Lack of proton pump inhibitor trial prior to commencing therapy for eosinophilic esophagitis is common in the community

Lack of proton pump inhibitor trial prior to commencing therapy for eosinophilic esophagitis is... Summary Eosinophilic esophagitis is characterized by eosinophil inflammation restricted to the esophagus and the resulting symptoms of esophageal dysfunction. Critical to the diagnosis of eosinophilic esophagitis is a trial of proton pump inhibitor therapy to exclude alternative causes of esophageal eosinophilia such as proton pump inhibitor-responsive esophageal eosinophilia. While consensus guidelines recommend a proton pump inhibitor trial prior to diagnosis, little is known about its implementation in clinical practice. The primary aim of this study is to assess the frequency of proton pump inhibitor trial prior to the diagnosis of eosinophilic esophagitis in community practice. The secondary aim is to assess the frequency of other treatments for eosinophilic esophagitis, including topical steroids and/or dietary therapy, in patients who did not undergo a proton pump inhibitor trial prior to diagnosis or who had an alternative diagnosis to eosinophilic esophagitis upon completed workup. We conducted a single-center, case series of patients referred to the Hospital of the University of Pennsylvania for eosinophilic esophagitis management between 2010 and 2015. This case series consisted of 125 patients who were referred from community practitioners with a presumptive diagnosis of eosinophilic esophagitis. Upon review, 90 out of 125 (72%) patients had not had a proton pump inhibitor trial or esophageal pH testing prior to the diagnosis of eosinophilic esophagitis being made. Of these patients, 77.8% (70/90) had already received either topical steroid or dietary therapy for presumed eosinophilic esophagitis. Of the 125 patients initially diagnosed with eosinophilic esophagitis, 32 (25.6%) were found to have an alternative diagnosis, and 79.2% of this subset of patients (25/32) had previously received topical steroid or dietary therapy. This study demonstrates that a substantial number of patients with presumed eosinophilic esophagitis have not had a proton pump inhibitor trial prior to diagnosis in community practice. This led to the misclassification of patients and potentially to the use of less optimal medical therapies in a substantial number of these patients. INTRODUCTION Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophil predominant infiltration of the esophagus and resulting esophageal dysfunction.1 Greater than 15 intraepithelial eosinophils per high power field (eos/hpf) are required to make a pathologic diagnosis.2 Clinically, presenting symptoms include feeding problems, abdominal pain, or vomiting in children and dysphagia, food impactions, or chest pain in adults.3 Treatment options for EoE include topical steroids, food elimination diets, and endoscopic dilation.4 More recently, a new entity named proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) has been described. PPI-REE is clinically, endoscopically, and histologically similar to EoE.5–7 The distinguishing factor is the clinical and histologic resolution with PPI therapy in patients with PPI-REE but not in patients with EoE.8,9 Recent research suggests that EoE and PPI-REE may in fact be the same disease entity responding to different therapies, rather than two independent diseases.7 Given the complexity in diagnosing and treating these patients, clinical guidelines have emphasized the need to exclude other causes of esophageal eosinophilia prior to commencing therapy for EoE.2 Earlier guidelines published in 200710 emphasized either pH testing or a PPI trial prior to an EoE diagnosis, while more recent guidelines have emphasized the need for a PPI trial to exclude PPI-REE. However, little is known about adherence to these guidelines among clinicians. The aims of this study are: (1) to assess the frequency of patients undergoing a PPI trial prior to a diagnosis of EoE and (2) to assess the frequency of potentially unwarranted EoE treatments in patients without a prior PPI trial and/or an alternative diagnosis to EoE. METHODS Study design, study population, and data source This is a retrospective case series conducted at the University of Pennsylvania consisting of all patients presenting to a single provider's clinical practice (GWF) with a diagnosis of “EoE” between January of 2010 and November of 2015. Potential subjects were identified using both the Penn EoE Registry Database and the University of Pennsylvania electronic medical record search engine (Pennseek). Keyword searches were conducted using the terms EoE, PPI-REE, esophageal eosinophilia, and dysphagia as well as ICD-10 codes for EoE and dysphagia. Inclusion criteria for the study included: (1) adult patients ≥18 years of age, (2) a prior diagnosis of EoE being made, and (3) diagnosis made by a community provider. For the purpose of this study, a community provider was defined as a gastroenterologist outside of the University of Pennsylvania Health System. Exclusion criteria included: (1) referral from noncommunity provider (i.e., other tertiary centers, direct referrals from the Penn Endoscopy Unit), (2) referral from a non-GI specialist, and (3) referral for a diagnosis other than EoE. Chart review and data abstraction was performed by one of two investigators (MJW, KLL). Information was abstracted from both the Penn Electronic Medical Record as well as the scanned-in documents from referring community physicians. Information abstracted included demographics, clinical symptoms, endoscopic findings at diagnostic EGD, histologic findings at diagnostic EGD (i.e. eos/hpf), prior evaluation (i.e. PPI trial, pH testing), prior treatments (i.e. topical steroids, dietary therapy), and final clinical diagnosis. This study was approved by the Institutional Review Board at the University of Pennsylvania. Definition of measures For the purposes of this study, a PPI trial was defined as either high-dose daily (equivalent of 40 mg omeprazole) or twice daily dosing (equivalent of 20 mg omeprazole twice daily) followed by an endoscopic evaluation with biopsies after at least 8 weeks of therapy. Dietary therapy was defined as a six-food elimination diet, elemental diet, or an allergy-directed elimination diet. Steroid therapy was defined as swallowed fluticasone, swallowed budesonide, or oral prednisone. Dual therapy is defined as some combination of both dietary and steroid therapy. Final diagnoses were defined as follows: EoE was defined by the presence of ≥15 eos/hpf on endoscopic biopsy after a PPI trial; PPI-REE was defined as the resolution of clinical symptoms and the histologic resolution of esophageal eosinophilia after a PPI trial (<15 eos/hpf). For patients previously on other medications for presumptive EoE in the absence of a prior PPI trial, these medications were stopped prior to completing a PPI trial in order to diagnose PPI-REE. Gastroesophageal reflux was defined as classic symptoms of reflux (i.e. heartburn, regurgitation) without typical EoE symptoms (i.e. dysphagia, food impaction) and the resolution of symptoms on PPI therapy or documentation by pH testing. Finally, lichen planus was defined by diagnostic results on pathology. Data analysis Descriptive statistics were used to quantify the results from this study using the mean value and standard deviation. We calculated the respective prevalence rates and 95% confidence intervals (CI) for the absence of prior PPI trial among the entire study cohort and receipt of EoE-specific medical therapy among those without a PPI trial prior to diagnosis and among those ultimately proven not to have EoE. RESULTS Study population A total of 833 patients were identified on the initial search with 256 of these patients (30.7%) being referred to the University of Pennsylvania with a prior diagnosis of EoE. In total, 125 patients (15.0%) were referred with a prior diagnosis of EoE made by community providers and included in the study population (Fig. 1). Fig. 1 View largeDownload slide Study population meeting inclusion criteria from initial search. Fig. 1 View largeDownload slide Study population meeting inclusion criteria from initial search. Patient characteristics The study population was predominantly male (63.2%) and