Technical Review on the Management of Eosinophilic Esophagitis: A Report From the AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters
2020; Elsevier BV; Volume: 158; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2020.02.039
ISSN1528-0012
AutoresMatthew A. Rank, Rajiv N. Sharaf, Glenn T. Furuta, Seema S. Aceves, Matthew Greenhawt, Jonathan M. Spergel, Yngve Falck–Ytter, Evan S. Dellon, Karen A. Chachu, Lukejohn W. Day, Benjamin Lebwohl, Thiruvengadam Muniraj, Amit Patel, Anne F. Peery, Raj Shah, Harminder Singh, Siddharth Singh, Stuart J. Spechler, Shahnaz Sultan, Grace L. Su, Aaron P. Thrift, Jennifer M. Weiss, Adam V. Weizman, Jonathan A. Bernstein, Chitra Dinakar, David B.K. Golden, David A. Khan, Phil Lieberman, John Oppenheimer, Marcus Shaker, David R. Stukus, Dana Wallace, Julie Wang,
Tópico(s)Eosinophilic Disorders and Syndromes
ResumoEosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to <15 per high-power field over a short-term treatment period of 4–12 weeks, but very low certainty about the effects of using topical glucocorticosteroids as maintenance therapy. Multiple dietary strategies may be effective in reducing esophageal eosinophil counts to <15 per high-power field over a short-term treatment period, with moderate certainty for elemental diets, low certainty for empiric 2-, 4-, and 6-food elimination diets, and very low certainty that allergy-based testing dietary eliminations have a higher failure rate compared to empiric diet elimination. There is very low certainty for the effect of proton pump inhibitors in patients with esophageal eosinophilia. Although esophageal dilation appears to be relatively safe, there is no evidence that it reduces esophageal eosinophil counts. There is very low certainty in the effects of multiple other medical treatments for EoE: anti–interleukin-5 therapy, anti–interleukin-13 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy. Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to <15 per high-power field over a short-term treatment period of 4–12 weeks, but very low certainty about the effects of using topical glucocorticosteroids as maintenance therapy. Multiple dietary strategies may be effective in reducing esophageal eosinophil counts to <15 per high-power field over a short-term treatment period, with moderate certainty for elemental diets, low certainty for empiric 2-, 4-, and 6-food elimination diets, and very low certainty that allergy-based testing dietary eliminations have a higher failure rate compared to empiric diet elimination. There is very low certainty for the effect of proton pump inhibitors in patients with esophageal eosinophilia. Although esophageal dilation appears to be relatively safe, there is no evidence that it reduces esophageal eosinophil counts. There is very low certainty in the effects of multiple other medical treatments for EoE: anti–interleukin-5 therapy, anti–interleukin-13 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy. Eosinophilic esophagitis (EoE) is a chronic, rare, and food antigen-driven Th2 inflammatory condition of the esophagus that is estimated to affect 1 in every 2000 people.1Dellon E.S. Hirano I. Epidemiology and natural history of eosinophilic esophagitis.Gastroenterology. 2018; 154: 319-332.e3Abstract Full Text Full Text PDF PubMed Google Scholar There is a large body of evidence that EoE subjects have aeroallergen sensitization and concurrent atopic diseases, including asthma, allergic rhinitis, and eczema. There is a close interaction between these organ-specific diseases and potential for common triggering antigens in EoE and other atopic conditions. The incidence of EoE is increasing. EoE can occur in children and adults and is more common in whites and males, and is associated with other atopic diseases. EoE negatively impacts the quality of life for patients and their families. Medical resource utilization costs in EoE may be significant for some.2Mukkada V. Falk G.W. Eichinger C.S. et al.Health-related quality of life and costs associated with eosinophilic esophagitis: a systematic review.Clin Gastroenterol Hepatol. 2018; 16: 495-503.e8Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,3Jensen E.T. Kappelman M.D. Martin C.F. et al.Health-care utilization, costs, and the burden of disease related to eosinophilic esophagitis in the United States.Am J Gastroenterol. 2015; 110: 626-632Crossref PubMed Google Scholar EoE can be characterized by the associated symptoms, visual esophageal endoscopic findings, and histopathology. In adolescents and adults, symptoms often include dysphagia and food impaction, but can be less specific in children, and can include failure to thrive, feeding problems, vomiting, heartburn, and abdominal discomfort. Direct visual inspection of the esophagus in many but not all EoE patients can reveal rings, linear furrows, white plaques or exudates, edema or decreased vascularity, strictures, or luminal narrowing. Histopathology will reveal eosinophils in the esophageal epithelium, which can be defined as a threshold of ≥15 eosinophils per high-power field (eos/hpf). The primary outcome for all of the interventions for this report was achieving <15 eos/hpf except for esophageal dilation. EoE has traditionally been distinguished from gastroesophageal reflux disease (GERD) by the failure of proton pump inhibitor (PPI) treatment to reduce esophageal eosinophilia below a prespecified threshold. Over the past 10 years, the diagnosis of EoE has been made in a patient who has symptoms of swallowing dysfunction and esophageal eosinophilia that persists despite PPI treatment, and this is the definition that is used as entry criteria for most of the studies presented in this technical report based on previous guidelines.4Dellon 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 (quiz 693): 679-692Crossref PubMed Scopus (606) Google Scholar, 5Furuta 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: 1342-1363Abstract Full Text Full Text PDF PubMed Scopus (1173) Google Scholar, 6Liacouras C.A. Furuta G.T. Hirano I. et al.Eosinophilic esophagitis: updated consensus recommendations for children and adults.J Allergy Clin Immunol. 