/j.giec.2015.08.006
  • Friedlander JA, Fleischer DM, Black JO, et al. Unsedated transnasal esophagoscopy with virtual reality distraction enables earlier monitoring of dietary therapy in eosinophilic esophagitis. J Allergy Clin Immunol Pract. 2021;9:3494–3496. doi:10.1016/j.jaip.2021.06.030
  • Schoepfer AM, Safroneeva E, Bussmann C, et al. Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology. 2013;145:1230–6 e1-2. doi:10.1053/j.gastro.2013.08.015
  • Dellon ES, Kim HP, Sperry SL, et al. A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease. Gastrointest Endosc. 2014;79:577–85 e4. doi:10.1016/j.gie.2013.10.027
  • Attwood SE, Smyrk TC, Demeester TR, et al. Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome. Dig Dis Sci. 1993;38:109–116. doi:10.1007/BF01296781
  • Straumann A, Spichtin HP, Bernoulli R, et al. [Idiopathic eosinophilic esophagitis: a frequently overlooked disease with typical clinical aspects and discrete endoscopic findings]. Schweiz Med Wochenschr. 1994;124:1419–1429. German.
  • Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology. 1995;109:1503–1512. doi:10.1016/0016-5085(95)90637-1
  • Liacouras CA, Wenner WJ, Brown K, et al. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr. 1998;26:380–385. doi:10.1097/00005176-199804000-00004
  • Faubion WA, Perrault J, Burgart LJ, et al. Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr. 1998;27:90–93. doi:10.1097/00005176-199807000-00016
  • Dellon ES, Aderoju A, Woosley JT, et al. Variability in diagnostic criteria for eosinophilic esophagitis: a systematic review. Am J Gastroenterol. 2007;102:2300–2313. doi:10.1111/j.1572-0241.2007.01396.x
  • Ngo P, Furuta GT, Antonioli DA, et al. Eosinophils in the esophagus–peptic or allergic eosinophilic esophagitis? Case series of three patients with esophageal eosinophilia. Am J Gastroenterol. 2006;101:1666–1670. doi:10.1111/j.1572-0241.2006.00562.x
  • Dranove JE, Horn DS, Davis MA, et al. Predictors of response to proton pump inhibitor therapy among children with significant esophageal eosinophilia. J Pediatr. 2009;154:96–100. doi:10.1016/j.jpeds.2008.07.042
  • Sayej WN, Patel R, Baker RD, et al. Treatment with high-dose proton pump inhibitors helps distinguish eosinophilic esophagitis from noneosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2009;49:393–399. doi:10.1097/MPG.0b013e31819c4b3e
  • 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. doi:10.1016/j.cgh.2010.09.019
  • Dellon ES, Gonsalves N, Hirano I, et al. ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol. 2013;108:679–92; quiz 693. doi:10.1038/ajg.2013.71
  • Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128:3–20 e6; quiz 21–2. doi:10.1016/j.jaci.2011.02.040
  • Rodrigo S, Abboud G, Oh D, et al. High intraepithelial eosinophil counts in esophageal squamous epithelium are not specific for eosinophilic esophagitis in adults. Am J Gastroenterol. 2008;103:435–442. doi:10.1111/j.1572-0241.2007.01594.x
  • Molina-Infante J, Lucendo AJ. Proton pump inhibitor therapy for eosinophilic esophagitis: a paradigm shift. Am J Gastroenterol. 2017;112:1770–1773. doi:10.1038/ajg.2017.404
  • Wen T, Dellon ES, Moawad FJ, et al. Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. J Allergy Clin Immunol. 2015;135:187–197. doi:10.1016/j.jaci.2014.08.043
  • Molina-Infante J, Bredenoord AJ, Cheng E, et al. Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut. 2016;65:524–531. doi:10.1136/gutjnl-2015-310991
  • Sodikoff J, Hirano I. Proton pump inhibitor-responsive esophageal eosinophilia does not preclude food-responsive eosinophilic esophagitis. J Allergy Clin Immunol. 2016;137:631–633. doi:10.1016/j.jaci.2015.07.008
  • Lucendo AJ, Molina-Infante J, Arias A, et al. Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults. United Eur Gastroenterol J. 2017;5:335–358. doi:10.1177/2050640616689525
  • Asher wolf W, Dellon ES. Eosinophilic esophagitis and proton pump inhibitors: controversies and implications for clinical practice. Gastroenterol Hepatol (N Y). 2014;10:427–432.