Caucasian (87.2%) with a mean age of 34.2 ± 12.1 years. Atopic features were described in 60% of all patients, with asthma being the most commonly reported. Eighty-six of the 111 patients (77.4%) who had prior endoscopic results available from their community provider had at least one documented endoscopic finding classic for EoE. Twenty five out of 111 (22.5%) patients had 0 features of EoE documented on endoscopy, 46 out of 111 (41.4%) of patients had 1 feature of EoE, 33 out of 111 (29.7%) had 2 features of EoE on endoscopy, and 7 out of 111 (6.3%) of patients had 3 or more features of EoE on endoscopy. Pathology results revealed an average of 46.7 ± 31.5 eos/hpf on endoscopic biopsy for these patients. Full demographic results can be seen in Table 1. Table 1 Demographic, clinical, and endoscopic data for study population Demographics (n = 125)        Age (mean ± SD)  34.2 ± 12.1 years    Male gender  79 (63.2%)    Caucasian  109 (87.2%)    First visit in 2014–2015  44 (35.2%)    Current/former smoker  12 (9.6%)    Referred to allergist  62 (49.6%)    History of prior dilation  32 (25.6%)  Atopic features (n = 125)        Asthma  49 (39.2%)    Eczema  31 (24.8%)    Rhinitis  28 (22.4%)    Any atopic feature  75 (60.0%)  Clinical symptoms at presentation (n = 123)†        Dysphagia  55 (44.7%)    Chest pain  27 (22.0%)    Heartburn  28 (22.8%)    Regurgitation  21 (17.1%)    History of food impaction  31 (25.2%)  Endoscopic findings at “EoE” diagnosis (n = 111)‡        Furrows  37 (33.3%)    Rings  55 (49.6%)    Loss of vascularity  4 (3.6%)    Exudate  16 (14.4%)    Stricture  23 (20.7%)    Esophagitis  19 (17.1%)  Histologic findings at “EoE” diagnosis (n = 103)§        Eos/hpf (mean ± SD)  46.7 ± 31.5  Demographics (n = 125)        Age (mean ± SD)  34.2 ± 12.1 years    Male gender  79 (63.2%)    Caucasian  109 (87.2%)    First visit in 2014–2015  44 (35.2%)    Current/former smoker  12 (9.6%)    Referred to allergist  62 (49.6%)    History of prior dilation  32 (25.6%)  Atopic features (n = 125)        Asthma  49 (39.2%)    Eczema  31 (24.8%)    Rhinitis  28 (22.4%)    Any atopic feature  75 (60.0%)  Clinical symptoms at presentation (n = 123)†        Dysphagia  55 (44.7%)    Chest pain  27 (22.0%)    Heartburn  28 (22.8%)    Regurgitation  21 (17.1%)    History of food impaction  31 (25.2%)  Endoscopic findings at “EoE” diagnosis (n = 111)‡        Furrows  37 (33.3%)    Rings  55 (49.6%)    Loss of vascularity  4 (3.6%)    Exudate  16 (14.4%)    Stricture  23 (20.7%)    Esophagitis  19 (17.1%)  Histologic findings at “EoE” diagnosis (n = 103)§        Eos/hpf (mean ± SD)  46.7 ± 31.5  †Two patients had clinical notes that did not specify presenting clinical symptoms. ‡Fourteen patients did not have endoscopic reports available for review. §Fifteen patients did not independent path reports other than noted information on referring physician's note. Seven additional patients had path reports that did not document specific number of eosinophils, but rather documented as “many” or “innumerable.” View Large Table 1 Demographic, clinical, and endoscopic data for study population Demographics (n = 125)        Age (mean ± SD)  34.2 ± 12.1 years    Male gender  79 (63.2%)    Caucasian  109 (87.2%)    First visit in 2014–2015  44 (35.2%)    Current/former smoker  12 (9.6%)    Referred to allergist  62 (49.6%)    History of prior dilation  32 (25.6%)  Atopic features (n = 125)        Asthma  49 (39.2%)    Eczema  31 (24.8%)    Rhinitis  28 (22.4%)    Any atopic feature  75 (60.0%)  Clinical symptoms at presentation (n = 123)†        Dysphagia  55 (44.7%)    Chest pain  27 (22.0%)    Heartburn  28 (22.8%)    Regurgitation  21 (17.1%)    History of food impaction  31 (25.2%)  Endoscopic findings at “EoE” diagnosis (n = 111)‡        Furrows  37 (33.3%)    Rings  55 (49.6%)    Loss of vascularity  4 (3.6%)    Exudate  16 (14.4%)    Stricture  23 (20.7%)    Esophagitis  19 (17.1%)  Histologic findings at “EoE” diagnosis (n = 103)§        Eos/hpf (mean ± SD)  46.7 ± 31.5  Demographics (n = 125)        Age (mean ± SD)  34.2 ± 12.1 years    Male gender  79 (63.2%)    Caucasian  109 (87.2%)    First visit in 2014–2015  44 (35.2%)    Current/former smoker  12 (9.6%)    Referred to allergist  62 (49.6%)    History of prior dilation  32 (25.6%)  Atopic features (n = 125)        Asthma  49 (39.2%)    Eczema  31 (24.8%)    Rhinitis  28 (22.4%)    Any atopic feature  75 (60.0%)  Clinical symptoms at presentation (n = 123)†        Dysphagia  55 (44.7%)    Chest pain  27 (22.0%)    Heartburn  28 (22.8%)    Regurgitation  21 (17.1%)    History of food impaction  31 (25.2%)  Endoscopic findings at “EoE” diagnosis (n = 111)‡        Furrows  37 (33.3%)    Rings  55 (49.6%)    Loss of vascularity  4 (3.6%)    Exudate  16 (14.4%)    Stricture  23 (20.7%)    Esophagitis  19 (17.1%)  Histologic findings at “EoE” diagnosis (n = 103)§        Eos/hpf (mean ± SD)  46.7 ± 31.5  †Two patients had clinical notes that did not specify presenting clinical symptoms. ‡Fourteen patients did not have endoscopic reports available for review. §Fifteen patients did not independent path reports other than noted information on referring physician's note. Seven additional patients had path reports that did not document specific number of eosinophils, but rather documented as “many” or “innumerable.” View Large Diagnosis and clinical evaluation Only 13 of 125 patients (10.4%) in the study population had undergone a PPI trial prior to being diagnosed with EoE in the community. An additional 19 other patients (15.2%) were unable to recall if they underwent a PPI trial prior to diagnosis and the reviewed records were unclear as to PPI status. Finally, three patients (2.4%) had undergone pH testing demonstrating no increase gastroesophageal reflux prior to a diagnosis of EoE being made. Ultimately, 90 of 125 patients (72.0%, 95% CI: 63–80%) did not have sufficient testing to exclude PPI-REE prior to a diagnosis of EoE being made in the community. Overall, eight out of 81 patients (9.9%) diagnosed between 2010 and 2013, and eight out of 44 patients (18.1%) had sufficient testing prior to diagnosis of EoE. On final diagnosis after assessment at the University of Pennsylvania, 75 of 125 patients (60.0%, 95% CI: 51–69%) were confirmed to have EoE and 32 patients (25.6%, 95% CI 18–34%) did not have EoE. Alternative diagnoses included PPI-REE (n = 29), GERD (n = 2), and lichen planus (n = 1). Finally, 18 patients had an as yet unknown final diagnosis (14.4%). Reasons for unknown final diagnosis included medication noncompliance, incomplete testing at time of analysis, or loss to follow up. Medical therapy Overall, 94 of 125 (75.2%) patients referred with a presumptive diagnosis of EoE had received prior medical therapy for EoE, including steroids, diet, or a combination of dietary and steroid therapy. In the subset of 90 patients that had insufficient testing prior to a diagnosis of EoE, 71 patients (78.9%, 95% CI: 69–87%) had already received medical therapy for EoE (Fig. 2). In the subset of 32 subjects who were found to have a final diagnosis other than EoE, 25 patients (78.1%, 95% CI: 60–91%) had already received medical therapy for EoE (Fig. 3). Fig. 2 View largeDownload slide Clinical testing performed prior to diagnosis of “EoE” in the community and the prior treatments for patients with insufficient testing prior to the diagnosis of “EoE.” Fig. 2 View largeDownload slide Clinical testing performed prior to diagnosis of “EoE” in the community and the prior treatments for patients with insufficient testing prior to the diagnosis of “EoE.” Fig. 3 View largeDownload slide Final diagnosis of patients referred from community with “EoE” and the prior treatments for patients with final diagnosis other than EoE. Fig. 3 View largeDownload slide Final diagnosis of patients referred from community with “EoE” and the prior treatments for patients with final diagnosis other than EoE. DISCUSSION In this study of 125 patients referred to the University of Pennsylvania with a presumptive diagnosis of EoE, we found that 72% of patients did not have an adequate PPI trial prior to the diagnosis of EoE. Furthermore, 15% of patients in this study could not explicitly recall their prior PPI exposure, and as such the number of patients with inadequate PPI trial may in fact be larger. A significant