2011; 128: 3-20Abstract Full Text Full Text PDF PubMed Scopus (1288) Google Scholar However, discerning EoE from GERD remains an area of controversy and active investigation, and the most recent diagnostic criteria for EoE leave the criterion of PPI failure to the clinician7Molina-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: 524-531Crossref PubMed Scopus (134) Google Scholar,8Lucendo A.J. Molina-Infante J. Arias A. et al.Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.United Eur Gastroenterol J. 2017; 5: 335-358Crossref PubMed Scopus (216) Google Scholar because PPI-responsive esophageal eosinophilia now is considered as part of the spectrum of EoE. As such, PPIs are increasingly considered as a treatment rather than as a diagnostic test for EoE, as described in a recent consensus document. In addition, the biological impact of PPIs to reduce expression of key EoE-related cytokines including eotaxin-3 in vitro and normalize the EoE transcriptome, and the multiple similarities between patients with suspected EoE who do and do not respond to a PPI, together underscore that PPI-responsive esophageal eosinophilia and EoE are potentially disorders in the same pathogenic spectrum. The most common management approaches for EoE are topical glucocorticosteroids, dietary elimination, and esophageal dilation. Many new studies have been published recently. Therefore, the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters (jointly sponsored by the American College of Allergy, Asthma, and Immunology and the American Academy of Allergy, Asthma, and Immunology) formed a team to provide up-to-date guidance for EoE management. This technical review addresses focused clinical questions regarding different therapeutic strategies for managing children and adults with EoE. The results of this technical review were used to inform the development of an accompanying clinical guideline for EoE. This technical review and the accompanying guideline were developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.9Schunemann H.J. Oxman A.D. Brozek J. et al.Grading quality of evidence and strength of recommendations for diagnostic tests and strategies.BMJ. 2008; 336: 1106-1110Crossref PubMed Google Scholar The members of the technical review panel were selected by the American Gastroenterological Association Clinical Guidelines Committee and the Joint Task Force on Allergy-Immunology Practice Parameters based on their clinical content and guidelines methodological expertise. Each member underwent a thorough vetting process for potential conflicts of interest. Through an iterative process, and in conjunction with the guideline panel, the participants developed focused clinical questions on the role of specific interventions in the management of EoE. After the focused questions were approved by the organization’s respective leadership groups, the technical review team identified relevant patient-important outcomes, systematically reviewed and summarized the evidence for each outcome across studies, and then rated the quality of the evidence across all outcomes for each clinical question using the GRADE framework. Using the PICO format, which frames a clinical question by defining a specific Population (P), Intervention (I), Comparator (C), and Outcomes (O), the team developed clinically relevant questions. The PICOs focused on the use of therapeutics in patients with symptomatic EoE. Each of the selected PICO questions was addressed in this review using the GRADE framework except for 2 PICO questions, which were addressed using a narrative review format. Studies with children and adults were included. When possible, the interventions were compared to placebo. When only trials compared to another intervention were available, the intervention was presented relative to another intervention (comparator). Supplementary Table 1 is a summary display of the 17 PICO questions in this technical report. Potentially relevant patient-important outcomes were considered and rated in terms of importance, as summarized in Supplementary Table 2. Through consensus of the expert panel, with no voting necessary during the face-to-face review, and based on precedent literature, failing to achieve histologic remission of <15 eos/hpf was considered critical for decision-making.10Reed C.C. Wolf W.A. Cotton C.C. et al.Optimal histologic cutpoints for treatment response in patients with eosinophilic esophagitis: analysis of data from a prospective cohort study.Clin Gastroenterol Hepatol. 2018; 16: 226-233.e2Abstract Full Text Full Text PDF PubMed Google Scholar,11Wolf W.A. Cotton C.C. Green D.J. et al.Evaluation of histologic cutpoints for treatment response in eosinophilic esophagitis.J Gastroenterol Hepatol Res. 2015; 4: 1780-1787Crossref PubMed Scopus (46) Google Scholar It was recognized that untreated inflammation can potentially lead to fibrostenotic disease,12Warners M.J. Oude Nijhuis R.A.B. de Wijkerslooth L.R.H. et al.The natural course of eosinophilic esophagitis and long-term consequences of undiagnosed disease in a large cohort.Am J Gastroenterol. 