  • 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. doi:10.1111/j.1572-0241.2007.01179.x
  • Yoshida N, Yoshikawa T, Tanaka Y, et al. A new mechanism for anti-inflammatory actions of proton pump inhibitors–inhibitory effects on neutrophil-endothelial cell interactions. Aliment Pharmacol Ther. 2000;14(Suppl 1):74–81. doi:10.1046/j.1365-2036.2000.014s1074.x
  • Odiase E, Zhang X, Chang Y, et al. In esophageal squamous cells from eosinophilic esophagitis patients, Th2 cytokines increase eotaxin-3 secretion through effects on intracellular calcium and a non-gastric proton pump. Gastroenterology. 2021;160:2072–2088 e6. doi:10.1053/j.gastro.2021.02.016
  • Rochman M, Xie YM, Mack L, et al. Broad transcriptional response of the human esophageal epithelium to proton pump inhibitors. J Allergy Clin Immunol. 2021;147:1924–1935. doi:10.1016/j.jaci.2020.09.039
  • Zhang X, Cheng E, Huo X, et al. Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic esophagitis cells. PLoS One. 2012;7:e50037. doi:10.1371/journal.pone.0050037
  • Cheng E, Zhang X, Huo X, et al. Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD. Gut. 2013;62:824–832. doi:10.1136/gutjnl-2012-302250
  • Caviglia R, Ribolsi M, Maggiano N, et al. Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure. Am J Gastroenterol. 2005;100:543–548. doi:10.1111/j.1572-0241.2005.40978.x
  • Ravelli AM, Villanacci V, Ruzzenenti N, et al. Dilated intercellular spaces: a major morphological feature of esophagitis. J Pediatr Gastroenterol Nutr. 2006;42:510–515. doi:10.1097/01.mpg.0000215312.78664.b9
  • Solcia E, Villani L, Luinetti O, et al. Altered intercellular glycoconjugates and dilated intercellular spaces of esophageal epithelium in reflux disease. Virchows Arch. 2000;436:207–216. doi:10.1007/s004280050032
  • Tobey NA, Carson JL, Alkiek RA, et al. Dilated intercellular spaces: a morphological feature of acid reflux–damaged human esophageal epithelium. Gastroenterology. 1996;111:1200–1205. doi:10.1053/gast.1996.v111.pm8898633
  • Villanacci V, Grigolato PG, Cestari R, et al. Dilated intercellular spaces as markers of reflux disease: histology, semiquantitative score and morphometry upon light microscopy. Digestion. 2001;64:1–8. doi:10.1159/000048833
  • Blanchard C, Stucke EM, Burwinkel K, et al. Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. J Immunol. 2010;184:4033–4041. doi:10.4049/jimmunol.0903069
  • Souza RF, Huo X, Mittal V, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009;137:1776–1784. doi:10.1053/j.gastro.2009.07.055
  • Blevins CH, Sharma AN, Johnson ML, et al. Influence of reflux and central obesity on intercellular space diameter of esophageal squamous epithelium. United Eur Gastroenterol J. 2016;4:177–183. doi:10.1177/2050640615598426
  • Katzka DA, Ravi K, Geno DM, et al. Endoscopic mucosal impedance measurements correlate with eosinophilia and dilation of intercellular spaces in patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2015;13:1242–1248 e1. doi:10.1016/j.cgh.2014.12.032
  • Liu CC, Lee JW, Liu TT, et al. Relevance of ultrastructural alterations of intercellular junction morphology in inflamed human esophagus. J Neurogastroenterol Motil. 2013;19:324–331. doi:10.5056/jnm.2013.19.3.324
  • Orlando LA, Orlando RC. Dilated intercellular spaces as a marker of GERD. Curr Gastroenterol Rep. 2009;11:190–194. doi:10.1007/s11894-009-0030-6
  • Vela MF, Craft BM, Sharma N, et al. Refractory heartburn: comparison of intercellular space diameter in documented GERD vs. functional heartburn. Am J Gastroenterol. 2011;106:844–850. doi:10.1038/ajg.2010.476
  • Neumann H, Monkemuller K, Fry LC, et al. Intercellular space volume is mainly increased in the basal layer of esophageal squamous epithelium in patients with GERD. Dig Dis Sci. 2011;56:1404–1411. doi:10.1007/s10620-010-1458-0
  • Calabrese C, Fabbri A, Bortolotti M, et al. Dilated intercellular spaces as a marker of oesophageal damage: comparative results in gastro-oesophageal reflux disease with or without bile reflux. Aliment Pharmacol Ther. 2003;18:525–532. doi:10.1046/j.1365-2036.2003.01713.x
  • Farre R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut. 2011;60:885–892. doi:10.1136/gut.2010.233049
  • Xie C, Sifrim D, Li Y, et al. Esophageal baseline impedance reflects mucosal integrity and predicts symptomatic outcome with proton pump inhibitor treatment. J Neurogastroenterol Motil. 2018;24:43–50. doi:10.5056/jnm17032
  • Kessing BF, Bredenoord AJ, Weijenborg PW, et al. Esophageal acid exposure decreases intraluminal baseline impedance levels. Am J Gastroenterol. 2011;106:2093–2097. doi:10.1038/ajg.2011.276
  • van Rhijn BD, Weijenborg PW, Verheij J, et al. Proton pump inhibitors partially restore mucosal integrity in patients with proton pump inhibitor-responsive esophageal eosinophilia but not eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2014;12:1815–23 e2. doi:10.1016/j.cgh.2014.02.037
  • Lim LG, Neumann J, Hansen T, et al. Confocal endomicroscopy identifies loss of local barrier function in the duodenum of patients with Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2014;20:892–900. doi:10.1097/MIB.0000000000000027
  • Marietta EV, Geno DM, Smyrk TC, et al. Presence of intraepithelial food antigen in patients with active eosinophilic oesophagitis. Aliment Pharmacol Ther. 2017;45:427–433. doi:10.1111/apt.13877
  • Ravi A, Marietta EV, Geno DM, et al. Penetration of the esophageal epithelium by dust mite antigen in patients with eosinophilic esophagitis. Gastroenterology. 2019;157:255–256. doi:10.1053/j.gastro.2019.02.042
  • Collins MH. Histopathologic features of eosinophilic esophagitis and eosinophilic gastrointestinal diseases. Gastroenterol Clin North Am. 2014;43:257–268. doi:10.1016/j.gtc.2014.02.007
  • Sherrill JD, Kc K, Wu D, et al. Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol. 2014;7:718–729. doi:10.1038/mi.2013.90
  • Calabrese C, Bortolotti M, Fabbri A, et al. Reversibility of GERD ultrastructural alterations and relief of symptoms after omeprazole treatment. Am J Gastroenterol. 2005;100:537–542. doi:10.1111/j.1572-0241.2005.40476.x