number of patients with an inadequate PPI trial were started on medical and/or dietary therapies (79%). This incomplete workup also resulted in a potentially incorrect diagnosis of approximately 25% of these patients. The exclusion of PPI-REE and GERD is an important and necessary component in correctly diagnosing EoE. As a result, the need for a PPI trial is highlighted in clinical guidelines.2 The process of diagnosing EoE has evolved over the past decade. While there are clear histologic criteria to diagnose EoE, there are many other entities that may lead to esophageal eosinophilia and mimic EoE. These diseases include achalasia, GERD, Crohn's disease, and hypereosinophilic disorders.4 In particular, distinguishing between GERD, PPI-REE, and EoE has remained challenging. Guidelines have moved away from suggesting pH testing as outlined in the 200710 to a recommendation of a PPI trial in the most recent clinical guidelines published in 2013.2,11 Currently, pH testing is reserved for cases of possible overlapping disease, although it appears to be of only limited benefit.12 In addition to addressing possible GERD, the PPI trial allows for the exclusion of PPI-REE, an entity that was first described in a small case series.13 Without this PPI trial, PPI-REE is indistinguishable from EoE endoscopically, histologically, and clinically.5 It is common for patients with esophageal eosinophilia to respond histologically to a proton pump inhibitor, with estimates ranging from 25% to 77%.14 A recent systematic review and meta-analysis demonstrated that approximately 50% of patients with EoE had histologic remission when treated with PPI therapy.15 These data again underline the need to adequately rule out this entity.16 However, in our study only 23.2% of patients (29 of 125) were ultimately found to have PPI-REE. This percentage is lower than previously reported rates as described above.7 This may have to do with the population we studied, as these patients were seeing at least a second gastroenterologist and other patients with PPI-REE may not have been part of this referred patient population In addition, 14.4% of our study patients (18/125) had an unknown diagnosis at the time of publication which may ultimately increase the number the number of patients diagnosed with PPI-REE. It remains unclear whether PPI-REE is truly a different entity from EoE or whether it is part of the spectrum of EoE. Studies on the pathobiology of EoE have shown that eotaxin-3, intracellular granules such as major basic protein, and tryptase are upregulated mediators of disease in patients with EoE.14 Recent studies have shown high levels of these same markers in patients with PPI-REE.17 It has been proposed that PPI treatment may impact these elevated markers through anti-inflammatory effects that reduce Th2-related mediators and eotaxin-3 secretion.18 Genetically PPI-REE and EoE also appear to be similar.19 The genetic expression in both PPI-REE and EoE is characterized by largely overlapping transcriptomes and similar reversal of their genetic signatures after introduction of appropriate therapy; PPI therapy for PPI-REE and topical steroids for EoE. Currently, it remains unclear if PPI-REE and EoE are a spectrum of disease that is just treated with different medical therapies, or instead, overlapping diseases that can resemble each other.14 These findings in part led to the European Society of Eosinophilic Oesophagitis (EUREOS) to consider PPI as a potential treatment for EoE and not just as a diagnostic test to rule out PPI-REE.7 If PPIs are to be considered a potential first-line therapy, these results may suggest that community providers did not frequently use PPIs as a first-line therapy for the treatment of EoE. The results from this study still show a surprisingly infrequent use of PPIs to diagnose and/or treat EoE. Other controversies regarding PPI-REE also remain. Currently, the necessary dose of PPI therapy to diagnose and/or treat PPI-REE remains unclear. Recent studies have suggested that a step-down approach may work for most patients20 while other patients may need longer term therapy. Data suggest that a minimum of 2 months of PPI therapy is necessary to best differentiate between EoE and PPI-REE.21 The differentiation between appropriate treatments and diagnosis may have long-term implications for patients as well. EoE is a progressive fibrostenotic disease22 that can ultimately progress to narrow caliber esophagus.23 Studies have demonstrated that medical treatment, both topical steroids and elimination diet, can reduce the esophageal fibrosis that has developed.24 It remains unknown if patients with PPI-REE progress along a similar fibrostenotic pathway and whether treatment with a PPI can prevent this in these patients. Further studies are needed to address this question. Despite these questions, it is clear that a PPI trial is an important and recommended step in the diagnosis and treatment of EoE. However, there are limited data in the literature addressing the adherence to these clinical guidelines and the resulting use of other more challenging medical therapies. To our knowledge this is one of the first reports of this issue. A recent publication from Lipka et al. demonstrated similar results to ours: 6.5% of patients (3/46) received a PPI trial in the community and 67.4% of patients (31/46) were treated with steroids irrespective of a PPI trial.25 Furthermore, those investigators also reported a sizable percentage of patients referred from the community who ultimately were diagnosed with PPI-REE (61%) further highlighting the underutilization of a PPI trial prior to a diagnosis of EoE. It is not entirely clear why adherence to the published clinical guidelines for EoE regarding a PPI trial was so low. Practitioner adherence to clinical guidelines is an issue not just in gastroenterology, but within medical practice at large. A systematic review of potential reasons for poor adherence to clinical guidelines identified lack of awareness, familiarity, outcome expectancy, and the inability to overcome the inertia of previous practice, as possible contributors.26 It is possible that recently changing guidelines regarding EoE and the clinical confusion regarding the role of PPI-REE contribute to a lack of awareness about the appropriate use of a PPI trial in the clinical approach to EoE. The importance of clarifying these diagnoses is evident in the resulting treatment options for both. 78% of patients in this study were started on medical therapy without a PPI trial, including 79% whose final diagnosis was not EoE. Patients using long-term topical steroids have a 10–20% risk of developing esophageal candidiasis4,27 and cases of herpes esophagitis have also been reported.28 While common side effects of oral steroids (i.e. mood changes, weight gain) have been rarely reported,4 a recent small, prospective study demonstrated adrenal suppression during a short course of topical steroids.29 Long-term studies of patients using topical steroids have not yet been completed. In addition to these side effects, multi-dose inhalers such as fluticasone can be difficult to administer resulting in inadequate dosing and both fluticasone and budesonide can be financially costly for patients given the off label use of both compounds. This is a similar problem for elimination diets, which can be difficult to adhere to and expensive for patients. While recent concerns have developed regarding PPI adverse events with long-term therapy, these studies are all characterized by modest effect rates and all demonstrate association instead of causation.30–32 PPIs are generally well tolerated, inexpensive, and easy to adhere to. The strengths of this study include the large number of patients studied in a “real world” practice setting outside a clinical trial. As such, this study offers a realistic snapshot of this issue. There was also extensive documentation regarding prior therapies and PPI trials. We readily recognize some of the limitations of this study. Given the retrospective design, data could be limited by a patient's recall or incomplete medical records. We aimed to offset this limitation by only documenting patients as lacking a PPI trial when it was clearly documented in the reviewed records. As such, 15.2% of patients (19 out of 125) identified