The efficacy of step-down therapy in adult patients with proton pump inhibitor-responsive oesophageal eosinophilia

Transcription

1 Alimentary Pharmacology and Therapeutics The efficacy of step-down therapy in adult patients with proton pump inhibitor-responsive oesophageal eosinophilia E. Gomez-Torrijos*, R. Garcıa-Rodrıguez*, A. Castro-Jimenez*, J. Rodrıguez-Sanchez,Y.Mendez Dıaz* & J. Molina-Infante *Department of Allergy Hospital, General Universitario de Ciudad Real, Ciudad Real, Spain. Department of Gastroenterology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain. Department of Gastroenterology, Hospital San Pedro de Alcantara, Caceres, Spain. Correspondence to: Dr E. Gomez-Torrijos, Department of Allergy, Hospital General Universitario de Ciudad Real, C/ Obispo Rafael Torija s/n Ciudad Real, Spain. Publication data Submitted 12 August 2015 First decision 26 August 2015 Resubmitted 17 September 2015 Resubmitted 2 November 2015 Accepted 16 November 2015 EV Pub Online 10 December 2015 This article was accepted for publication after full peer-review. SUMMARY Background Proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE) is common in patients with suspected eosinophilic oesophagitis (EoE). However, the long-term efficacy of PPIs and the best maintenance doses are yet to be defined. Aim To evaluate the durability of the response to PPI therapy after tapering PPI doses in PPI-REE patients. Methods Prospective study conducted on PPI-REE patients. Upon complete remission on high-dose PPI therapy (omeprazole 40 mg b.d. for 8 weeks), PPI doses were tapered followed by an endoscopic procedure after each dose reduction. The primary outcomes were sustained clinical and histological remission (<15 eos/hpf) after decreasing PPI doses. Results From a total of 121 patients with suspected EoE, 40 (33%) achieved complete remission on high-dose PPIs and were given a diagnosis of PPI-REE. No patient in histological remission showed symptom relapse, but half of patients with relapsing oesophageal inflammation were in clinical remission. After reduction to omeprazole 40 mg once daily, 38/31 (81%) remained in complete remission. Among these latter patients, 15/18 (83%) were kept in remission with omeprazole 20 mg once daily. As for side effects, only asymptomatic hypertransaminasemia and oesophageal candidiasis were observed in two patients while receiving high doses of omeprazole. Conclusions Most PPI-responsive oesophageal eosinophilia patients show sustained clinical and histological remission with daily PPI doses equal to or below 40 mg of omeprazole. As adverse effects only appeared with the highest dose of omeprazole, it would be advisable to individualise the dose of PPIs for each patient, lowering it to the minimum capable of maintaining the disease controlled. Aliment Pharmacol Ther 2016; 43: doi: /apt.13496

2 PPI therapy step-down in PPI-responsive oesophageal eosinophilia INTRODUCTION The existence of proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE) was first reported in and the first prospective series published in , 3 Accordingly, the 2011 updated consensus recommendations for the diagnosis and management of eosinophilic oesophagitis (EoE) accepted the existence of this new entity referring to patients with clinical, endoscopic and histological features suggestive of EoE which fully remit on PPI therapy. A recent first meta-analysis comprising 619 patients has revealed that up to 50% of patients with symptomatic oesophageal eosinophilia compatible with EoE may achieve clinical and histological remission on PPI therapy. 4 Over the past few years, notable scientific advances have helped us to begin to gain an understanding of PPI-REE. Clinical, endoscopic, histological, molecular and genetic markers are indistinguishable between PPI-REE and EoE patients. 3, 5 10 Furthermore, PPIs have been shown their ability to downregulate Th2 inflammation 8 10 and the oesophageal transcriptome associated with EoE, 10 in the same way as topical corticosteroids do. As such, EoE and PPI-REE remain phenotypically, mechanistically and genetically indistinguishable, raising therefore concerns about whether PPI-REE is actually a subphenotype of EoE. 11 We do not know which dose of PPIs or for how long these drugs should be maintained in PPI-REE. An approach where the dose is progressively decreased to the lowest dose that keeps the disease in remission seems reasonable until more data are available. 12 Two recent randomised placebo-controlled trials have confirmed that a relevant proportion of patients lose previous complete response to topical steroids therapy after tapering maintenance doses. 