  • Abdulnour-Nakhoul SM, Al-Tawil Y, Gyftopoulos AA, et al. Alterations in junctional proteins, inflammatory mediators and extracellular matrix molecules in eosinophilic esophagitis. Clin Immunol. 2013;148:265–278. doi:10.1016/j.clim.2013.05.004
  • Blevins CH, Iyer PG, Vela MF, et al. The esophageal epithelial barrier in health and disease. Clin Gastroenterol Hepatol. 2018;16:608–617. doi:10.1016/j.cgh.2017.06.035
  • Zihni C, Mills C, Matter K, et al. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016;17:564–580. doi:10.1038/nrm.2016.80
  • Tsukita S, Tanaka H, Tamura A. The claudins: from tight junctions to biological systems. Trends Biochem Sci. 2019;44:141–152. doi:10.1016/j.tibs.2018.09.008
  • Nguyen N, Fernando SD, Biette KA, et al. TGF-beta1 alters esophageal epithelial barrier function by attenuation of claudin-7 in eosinophilic esophagitis. Mucosal Immunol. 2018;11:415–426. doi:10.1038/mi.2017.72
  • D’Souza-Schorey C. Disassembling adherens junctions: breaking up is hard to do. Trends Cell Biol. 2005;15:19–26. doi:10.1016/j.tcb.2004.11.002
  • Green KJ, Jaiganesh A, Broussard JA. Desmosomes: essential contributors to an integrated intercellular junction network. F1000Res. 2019;8:2150. doi:10.12688/f1000research.20942.1
  • Politi E, Angelakopoulou A, Grapsa D, et al. Filaggrin and periostin expression is altered in eosinophilic esophagitis and normalized with treatment. J Pediatr Gastroenterol Nutr. 2017;65:47–52. doi:10.1097/MPG.0000000000001419
  • Jovov B, Que J, Tobey NA, et al. Role of E-cadherin in the pathogenesis of gastroesophageal reflux disease. Am J Gastroenterol. 2011;106:1039–1047. doi:10.1038/ajg.2011.102
  • Davis BP. Pathophysiology of eosinophilic esophagitis. Clin Rev Allergy Immunol. 2018;55:19–42. doi:10.1007/s12016-017-8665-9
  • Frazzoni M, Penagini R, Frazzoni L, et al. Role of reflux in the pathogenesis of eosinophilic esophagitis: comprehensive appraisal with off- and on PPI impedance-ph monitoring. Am J Gastroenterol. 2019;114:1606–1613. doi:10.14309/ajg.0000000000000379
  • Roan F, Obata-Ninomiya K, Ziegler SF. Epithelial cell-derived cytokines: more than just signaling the alarm. J Clin Invest. 2019;129:1441–1451. doi:10.1172/JCI124606
  • Afonina IS, Zhong Z, Karin M, et al. Limiting inflammation-the negative regulation of NF-kappaB and the NLRP3 inflammasome. Nat Immunol. 2017;18:861–869. doi:10.1038/ni.3772
  • Erger RA, Casale TB. Interleukin-8 is a potent mediator of eosinophil chemotaxis through endothelium and epithelium. Am J Physiol. 1995;268:L117–22. doi:10.1152/ajplung.1995.268.1.L117
  • Rot A, Krieger M, Brunner T, et al. RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. J Exp Med. 1992;176:1489–1495. doi:10.1084/jem.176.6.1489
  • Fahey E, Doyle SL. IL-1 family cytokine regulation of vascular permeability and angiogenesis. Front Immunol. 2019;10:1426. doi:10.3389/fimmu.2019.01426
  • Persad R, Huynh HQ, Hao L, et al. Angiogenic remodeling in pediatric EoE is associated with increased levels of VEGF-A, angiogenin, IL-8, and activation of the TNF-alpha-NFkappaB pathway. J Pediatr Gastroenterol Nutr. 2012;55:251–260. doi:10.1097/MPG.0b013e31824b6391
  • Barthel SR, Annis DS, Mosher DF, et al. Differential engagement of modules 1 and 4 of vascular cell adhesion molecule-1 (CD106) by integrins alpha4beta1 (CD49d/29) and alphaMbeta2 (CD11b/18) of eosinophils. J Biol Chem. 2006;281:32175–32187.
  • Min JY, Ocampo CJ, Stevens WW, et al. Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: possible role of the nongastric H,K-ATPase. J Allergy Clin Immunol. 2017;139:130–141 e11. doi:10.1016/j.jaci.2016.07.020
  • Uhlen M, Fagerberg L, Hallstrom BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419. doi:10.1126/science.1260419
  • Kewley RJ, Whitelaw ML, Chapman-Smith A. The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol. 2004;36:189–204. doi:10.1016/S1357-2725(03)00211-5
  • Esser C, Rannug A, Ma Q. The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol Rev. 2015;67:259–279. doi:10.1124/pr.114.009001
  • Fritsche E, Schafer C, Calles C, et al. Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci U S A. 2007;104:8851–8856. doi:10.1073/pnas.0701764104
  • Furue M, Hashimoto-Hachiya A, Tsuji G. Antioxidative phytochemicals accelerate epidermal terminal differentiation via the AHR-OVOL1 pathway: implications for atopic dermatitis. Acta Derm Venereol. 2018;98:918–923. doi:10.2340/00015555-3003
  • Magiatis P, Pappas P, Gaitanis G, et al. Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin. J Invest Dermatol. 2013;133:2023–2030. doi:10.1038/jid.2013.92
  • Takei K, Mitoma C, Hashimoto-Hachiya A, et al. Antioxidant soybean tar Glyteer rescues T-helper-mediated downregulation of filaggrin expression via aryl hydrocarbon receptor. J Dermatol. 2015;42:171–180. doi:10.1111/1346-8138.12717
  • Furue M, Tsuji G, Mitoma C, et al. Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor. J Dermatol Sci. 2015;80:83–88. doi:10.1016/j.jdermsci.2015.07.011
  • Tsuji G, Hashimoto-Hachiya A, Kiyomatsu-Oda M, et al. Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis. Cell Death Dis. 2017;8:e2931. doi:10.1038/cddis.2017.322
  • van den Bogaard EH, Podolsky MA, Smits JP, et al. Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation. J Invest Dermatol. 2015;135:1320–1328. doi:10.1038/jid.2015.6
  • van den Bogaard EH, Bergboer JG, Vonk-Bergers M, et al. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J Clin Invest. 2013;123:917–927. doi:10.1172/JCI65642
  • Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol. 2019;19:184–197. doi:10.1038/s41577-019-0125-8
  • Barroso A, Mahler JV, Fonseca-Castro PH, et al. The aryl hydrocarbon receptor and the gut–brain axis. Cell Mol Immunol. 2021;18(2):259–268. doi:10.1038/s41423-020-00585-5
  • Quattrochi LC, Tukey RH. Nuclear uptake of the Ah (dioxin) receptor in response to omeprazole: transcriptional activation of the human CYP1A1 gene. Mol Pharmacol. 1993;43:504–508.