themselves as not being able to recall if testing on PPI therapy was completed. An additional potential limitation is referral bias. As a tertiary care center, the patients’ referred to our center and included in this study may not reflect the “standard” EoE case, but rather cases that were difficult to manage or did not respond to a first treatment. This may be reflected in the fact that a majority of patients included in this trial had previously received some form of treatment. Studying this group of referred patients may lead to either an over or underestimate of patients with EoE who have undergone a PPI trial in the general population. As mentioned previously, in our study only 23.2% of patients were ultimately found to have PPI-REE, which is a smaller percentage than what is reported in the literature today. Last, this study took place in a tertiary urban referral center in a practice of one physician with a dedicated interest in EoE. As such, we may not have captured the full spectrum of the patient population referred to the University of Pennsylvania for eosinophilic disorders. In conclusion, we found that the majority of patients referred to a tertiary care center for the management of EoE had not had a PPI trial prior to the presumptive diagnosis of EoE. This led to an inappropriate diagnosis of EoE in over 25% of patients with subsequent unwarranted medical and dietary therapies in the majority of these patients. Given the ease of treatment of PPI-REE compared to EoE, more emphasis should be placed on clearly separating out both entities. ACKNOWLEDGMENTS We acknowledge U54AI117804 (CEGIR), which is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. In addition, we acknowledge the Penn-CHOP Joint Center in Digestive, Liver and Pancreatic Medicine for their support. Notes Declaration of interests: Matthew J. Whitson, nothing to declare; Kristle L. Lynch, nothing to declare; Yu-Xiao Yang, nothing to declare; David C. Metz, nothing to declare; Gary W. Falk, Research support from Celgene, Shire, Regeneron, Adare. Consultant for Adare Pharmaceuticals and Banner Life Sciences. Specific author contributions: Design of research study: Matthew J. Whitson, David C. Metz, Gary W. Falk; Collection and analysis of data: Matthew J. Whitson, Kristle L. Lynch; Paper authorship: Matthew J. Whitson, Kristle L. Lynch, Yu-Xiao Yang, David C. Metz, Gary W. Falk; Final approval of paper: Matthew J. Whitson, Kristle L. Lynch, Yu-Xiao Yang, David C. Metz, Gary W. Falk; Analysis of data: Yu-Xiao Yang, Gary W. Falk; Guarantor of article: Gary W. Falk; All authors approved the final draft of this manuscript, the decision to submit the manuscript for publication, and the final order of authorship. References 1 Singla M B, Moawad F J. An overview of the diagnosis and management of eosinophilic esophagitis. Clin Trans Gastroenterol  2016; 7: e155. Google Scholar CrossRef Search ADS   2 Dellon E S, 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. Google Scholar CrossRef Search ADS PubMed  3 Furuta G T, Katzka D A. Eosinophilic esophagitis. N Engl J Med  2015; 373: 1640– 8. Google Scholar CrossRef Search ADS PubMed  4 Dellon E S, Liacouras C A. Advances in clinical management of eosinophilic esophagitis. Gastroenterology  2014; 147: 1238– 54. Google Scholar CrossRef Search ADS PubMed  5 Dellon E S, 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– 60. Google Scholar CrossRef Search ADS PubMed  6 Moawad F J, Schoepfer A M, 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: 603– 8. Google Scholar CrossRef Search ADS PubMed  7 Molina-Infante J, Bredenoord A J, Cheng E et al.   Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut  2016; 65: 524– 31. Google Scholar CrossRef Search ADS PubMed  8 van Rhijn B D, Weijenborg P W, 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. Google Scholar CrossRef Search ADS PubMed  9 Molina-Infante J, Ferrando-Lamana L, Ripoli C et al.   Esophageal eosinophilic infiltration responds to proton pump inhibition in most adults. Clin Gastroenterol Hepatol  2011; 9: 110– 7. Google Scholar CrossRef Search ADS PubMed  10 Furuta G T, Liacouras C A, Collins M H et al.   Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology  2007; 133: 1342– 63. Google Scholar CrossRef Search ADS PubMed  11 Liacouras C A, Furuta G T, Hirano I et al.   Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol  2011; 128: 3– 20. e6. Google Scholar CrossRef Search ADS PubMed  12 Francis D L, Foxx-Orenstein A, Arora A S 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– 7. Google Scholar CrossRef Search ADS PubMed  13 Ngo P, Furuta G T, Antonioli D A 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– 70. Google Scholar CrossRef Search ADS PubMed  14 Eluri S, Dellon E S. Proton pump inhibitor-responsive oesophageal eosinophilia and eosinophilic oesophagitis. Curr Opin Gastroenterol  2015; 31: 309– 15. Google Scholar CrossRef Search ADS PubMed  15 Lucendo A J, 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. Google Scholar CrossRef Search ADS PubMed  16 Molina-Infante J, Katzka D A, Gisbert J P. Review article: proton pump inhibitor therapy for suspected eosinophilic oesophagitis. Aliment Pharmacol Ther  2013; 37: 1157– 64. Google Scholar CrossRef Search ADS PubMed  17 Dellon E S, Chen X, Miller C R et al.   Markers of eosinophilic inflammation for diagnosis of eosinophilic esophagitis and proton pump inhibitor-responsive esophageal eosinophilia: a prospective study. Clin Gastroenterol Hepatol  2014; 12: 2015– 22. Google Scholar CrossRef Search ADS PubMed  18 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. Google Scholar CrossRef Search ADS PubMed  19 Wen T, Dellon E S, Moawad F J 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– 97. e4. Google Scholar CrossRef Search ADS PubMed  20 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– 40. Google Scholar CrossRef Search ADS PubMed  21 DiGiovanni E L, Champeaux A L, Arroyo M R et al.   Esophageal eosinophilia treated with long-duration proton pump inhibitor therapy. ACGCR  2016; 3: 95– 7. Google Scholar CrossRef Search ADS PubMed  22 Dellon E S, Kim H P, Sperry S L et al.   A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease. Gastrointest Endosc  2014; 79: 577– 85.e4. Google Scholar CrossRef Search ADS PubMed  23 Eluri S, Runge T M, Cotton C C et al.   The extremely narrow-caliber esophagus is a treatment-resistant subphenotype of eosinophilic esophagitis. Gastrointest Endosc  2016; 83: 1142– 8. Google Scholar CrossRef Search ADS PubMed  24 Straumann A, Schoepfer A. Update on basic and clinical aspects of eosinophilic oesophagitis. Gut  2014; 63: 1355– 63. Google Scholar CrossRef Search ADS PubMed  25 Lipka S, Kumar A, Richter J E. PPI Trial for eosinophilic esophagitis. J Clin Gastroenterol  2017; Mar 13: Epub ahead of print. 26 Cabana M D, Rand C S, Powe N R et al.   Why do not physicians follow clinical practice guidelines?. JAMA  1999; 282: 1458– 65. Google Scholar CrossRef Search ADS PubMed  27 Chuang M, Chinnaratha M A, Hancock D G et al.   Topical steroid therapy for the treatment of eosinophilic esophagitis (EoE): a systematic review and meta-analysis. Clin Trans Gastroenterol  2015; 6: e82. Google Scholar CrossRef Search ADS   28 Lindberg G M, Van Eldik R, Saboorian M H. A case of herpes esophagitis after fluticasone propionate for eosinophilic esophagitis. Nat Clin Pract Gastroenterol Hepatol  2008; 5: 527– 30. Google Scholar CrossRef Search ADS PubMed  29 Ahmet A, Benchimol E I, Goldbloom E B et al.   Adrenal suppression in children treated with swallowed fluticasone and oral viscous budesonide for eosinophilic esophagitis. Allergy Asthma Clin Immunol  2016; 12: 49– 55. Google Scholar CrossRef Search ADS PubMed  30 Reimer C. Safety of long-term PPI therapy. Best Pract Res Clin Gastroenterol  2013; 27: 443– 54. Google Scholar CrossRef Search ADS PubMed  31 Moledina D G, Perazella M A. PPIs and kidney disease: from AIN to CKD. J Nephrol  2016; 29: 611– 6. Google Scholar CrossRef Search ADS PubMed  32 Gomm W, von Holt K, Thome F et al.   Association of proton pump inhibitors with risk of dementia. JAMA Neurol  2016; 73: 410– 6. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Lack of proton pump inhibitor trial prior to commencing therapy for eosinophilic esophagitis is common in the community

Loading next page...