13, 14 As for PPI-REE, available evidence on the sustained efficacy of PPIs is limited to two retrospective series, comprising six paediatric PPI-REE patients who all had recurrence of oesophageal eosinophilia and symptoms over time while on maintenance PPI therapy. 15, 16 These drugs have a good safety profile in both the short and long term, 17 although there have been several published papers on adverse effects of PPIs: allergy, 18 candidiasis, 19, 20 pneumonia, Clostridium difficile infection, osteoporosis, risk of fractures, thrombocytopenia, rhabdomyolysis, anaemia, iron deficiency, hypomagnesemia and nephritis, etc. 21 The aims of the present study were to determine the prevalence of PPI-REE in our geographical area, to assess the minimum PPI doses necessary to keep the disease in remission, and to monitor the occurrence of PPI-related side effects during follow-up. MATERIAL AND METHODS Patient selection and eligibility This was an observational prospective study including consecutive adult PPI-REE patients (>18 years old) evaluated in a multidisciplinary specialised EoE unit in a tertiary referral centre (Ciudad Real University Hospital) from January 2013 to June All included patients gave their written consent to participate in the study. The study was designed according to the principles of the Helsinki Declaration and was approved by the Ethics Committee of Ciudad Real University Hospital. PPI-REE was diagnosed upon symptoms of oesophageal dysfunction, infiltration of the oesophageal epithelium with at least 15 eosinophils per high power field, and clinical and histological remission (<15 eos/hpf) after high-dose PPI therapy (omeprazole 40 mg b.d. for 8 weeks). 1 Patients who had a history of other causes of oesophageal eosinophilia (drugs, inflammatory bowel disease, parasites, blood diseases, caustics) were excluded. PPI therapy was the first instituted treatment for all included patients, so no patient followed any specific treatment (topical steroid therapy, elimination diet) for EoE during the study. All patients received written information about their PPI treatment (drug, daily dose and duration of treatment). PPIs were given 30 min before breakfast and dinner when administered twice daily and 30 min before breakfast when given once daily. Patients were given a contact number and for possible questions. Dietary interventions and systemic/topical/inhaled corticosteroids were not allowed during the study period. Those patients who required treatment with bronchodilators such as B2 adrenergic agonists, anti-cholinergics and anti-histamines, due to exacerbation of atopic diseases (asthma and rhinitis), were not excluded from the analysis. Study design (PPI doses step-down approach) After documenting complete response to omeprazole 40 mg b.d. for 2 months, PPI doses were gradually tapered for a minimum of 8 weeks followed by an endoscopic procedure after each dose reduction. At first, patients received omeprazole 40 mg once daily. An intermediate dose of 60 mg of omeprazole was Aliment Pharmacol Ther 2016; 43:

3 E. Gomez-Torrijos et al. offered to all the patients who did not achieve total remission with 40 mg of omeprazole. Upon sustained clinical and histological response, patients were offered to taper PPI doses to omeprazole 20 mg once daily. Finally, a further reduction to omeprazole 20 mg once daily every other day was offered to those patients who kept in remission with omeprazole 20 mg/day. Clinical and histological assessment Symptoms were evaluated through the ELSA index (VAS-EoE score) 22 consisting of a nonvalidated visual analogue scale (0 10 points) for each of the seven most common symptoms of EoE in adults (dysphagia, chest pain, sensation of lump, regurgitation, heartburn, epigastric pain, impaction with solids). The overall score comes to the sum of each of the items (0 70 points). The intensity of each symptom was assessed as follows: 1 3 points (mild), 4 6 (moderate) and 7 10 (severe). A decrease >50% of baseline score after therapy was defined as clinical remission. All upper endoscopies were performed under propofol-based deep sedation. A minimum of eight biopsies (four from the distal third and four from the midupper oesophagus) were taken in each procedure, apart from gastric and duodenal biopsies in order to rule out eosinophilic gastroenteritis. Mucosal biopsy specimens were fixed in formalin, embedded in paraffin and stained with haematoxylin and eosin for pathological examination. One HPF had an area of 0.24 mm optical microscopy and 9400 magnification. The peak count of intraepithelial eosinophils/hpf was determined in the area of highest density of eosinophils by the most densely populated HPF and oesophageal eosinophilia was established upon the presence of 15 eos/hpf in at least one field. 