  • Curi-Pedrosa R, Daujat M, Pichard L, et al. Omeprazole and lansoprazole are mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture. J Pharmacol Exp Ther. 1994;269:384–392.
  • Hu W, Sorrentino C, Denison MS, et al. Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol. 2007;71:1475–1486. doi:10.1124/mol.106.032748
  • Vinit C, Dieme A, Courbage S, et al. Eosinophilic esophagitis: pathophysiology, diagnosis, and management. Arch Pediatr. 2019;26:182–190. doi:10.1016/j.arcped.2019.02.005
  • Molina-Infante J, Rivas MD, Hernandez-Alonso M, et al. Proton pump inhibitor-responsive oesophageal eosinophilia correlates with downregulation of eotaxin-3 and Th2 cytokines overexpression. Aliment Pharmacol Ther. 2014;40:955–965. doi:10.1111/apt.12914
  • Park JY, Zhang X, Nguyen N, et al. Proton pump inhibitors decrease eotaxin-3 expression in the proximal esophagus of children with esophageal eosinophilia. PLoS One. 2014;9:e101391. doi:10.1371/journal.pone.0101391
  • Iwakura N, Fujiwara Y, Tanaka F, et al. Basophil infiltration in eosinophilic oesophagitis and proton pump inhibitor-responsive oesophageal eosinophilia. Aliment Pharmacol Ther. 2015;41:776–784. doi:10.1111/apt.13141
  • Bolton SM, Kagalwalla AF, Arva NC, et al. Mast cell infiltration is associated with persistent symptoms and endoscopic abnormalities despite resolution of eosinophilia in pediatric eosinophilic esophagitis. Am J Gastroenterol. 2020;115:224–233. doi:10.14309/ajg.0000000000000474
  • Kanagaratham C, El Ansari YS, Sallis BF, et al. Omeprazole inhibits IgE-mediated mast cell activation and allergic inflammation induced by ingested allergen in mice. J Allergy Clin Immunol. 2020;146:884–893 e5. doi:10.1016/j.jaci.2020.02.032
  • Lucendo AJ, Arias A, Molina-Infante J. Efficacy of proton pump inhibitor drugs for inducing clinical and histologic remission in patients with symptomatic esophageal eosinophilia: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2016;14:13–22 e1. doi:10.1016/j.cgh.2015.07.041
  • Peterson KA, Thomas KL, Hilden K, et al. Comparison of esomeprazole to aerosolized, swallowed fluticasone for eosinophilic esophagitis. Dig Dis Sci. 2010;55:1313–1319. doi:10.1007/s10620-009-0859-4
  • Moawad FJ, Veerappan GR, Dias JA, et al. Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for esophageal eosinophilia. Am J Gastroenterol. 2013;108:366–372. doi:10.1038/ajg.2012.443
  • Mangla S, Goldin AH, Singal G, et al. Endoscopic features and eosinophil density are associated with food impaction in adults with esophageal eosinophilia. Dig Dis Sci. 2016;61:2578–2584. doi:10.1007/s10620-016-4190-6
  • Dellon ES, Speck O, Woodward K, et al. 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;108:1854–1860. doi:10.1038/ajg.2013.363
  • Fujiwara Y, Sugawa T, Tanaka F, et al. A multicenter study on the prevalence of eosinophilic esophagitis and PPI-responsive esophageal eosinophilic infiltration. Intern Med. 2012;51:3235–3239. doi:10.2169/internalmedicine.51.8670
  • Francis DL, Foxx-Orenstein A, Arora AS, et al. Results of ambulatory pH monitoring do not reliably predict response to therapy in patients with eosinophilic oesophagitis. Aliment Pharmacol Ther. 2012;35:300–307. doi:10.1111/j.1365-2036.2011.04922.x
  • Vazquez-Elizondo G, Ngamruengphong S, Khrisna M, et al. The outcome of patients with oesophageal eosinophilic infiltration after an eight-week trial of a proton pump inhibitor. Aliment Pharmacol Ther. 2013;38:1312–1319. doi:10.1111/apt.12513
  • Martinek A, Spicak J, Spicak J, Spicak J, Spicak J. Treatment with proton pump inhibitors is effective in a majority of adults patients with eosinophilic esophagitis. Gastroenterology. 2013;144:S493. doi:10.1016/S0016-5085(13)61823-5
  • Gomez-Torrijos E, Garcia-Rodriguez R, Castro-Jimenez A, et al. The efficacy of step-down therapy in adult patients with proton pump inhibitor-responsive oesophageal eosinophilia. Aliment Pharmacol Ther. 2016;43:534–540. doi:10.1111/apt.13496
  • Philpott H, Nandurkar S, Royce SG, et al. A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis. Aliment Pharmacol Ther. 2016;43:985–993. doi:10.1111/apt.13576
  • DiGiovanni EL, Champeaux AL, Arroyo MR, et al. Esophageal eosinophilia treated with long-duration proton pump inhibitor therapy. ACG Case Rep J. 2016;3:95–97. doi:10.14309/crj.2016.11
  • Potter JW, Saeian K, Staff D, et al. Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features. Gastrointest Endosc. 2004;59:355–361. doi:10.1016/S0016-5107(03)02713-5