 
/lp/ou_press/lack-of-proton-pump-inhibitor-trial-prior-to-commencing-therapy-for-6Jc90CY7RH
Publisher
The International Society for Diseases of the Esophagus
Copyright
© The Author(s) 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
ISSN
1120-8694
eISSN
1442-2050
D.O.I.
10.1093/dote/dox143
Publisher site
See Article on Publisher Site

Abstract

Summary Eosinophilic esophagitis is characterized by eosinophil inflammation restricted to the esophagus and the resulting symptoms of esophageal dysfunction. Critical to the diagnosis of eosinophilic esophagitis is a trial of proton pump inhibitor therapy to exclude alternative causes of esophageal eosinophilia such as proton pump inhibitor-responsive esophageal eosinophilia. While consensus guidelines recommend a proton pump inhibitor trial prior to diagnosis, little is known about its implementation in clinical practice. The primary aim of this study is to assess the frequency of proton pump inhibitor trial prior to the diagnosis of eosinophilic esophagitis in community practice. The secondary aim is to assess the frequency of other treatments for eosinophilic esophagitis, including topical steroids and/or dietary therapy, in patients who did not undergo a proton pump inhibitor trial prior to diagnosis or who had an alternative diagnosis to eosinophilic esophagitis upon completed workup. We conducted a single-center, case series of patients referred to the Hospital of the University of Pennsylvania for eosinophilic esophagitis management between 2010 and 2015. This case series consisted of 125 patients who were referred from community practitioners with a presumptive diagnosis of eosinophilic esophagitis. Upon review, 90 out of 125 (72%) patients had not had a proton pump inhibitor trial or esophageal pH testing prior to the diagnosis of eosinophilic esophagitis being made. Of these patients, 77.8% (70/90) had already received either topical steroid or dietary therapy for presumed eosinophilic esophagitis. Of the 125 patients initially diagnosed with eosinophilic esophagitis, 32 (25.6%) were found to have an alternative diagnosis, and 79.2% of this subset of patients (25/32) had previously received topical steroid or dietary therapy. This study demonstrates that a substantial number of patients with presumed eosinophilic esophagitis have not had a proton pump inhibitor trial prior to diagnosis in community practice. This led to the misclassification of patients and potentially to the use of less optimal medical therapies in a substantial number of these patients. INTRODUCTION Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophil predominant infiltration of the esophagus and resulting esophageal dysfunction.1 Greater than 15 intraepithelial eosinophils per high power field (eos/hpf) are required to make a pathologic diagnosis.2 Clinically, presenting symptoms include feeding problems, abdominal pain, or vomiting in children and dysphagia, food impactions, or chest pain in adults.3 Treatment options for EoE include topical steroids, food elimination diets, and endoscopic dilation.4 More recently, a new entity named proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) has been described. PPI-REE is clinically, endoscopically, and histologically similar to EoE.5–7 The distinguishing factor is the clinical and histologic resolution with PPI therapy in patients with PPI-REE but not in patients with EoE.8,9 Recent research suggests that EoE and PPI-REE may in fact be the same disease entity responding to different therapies, rather than two independent diseases.7 Given the complexity in diagnosing and treating these patients, clinical guidelines have emphasized the need to exclude other causes of esophageal eosinophilia prior to commencing therapy for EoE.2 Earlier guidelines published in 200710 emphasized either pH testing or a PPI trial prior to an EoE diagnosis, while more recent guidelines have emphasized the need for a PPI trial to exclude PPI-REE. However, little is known about adherence to these guidelines among clinicians. The aims of this study are: (1) to assess the frequency of patients undergoing a PPI trial prior to a diagnosis of EoE and (2) to assess the frequency of potentially unwarranted EoE treatments in patients without a prior PPI trial and/or an alternative diagnosis to EoE. METHODS Study design, study population, and data source This is a retrospective case series conducted at the University of Pennsylvania consisting of all patients presenting to a single provider's clinical practice (GWF) with a diagnosis of “EoE” between January of 2010 and November of 2015. Potential subjects were identified using both the Penn EoE Registry Database and the University of Pennsylvania electronic medical record search engine (Pennseek). Keyword searches were conducted using the terms EoE, PPI-REE, esophageal eosinophilia, and dysphagia as well as ICD-10 codes for EoE and dysphagia. Inclusion criteria for the study included: (1) adult patients ≥18 years of age, (2) a prior diagnosis of EoE being made, and (3) diagnosis made by a community provider. For the purpose of this study, a community provider was defined as a gastroenterologist outside of the University of Pennsylvania Health System. Exclusion criteria included: (1) referral from noncommunity provider (i.e., other tertiary centers, direct referrals from the Penn Endoscopy Unit), (2) referral from a non-GI specialist, and (3) referral for a diagnosis other than EoE. Chart review and data abstraction was performed by one of two investigators (MJW, KLL). Information was abstracted from both the Penn Electronic Medical Record as well as the scanned-in documents from referring community physicians. Information abstracted included demographics, clinical symptoms, endoscopic findings at diagnostic EGD, histologic findings at diagnostic EGD (i.e. eos/hpf), prior evaluation (i.e. PPI trial, pH testing), prior treatments (i.e. topical steroids, dietary therapy), and final clinical diagnosis. This study was approved by the Institutional Review Board at the University of Pennsylvania. Definition of measures For the purposes of this study, a PPI trial was defined as either high-dose daily (equivalent of 40 mg omeprazole) or twice daily dosing (equivalent of 20 mg omeprazole twice daily) followed by an endoscopic evaluation with biopsies after at least 8 weeks of therapy. Dietary therapy was defined as a six-food elimination diet, elemental diet, or an allergy-directed elimination diet. Steroid therapy was defined as swallowed fluticasone, swallowed budesonide, or oral prednisone. Dual therapy is defined as some combination of both dietary and steroid therapy. Final diagnoses were defined as follows: EoE was defined by the presence of ≥15 eos/hpf on endoscopic biopsy after a PPI trial; PPI-REE was defined as the resolution of clinical symptoms and the histologic resolution of esophageal eosinophilia after a PPI trial (<15 eos/hpf). For patients previously on other medications for presumptive EoE in the absence of a prior PPI trial, these medications were stopped prior to completing a PPI trial in order to diagnose PPI-REE. Gastroesophageal reflux was defined as classic symptoms of reflux (i.e. heartburn, regurgitation) without typical EoE symptoms (i.e. dysphagia, food impaction) and the resolution of symptoms on PPI therapy or documentation by pH testing. Finally, lichen planus was defined by diagnostic results on pathology. Data analysis Descriptive statistics were used to quantify the results from this study using the mean value and standard deviation. We calculated the respective prevalence rates and 95% confidence intervals (CI) for the absence of prior PPI trial among the entire study cohort and receipt of EoE-specific medical therapy among those without a PPI trial prior to diagnosis and among those ultimately proven not to have EoE. RESULTS Study population A total of 833 patients were identified on the initial search with 256 of these patients (30.7%) being referred to the University of Pennsylvania with a prior diagnosis of EoE. In total, 125 patients (15.0%) were referred with a prior diagnosis of EoE made by community providers and included in the study population (Fig. 1). Fig. 1 View largeDownload slide Study population meeting inclusion criteria from initial search. Fig. 1 View largeDownload slide Study population meeting inclusion