1 Histological remission was defined by <15 eos/hpf (complete <5 eos/hpf at both distal and proximal oesophagus, partial 5 14 eos/hpf at one or both oesophageal sites). Both symptoms and oesophageal eosinophilia were measured at baseline and after each de-escalating dose in PPI therapy. Total remission was defined by both clinical and histological remission. Follow-up All the endoscopic procedures were performed at least 8 weeks after the institution of the new PPI doses. Symptoms and PPI-related side effects were checked through a specific questionnaire and blood test on a quarter basis for a 6-month period. RESULTS Baseline characteristics of PPI-REE patients From a series of 120 adult patients diagnosed with EoE, 40 patients (33%) achieved clinical and histological remission on high-dose PPI therapy and were given a diagnosis of PPI-REE. Baseline characteristics of these 40 patients are summarised in Table 1. Sustained response after tapering PPI doses No patient on histological remission during the de-escalating process showed symptom relapse. However, half of patients with relapsing oesophageal inflammation were on clinical remission. The results of the step-down in PPI doses process are displayed in Figure 1. Of the 40 patients with PPI- REE on high-dose, two patients refused to step-down PPI doses. The remaining 38 patients agreed to participate in the study. After tapering PPI doses to 40 mg once a day for 2 months, 31/38 (81%) remained in total remission. Three patients were treated with 60 mg of omeprazole and all of them achieved remission. Among these latter patients, 15/18 (83%) were kept in Table 1 Demographic, clinical and histological characteristic of the 40 PPI-REE patients included in the study, at baseline and after initial high-dose PPI therapy Demographics Sex (male/female) 25/15 Age, mean (range) 41 (15 68) Previous history of atopy (%) 33 (82.5) Symptoms ELSA score; mean (range) Baseline After PPI therapy Dysphagia 4.6 (0 9) 1.2 (0 7) Food impactions 4.7 (0 10) 1.2 (0 6) Regurgitation 2.3 (0 10) 0.7 (0 5) Lump in throat 4.2 (0 10) 0.6 (0 5) Heartburn 4.4 (0 10) 1.1 (0 6) Stomach pain 3.5 (0 10) 1.1 (0 5) Chest pain 1.9 (0 8) 0.3 (0 5) Histological findings eos/hpf, mean (range) Baseline After therapy Proximal oesophagus 32 (16 100) 2.4 (0 10) Distal oesophagus 69 (15 100) 3.1 (0 9) Basal hyperplasia (%) 15 (37.5) 3 (7.5) Endoscopic findings Baseline After therapy Furrows (%) 10 (25) 3 (7.5) Rings (%) 15 (37.5) 5 (12.5) Exudates (%) 5 (12.5) 1 (2.5) Oesophageal stenosis (%) 0 (0) 0 (0) 536 Aliment Pharmacol Ther 2016; 43:

4 PPI therapy step-down in PPI-responsive oesophageal eosinophilia remission with omeprazole 20 mg/day. Two of these patients still showed sustained remission with 20 mg every other day. Three patients that achieved partial remission refused to continue in the study (two with omeprazole 80 mg daily and one with omeprazole 20 mg daily) after been informed about the possibility of a reactivation of the oesophageal disease with a reduction in the dose of omeprazole. Other patients also left the study because they did not want to undergo new endoscopies, as they were asymptomatic (13/31 with omeprazole 40 mg daily and 12/14 with omeprazole 20 mg daily). Side effects Only an asymptomatic mild hypertransaminasemia (increase to twofold higher than normal) and an oesophageal candidiasis were observed in two different patients while on omeprazole 40 b.d. during the study. Both adverse events were reversed upon reducing PPI therapy doses, with addition of fluconazole in the latter patient. No side effects were observed with PPI doses equal to or below 40 mg of omeprazole once daily. DISCUSSION The present study demonstrates that a majority of PPI- REE patients diagnosed after a high-dose PPI initial trial (e.g. omeprazole 40 mg b.d.) show sustained clinical and histological remission on daily PPI doses equal to or below 40 mg of omeprazole. Therefore, response to PPI therapy in adult patients with symptomatic oesophageal eosinophilia may not be a transient phenomenon, as previously suggested in six paediatric patients. 