  • Nantes Castillejo O, Zozaya JM, Jimenez-Perez FJ, et al. [Incidence and characteristics of eosinophilic esophagitis in adults]. An Sist Sanit Navar. 2009;32:227–234. Spanish. doi:10.23938/ASSN.0161
  • Garrean CP, Zhang Q, Gonsalves N, et al. Acid reflux detection and symptom-reflux association using 4-day wireless pH recording combining 48-hour periods off and on PPI therapy. Am J Gastroenterol. 2008;103:1631–1637. doi:10.1111/j.1572-0241.2008.01829.x
  • Jung YM, Lee HS, Lee DH, et al. [Clinical significance of incidentally detected eosinophilic esophagitis with pathologic review]. Korean J Gastroenterol. 2010;55:162–168. Korean. doi:10.4166/kjg.2010.55.3.162
  • Abe Y, Iijima K, Ohara S, et al. A Japanese case series of 12 patients with esophageal eosinophilia. J Gastroenterol. 2011;46:25–30. doi:10.1007/s00535-010-0295-4
  • Levy AN, Rahaman SM, Bonis PA, et al. Hiccups as a presenting symptom of eosinophilic esophagitis. Case Rep Gastroenterol. 2012;6:340–343. doi:10.1159/000338739
  • Tomomatsu Y, Yoshino J, Inui K, et al. Clinical features of eosinophilic esophagitis: ten Japanese cases. Dig Endosc. 2013;25:117–124. doi:10.1111/j.1443-1661.2012.01340.x
  • Lee JH, Kim MJ, Kim JH, et al. Clinical analysis of primary eosinophilic esophagitis. J Neurogastroenterol Motil. 2013;19:204–209. doi:10.5056/jnm.2013.19.2.204
  • Lipka S, Muhammad A, Champeaux A, et al. Case report of proton pump inhibitor responsive esophageal eosinophilia: why 2 months of proton pump inhibitors is required. Dis Esophagus. 2016;29:700–703. doi:10.1111/dote.12237
  • Ahn B, Lee DH, Lee CM, et al. [Proton pump inhibitor-responsive esophageal eosinophilia: an overview of cases from One University Hospital Center]. Korean J Gastroenterol. 2016;67:178–182. Korean. doi:10.4166/kjg.2016.67.4.178
  • Frazzoni M, Frazzoni L, De Bortoli N, et al. Response of eosinophilic oesophagitis to proton pump inhibitors is associated with impedance-pH parameters implying anti-reflux mechanism of action. Aliment Pharmacol Ther. 2021;53:1183–1189. doi:10.1111/apt.16371
  • Peterson KA, Yoshigi M, Hazel MW, et al. RNA sequencing confirms similarities between PPI-responsive oesophageal eosinophilia and eosinophilic oesophagitis. Aliment Pharmacol Ther. 2018;48:219–225. doi:10.1111/apt.14825
  • Laserna-Mendieta EJ, Casabona S, Guagnozzi D, et al. Efficacy of proton pump inhibitor therapy for eosinophilic oesophagitis in 630 patients: results from the EoE connect registry. Aliment Pharmacol Ther. 2020;52:798–807. doi:10.1111/apt.15957
  • Eke R, Li T, White A, et al. Systematic review of histological remission criteria in eosinophilic esophagitis. JGH Open. 2018;2:158–165. doi:10.1002/jgh3.12059
  • McElhiney J, Lohse MR, Arora AS, et al. The Mayo Dysphagia Questionnaire-30: documentation of reliability and validity of a tool for interventional trials in adults with esophageal disease. Dysphagia. 2010;25:221–230. doi:10.1007/s00455-009-9246-8
  • Laserna-Mendieta EJ, FitzGerald JA, Arias-Gonzalez L, et al. Esophageal microbiome in active eosinophilic esophagitis and changes induced by different therapies. Sci Rep. 2021;11:7113. doi:10.1038/s41598-021-86464-z
  • Rank MA, Sharaf RN, Furuta GT, et al. Technical review on the management of eosinophilic esophagitis: a report from the AGA institute and the joint task force on allergy-immunology practice parameters. Gastroenterology. 2020;158:1789–1810 e15. doi:10.1053/j.gastro.2020.02.039
  • Sultan S, Falck-Ytter Y, Inadomi JM. The AGA institute process for developing clinical practice guidelines part one: grading the evidence. Clin Gastroenterol Hepatol. 2013;11:329–332. doi:10.1016/j.cgh.2013.02.001
  • Reed CC, Wolf WA, Cotton CC, et al. Optimal histologic cutpoints for treatment response in patients with eosinophilic esophagitis: analysis of data from a prospective cohort study. Clin Gastroenterol Hepatol. 2018;16:226–233 e2. doi:10.1016/j.cgh.2017.09.046
  • Molina-Infante J, Rodriguez-Sanchez J, Martinek J, et al. Long-term loss of response in proton pump inhibitor-responsive esophageal eosinophilia is uncommon and influenced by CYP2C19 genotype and rhinoconjunctivitis. Am J Gastroenterol. 2015;110:1567–1575. doi:10.1038/ajg.2015.314
  • Thakkar M, Keene S, Dellon ES, Dellon ES. Long-term outcomes and durability of response of proton pump inhibitor treatment in eosinophilic esophagitis. Gastroenterology. 2021;160:S-256:S-257. doi:10.1016/S0016-5085(21)01351-2
  • Agency for Healthcare Research and Quality. 2019 Prescribed Medicines. Medical Expenditure Panel Survey (MEPS). Rockville, MD: Agency for Healthcare Research and Quality; 2021.