criteria from initial search. Patient characteristics The study population was predominantly male (63.2%) and Caucasian (87.2%) with a mean age of 34.2 ± 12.1 years. Atopic features were described in 60% of all patients, with asthma being the most commonly reported. Eighty-six of the 111 patients (77.4%) who had prior endoscopic results available from their community provider had at least one documented endoscopic finding classic for EoE. Twenty five out of 111 (22.5%) patients had 0 features of EoE documented on endoscopy, 46 out of 111 (41.4%) of patients had 1 feature of EoE, 33 out of 111 (29.7%) had 2 features of EoE on endoscopy, and 7 out of 111 (6.3%) of patients had 3 or more features of EoE on endoscopy. Pathology results revealed an average of 46.7 ± 31.5 eos/hpf on endoscopic biopsy for these patients. Full demographic results can be seen in Table 1. Table 1 Demographic, clinical, and endoscopic data for study population Demographics (n = 125)        Age (mean ± SD)  34.2 ± 12.1 years    Male gender  79 (63.2%)    Caucasian  109 (87.2%)    First visit in 2014–2015  44 (35.2%)    Current/former smoker  12 (9.6%)    Referred to allergist  62 (49.6%)    History of prior dilation  32 (25.6%)  Atopic features (n = 125)        Asthma  49 (39.2%)    Eczema  31 (24.8%)    Rhinitis  28 (22.4%)    Any atopic feature  75 (60.0%)  Clinical symptoms at presentation (n = 123)†        Dysphagia  55 (44.7%)    Chest pain  27 (22.0%)    Heartburn  28 (22.8%)    Regurgitation  21 (17.1%)    History of food impaction  31 (25.2%)  Endoscopic findings at “EoE” diagnosis (n = 111)‡        Furrows  37 (33.3%)    Rings  55 (49.6%)    Loss of vascularity  4 (3.6%)    Exudate  16 (14.4%)    Stricture  23 (20.7%)    Esophagitis  19 (17.1%)  Histologic findings at “EoE” diagnosis (n = 103)§        Eos/hpf (mean ± SD)  46.7 ± 31.5  Demographics (n = 125)        Age (mean ± SD)  34.2 ± 12.1 years    Male gender  79 (63.2%)    Caucasian  109 (87.2%)    First visit in 2014–2015  44 (35.2%)    Current/former smoker  12 (9.6%)    Referred to allergist  62 (49.6%)    History of prior dilation  32 (25.6%)  Atopic features (n = 125)        Asthma  49 (39.2%)    Eczema  31 (24.8%)    Rhinitis  28 (22.4%)    Any atopic feature  75 (60.0%)  Clinical symptoms at presentation (n = 123)†        Dysphagia  55 (44.7%)    Chest pain  27 (22.0%)    Heartburn  28 (22.8%)    Regurgitation  21 (17.1%)    History of food impaction  31 (25.2%)  Endoscopic findings at “EoE” diagnosis (n = 111)‡        Furrows  37 (33.3%)    Rings  55 (49.6%)    Loss of vascularity  4 (3.6%)    Exudate  16 (14.4%)    Stricture  23 (20.7%)    Esophagitis  19 (17.1%)  Histologic findings at “EoE” diagnosis (n = 103)§        Eos/hpf (mean ± SD)  46.7 ± 31.5  †Two patients had clinical notes that did not specify presenting clinical symptoms. ‡Fourteen patients did not have endoscopic reports available for review. §Fifteen patients did not independent path reports other than noted information on referring physician's note. Seven additional patients had path reports that did not document specific number of eosinophils, but rather documented as “many” or “innumerable.” View Large Table 1 Demographic, clinical, and endoscopic data for study population Demographics (n = 125)        Age (mean ± SD)  34.2 ± 12.1 years    Male gender  79 (63.2%)    Caucasian  109 (87.2%)    First visit in 2014–2015  44 (35.2%)    Current/former smoker  12 (9.6%)    Referred to allergist  62 (49.6%)    History of prior dilation  32 (25.6%)  Atopic features (n = 125)        Asthma  49 (39.2%)    Eczema  31 (24.8%)    Rhinitis  28 (22.4%)    Any atopic feature  75 (60.0%)  Clinical symptoms at presentation (n = 123)†        Dysphagia  55 (44.7%)    Chest pain  27 (22.0%)    Heartburn  28 (22.8%)    Regurgitation  21 (17.1%)    History of food impaction  31 (25.2%)  Endoscopic findings at “EoE” diagnosis (n = 111)‡        Furrows  37 (33.3%)    Rings  55 (49.6%)    Loss of vascularity  4 (3.6%)    Exudate  16 (14.4%)    Stricture  23 (20.7%)    Esophagitis  19 (17.1%)  Histologic findings at “EoE” diagnosis (n = 103)§        Eos/hpf (mean ± SD)  46.7 ± 31.5  Demographics (n = 125)        Age (mean ± SD)  34.2 ± 12.1 years    Male gender  79 (63.2%)    Caucasian  109 (87.2%)    First visit in 2014–2015  44 (35.2%)    Current/former smoker  12 (9.6%)    Referred to allergist  62 (49.6%)    History of prior dilation  32 (25.6%)  Atopic features (n = 125)        Asthma  49 (39.2%)    Eczema  31 (24.8%)    Rhinitis  28 (22.4%)    Any atopic feature  75 (60.0%)  Clinical symptoms at presentation (n = 123)†        Dysphagia  55 (44.7%)    Chest pain  27 (22.0%)    Heartburn  28 (22.8%)    Regurgitation  21 (17.1%)    History of food impaction  31 (25.2%)  Endoscopic findings at “EoE” diagnosis (n = 111)‡        Furrows  37 (33.3%)    Rings  55 (49.6%)    Loss of vascularity  4 (3.6%)    Exudate  16 (14.4%)    Stricture  23 (20.7%)    Esophagitis  19 (17.1%)  Histologic findings at “EoE” diagnosis (n = 103)§        Eos/hpf (mean ± SD)  46.7 ± 31.5  †Two patients had clinical notes that did not specify presenting clinical symptoms. ‡Fourteen patients did not have endoscopic reports available for review. §Fifteen patients did not independent path reports other than noted information on referring physician's note. Seven additional patients had path reports that did not document specific number of eosinophils, but rather documented as “many” or “innumerable.” View Large Diagnosis and clinical evaluation Only 13 of 125 patients (10.4%) in the study population had undergone a PPI trial prior to being diagnosed with EoE in the community. An additional 19 other patients (15.2%) were unable to recall if they underwent a PPI trial prior to diagnosis and the reviewed records were unclear as to PPI status. Finally, three patients (2.4%) had undergone pH testing demonstrating no increase gastroesophageal reflux prior to a diagnosis of EoE being made. Ultimately, 90 of 125 patients (72.0%, 95% CI: 63–80%) did not have sufficient testing to exclude PPI-REE prior to a diagnosis of EoE being made in the community. Overall, eight out of 81 patients (9.9%) diagnosed between 2010 and 2013, and eight out of 44 patients (18.1%) had sufficient testing prior to diagnosis of EoE. On final diagnosis after assessment at the University of Pennsylvania, 75 of 125 patients (60.0%, 95% CI: 51–69%) were confirmed to have EoE and 32 patients (25.6%, 95% CI 18–34%) did not have EoE. Alternative diagnoses included PPI-REE (n = 29), GERD (n = 2), and lichen planus (n = 1). Finally, 18 patients had an as yet unknown final diagnosis (14.4%). Reasons for unknown final diagnosis included medication noncompliance, incomplete testing at time of analysis, or loss to follow up. Medical therapy Overall, 94 of 125 (75.2%) patients referred with a presumptive diagnosis of EoE had received prior medical therapy for EoE, including steroids, diet, or a combination of dietary and steroid therapy. In the subset of 90 patients that had insufficient testing prior to a diagnosis of EoE, 71 patients (78.9%, 95% CI: 69–87%) had already received medical therapy for EoE (Fig. 2). In the subset of 32 subjects who were found to have a final diagnosis other than EoE, 25 patients (78.1%, 95% CI: 60–91%) had already received medical therapy for EoE (Fig. 3). Fig. 2 View largeDownload slide Clinical testing performed prior to diagnosis of “EoE” in the community and the prior treatments for patients with insufficient testing prior to the diagnosis of “EoE.” Fig. 2 View largeDownload slide Clinical testing performed prior to diagnosis of “EoE” in the community and the prior treatments for patients with insufficient testing prior to the diagnosis of “EoE.” Fig. 3 View largeDownload slide Final diagnosis of patients referred from community with “EoE” and the prior treatments for patients with final diagnosis other than EoE. Fig. 3 View largeDownload slide Final diagnosis of patients referred from community with “EoE” and the prior treatments for patients with final diagnosis other than EoE. DISCUSSION In this study of 125 patients referred to the University of Pennsylvania with a presumptive diagnosis of EoE, we found that 72% of patients did not have an adequate PPI trial prior to the diagnosis of EoE. Furthermore, 15% of patients in this study could not explicitly recall their prior PPI exposure, and as such the number of patients with inadequate PPI trial may in fact be larger. A significant number of patients with an inadequate PPI trial were started on medical and/or dietary therapies (79%). This incomplete workup also resulted in a potentially incorrect diagnosis of approximately 25% of these patients. The exclusion of PPI-REE and GERD is an important and necessary component in correctly diagnosing EoE. As a result, the need for a PPI trial is highlighted in clinical guidelines.2 The process of diagnosing EoE has evolved over the past decade. While there are clear histologic criteria to diagnose EoE, there are many other entities that may lead to esophageal eosinophilia and mimic EoE. These diseases include achalasia, GERD, Crohn's disease, and hypereosinophilic disorders.4 In particular, distinguishing between GERD, PPI-REE, and EoE has remained challenging. Guidelines have moved away from suggesting pH testing as outlined in the 200710 to a recommendation of a PPI trial in the most recent clinical guidelines published in 2013.2,11 Currently, pH testing is reserved for cases of possible overlapping disease, although it appears to be of only limited benefit.12 In addition to addressing possible GERD, the PPI trial allows for the exclusion of PPI-REE, an entity that was first described in a small case series.13 Without this PPI trial, PPI-REE is indistinguishable from EoE endoscopically, histologically, and clinically.5 It is common for patients with esophageal eosinophilia to respond histologically to a proton pump inhibitor, with estimates ranging from 25% to 77%.14 A recent systematic review and meta-analysis demonstrated that approximately 50% of patients with EoE had histologic remission when treated with PPI therapy.15 These data again underline the need to adequately rule out this entity.16 However, in our study only 23.2% of patients (29 of 125) were ultimately found to have PPI-REE. This percentage is lower than previously reported rates as described above.7 This may have to do with the population we studied, as these patients were seeing at least a second gastroenterologist and other patients with PPI-REE may not have been part of this referred patient population In addition, 14.4% of our study patients (18/125) had an unknown diagnosis at the time of publication which may ultimately increase the number the number of patients diagnosed with PPI-REE. It remains unclear whether PPI-REE is truly a different entity from EoE or whether it is part of the spectrum of EoE. Studies on the pathobiology of EoE have shown that eotaxin-3, intracellular granules such as major basic protein, and tryptase are upregulated mediators of disease in patients with EoE.14 Recent studies have shown high levels of these same markers in patients with PPI-REE.17 It has been proposed that PPI treatment may impact these elevated markers through anti-inflammatory effects that reduce Th2-related mediators and eotaxin-3 secretion.18 Genetically PPI-REE and EoE also appear to be similar.19 The genetic expression in both PPI-REE and EoE is characterized by largely overlapping transcriptomes and similar reversal of their genetic signatures after introduction of appropriate therapy; PPI therapy for PPI-REE and topical steroids for EoE. Currently, it remains unclear if PPI-REE and EoE are a spectrum of disease that is just treated with different medical therapies, or instead, overlapping diseases that can resemble each other.14 These findings in part led to the European Society of Eosinophilic Oesophagitis (EUREOS) to consider PPI as a potential treatment for EoE and not just as a diagnostic test to rule out PPI-REE.7 If PPIs are to be considered a potential first-line therapy, these results may suggest that community providers did not frequently use PPIs as a first-line therapy for the treatment of EoE. The results from this study still show a surprisingly infrequent use of PPIs to diagnose and/or treat EoE. Other controversies regarding PPI-REE also remain. Currently, the necessary dose of PPI therapy to diagnose and/or treat PPI-REE remains unclear. Recent studies have suggested that a step-down approach may work for most patients20 while other patients may need longer term therapy. Data suggest that a minimum of 2 months of PPI therapy is necessary to best differentiate between EoE and PPI-REE.21 The differentiation between appropriate treatments and diagnosis may have long-term implications for patients as well. EoE is a progressive fibrostenotic disease22 that can ultimately progress to narrow caliber esophagus.23 Studies have demonstrated that medical treatment, both topical steroids and elimination diet, can reduce the esophageal fibrosis that has developed.24 It remains unknown if patients with PPI-REE progress along a similar fibrostenotic pathway and whether treatment with a PPI can prevent this in these patients. Further studies are needed to address this question. Despite these questions, it is clear that a PPI trial is an important and recommended step in the diagnosis and treatment of EoE. However, there are limited data in the literature addressing the adherence to these clinical guidelines and the resulting use of other more challenging medical therapies. To our knowledge this is one of the first reports of this issue. A recent publication from Lipka et al. demonstrated similar results to ours: 6.5% of patients (3/46) received a PPI trial in the community and 67.4% of patients (31/46) were treated with steroids irrespective of a PPI trial.25 Furthermore, those investigators also reported a sizable percentage of patients referred from the community who ultimately were diagnosed with PPI-REE (61%) further highlighting the underutilization of a PPI trial prior to a diagnosis of EoE. It is not entirely clear why adherence to the published clinical guidelines for EoE regarding a PPI trial was so low. Practitioner adherence to clinical guidelines is an issue not just in gastroenterology, but within medical practice at large. A systematic review of potential reasons for poor adherence to clinical guidelines identified lack of awareness, familiarity, outcome expectancy, and the inability to overcome the inertia of previous practice, as possible contributors.26 It is possible that recently changing guidelines regarding EoE and the clinical confusion regarding the role of PPI-REE contribute to a lack of awareness about the appropriate use of a PPI trial in the clinical approach to EoE. The importance of clarifying these diagnoses is evident in the resulting treatment options for both. 78% of patients in this study were started on medical therapy without a PPI trial, including 79% whose final diagnosis was not EoE. Patients using long-term topical steroids have a 10–20% risk of developing esophageal candidiasis4,27 and cases of herpes esophagitis have also been reported.28 While common side effects of oral steroids (i.e. mood changes, weight gain) have been rarely reported,4 a recent small, prospective study demonstrated adrenal suppression during a short course of topical steroids.29 Long-term studies of patients using topical steroids have not yet been completed. In addition to these side effects, multi-dose inhalers such as fluticasone can be difficult to administer resulting in inadequate dosing and both fluticasone and budesonide can be financially costly for patients given the off label use of both compounds. This is a similar problem for elimination diets, which can be difficult to adhere to and expensive for patients. While recent concerns have developed regarding PPI adverse events with long-term therapy, these studies are all characterized by modest effect rates and all demonstrate association instead of causation.30–32 PPIs are generally well tolerated, inexpensive, and easy to adhere to. The strengths of this study include the large number of patients studied in a “real world” practice setting outside a clinical trial. As such, this study offers a realistic snapshot of this issue. There was also extensive documentation regarding prior therapies and PPI trials. We readily recognize some of the limitations of this study. Given the retrospective design, data could be limited by a patient's recall or incomplete medical records. We aimed to offset this limitation by only documenting patients as lacking a PPI trial when it was clearly documented in the reviewed records. As