2018; 113: 836-844Crossref PubMed Scopus (25) Google Scholar, 13Schoepfer A.M. Safroneeva E. Bussmann C. et al.Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.Gastroenterology. 2013; 145 (e1–e2): 1230-1236Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 14Lipka S. Kumar A. Richter J.E. Impact of diagnostic delay and other risk factors on eosinophilic esophagitis phenotype and esophageal diameter.J Clin Gastroenterol. 2016; 50: 134-140Crossref PubMed Scopus (50) Google Scholar, 15Dellon 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: 577-585.e4Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar but also that symptoms do not always correspond with histology.16Gupta S. Vitanza J. Collins M. Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2015; 13: 66-76.e3Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 17Reed C.C. Wolf W.A. Cotton C.C. et al.A visual analogue scale and a Likert scale are simple and responsive tools for assessing dysphagia in eosinophilic oesophagitis.Aliment Pharmacol Ther. 2017; 45: 1443-1448Crossref PubMed Scopus (10) Google Scholar, 18Safroneeva E. Straumann A. Coslovsky M. et al.Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis.Gastroenterology. 2016; 150: 581-590.e4Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Symptoms, changes in peak tissue eosinophil levels, and adverse effects were considered important for decision-making. If data on certain outcomes were not available, the a priori plan was to use indirect evidence to guide decision making if additional data were not provided after contacting the investigators. Outcomes that are reported in the evidence profiles are those that were found in the literature. Several outcomes that were rated as important by the expert panel are not reported in the evidence profiles because they were not assessed in the included literature. Symptoms were reported using many different scales. Validated EoE symptom questionnaires were not available when most of the studies were performed. Therefore, symptom severity was an outcome that could not be synthesized in a summary estimate due to this heterogeneity in reporting. Similarly, not all studies utilized a validated endoscopy score, and endoscopic outcomes could not be synthesized. Finally, a key decision in forming the estimate of the effect for observational studies lacking a contemporaneous control group was to use the placebo control arm rate for failing to achieve histologic remission from topical corticosteroid studies. The expert panel was in consensus, with no voting needed, that the 86.7% estimate for failing to achieve histologic remission (≥15 eosinophils/hpf) in the placebo arm during a study period of 8 weeks was reasonable based on the overall information available in the literature.19Alexander J. Jung K. Arora A. et al.Swallowed fluticasone improves histologic but not symptomatic response of adults with eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2012; 10: 742-749.e1Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 20Butz B. Wen T. Gleich G. et al.Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis.Gastroenterology. 2014; 147: 324-333.e5Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 21Dellon E. Katzka D. Collins M. et al.Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.Gastroenterology. 2017; 152: 776-786.e5Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 22Dohil R. Newbury R. Fox L. et al.Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial.Gastroenterology. 2010; 139: 418-429.e1Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 23Konikoff M. Noel R. Blanchard C. et al.A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.Gastroenterology. 2006; 131: 1381-1391Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar, 24Miehlke S. Hruz P. Vieth M. et al.A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.Gut. 2016; 65: 390-399Crossref PubMed Scopus (91) Google Scholar, 25Straumann A. Conus S. Degen L. et al.Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.Gastroenterology. 2010; 139 (1537.e1): 1526-1537Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar A common approach to study selection was used for each question. For all PICOs, we first considered high-quality systematic reviews for evidence synthesis, particularly those that synthesized data from randomized controlled trials (RCTs). If systematic reviews of RCTs were not available, we then looked to individual RCTs and generated summary estimates as needed. Systematic reviews of observational studies, and in particular, single-arm cohort/observational studies, were considered as the least-preferred option to inform the evidence, with rates pooled when possible. Case series with <5 cases and case reports were excluded, unless no other evidence for the question was available. Systematic reviews that were missing recent trial data were updated and re-analyzed rather than creating a de novo systematic review. When well-done systematic reviews were unavailable, we searched for primary articles using a preliminary search strategy. Next, preliminary evidence profiles were constructed using GRADEPRO (https://gradepro.org/), and were reviewed iteratively with the clinical experts (S.A.A., G.T.F., M.G., J.M.S., and E.S.D.), where feedback was provided about missing studies, missing data, and preliminary evidence ratings. An additional, final systematic literature search was performed after the preliminary evidence profiles were constructed and reviewed with the expert panel to ensure completeness. Details of the search strategy are reported in the Supplementary Table 3. We conducted an electronic search using MEDLINE, EMBASE, and the Cochrane Library until May 13, 2018. A research librarian (K.K.) developed a single search strategy for MEDLINE and then adapted to EMBASE and Cochrane. The search strategy was iteratively refined to maximize sensitivity, working directly with the clinical experts. The search excluded letters, commentaries, editorials, notes, conference abstracts, and nonhuman studies. We only searched for clinical trials in the electronic literature search for all PICO questions except for the dietary interventions where observational studies were considered, a decision made by the expert panel after considering the preliminary evidence profiles. We searched the World Health Organization clinical trial registry to identify additional studies (http://apps.who.int/trialsearch/). An additional search to identify health disparities or other equity issues associated with the selected PICOs was carried out using the MEDLINE Health Disparities and Minority Health Search Strategy filter (https://www.nlm.nih.gov/services/queries/health_disparities_details.html). Titles and abstracts were reviewed in duplicate by 2 authors (M.R. and R.S.). One methodologist (R.S. or M.R.) extracted data from eligible reports and a second methodologist (R.S. or M.R.) evaluated the accuracy of the data extraction. We contacted authors when key data were missing, first by attempting to reach the corresponding author by e-mail and then by trying a second author from the article if no response was received from the corresponding author. Disagreements were resolved by discussion with a third methodologist (Y.F.Y.). A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram was constructed (see Supplementary Figure 1). Pooled risk ratios with 95% confidence intervals (CI) were calculated when possible, using RevMan, version 5.3 (Cochrane Collaboration, Copenhagen, Denmark), or Open Meta[analyst] (Brown University, Providence, RI), particularly when single-arm rates were pooled. In RevMan, analyses were performed using a random-effects model. In OpenMeta[analyst], we used binary random effects using the DerSimonian-Laird method. Statistical heterogeneity was assessed using the I2 statistic. Publication bias was assessed using funnel plots when possible. GRADEpro software was used to construct the evidence profiles and calculate the absolute effects. When historical controls were used, risk ratios (RRs) were presented and the resulting absolute effects were informed by applying the baseline risk from the untreated control arms from steroid RCTs to the RR. It is important to note that RR refers, in this technical report, to the risk of not achieving histologic remission in the treatment vs a comparator. We identified 23 observational studies, which reported that 58.3% (unweighted) of subjects on PPI failed to achieve histopathologic remission (<15 eos/hpf) compared to 86.7% (unweighted) of a placebo comparison group. The certainty in the effect estimate was very low (see Table 1 and Supplementary Figure 2, PICO Question 1). The certainty in the estimate was downgraded for inconsistency.Table 1Summary of Findings for PICO Question 1aThe risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).PPI compared to placebo for EoEOutcomes and follow-upNo. of participants (studies)26Garrean C. Hirano I. 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Cilleruelo M.L. et al.High prevalence of response to proton-pump inhibitor treatment in children with esophageal eosinophilia.J Pediatr Gastroenterol Nutr. 2016; 62: 704-710Crossref PubMed Scopus (35) Google ScholarCertainty of the evidence (GRADE)Relative effect, RR (95% CI)Anticipated absolute effectsRisk with placeboRisk difference with PPINot achieving histologic remission (<15 eos/hpf); follow-up: mean 8 wk1051 (23 observational studies)bIncluded 2 RCTs of PPI vs topical steroids.⊕◯◯◯VERY LOWcI2 = 81%; very inconsistent results in absolute terms.,dPatients are different than for other interventions where PPI responders were excluded.0.66 (0.61–0.72)eUsed historical control cohort of placebo arm of topical steroid studies.867 per 1000295 fewer per 1000 (338 fewer to 243 fewer)a The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).b Included 2 RCTs of PPI vs topical steroids.c I2 = 81%; very inconsistent results in absolute terms.d Patients are different than for other interventions where PPI responders were excluded.e Used historical control cohort of placebo arm of topical steroid studies. Open table in a new tab This question is related to patients with esophageal eosinophilia, who, depending on the study and inclusion criteria, may be different than patients with EoE. It is important to note that this is an indirect comparison because participants in the topical corticosteroid studies had failed PPI treatment. Understanding PPI response in EoE remains an active area of investigation. The inconsistency seen in the point estimates for histologic response was not clearly explained by any specific criteria (eg, pediatrics vs adult or inclusion/exclusion criteria). There were 2 RCTs identified that compared PPI to topical corticosteroid, and found similar rates of histologic remission (see Supplementary Table 4). Eight double-blind pl
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