  • Business Wire. Global Proton Pump Inhibitors Market to Surpass US$ 3.5 Billion by 2027, Says Coherent Market Insights (CMI). Seattle, WA: Business Wire; 2020.
  • Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology. 2010;139:1115–1127. doi:10.1053/j.gastro.2010.08.023
  • Brisebois S, Merati A, Giliberto JP. Proton pump inhibitors: review of reported risks and controversies. Laryngoscope Investig Otolaryngol. 2018;3:457–462. doi:10.1002/lio2.187
  • De Bruyne P, Ito S. Toxicity of long-term use of proton pump inhibitors in children. Arch Dis Child. 2018;103:78–82. doi:10.1136/archdischild-2017-314026
  • Administration USFaD. FDA drug safety communication: Clostridium difficile associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). 2012.
  • Administration USFaD. FDA drug safety communication: possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. 2011.
  • Administration USFaD. FDA drug safety communication: low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs), 2011.
  • Filion KB, Chateau D, Targownik LE, et al. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis. Gut. 2014;63:552–558. doi:10.1136/gutjnl-2013-304738
  • Giuliano C, Wilhelm SM, Kale-Pradhan PB. Are proton pump inhibitors associated with the development of community-acquired pneumonia? A meta-analysis. Expert Rev Clin Pharmacol. 2012;5:337–344. doi:10.1586/ecp.12.20
  • Nguyen PA, Islam M, Galvin CJ, et al. Meta-analysis of proton pump inhibitors induced risk of community-acquired pneumonia. Int J Qual Health Care. 2020;32:292–299. doi:10.1093/intqhc/mzaa041
  • Wang CH, Li CH, Hsieh R, et al. Proton pump inhibitors therapy and the risk of pneumonia: a systematic review and meta-analysis of randomized controlled trials and observational studies. Expert Opin Drug Saf. 2019;18:163–172. doi:10.1080/14740338.2019.1577820
  • Xun X, Yin Q, Fu Y, et al. Proton pump inhibitors and the risk of community-acquired pneumonia: an updated meta-analysis. Ann Pharmacother. 2021;10600280211039240. doi:10.1177/10600280211039240
  • Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther. 2011;34:1269–1281. doi:10.1111/j.1365-2036.2011.04874.x
  • Hafiz RA, Wong C, Paynter S, et al. The risk of community-acquired enteric infection in proton pump inhibitor therapy: systematic review and meta-analysis. Ann Pharmacother. 2018;52:613–622. doi:10.1177/1060028018760569
  • Vilcu AM, Sabatte L, Blanchon T, et al. Association between acute gastroenteritis and continuous use of proton pump inhibitors during winter periods of highest circulation of enteric viruses. JAMA Netw Open. 2019;2:e1916205. doi:10.1001/jamanetworkopen.2019.16205
  • Cheung KS, Leung WK. Long-term use of proton-pump inhibitors and risk of gastric cancer: a review of the current evidence. Therap Adv Gastroenterol. 2019;12:1756284819834511. doi:10.1177/1756284819834511
  • Li Z, Wu C, Li L, et al. Effect of long-term proton pump inhibitor administration on gastric mucosal atrophy: a meta-analysis. Saudi J Gastroenterol. 2017;23:222–228. doi:10.4103/sjg.SJG_573_16
  • Abbas MK, Zaidi ARZ, Robert CA, et al. The safety of long-term daily usage of a proton pump inhibitor: a literature review. Cureus. 2019;11:e5563. doi:10.7759/cureus.5563
  • Vengrus CS, Delfino VD, Bignardi PR. Proton pump inhibitors use and risk of chronic kidney disease and end-stage renal disease: systematic review and meta-analysis. Minerva Urol Nephrol. 2021;73. doi:10.23736/S2724-6051.21.04116-3
  • Wijarnpreecha K, Thongprayoon C, Chesdachai S, et al. Associations of proton-pump inhibitors and h2 receptor antagonists with chronic kidney disease: a meta-analysis. Dig Dis Sci. 2017;62:2821–2827. doi:10.1007/s10620-017-4725-5
  • Hussain S, Singh A, Habib A, et al. Proton pump inhibitors use and risk of chronic kidney disease: evidence-based meta-analysis of observational studies. Clin Epidemiol Glob Health. 2019;7:46–52. doi:10.1016/j.cegh.2017.12.008
  • Nochaiwong S, Ruengorn C, Awiphan R, et al. The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant. 2018;33:331–342. doi:10.1093/ndt/gfw470
  • Cheema E. Investigating the association of proton pump inhibitors with chronic kidney disease and its impact on clinical practice and future research: a review. J Pharm Policy Pract. 2019;12:6. doi:10.1186/s40545-019-0167-0
  • Peng CC, Tu YK, Lee GY, et al. Effects of proton pump inhibitors on glycemic control and incident diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2021;106:3354–3366. doi:10.1210/clinem/dgab353
  • Sanchez-Garcia A, Simental-Mendia M, Simental-Mendia LE. Effect of proton-pump inhibitors on glucose and insulin metabolism on patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Curr Pharm Des. 2020;26:4007–4013. doi:10.2174/1381612826666200523170718
  • Janetzki JL, Sykes MJ, Ward MB, et al. Proton pump inhibitors may contribute to progression or development of chronic obstructive pulmonary disease-a sequence symmetry analysis approach. J Clin Pharm Ther. 2021;46:1687–1694. doi:10.1111/jcpt.13520
  • Kikuchi S, Imai H, Tani Y, et al. Proton pump inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2020;8:CD013113. doi:10.1002/14651858.CD013113.pub2
  • Desai M, Nutalapati V, Srinivasan S, et al. Proton pump inhibitors do not increase the risk of dementia: a systematic review and meta-analysis of prospective studies. Dis Esophagus. 2020;33. doi:10.1093/dote/doaa041
  • Zhang Y, Liang M, Sun C, et al. Proton pump inhibitors use and dementia risk: a meta-analysis of cohort studies. Eur J Clin Pharmacol. 2020;76:139–147. doi:10.1007/s00228-019-02753-7
  • Zhang Y, Zhan J, Bao Q, et al. Possible dementia risk of proton pump inhibitors and H2 receptor blockers use in the treatment of Helicobacter pylori: a meta-analysis study. Med Hypotheses. 2020;144:109989. doi:10.1016/j.mehy.2020.109989
  • Wijarnpreecha K, Thongprayoon C, Panjawatanan P, et al. Proton pump inhibitors and risk of dementia. Ann Transl Med. 2016;4:240. doi:10.21037/atm.2016.06.14
  • Song YQ, Li Y, Zhang SL, et al. Proton pump inhibitor use does not increase dementia and Alzheimer’s disease risk: an updated meta-analysis of published studies involving 642305 patients. PLoS One. 2019;14:e0219213. doi:10.1371/journal.pone.0219213
  • Khan MA, Yuan Y, Iqbal U, et al. No association linking short-term proton pump inhibitor use to dementia: systematic review and meta-analysis of observational studies. Am J Gastroenterol. 2020;115:671–678. doi:10.14309/ajg.0000000000000500
  • Huang B, Huang Y, Li Y, et al. Adverse cardiovascular effects of concomitant use of proton pump inhibitors and clopidogrel in patients with coronary artery disease: a systematic review and meta-analysis. Arch Med Res. 2012;43:212–224. doi:10.1016/j.arcmed.2012.04.004
  • Niu Q, Wang Z, Zhang Y, et al. Combination use of clopidogrel and proton pump inhibitors increases major adverse cardiovascular events in patients with coronary artery disease: a meta-analysis. J Cardiovasc Pharmacol Ther. 2017;22:142–152. doi:10.1177/1074248416663647
  • Hu W, Tong J, Kuang X, et al. Influence of proton pump inhibitors on clinical outcomes in coronary heart disease patients receiving aspirin and clopidogrel: a meta-analysis. Medicine (Baltimore). 2018;97:e9638. doi:10.1097/MD.0000000000009638
  • Sun S, Cui Z, Zhou M, et al. Proton pump inhibitor monotherapy and the risk of cardiovascular events in patients with gastro-esophageal reflux disease: a meta-analysis. Neurogastroenterol Motil. 2017;29:e12926. doi:10.1111/nmo.12926
  • Sherwood MW, Melloni C, Jones WS, et al. Individual proton pump inhibitors and outcomes in patients with coronary artery disease on dual antiplatelet therapy: a systematic review. J Am Heart Assoc. 2015;4. doi:10.1161/JAHA.115.002245
  • Juurlink DN, Dormuth CR, Huang A, et al. Proton pump inhibitors and the risk of adverse cardiac events. PLoS One. 2013;8:e84890. doi:10.1371/journal.pone.0084890
  • Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology. 2019;157:682–691 e2. doi:10.1053/j.gastro.2019.05.056
  • Maggio M, Corsonello A, Ceda GP, et al. Proton pump inhibitors and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals. JAMA Intern Med. 2013;173:518–523. doi:10.1001/jamainternmed.2013.2851
  • Xie Y, Bowe B, Yan Y, et al. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 2019;365:l1580. doi:10.1136/bmj.l1580
  • Ben-Eltriki M, Green CJ, Maclure M, et al. Do proton pump inhibitors increase mortality? A systematic review and in-depth analysis of the evidence. Pharmacol Res Perspect. 2020;8:e00651. doi:10.1002/prp2.651
  • Brown JP, Tazare JR, Williamson E, et al. Proton pump inhibitors and risk of all-cause and cause-specific mortality: a cohort study. Br J Clin Pharmacol. 2021;87:3150–3161. doi:10.1111/bcp.14728
  • Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152:706–715. doi:10.1053/j.gastro.2017.01.031
  • Jena AB, Sun E, Goldman DP. Confounding in the association of proton pump inhibitor use with risk of community-acquired pneumonia. J Gen Intern Med. 2013;28:223–230. doi:10.1007/s11606-012-2211-5
  • Freedberg DE, Abrams JA. Does confounding explain the association between PPIs and Clostridium difficile-related diarrhea? Am J Gastroenterol. 2013;108:278–279. doi:10.1038/ajg.2012.395
  • Lima JJ, Thomas CD, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C19 and proton pump inhibitor dosing. Clin Pharmacol Ther. 2021;109:1417–1423. doi:10.1002/cpt.2015
  • Schroeder S, Capocelli KE, Masterson JC, et al. Effect of proton pump inhibitor on esophageal eosinophilia. J Pediatr Gastroenterol Nutr. 2013;56:166–172. doi:10.1097/MPG.0b013e3182716b7a
  • Rea F, Caldaro T, Tambucci R, et al. Eosinophilic esophagitis: is it also a surgical disease? J Pediatr Surg. 2013;48:304–308. doi:10.1016/j.jpedsurg.2012.11.006
  • Gutierrez-Junquera C, Fernandez-Fernandez S, Cilleruelo ML, et al. High prevalence of response to proton-pump inhibitor treatment in children with esophageal eosinophilia. J Pediatr Gastroenterol Nutr. 2016;62:704–710. doi:10.1097/MPG.0000000000001019
  • Gomez Torrijos E, Donado Palencia P, Sanchez Miranda MP, et al. Eosinophilic esophagitis: treatment with different doses of omeprazole in children under 16 years. J Investig Allergol Clin Immunol. 2018;28:191–192. doi:10.18176/jiaci.0230
  • Vieira GG, Ribeiro LBM, Truppel SK, et al. Endoscopic and histological characteristics in patients with eosinophilic esophagitis responsive and non-responsive to proton pump inhibitors. J Pediatr (Rio J). 2020;96:638–643. doi:10.1016/j.jped.2019.05.005
  • Dohil R, Newbury RO, Aceves S. Transient PPI responsive esophageal eosinophilia may be a clinical sub-phenotype of pediatric eosinophilic esophagitis. Dig Dis Sci. 2012;57:1413–1419. doi:10.1007/s10620-011-1991-5
  • Gutierrez-Junquera C, Fernandez-Fernandez S, Cilleruelo ML, et al. Long-term treatment with proton pump inhibitors is effective in children with eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2018;67:210–216. doi:10.1097/MPG.0000000000001952
  • Schmidt E, Peiper U. [Influence of initial stretch on the dynamics of vascular smooth muscle]. Pflugers Arch. 1972;333:314–325. German. doi:10.1007/BF00586211
  • Barron JJ, Tan H, Spalding J, et al. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr. 2007;45:421–427. doi:10.1097/MPG.0b013e31812e0149
  • Blank ML, Parkin L. National study of off-label proton pump inhibitor use among New Zealand Infants in the first year of life (2005–2012). J Pediatr Gastroenterol Nutr. 2017;65:179–184. doi:10.1097/MPG.0000000000001596
  • El Rouby N, Lima JJ, Johnson JA. Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine. Expert Opin Drug Metab Toxicol. 2018;14:447–460. doi:10.1080/17425255.2018.1461835
  • Kuhn BR, Young AJ, Justice AE, et al. Infant acid suppression use is associated with the development of eosinophilic esophagitis. Dis Esophagus. 2020;33. doi:10.1093/dote/doaa073
  • Jensen ET, Kuhl JT, Martin LJ, et al. Prenatal, intrapartum, and postnatal factors are associated with pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2018;141:214–222. doi:10.1016/j.jaci.2017.05.018
  • Canani RB, Cirillo P, Roggero P, et al. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006;117:e817–20. doi:10.1542/peds.2005-1655
  • Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66:516–554. doi:10.1097/MPG.0000000000001889
  • Rosh JR, Hassall E. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. J Pediatr Gastroenterol Nutr. 2006;43:545. doi:10.1097/01.mpg.0000239994.20270.a8
  • Lima JJ, Lang JE, Mougey EB, et al. Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects in children. J Pediatr. 2013;163:686–691. doi:10.1016/j.jpeds.2013.03.017
  • Wechsler JB, Hirano I. Biological therapies for eosinophilic gastrointestinal diseases. J Allergy Clin Immunol. 2018;142:24–31 e2. doi:10.1016/j.jaci.2018.05.018
  • Ko E, Chehade M. Biological therapies for eosinophilic esophagitis: where do we stand? Clin Rev Allergy Immunol. 2018;55:205–216. doi:10.1007/s12016-018-8674-3
  • Huang C, Chen L, Savage SR, et al. Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma. Cancer Cell. 2021;39:361–379 e16. doi:10.1016/j.ccell.2020.12.007
  • Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019;105:1095–1105. doi:10.1002/cpt.1304
  • Shoda T, Wen T, Aceves SS, et al. Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study. Lancet Gastroenterol Hepatol. 2018;3:477–488. doi:10.1016/S2468-1253(18)30096-7
  • Canas JA, Tabares A, Barbero C, et al. Proton-pump inhibitor response prediction using esophageal microRNAs in children with eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2020;71:755–763. doi:10.1097/MPG.0000000000002957
  • Cicali EJ, Blake K, Gong Y, et al. Novel implementation of genotype-guided proton pump inhibitor medication therapy in children: a pilot, randomized, multisite pragmatic trial. Clin Transl Sci. 2019;12:172–179. doi:10.1111/cts.12589
  • Jensen ET, Dellon ES. Environmental factors and eosinophilic esophagitis. J Allergy Clin Immunol. 2018;142:32–40. doi:10.1016/j.jaci.2018.04.015
  • Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36:1–48. doi:10.18637/jss.v036.i03
  • Garrean CP, Patil D, Gonsalves N, et al. S1860 comparison of endoscopic and histologic response in patients with eosinophilic esophagitis treated with proton pump inhibition, topical fluticasone, and dietary elimination. Gastroenterology. 2009;136:A–279. doi:10.1016/S0016-5085(09)61275-0
  • Mangla S, Singal G, Hornick JL, et al. Su1866 clinical predictors of response to proton pump inhibitors in patients with esophageal eosinophilia. Gastroenterology. 2013;144:S-495–S-496. doi:10.1016/S0016-5085(13)61831-4
  • Harris BR, Hon E, Gupta SK. Implementation of guidelines in eosinophilic esophagitis at an academic pediatric practice. Dis Esophagus. 2018;31. doi:10.1093/dote/doy029
  • Rosen I, Mahamed A, Garah J, et al. The management and course of eosinophilic oesophagitis in Israeli children. Acta Paediatr. 2021;110:1653–1657. doi:10.1111/apa.15746
  • Shoda T, Matsuda A, Nomura I, et al. Eosinophilic esophagitis versus proton pump inhibitor-responsive esophageal eosinophilia: transcriptome analysis. J Allergy Clin Immunol. 2017;139:2010–2013 e4. doi:10.1016/j.jaci.2016.11.028
  • Moawad FJ, Wells JM, Johnson RL, et al. Comparison of eotaxin-3 biomarker in patients with eosinophilic oesophagitis, proton pump inhibitor-responsive oesophageal eosinophilia and gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2015;42:231–238. doi:10.1111/apt.13258
  • Votto M, De Filippo M, Castagnoli R, et al. Non-invasive biomarkers of eosinophilic esophagitis. Acta Biomed. 2021;92:e2021530. doi:10.23750/abm.v92iS7.12401