15, 16 Our findings corroborate the results of the first long-term follow-up multicentre study including 75 PPI-REE patients, in which 73% of patients had sustained histological remission after 12 months or longer on tapering PPI doses to the minimum effective clinical dose. 22 The present study also provides valuable information regarding the minimum maintenance PPI dose necessary for this subset of patients. Evolving evidence underscores that EoE and PPI-REE share a common genetic (EoE diagnostic panel) and molecular (eotaxin-3 and Th2 markers) basis, responsible in EoE for persistent oesophageal inflammation and fibrostenotic long-term complications. 12, 23, 24 As such, it is highly conceivable that PPI-REE may require lifelong maintenance therapy and careful follow-up as provided in EoE. Whether 40 p PPI-REE 80 mg omeprazole daily (TR) 38 p TR 2 p PR 40 mg omeprazole daily 4 p PR 31p TR 3 p NR 60 mg omeprazole daily 3 p TR 13 p LS 18 p 20 mg omeprazol daily 1 p PR 3 p NR 14 p TR 2 p 10 mg omeprazol daily 2 p TR Figure 1 Results of the stepdown in PPI doses. 12 p LS p :patients; LS :leaving the study; NR: no remission; TR: total remission; PR: partial remission Aliment Pharmacol Ther 2016; 43:

5 E. Gomez-Torrijos et al. maintenance PPI therapy can reverse not only oesophageal inflammation but also fibrotic remodelling (similarly to topical steroids 25, 26 and diet 27 ) remains to be elucidated. In the present study, the maximum high-dose PPI therapy (omeprazole 40 mg b.d.) was used for the initial diagnosis of PPI-REE, according to the most recent EoE guidelines. 1, 28 A recent first meta-analysis on PPI-REE has highlighted that evidence supporting any PPI doses is still poor and heterogeneous, as there does not seem to be a relation between the medication dose and response rate in prospective studies. 4 A nonsignificant advantage, however, was suggested when PPIs were administered twice daily compared to once daily. We decided to go for the maximum doses split twice daily due to the high rate of CYP2C19 rapid metabolisers in westerns countries. An initial high-dose PPI trial would likely ensure a similar clinical efficacy for rapid, intermediate and poor metabolisers. The rate of CYP2C19 rapid metabolisers has been proven to be higher in Europe and in North America (56 81%), while the proportion is smaller (27 38%) in the Asian population. 29, 30 Proton pump inhibitor (PPI) therapy (omeprazole, lansoprazole, pantoprazole, rabeprazole and esomerpazole) undergo hepatic metabolism via the CYP450 pathways and the isoforms CYP2C19 and, to a lesser extent, CYP3A4. There are different CYP2C19 genotypes (extensive or rapid, intermediate and poor metabolisers), so that the clinical efficacy of PPIs is notably decreased in rapid metabolisers in PPI-based therapies A recent study has shown for the first time a high rate of PPI rapid metabolisers (66%) among 50 European PPI-REE patients coming from Spain, Czech Republic and the Netherlands. 23 There are a number of reasons that oesophageal eosinophilia could recur after an initial successful PPI trial. These include lack of adherence to long-term PPI treatment, sampling error in oesophageal biopsies with missed detection of mucosal inflammation in the previous endoscopy, or variation in allergenic exposures or season of endoscopy. The aforementioned study showed that allergic rhinconjunctivitis and a CYP2C19 rapid metaboliser genotype were independent predictors of loss of response to PPI therapy during follow-up of PPI- REE patients. 23 Undoubtedly, future prospective doseand interval dosing-ranging studies of PPIs in patients with symptomatic oesophageal eosinophilia would be helpful in providing more definitive dose and duration recommendations for initial and maintenance PPI therapy. As for side effects, PPI displayed a good safety profile in the study (5% of patients in our series). Side effects appeared in our patients as well as in other published cases 19 with high doses of the drug, and reversed with PPI tapering doses and specific treatment. No adverse effects were detected at lower doses of omeprazole (40 and 20 mg) in any patient. Of note, we observed a case of oesophageal candidiasis after omeprazole 40 mg b.d. in a 16-year-old atopic patient. She recovered after been treated with 100 mg/day of fluconazole for 15 days, and lowering the omeprazole dose to 40 mg/day. This complication has been largely described in 15 25% of adult EoE patients after topical steroid therapy 34 and omeprazole has been considered by some authors as a risk factor for the development of oesophageal candidiasis. 