such, 15.2% of patients (19 out of 125) identified themselves as not being able to recall if testing on PPI therapy was completed. An additional potential limitation is referral bias. As a tertiary care center, the patients’ referred to our center and included in this study may not reflect the “standard” EoE case, but rather cases that were difficult to manage or did not respond to a first treatment. This may be reflected in the fact that a majority of patients included in this trial had previously received some form of treatment. Studying this group of referred patients may lead to either an over or underestimate of patients with EoE who have undergone a PPI trial in the general population. As mentioned previously, in our study only 23.2% of patients were ultimately found to have PPI-REE, which is a smaller percentage than what is reported in the literature today. Last, this study took place in a tertiary urban referral center in a practice of one physician with a dedicated interest in EoE. As such, we may not have captured the full spectrum of the patient population referred to the University of Pennsylvania for eosinophilic disorders. In conclusion, we found that the majority of patients referred to a tertiary care center for the management of EoE had not had a PPI trial prior to the presumptive diagnosis of EoE. This led to an inappropriate diagnosis of EoE in over 25% of patients with subsequent unwarranted medical and dietary therapies in the majority of these patients. Given the ease of treatment of PPI-REE compared to EoE, more emphasis should be placed on clearly separating out both entities. ACKNOWLEDGMENTS We acknowledge U54AI117804 (CEGIR), which is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. In addition, we acknowledge the Penn-CHOP Joint Center in Digestive, Liver and Pancreatic Medicine for their support. Notes Declaration of interests: Matthew J. Whitson, nothing to declare; Kristle L. Lynch, nothing to declare; Yu-Xiao Yang, nothing to declare; David C. Metz, nothing to declare; Gary W. Falk, Research support from Celgene, Shire, Regeneron, Adare. Consultant for Adare Pharmaceuticals and Banner Life Sciences. Specific author contributions: Design of research study: Matthew J. Whitson, David C. Metz, Gary W. Falk; Collection and analysis of data: Matthew J. Whitson, Kristle L. Lynch; Paper authorship: Matthew J. Whitson, Kristle L. Lynch, Yu-Xiao Yang, David C. Metz, Gary W. Falk; Final approval of paper: Matthew J. Whitson, Kristle L. Lynch, Yu-Xiao Yang, David C. Metz, Gary W. Falk; Analysis of data: Yu-Xiao Yang, Gary W. Falk; Guarantor of article: Gary W. Falk; All authors approved the final draft of this manuscript, the decision to submit the manuscript for publication, and the final order of authorship. References 1 Singla M B, Moawad F J. An overview of the diagnosis and management of eosinophilic esophagitis. Clin Trans Gastroenterol  2016; 7: e155. Google Scholar CrossRef Search ADS   2 Dellon E S, 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. Google Scholar CrossRef Search ADS PubMed  3 Furuta G T, Katzka D A. Eosinophilic esophagitis. N Engl J Med  2015; 373: 1640– 8. Google Scholar CrossRef Search ADS PubMed  4 Dellon E S, Liacouras C A. Advances in clinical management of eosinophilic esophagitis. Gastroenterology  2014; 147: 1238– 54. Google Scholar CrossRef Search ADS PubMed  5 Dellon E S, 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– 60. Google Scholar CrossRef Search ADS PubMed  6 Moawad F J, Schoepfer A M, 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: 603– 8. Google Scholar CrossRef Search ADS PubMed  7 Molina-Infante J, Bredenoord A J, Cheng E et al.   Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut  2016; 65: 524– 31. Google Scholar CrossRef Search ADS PubMed  8 van Rhijn B D, Weijenborg P W, 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. Google Scholar CrossRef Search ADS PubMed  9 Molina-Infante J, Ferrando-Lamana L, Ripoli C et al.   Esophageal eosinophilic infiltration responds to proton pump inhibition in most adults. Clin Gastroenterol Hepatol  2011; 9: 110– 7. Google Scholar CrossRef Search ADS PubMed  10 Furuta G T, Liacouras C A, Collins M H et al.   Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology  2007; 133: 1342– 63. Google Scholar CrossRef Search ADS PubMed  11 Liacouras C A, Furuta G T, Hirano I et al.   Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol  2011; 128: 3– 20. e6. Google Scholar CrossRef Search ADS PubMed  12 Francis D L, Foxx-Orenstein A, Arora A S 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– 7. Google Scholar CrossRef Search ADS PubMed  13 Ngo P, Furuta G T, Antonioli D A 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– 70. Google Scholar CrossRef Search ADS PubMed  14 Eluri S, Dellon E S. Proton pump inhibitor-responsive oesophageal eosinophilia and eosinophilic oesophagitis. Curr Opin Gastroenterol  2015; 31: 309– 15. Google Scholar CrossRef Search ADS PubMed  15 Lucendo A J, 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. Google Scholar CrossRef Search ADS PubMed  16 Molina-Infante J, Katzka D A, Gisbert J P. Review article: proton pump inhibitor therapy for suspected eosinophilic oesophagitis. Aliment Pharmacol Ther  2013; 37: 1157– 64. Google Scholar CrossRef Search ADS PubMed  17 Dellon E S, Chen X, Miller C R et al.   Markers of eosinophilic inflammation for diagnosis of eosinophilic esophagitis and proton pump inhibitor-responsive esophageal eosinophilia: a prospective study. Clin Gastroenterol Hepatol  2014; 12: 2015– 22. Google Scholar CrossRef Search ADS PubMed  18 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. Google Scholar CrossRef Search ADS PubMed  19 Wen T, Dellon E S, Moawad F J 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– 97. e4. Google Scholar CrossRef Search ADS PubMed  20 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– 40. Google Scholar CrossRef Search ADS PubMed  21 DiGiovanni E L, Champeaux A L, Arroyo M R et al.   Esophageal eosinophilia treated with long-duration proton pump inhibitor therapy. ACGCR  2016; 3: 95– 7. Google Scholar CrossRef Search ADS PubMed  22 Dellon E S, Kim H P, Sperry S L et al.   A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease. Gastrointest Endosc  2014; 79: 577– 85.e4. Google Scholar CrossRef Search ADS PubMed  23 Eluri S, Runge T M, Cotton C C et al.   The extremely narrow-caliber esophagus is a treatment-resistant subphenotype of eosinophilic esophagitis. Gastrointest Endosc  2016; 83: 1142– 8. Google Scholar CrossRef Search ADS PubMed  24 Straumann A, Schoepfer A. Update on basic and clinical aspects of eosinophilic oesophagitis. Gut  2014; 63: 1355– 63. Google Scholar CrossRef Search ADS PubMed  25 Lipka S, Kumar A, Richter J E. PPI Trial for eosinophilic esophagitis. J Clin Gastroenterol  2017; Mar 13: Epub ahead of print. 26 Cabana M D, Rand C S, Powe N R et al.   Why do not physicians follow clinical practice guidelines?. JAMA  1999; 282: 1458– 65. Google Scholar CrossRef Search ADS PubMed  27 Chuang M, Chinnaratha M A, Hancock D G et al.   Topical steroid therapy for the treatment of eosinophilic esophagitis (EoE): a systematic review and meta-analysis. Clin Trans Gastroenterol  2015; 6: e82. Google Scholar CrossRef Search ADS   28 Lindberg G M, Van Eldik R, Saboorian M H. A case of herpes esophagitis after fluticasone propionate for eosinophilic esophagitis. Nat Clin Pract Gastroenterol Hepatol  2008; 5: 527– 30. Google Scholar CrossRef Search ADS PubMed  29 Ahmet A, Benchimol E I, Goldbloom E B et al.   Adrenal suppression in children treated with swallowed fluticasone and oral viscous budesonide for eosinophilic esophagitis. Allergy Asthma Clin Immunol  2016; 12: 49– 55. Google Scholar CrossRef Search ADS PubMed  30 Reimer C. Safety of long-term PPI therapy. Best Pract Res Clin Gastroenterol  2013; 27: 443– 54. Google Scholar CrossRef Search ADS PubMed  31 Moledina D G, Perazella M A. PPIs and kidney disease: from AIN to CKD. J Nephrol  2016; 29: 611– 6. Google Scholar CrossRef Search ADS PubMed  32 Gomm W, von Holt K, Thome F et al.   Association of proton pump inhibitors with risk of dementia. JAMA Neurol  2016; 73: 410– 6. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Diseases of the EsophagusOxford University Press

Published: Dec 22, 2017

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off