20 A specific oesophageal microbiome profile in EoE leading to oesophageal 35, 36 inflammation has been recently suggested. It is tempting to speculate whether topical steroids and PPI therapy, when solving oesophageal inflammation, can also imbalance oesophageal microbiota and predispose to local Candida overgrowth. The main strengths of the present study are its prospective design and both clinical and histological assessment after each PPI decreasing doses. Nevertheless, some limitations should be recognised, such as the small sample size and short follow-up period. Whether our findings will translate into long-term remission on a low-dose PPI needs further research. Furthermore, escalation of PPI dose following relapse was not performed, which would strengthened our findings. Symptom assessment was made through a nonvalidated local questionnaire. We started the study in 2013, where only other nonvalidated tools, such as the Mayo Dysphagia Questionnaire 37 or the Dysphagia Symptom Score, 38 were used for clinical assessment in EoE. Adherence to PPI therapy was not specifically assessed by questionnaire and recovery of empty envelopes of medications. Finally, our results in adults may not be necessary extrapolated to the paediatric population. In conclusion, the large majority of adult patients with a diagnosis of PPI-REE after high-dose PPIs have persistent clinico-histological remission on de-escalating doses of PPI therapy. Relapsing oesophageal inflammation can occur in an asymptomatic patient, so histological assessment is mandatory. As adverse effects only appeared with the highest dose of omeprazole, it would be advisable to individualise the dose of PPIs for each patient, lowering it to the minimum capable of maintaining controlled the oesophageal disease. Further comparative 538 Aliment Pharmacol Ther 2016; 43:

6 PPI therapy step-down in PPI-responsive oesophageal eosinophilia studies should elucidate definitive dose and duration recommendations for both initial and maintenance PPI therapy in PPI-REE patients. AUTHORSHIP Guarantor of the article: Rosa Garcıa Rodrıguez. Author contributions: All authors participated in the conception and design of the study. Each author has worked further on the following tasks: Gomez Torrijos, Elisa: designed the study and wrote the manuscript. Garcıa Rodrıguez, Rosa: data collection and correction of the manuscript. Castro Jimenez, Araceli: recruitment and followup of the patients. Rodriguez Sanchez, Joaquin: performed the endoscopies and assessed the digestive symptoms. Mendez Dıaz Yesica: data collection. Molina-Infante Javier: critical review of the manuscript. All authors reviewed and approved the final version of the manuscript to be published. Personal and funding interests: None. ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allerg Clin Immunol 2011; 128: 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: Molina-Infante J, Ferrando-Lamana A, Ripoll C, et al. Esophageal eosinophilic infiltration responds to proton pump inhibition in most adults. Clin Gastroenterol Hepatol 2011; 9: Lucendo AJ, Arias A, Molina-Infante J. Efficacy of proton pump inhibitor drugs for inducing clinical and histological remission in patients with symptomatic esophageal eosinophilia: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2015; Published online: August 03, 2015 doi: /j.cgh [Epub ahead of print] 5. Vazquez-Elizondo G, Ngamruengphong S, Khrisna M, Devault KR, Talley NJ, Achem SR. The outcome of patients with oesophageal eosinophilic infiltration after an eight-week trial of a proton pump inhibitor. Aliment Pharmacol Ther 2013; 38: Dellon ES, Speck O, Woodward K, et al. Clinical and endoscopic characteristics do not reliably differentiate PPIresponsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. Am J Gastroenterol 2013; 108: Moawad FJ, Schoepfer AM, Safroneeva E, et al. Eosinophilic oesophagitis and proton pump inhibitor-responsive oesophageal eosinophilia have similar clinical, endoscopic and histological findings. Aliment Pharmacol Ther 2014; 39: Molina-Infante J, Rivas MD, Hernandez-Alonso M, et al. Remission in proton pump inhibitor-responsive esophageal eosinophilia correlates with downregulation of eotaxin-3 and TH2 cytokines, similarly to eosinophilic esophagitis after steroids. Aliment Pharmacol Ther 2014; 40: van Rhijn BD, Weijenborg PW, Verheij J, et al. Proton pump inhibitors partially restore mucosal integrity in patients with proton pump inhibitorresponsive esophageal eosinophilia but not eosinophilic esophagitis. Clin Gastroenterol Hepatol 2014;12: Wen T, Dellon ES, Moawad FJ, Furuta GT, Acebes SS, Rothenberg ME. Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. J Allergy Clin Immunol 2015; 135: Katzka DA. eosinophilic esophagitis and proton pump-responsive esophageal eosinophilia: what is in a name? Clin Gastroenterol Hepatol 2014; 12: Dellon ES, Liacouras CA. Advances in clinical management of eosinophilic esophagitis. Gastroenterology 2014; 147: Straumann A, Conus S, Degen L, et al. Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2011; 9: Butz BK, Wen T, Gleich GJ, et al. Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis. Gastroenterology 2014; 147: Schroeder S, Capocelli KE, Masterson JC, et al. Effect of proton pump inhibitor on esophageal eosinophilia. J Pediatr Gastroenterol Nutr 2013; 56: Dohil R, Newbury RO, Aceves S. Transient PPI responsive esophageal eosinophilia may be a clinical subphenotype of pediatric eosinophilic esophagitis. Dig Dis Sci 2012; 57: de Martin Argila C. Seguridad de los inhibidores de la bomba de protones (IBP). Rev Esp Enferm Dig (Madrid), 2011; 103: Galindo PA, Borja JM, Feo JF, et al. Anaphylaxis to omeprazole. Ann Allergy Asthma Immunol 1999; 82: Palacios Martınez D, Dıaz Alonso RA, Gutierrez Lopez M, Gordillo Lopez FJ, Arranz Martınez E, Ruiz Garcıa A. Candida esophagitis in an immunocompetent woman. A case report. An Sist Sanit Navar 2013; 36: Chocarro Martınez A, Galindo Tobal F, Ruiz-Irastorza G, et al. Risk factors for esophageal candidiasis. Eur J Microbiol Infect Dis 2000; 19: Wilhelm SM, Rjater RG, Kale-Pradham PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol 2013; 6: Rodrıguez Sanchez J, Gomez Torrijos E, De La Santa Belda E, Martın Escobedo R, Martın Davila F, Lopez Viedma B. VAS-EoE score: a new symptoms assessment tool for eosinophilic esophagitis. Gastroenterology 2013; 144 (5 Suppl. 1): S Molina-Infante J, Rodriguez-Sanchez J, Martinek J, et al. Long-term loss of response in proton pump inhibitorresponsive esophageal eosinophilia is uncommon and influenced by CYP2C19 genotype and rhinoconjunctivitis. Am J Gastroenterol 2015; 110: Rothenberg ME. Molecular, genetic, and cellular bases for treating eosinophilic esophagitis. Gastroenterology 2015; 148: Aceves SS, Newbury RO, Chen D, et al. Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical Aliment Pharmacol Ther 2016; 43:

7 E. Gomez-Torrijos et al. corticosteroids. Allergy 2010; 65: Rajan J, Newbury RO, Anilkumar A, Dohil R, Broide DH, Aceves SS. Longterm assessment of esophageal remodeling in patients with pediatric eosinophilic esophagitis treated with topical corticosteroids. J Allergy Clin Immunol 2015; doi: / j.jaci [Epub ahead of print] 27. Lieberman JA, Morotti RA, Konstantinou GN,YershovO,ChehadeM.Dietary therapy can reverse esophageal subepithelial fibrosis in patients with eosinophilic esophagitis: a historical cohort. Allergy 2012; 67: Dellon ES, Gonsalves N, Hirano I, Furuta GT, Liacouras C, Katzka DA. ACG Clinical Guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis. Am J Gastroenterol 2013; 108: Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol 2004; 95: Furuta T, Shirai N, Sugimoto M, Nakamura A, Hishida A, Ishizaki T. Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies. Drug Metab Pharmacokinet 2005; 20: Shimatani T, Inoue M, Kuroiwa T, et al. Acid-suppressive effects of rabeprazole, omeprazole, and lansoprazole at reduced and standard doses: a crossover comparative study in homozygous extensive metabolizers of cytochrome P450 2C19. Clin Pharmacol Ther 2006; 79: Tang HL, Li Y, Hu YF, Xie HG, Zhai SD. Effects of CYP2C19 loss-of function variants on the eradication of H. pylori infection in patients treated with proton pump inhibitorbased triple therapy regimens: a meta analysis of randomized clinical trials. PLoS ONE 2013; 2013: e Furuta T, Sugimoto M, Shirai N. Individualized therapy for gastroesophageal reflux disease: potential impact of pharmacogenetic testing based on CYP2C19. Mol Diagn Ther 2012; 16: Alexander JA. Steroid treatment of eosinophilic esophagitis in adults. Gastroenterol Clin North Am 2014; 43: Harris JK, Fang R, Wagner BD, et al. Esophageal microbiome in eosinophilic esophagitis. PLoS ONE 2015; 10: e Benitez AJ, Hoffmann C, Muir AB, et al. Inflammation-associated microbiota in pediatric eosinophilic esophagitis. Microbiome 2015; 1: Moawad FJ, Veerappan GR, Dias JA, Baker TP, Maydonovitch CL, Wong RK. Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for esophageal eosinophilia. Am J Gastroenterol 2013; 108: Molina-Infante J, Arias A, Barrio J, Rodrıguez-Sanchez J, Sanchez-Cazalilla M, Lucendo AJ. Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study. J Allergy Clin Immunol 2014; 134: Aliment Pharmacol Ther 2016; 43: