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MEDICAL POSITION PAPER Management Guidelines of Eosinophilic Esophagitis A. Papadopoulou, yS. Koletzko, zR. Heuschkel, J.A. Dias, jjK.J. Allen, S.H. Murch, S. Chong, F. Gottrand, yyS. Husby, zzP. Lionetti, M.L. Mearin, jjjjF.M. Ruemmele, M.G. Scha¨ppi, A. Staiano, M. Wilschanski, and yyyY. Vandenplas, for the ESPGHAN Eosinophilic Esophagitis Working Group and the Gastroenterology Committee esophageal stenosis unresponsive to drug therapy. Maintenance treatment Objectives: Eosinophilic esophagitis (EoE) represents a chronic, immune/ may be required in case of frequent relapse, although an optimal regimen antigen-mediated esophageal disease characterized clinically by symptoms still needs to be determined.
related to esophageal dysfunction and histologically by eosinophil-predo- Conclusions: EoE is a chronic, relapsing inflammatory disease with largely minant inflammation. With few exceptions, 15 eosinophils per high-power unquantified long-term consequences. Investigations and treatment are field (peak value) in 1 biopsy specimens are considered a minimum tailored to the individual and must not create more morbidity for the threshold for a diagnosis of EoE. The disease is restricted to the esophagus, patient and family than the disease itself. Better maintenance treatment and other causes of esophageal eosinophilia should be excluded, specifically as well as biomarkers for assessing treatment response and predicting long- proton pump inhibitor–responsive esophageal eosinophilia. This position term complications is urgently needed.
paper aims at providing practical guidelines for the management of childrenand adolescents with EoE.
Key Words: amino acid – based formula, empiric elimination diet, Methods: Relevant literature from searches of PubMed, CINAHL, and eosinophilic esophagitis, local steroids, systemic steroids, targeted recent guidelines was reviewed. In the absence of an evidence base, recommendations reflect the expert opinion of the authors. Finalconsensus (JPGN 2014;58: 107–118) Gastroenterology Committee and 1 teleconference.
Results: The cornerstone of treatment is an elimination diet (targeted orempiric elimination diet, amino acid–based formula) and/or swallowed,topical corticosteroids. Systemic corticosteroids are reserved for severe Eosinophilic esophagitis (EoE) is a chronic immune/antigen- mediated esophageal inflammatory disease associated with symptoms requiring rapid relief or where other treatments have failed.
esophageal dysfunction resulting from severe eosinophil-predomi- Esophageal dilatation is an option in children with EoE who have nant inflammation In 2007, a multidisciplinary group of Accepted July 14, 2013.
From the Division of Gastroenterology & Nutrition, First Department of Pediatrics, University of Athens, Children's Hospital Agia Sophia, Athens, Greece, the yDr. von Haunersches Kinderspital, Ludwig-Maximilians-University, Munich, Germany, the zDepartment of Pediatric Gastroenterology, Adden-brookes Hospital, Cambridge, UK, the §Department of Pediatrics, Hospital S. Joa˜o, Porto, Portugal, the jjDepartment of Allergy and Immunology,Department of Gastroenterology, University of Melbourne Department of Paediatrics, Murdoch Children's Research Institute, Royal Children's Hospital,Parkville, Victoria, Australia, the ôDivision of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK, the#Queen Mary's Hospital for Children, Epsom & St Helier University Hospitals NHS Trust, Carshalton, Surrey, UK, the Department of PediatricGastroenterology, Hepatology, and Nutrition, Jeanne de Flandre University Hospital, University of Lille, Lille, France, the yyHans Christian AndersenChildren's Hospital, OUH, Odense, Denmark, the zzPediatric Gastroenterology & Nutrition Unit, Department of Sciences for Woman and Child Health,University of Florence, Meyer Children's Hospital, Florence, Italy, the §§Department of Pediatrics, Leiden University Medical Center, Leiden, TheNetherlands, the jjjjUniversite´ Paris Descartes, Sorbonne Cite´, Paris, and APHP, Hoˆpital Necker Enfants Malades, Pediatric Gastroenterology, Paris,France, the ôôPediatric Center, Clinique des Grangettes, Geneva and Centre Me´dical Universitaire, Geneva, Switzerland, the ##Department of Pediatrics,University of Naples ‘‘Federico II,'' Naples, Italy, the Pediatric Gastroenterology Unit, Division of Pediatrics, Hadassah University Hospital,Jerusalem, Israel, and the yyyVrije Universiteit Brussel, Brussels, Belgium.
Address correspondence and reprint requests to Alexandra Papadopoulou, Division of Gastroenterology and Nutrition, First Department of Pediatrics, University of Athens, Children's Hospital Agia Sophia, Thivon & Papadiamantopoulou, 11527 Athens, Greece (e-mail: A.P. has received speaker's honoraria from Danone and Ferring and a research grant from Biogaia. S.K. is a consultant and speaker for Abbott, Danone (Nutricia), Merck-Sharpe-Dohme, and Nestle´ Nutrition, and has received research grants from Mead Johnson and Nestle´ Nutrition. R.H. is a lecturer forDanone, Mead Johnson, and Merck-Sharpe-Dohme, and has received unrestricted support for educational events from Nestle, Biogaia, and Merck-Sharpe-Dohme. J.A.D. is a lecturer for Danone, Mead Johnson, and United Pharmaceuticals (Novolac). K.J.A. has received speaker's honoraria from Nutricia,Abbott, and Pfizer. S.H.M. has received compensation for lectures and is a member of advisory panels for Danone, Nutricia, and Mead Johnson. F.G. is aconsultant for Nutricia Clinical Nutrition and has received research grants from Danone and Nestle´. S.H. has received speaker's honorarium from Thermo-Fisher. P.L. serves on the advisory board of Abvie and is a lecturer for Danone, Nutricia, and Nestle´ Nutrition. F.M.R. is a consultant, advisory boardmember, or speaker for Merck-Sharpe-Dohme, Janssen, Nestle´, Danone, and Biocodex. A.S. is on the advisory board of Movetis, is a consultant for D.M.G.
Italy, and serves on the speakers' bureaus of Valeas and Mead Johnson. Y.V. lectures for Abbott, Biocodex, Danone (Nutricia), Mead Johnson, Nestle´Nutrition, and United Pharmaceuticals (Novalac). The other authors report no conflicts of interest.
Copyright # 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition JPGN  Volume 58, Number 1, January 2014 Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
ESPGHAN EoE Working Group/GI Committee JPGN  Volume 58, Number 1, January 2014 experts published the first consensus recommendations for the failure to thrive. During childhood, vomiting and/or abdominal or diagnosis and treatment of EoE which were recently updated retrosternal pain are reported, whereas during adolescence, gastro- The updated definition of the disease includes the histological esophageal reflux disease (GERD) symptoms, dysphagia, and food presence of 15 eosinophils per high power field (eos/hpf) in at impaction are the most frequent symptoms least 1 endoscopic esophageal mucosal biopsy (peak value) taken at Peripheral eosinophilia (>700 cells/mm3) has been reported upper gastrointestinal endoscopy; and/or the presence of other in children with EoE Furthermore, specific immunoglobulin E microscopic features of eosinophilic inflammation such as eosino- (IgE) antibodies to foods may be found in children with EoE philic microabscesses, superficial layering, or extracellular eosino- identifying sensitization to foods which may (or may not) be the phil granules These publications provide extensive information causative foods of the disease. Typical endoscopic findings include on pathogenesis, epidemiology, clinical presentation, diagnosis, esophageal rings, a thickened, sometimes pale mucosa with linear and management of EoE in both adults and children; however, a furrows and white exudates and less often, narrowing of the caliber practical algorithm on the optimal treatment of children with EoE, of the esophagus. A normal esophagus at endoscopy does not to guide clinical practice, is lacking. This position paper of the exclude the diagnosis of EoE. Mucosal breaks (erosions or ulcera- Eosinophilic Esophagitis Working Group (see Appendix) and the tion) are not findings of EoE and are indicative for GERD, Crohn Gastroenterology Committee of ESPGHAN aims at providing disease, or other diagnoses. According to Shah et al, at least 3 practical guidelines for the management of children and adolescents esophageal biopsy specimens taken from different parts of the with EoE, based on available evidence where possible. If sufficient esophagus are necessary to achieve a diagnosis of EoE in 97% evidence is lacking, our recommendations are based on expert of patients According to Gonsalves et al 1 biopsy opinion and personal practice.
specimen has a sensitivity of only 55%, whereas 5 biopsies increasethis to 100%. To maximize diagnostic sensitivity, it is therefore PREVALENCE AND INCIDENCE OF EoE recommended that at least 2 to 4 biopsies should be taken from boththe proximal and distal esophagus, regardless of the endoscopic Data mainly come from pediatric regional referral centers for upper endoscopy. Noel et al reported between the years 2000 appearance of the esophagus The main histological findings are and 2003 an annual incidence of EoE in children in Ohio of 1/ dense eosinophilia of the esophageal mucosa, which tends to bepanesophageal, basal zone hyperplasia, lamina propria fibrosis, and 10,000, leading to an estimated prevalence of 4/10,000 children by sometimes eosinophilic microabcesses It should be noted, the end of 2003. Cherian et al reported a prevalence of 0.89/10,000 in 2004 in Western Australia, whereas Dalby et al however, that the size of a high-power field has not been standar-dized. This may alter the sensitivity/specificity of the lower reported an incidence of 0.16/10,000 in the region of southern threshold of diagnosis at 15 eos/hpf. Furthermore, it should be Denmark. It is not clear whether childhood EoE is increasing inincidence and, if so, to what extent. Re-evaluations for eosinophilic considered that diagnostic biopsies are predominantly or entirely counts of esophageal biopsies from a histopathologogy database epithelial and as such may underestimate deeper disease activity,particularly as eosinophil recruitment begins within the subepithe- taken from pediatric patients during the years 1982–1999 applying lial compartment Moreover, esophageal wall thickening, the same criteria (<5, 5–14, and 15 eos/hpf) identified 198patients fulfilling the criteria for EoE (15 eos/hpf) After subepithelial fibrosis, and neural dysfunction occur beneath the correcting for the 40-fold increase in the total number of endos- epithelium This recruitment pattern has implications forboth diagnosis and treatment.
copies during this time period, the proportion of biopsies with thediagnosis of EoE did not change. In contrast, van Rhijn et al checked through a nationwide registry the pathology reports in the DIFFERENTIAL DIAGNOSIS AMONG EoE, Netherlands from 1996 through 2010 and classified according to the PROTON PUMP INHIBITOR–RESPONSIVE diagnosis made by the pathologist. Of 674 cases with newly ESOPHAGEAL EOSINOPHILIA, AND GERD diagnosed EoE, 20% were younger than 18 years and 74% weremale patients. The incidence of the diagnosis increased from 0.01/ The main differential diagnosis for symptoms and histopatho- 100,000 people in 1996 to 1.31 in 2010. Fifty-six percent of all cases logical findings is GERD, although other diseases that are also were diagnosed within the last 2 years of the registry. These results associated with esophageal eosinophilia, such as infectious esopha- are heavily biased because of the higher awareness and knowledge gitis, esophageal achalasia, celiac disease, Crohn disease, connective of EoE from 2000 onwards. Neither the same objective criteria (eos/ tissue disorders, graft-versus-host disease, drug hypersensitivity, and hpf) nor the proportion of biopsies taken in the different age groups hypereosinophilic syndromes, should also be excluded The was taken into account. Therefore, the reported changes in the relation between GERD and EoE is complex. GERD with mucosal incidence of the disease depend on the methods that were applied breaks because of erosions and ulcerations may impair the barrier and must be interpreted with caution. Population-based prevalence function and increase the risk for food sensitization. This mechanism data of EoE are only available from the study by Ronkainen et al may explain that patients with an increased risk for GERD, such as in which 1000 unselected Swedish adults underwent esophagogas- children after esophageal atresia repair, have an increased risk for troduodenoscopy (EGD), of which 1.1% fulfilled the histological developing EoE however, food allergy may induce upper criteria of EoE.
gastrointestinal dysmotility, including gastric dysrhythmia, andincreased numbers of transient lower esophageal sphincter relax-ations, promoting GERD. EoE may also induce dysmotility, impair- CLINICAL, ENDOSCOPIC, AND HISTOLOGICAL ing the clearance of the esophagus after GER episodes. Furthermore, the inflammatory process of EoE may lead to a hypersensitivity to There are no pathognomonic clinical or endoscopic features.
acid exposure, even in the absence of erosions, comparable with Epidemiologic studies and case series show that EoE is more nonerosive reflux disease. In summary, EoE and GERD (both erosive commonly seen in male patients and in patients with atopic diseases and nonerosive reflux disease) are not mutually exclusive or may such as food allergy, asthma, and allergic rhinitis Clinical even exacerbate each other. The differentiation based on clinical symptoms vary according to age. Infants and toddlers develop symptoms remains almost impossible in pediatrics.
mainly nonspecific symptoms with feeding difficulties (including Recently, Mulder et al proposed a scoring system of vomiting, regurgitation and feeding refusal), which can result in clinical and endoscopic features (male gender, dysphagia, history of Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 58, Number 1, January 2014 Management Guidelines of EoE in Childhood food impaction, absence of pain/heartburn, linear furrowing, and esophageal eosinophilia are unlikely, then the diagnosis of EoE can white papules) to differentiate EoE from GERD, which may be be confirmed In this case, specific treatment for EoE is useful in older children and adolescents. Histopathological differ- initiated whereas the decision to continue or not continue entiation between EoE (atopic and nonatopic) and reflux esopha- PPIs is individualized. If there is evidence for coexisting GERD, gitis may also be attempted by immunohistochemical staining for PPIs may need to be continued for a longer period.
intraepithelial mast cells and IgE-bearing cells Furthermore, a Further studies are required to show whether the diagnosis of recent study reported that the measurement of eosinophil-derived EoE can be assumed without PPI treatment in individual, often older proteins in luminal secretions could be used to distinguish children children with specific symptoms of dysphagia or food impaction and with EoE from those with GERD typical microscopic and endoscopic findings of EoE. Well-designedprospective randomized studies of PPIs versus placebo are required intreatment-naı¨ve children with esophageal eosinophilia (without THE ROLE OF ANTISECRETORY DRUGS IN additional dietary intervention) to help clarify any spontaneous ESTABLISHING THE DIAGNOSIS OF EoE fluctuation of eosinophil numbers and characterize PPI-responsive In patients with esophageal dysfunction and esophageal and PPI-nonresponsive children with esophageal eosinophilia.
eosinophilia, taking proton pump inhibitors (PPIs) for 8 weeks Furthermore, there are some prospective data from healthy are useful to help eliminate PPI-REE (responsive esophageal adults indicating that PPI therapy increases the risk of sensitization eosinophilia) The mechanisms responsible for the clinical to dietary antigens and even manifestation of food allergy PPIs effect of PPIs on esophageal eosinophilia are unclear. It is postu- should ideally not be given for prolonged periods of time, unless lated that GERD mechanisms are also activated in esophageal there is a clear and sustained benefit for the child. Without any eosinophilia Yoshida et al suggested that lansoprazole clinical improvement after a trial of PPI, particularly in young and omeprazole (but not famotidine and ranitidine), in addition to children and infants with significant symptoms (eg, vomiting, food their acid-suppressing effects, modulate inflammatory status. In refusal, failure to thrive), a repeat endoscopy may be performed vitro studies have shown that PPIs inhibit the increased expression earlier than 8 weeks to allow prompt treatment escalation. In of vascular adhesion molecules, the activation of neutrophils, and children with <15 eos/hpf in the esophageal biopsies following the production of proinflammatory cytokines A more recent PPI treatment, factors such as compliance and/or premature dis- study showed that PPIs inhibit interleukin (IL)-4–stimulated continuation of treatment should be considered and a close follow- eotaxin-3 expression in EoE esophageal cells and block STAT6 up for future changes is suggested.
binding to the promoter Although the mechanism of PPIs isthought to primarily involve acid blockade, PPIs may also affectesophageal eosinophilia by means of other mechanisms and thus behelpful in a subset of patients described as having PPI-REE however, the proportion of children with esophageal eosinophil In symptomatic children with histological findings of counts 15 eos/hpf that are PPI responsive is unclear because only esophageal eosinophilia, a trial of PPIs is recommended for retrospective data on selected patients are presently available. Sayej 8 weeks. A second EGD should be performed under PPI therapy et al reported that treatment with PPI was associated with in all children, even if symptoms resolve If histology is histological improvement in 14 of 36 (39%) patients, with at least still suggestive of EoE and other causes of esophageal eosino- 15 eos/hpf in esophageal biopsies taken from 1 esophageal levels.
philia are unlikely, then the diagnosis of EoE can be made. If the Three of these 14 responders showed macroscopic signs of EoE first endoscopy is performed after the patient has already had an (furrows) during EGD, whereas 6 had erosions or a normal mucosa.
adequate trial of PPI, the diagnosis of EoE can also be made and In some PPI-responsive children, symptomatic and histopatholo- specific treatment for EoE be initiated.
gical relapses have been reported in spite of continuing PPI treat-ment Another retrospective study showed that 40% of childrenwith significant esophageal eosinophilia demonstrated histologicalresponse to PPI therapy at endoscopies carried out at 4 to 5 months TREATMENT OF PROVEN EoE following the start of treatment According to the authors, the The management of the disease includes dietary and phar- response could not be predicted by either the symptoms or the maceutical interventions, each with its own advantages and draw- results of a preceding pH study A study in 35 adults with backs. The goal of the treatment should ideally be both the symptoms suggesting either GERD or EoE evaluated the histologi- resolution of symptoms and the normalization of the macroscopic cal response to a 2-month treatment with rabeprazole. Significant and microscopic abnormalities. Although there are no follow-up regression of eosinophilic infiltration was reported in both groups, studies assessing the long-term consequences of persisting esopha- with 50% of patients with EoE symptoms responding to rabeprazole geal eosinophilia in asymptomatic patients, the possibility of eso- therapy The only data from a prospective randomized con- phageal fibrosis and narrowing cannot be excluded. Moreover, trolled double-blind trial in children with confirmed EoE showed patient-reported outcome measures may be difficult to assess in that lansoprazole alone failed to induce histological response or children, particularly in infants, and young or learning-disabled symptom improvement compared with lansoprazole combined with children who are unable to provide accurate information on their oral viscous budenoside symptoms Hence, at present, histology with absolute eosino- To identify children with PPI-REE and avoid unnecessary phil counts remains the best marker objective measure of the elimination diets or drug treatment, a trial of 8 weeks of PPIs is inflammatory disease activity.
recommended. The optimal dose of PPI depends on the chosen PPI Although EoE is considered a chronic, relapsing disease, its preparation. In general, the PPI dose ranges between 1 and 2 mg  natural history is difficult to define as long-term data are available kg1  day1, with maximum dose reaching adult dose 20 to 40 mg only in selected individuals. A long-term follow-up of >500 once or twice daily depending on the patient and PPI. This should children treated with different regimens identified 11 patients then be followed by endoscopic and histological reassessment, who maintained complete remission on a normal diet without irrespective of whether or not there is symptom relief. If eosino- any medication Another subgroup of 24 patients, in which philic inflammation persists after PPI treatment, and other causes of parents had decided against any intervention, showed no Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
ESPGHAN EoE Working Group/GI Committee JPGN  Volume 58, Number 1, January 2014 Evaluation of child/adolescent with symptoms suggestive of EoE (otherwise unexplained feeding difficulty, vomiting, dysphagia, hx. of food impaction) On PPI treatment? EGD with biopsies of proximal and distal parts of esophagus Trial of PPI's for 8 weeks (*).
Monitor for symptoms EGD with biopsies on PPIs (independent of symptoms) (*) PPI trial may be stopped earlier if no improvement occurs in young children and infants with clinically significant symptoms (eg, frequent vomiting and/or feeding refusal with failure to thrive) to avoid delay in making diagnosis and commencing treatment.
FIGURE 1. Algorithm for the evaluation of children and adolescents with symptoms suggestive of eosinophilic esophagitis (EoE).
EGD ¼ esophagogastroduodenoscopy; eos/hpf ¼ eosinophils per high-power field; GERD ¼ gastroesophageal reflux disease; NERD ¼ nonerosivereflux disease; PPI ¼ proton pump inhibitors; PPI-REE ¼ proton pump inhibitor–responsive esophageal eosinophilia.
Confirmed diagnosis of EoE Consider allergy history +/– food allergy testing Discuss therapeutic options (diet and/or steroids) Empiric elimination diet Off-label topical swallowed steroids Targeted elimination diet Rarely - systemic oral steroids Amino acid formula Follow-up endoscopy Monitor for symptoms! • If symptoms reoccur Repeat EGD and biopsies in 4–12 weeks • If asymptomatic — consider on individual basis Drug titration and/or stepwise food reintroduction FIGURE 2. Algorithm for the management of children and adolescents with eosinophilic esophagitis (EoE). EGD ¼ esophagogastroduodeno-scopy.
Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 58, Number 1, January 2014 Management Guidelines of EoE in Childhood histological improvement during a 6.2  3.6–year follow-up with them The authors introduced AAF for a minimum of symptoms worsening over time, including dysphagia and food 6 weeks and reported resolution of symptoms in 8 and improvement in 2 patients. Esophageal eosinophilia reversed withthe median maximal intraepithelial eosinophil count decreasing from Dietary Aspects of EoE Management an average of 41 eos/hpf pre-AAF to 0.5 eos/hpf post-AAF Markowitz et al introduced AAF for 4 weeks in 51 children Amino acid feeds were the first dietary intervention assessed with vomiting, abdominal pain, or dysphagia with biopsy-proven for efficacy in reducing esophageal eosinophilia and treating the EoE A significant improvement was seen at a median of symptoms of EoE Only later were the efficacies of other 8.5 days following the introduction of the diet, whereas esophageal elimination diets more formally assessed.
eosinophilia was reversed at the end of 4 weeks, with the mediannumber of esophageal eos/hpf decreasing from 33.7 before the diet Elimination Diets for Inducing Remission to 1.0 after the diet (P < 0.01) Peterson et al introduced AAF for 4 weeks to 20 adults Elimination diets are successful at achieving resolution of with esophageal obstructive symptoms such as dysphagia, chest symptoms and normalization of eosinophil counts in eosophageal pain, food impaction, or heartburn resulting from EoE (>20 eos/hpf biopsies in children with EoE Spergel et al in esophageal biopsies, taken on 2 separate occasions 2–3 weeks reported that within a definitive EoE population, approximately apart while receiving high-dose acid suppression). A decrease in one-third of children were clinically responding after excluding 1 esophageal eosinophilia was reported at 2 weeks from the initiation food, whereas approximately 25% of children had multiple food of AAF (median distal and proximal esophageal eosinophil counts allergies requiring the exclusion of 4 foods. There was an inverse decreased from 44 and 33 eos/hpf to 13 and 14 eos/hpf, respectively, relation between number of foods to be excluded and age Milk at 2 weeks, and to 11 and 8 eos/hpf, respectively, at 4 weeks). This was the most common food identified, followed by wheat, soy, and improvement was associated with a clinical response at 4 weeks eggs; however, the combination of skin prick testing (SPT) and Of the patients, 52% were reported to have <8 eos/hpf after atopy patch testing identified only half of the patients who posi- 4 weeks of receiving AAF tively responded to milk elimination The positive and negative In infants, dietary treatment with AAF is better accepted and likelihood ratios for these tests for the different foods were mostly tolerated than in older children. In older patients, despite the unhelpful for clinical decision making. Erwin et al reported sen- encouraging reports on remission induction with the use of AAF, sitization to cow's milk, identified either by specific serum IgE its use is limited by several disadvantages. The principal disadvan- antibodies or by positive SPTs, in 43% of children with EoE, tage is the significant burden of such a severe food restriction in whereas sensitization to other food allergens (most commonly to children, whereas the frequent need for nasogastric tube or gastro- rye, wheat, and soy), identified by positive atopy patch tests (APT), stomy placement and the high cost are also problematic. For these in 39% of patients. It should be noted, however, that food antigens reasons, AAF is mostly an option for treating EoE in children with triggering the disease vary from patient to patient and the detection multiple food allergies, failure to thrive, and severe disease in which of sensitization to foods may be indicative of concomitant food a strict diet with multiple eliminations is ineffective or impossible.
allergies and does not mean necessarily that these foods arecausative of EoE The elimination of the responsible foodallergens from the child's diet was associated with disease remis- TED has evolved because of the perception of its better sion. It should be noted, however, that food antigens triggering the long-term tolerability. In a study by Spergel et al 77% of disease vary from patient to patient. Therefore, the optimal dietary children responded well to TED and only 10% did not respond.
intervention needs to be individualized and requires dietetic support SPTs detected egg, dairy, and soy as triggering foods, whereas to ensure nutritional adequacy, whereas ongoing difficulties in delayed hypersensitivity with APT revealed delayed reactions to adhering to a complex exclusion diet may require additional corn, soy, and wheat In a retrospective study in 63 children psychosocial support with EoE (mean age of 11.9 years), who all underwent SPT and Three different dietary approaches to induce a remission in APT for up to 20 foods, at least 1 positive test was reported in 61% EoE have been developed: amino acid–based formula (AAF) for of patients. Sixteen patients (26%) were managed effectively by complete removal of food allergens from the diet targeted TED alone, 27 patients (42%) failed TED, whereas 20 patients elimination diet (TED), which removes foods based on a suggestive (32%) had negative food allergy testing and chose not to pursue history of food triggers and results of specific IgEs, SPT, and APT dietary elimination but use drug therapy Teitelbaum et al (where available) and empiric elimination diet, which removes prospectively assessed the response of 19 children with EoE from the diet the most common food allergens that have been clinically presenting with dysphagia, food impaction, vomiting, associated with EoE, that is, dairy, soy, eggs, wheat, peanuts, fish/ chest pain, and food refusal to TED and/or to topical fluticasone propionate. None of the 11 children who received TED for 8 weeks It should be noted that to date, there are no randomized showed clinical improvement. In contrast, the administration of controlled trials investigating the efficacy of any of these diets in fluticasone propionate in 13 patients (9 with positive and 4 with unselected patients with EoE, although large case series suggest negative allergy testing) was associated with resolution of they can be highly effective At least in part, this is because of symptoms. Furthermore, drug treatment in 11 children with EoE the lack of agreement on clear and objective measures of efficacy. A was associated with a significant reduction in the number of single retrospective study in 98 children comparing the efficacy of eosinophils, CD3, CD8, and CD1a cells in the esophageal AAF formula, 6-food elimination diet (SFED), and TED at decreas- ing esophageal eosinophilia suggested that AAF is more The failure of TED to induce remission of EoE reported in effective than SFED and TED.
some studies has been attributed to the inability of allergy tests toaccurately detect causal food antigens. A recent study in children AAF was first used >15 years ago in 10 children with with EoE showed that positive and negative predictive values of chronic symptoms attributed to GERD that persisted despite SPTs ranged between 26% (for pork) and 86% (for milk) and 29% antireflux treatment, including a Nissen fundoplication in 6 of (for milk) and 99% (for peanut), respectively, whereas sensitivity Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
ESPGHAN EoE Working Group/GI Committee JPGN  Volume 58, Number 1, January 2014 and specificity of the tests varied between 18% and 88% and 82% Spergel et al only 53% went into remission. This elimination and 97%, respectively Elimination diets based on serum was carried out independently of any known food sensitizations.
radioallergosorbent test and/or SPT alone failed to achieve remis- It is critical that both EED and TED are supervised by an sion With regard to APT, its negative predicted value in adults experienced dietitian to maintain nutritional adequacy and mini- has been reported to be >90% but in children, the test has yet to mize nonadherence to the diet. Key foods that are removed from a be validated and standardized. It should be noted, however, that an child's diet should be substituted appropriately.
elimination diet based on a combination of SPT and APT was The optimal duration of elimination diet to achieve remission reported to achieve resolution of both symptoms and histological in EoE is not clear. It seems that AAF needs less time to achieve abnormalities in 77% of children with EoE Recently presented clinical and histological remission than either SFED or TED follow-up data for this study showed a lower level of response Furthermore, it is poorly defined which dietary (53%), which increased to 77% if the elimination of foods identified intervention is associated with better mucosal healing of the on SPTs/APTs was combined with the empiric elimination of cow's esophagus. Rea et al evaluated the efficacy of 3 therapeutic milk This recent follow-up study showed that APTs had a high interventions (AAF, SFED, and topical fluticasone propionate) to negative predictive value (>95%) for all foods except for milk, egg, induce remodeling of the esophagus in 18 children with EoE. The wheat, and soy, whereas the positive predictive values were low for authors assessed resolution of epithelial mesenchymal transition peanut, potato, and pork (0%–30%), with higher values (30% to (EMT), a measure that contributes to airway remodeling and 90%) for corn, beef, chicken, soy, wheat, egg, and milk fibrosis following environmental challenge in asthma The Furthermore, the authors reported a high average negative predic- investigators used a numerical EMT score based on 6 key factors.
tive value for the combination of SPTs and APTs (92%), with the These included the number and location of vimentin-positive exception of milk (44%), with an average positive predictive value mesenchymal cells within the hyperplastic epithelium, and the loss of cytokeratin staining of the epithelium. The authors reported The foods most commonly tested for with SPT and APT that both the pre- and posttreatment EMT scores highly correlated include milk protein, egg, peanuts, soy, a variety of grains (wheat, with peak eos/hpf in all treatment groups and that all 3 treatment rice, corn, rye, oats, barley), and meat (beef, pork, chicken, turkey).
approaches led to equal resolution in EMT score: AAF r ¼ 0.820 Some centers also test for vegetables and fruits; however, even (P < 0.001); SFED r ¼ 0.857 (P < 0.001); topical fluticasone pro- extensive testing may return false-negative results, potentially pionate, r ¼ 0.868 (P < 0.001) leading to incomplete elimination of offending food antigens ifthese results are taken in isolation. In particular, detecting cow's- Food Reintroduction Following Remission and milk sensitivity in patients with EoE, SPT, and APT were reported Ongoing Monitoring to have a negative predictive value, from 41% to 44% Theconcordance rate between specific IgE antibodies and SPT results is Following remission, foods can be gradually reintroduced, not satisfactory, with 23% of discrepant results for milk and also a with careful observation for recurrence of symptoms of EoE poor correlation for the quantitative results In children with Food reintroduction is a key aspect of the long-term management of gastrointestinal manifestations of cow's-milk protein allergy, EoE. A recent study in adults suggested that a step-wise reintroduc- specific IgE tests results are commonly negative without excluding tion of eliminated foods may be a better method to identify the the diagnosis of cow's-milk protein allergy precipitating food product than SPT Because cow's-milk protein is a common food antigen and No clear guidelines exist on how to reintroduce eliminated the leading cause of food allergy in infants and children younger foods; however, Spergel and Shuker suggest reintroducing the than 3 years the authors suggest that it is eliminated from least allergic foods first, whereas the most allergenic foods (such as the diet in this age group, regardless of the results of specific IgE or wheat, soy, beef, peanuts, egg, milk) are left to last. Some units SPT/APT testing. More studies assessing the sensitivity and speci- advise that regular upper endoscopy should be performed to ensure ficity of the above tests in children with EoE are required.
maintenance of a histological remission, although the clinical value Whether TED has a role in maintaining clinical and histo- of repeat endoscopy with each food group has yet to be validated in logical remission of EoE is not clear. Although there are no long- larger prospective studies. Foods that repeatedly trigger recurrence term data available for children, Gonsalves et al presented in of EoE symptoms may need to be eliminated indefinitely.
abstract form data in 9 adults with EoE who completed 1 year The long-term follow-up requirements for asymptomatic of TED, following 6 weeks of SFED to induce a remission. In this patients are poorly defined and differ widely among centers.
study, 8 of 9 patients remained asymptomatic and 1 of 9 had Until better evidence is available on the long-term outcome of minimal symptoms Food triggers identified on single-food asymptomatic children with EoE, routine follow-up endoscopy in reintroduction following elimination were the following: milk these children is a matter of local practice.
(55%), wheat (33%), nuts (33%), and seafood (11%), whereas 4patients had >1 food trigger. The highest median eos/hpf pretreat-ment, following 6 weeks of SFED and after 1 year of TED were 19, Recognition and Management of Seasonal 0, and 0, respectively, in the proximal esophagus and 60, 0, and 6, respectively, in the distal esophagus According to the authors,all patients maintained >50% reduction in peak eos/hpf from There is evidence in both humans and experimental models baseline, 33% had 5 eos/hpf, and 67% had 10 eos/hpf at 1 year that inhaled aeroallergens (including pollens and molds) can induce esophageal epithelial eosinophilia and thus trigger symptom relapseThe clinical consequence may be a seasonal exacerbation inatopic patients, often characterized by food bolus impaction. It is The avoidance of only the 6 most commonly accepted important to enquire about seasonal exacerbations and, if present, to allergenic food antigens (cow's milk, egg, wheat, soy, peanuts, and attempt to characterize potential triggering aeroallergens. There is fish/shellfish) for at least 6 weeks was reported in an observational not sufficient published data to make definitive recommendations; study to achieve clinical and histological (<10 eos/hpf) remission in however, if there is an annually established pattern of significant 74% of 35 children with EoE but in the most recent report from exacerbation, planned increase in treatment (more stringent dietary Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 58, Number 1, January 2014 Management Guidelines of EoE in Childhood restrictions and/or augmented topical corticosteroids) should be with EoE A small, open-label cohort study of 11 children considered. Evidence that nasal corticosteroids may attenuate with EoE showed that swallowed FP achieved a significant reduction asthma symptoms in patients with allergic rhinitis suggests in the number of eosinophils, as well as CD3(þ) and CD8(þ) that this treatment approach may also benefit children with trou- lymphocytes in the proximal and distal esophageal mucosa blesome seasonal exacerbation of their EoE.
In the largest controlled trial, only 36 children with EoE were randomly assigned to swallowed FP (880 mg/day in 2 divided doses)or placebo during a 3-month period. In these children, a resolution of vomiting occurred in 67% receiving FP and in 27% of those Dietary treatment for 4 to 12 weeks is a therapeutic option receiving placebo, whereas histological remission was reported in in all children with confirmed diagnosis of EoE The 50% and 9%, respectively A recent 6-week double-blind decision as to which of the specific dietary approaches to use randomized trial comparing 21 FP-treated adults with 21 who should be individualized according to the child's specific needs received placebo reported comparable improvement of clinical and family circumstances. TED for 8 to 12 weeks is recom- symptoms in the 2 groups (57% and 33%, respectively), whereas mended if allergy to specific foods is strongly suspected by histological resolution was reported in 62% of patients receiving FP history and sensitization is supported by formal testing. In the compared with 0% of those receiving placebo absence of specific food sensitization, EED can be used for 8 to Another randomized controlled trial comparing swallowed 12 weeks. AAF for 4 weeks is an option in patients with multiple FP with oral prednisolone showed that both were equally food allergy, failure to thrive, or those with severe disease who effective in achieving initial histological and clinical improvement do not respond, or are unable, to follow a highly restricted diet.
at week 4, but discontinuation of therapy was associated in both Counseling by a dietitian experienced in pediatric nutrition is groups with symptom relapse by week 24.
highly recommended to avoid hidden or cross-reactive antigens, On the basis of expert opinion and present literature, the to maintain nutritional adequacy and minimize nonadherence to suggested starting dosages range from 88 to 440 mg 2 to 4 times the diet. Key foods that are removed from a child's diet should be daily for children, and 440 to 880 mg twice daily for adolescents/ substituted appropriately. The efficacy of the dietary interven- adults Recommendations suggest patients should swallow the tion should be monitored by assessment of symptoms and metered dose that is delivered into the oral cavity (and not inhaled), evaluation of endoscopic and histological response. If there is then not eat, drink, or rinse their mouth for 30 minutes no improvement at endoscopy, without resolution of eosino-philic inflammation, adherence to the diet should be evaluated The use of OVB was first described in 2005 in 2 children and the elimination of other food antigens or initiation of drug in whom FP had failed to achieve remission. OVB was prepared by therapy be considered, particularly if symptoms persist. In cases the local pharmacy, by mixing a liquid solution of budesonide (the of clinical and histological remission, reintroduction of foods preparation used in nebulizers at a dose of 5 mg twice daily) and begins with the least allergenic food. If there is symptom sucralose (a synthetic sugar substitute). In both children, resolution recurrence following the reintroduction of a specific food, the of symptoms and of histological abnormalities was reported triggering food should be avoided. Long-term follow-up of Another retrospective study in 20 children (mean age 5.5 years) asymptomatic patients remains individualized and depends on with EoE reported OVB to be effective in achieving both clinical local practice.
and histological remission (<7 eos/hpf) in 80% of patients The first double-blind randomized controlled trial was carried out in 24 children (mean age 7.8 years) with EoE in whom NONDIETARY ASPECTS OF EoE MANAGEMENT a 3-month treatment with OVB was compared with placebo Corticosteroids (systemic and topical) have been successful Both groups received concomitant treatment with lansoprazole.
in treating pediatric patients with EoE, whereas other medications Eleven of these patients were food-sensitized/allergic children.
(sodium cromoglycate, leucotriene receptor antagonists, immuno- The dose of OVB was 1 mg for patients <5 feet (1.52 m) in height suppressive drugs, and biologics) have generally not been found to and 2 mg for those >5 feet in height. OVB was associated with be useful. It should be noted, however, that extremely few high- improvement of symptoms in 86.7% of children, whereas no patient quality randomized controlled trials assessing the efficacy of improved while receiving placebo. Esophageal eosinophil counts different drugs exist. This highlights the urgent need for prospective decreased significantly in patients receiving OVB (mean pre-/ intervention studies to achieve a more uniform, evidence-based posttreatment peak esophageal eosinophil counts were 66.7 and approach to nondietary interventions in EoE treatment 4.8 eos/hpf, respectively; P < 0.0001) but not in those receiving placebo (mean pre-/posttreatment peak esophageal eosinophilcounts were 83.9 and 65.6 eos/hpf, respectively; P ¼ 0.3) Similar benefits have been described in adult studies A Corticosteroid preparations can be extremely effective at recent double-blind randomized trial in 36 adolescents and adults inducing remission in patients with EoE, but discontinuing treat- with EoE compared the effect of swallowed OVB (1 mg twice daily) ment often results in symptom recurrence. The potential toxicity of and placebo for 15 days The authors reported a significantly long-term systemic steroids has led to the off-label use of topical greater improvement in dysphagia (72%) in patients receiving OVB corticosteroid preparations such as swallowed fluticasone propio- compared with placebo (22%) (P < 0.0001), whereas endoscopic nate (FP) and oral viscous budesonide (OVB) When findings—white exudates and red furrows—were reversed only in swallowed, both are effective at achieving resolution of symptoms patients given OVB. Furthermore, a reduction in the number of in patients with EoE. The most important adverse effect of topical esophageal eosinophils posttreatment was observed in patients steroid preparations is esophageal candidiasis, which responds well receiving OVB (68.2–5.5 eos/hpf, respectively; P < 0.0001), and to antifungal treatment not in those receiving placebo (62.3–56.5 eos/hpf, respectively; P ¼ 0.48). Moreover, only OVB reduced apoptosis of epithelialcells and molecular remodeling in the esophagus. The authors Swallowed FP.
The efficacy of topical steroids in achieving reported that treatment with OVB was not associated with serious remission has been reported in both adults and in children Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
ESPGHAN EoE Working Group/GI Committee JPGN  Volume 58, Number 1, January 2014 The optimal dose of OVB in children with EoE has not refractory patients have higher tyrosine kinase activation in their been formally assessed; however, Gupta et al evaluated the esophageal epithelium efficacy and safety of different doses of OVB in treating child-hood EoE in the Pediatric Eosinophilic Esophagitis Research Maintenance Treatment With Topical Steroids.
(PEER) study, although these have only been presented in treatment of acute symptoms with topical steroids proves effective abstract form. Eighty-one children and adolescents ages 2 to in achieving an apparent disease remission in adult and pediatric 18 years with EoE symptoms were randomized to 12 weeks of EoE, symptoms relapse following discontinuation of treatment. A treatment with placebo, low-dose, medium-dose, or high-dose study of 21 adults receiving 220 mg swallowed FP twice daily for OVB. Children 2 to 9 years old received placebo or 0.35 mg 6 weeks reported relief of dysphagia lasting at least 4 months once-daily (QD), 1.4 mg QD, or 1.4 mg twice daily OVB; whereas another retrospective study in 51 adults showed that 91% children and adolescents 10 to 18 years old received placebo of the patients receiving FP for 6 weeks reported recurrent or 0.5 mg QD, 2 mg QD, or 2 mg twice daily OVB. Endoscopies symptoms after a mean of 8.8 months which may be with biopsies were performed at baseline and the end of treat- because of inadequate duration of drug therapy, loss of treatment ment. Seventy-one subjects (mean age 9.2 years; 80.3% boys) effect, or to other factors such as seasonal variation.
completed all efficacy assessments. Baseline median peak intrae- Straumann et al carried out a randomized double-blind pithelial eosinophil count was 105 eos/hpf. At the end of treat- placebo-controlled 50-week trial in 28 adult patients with EoE and ment, there were significantly greater percentages of responders evaluated the efficacy of a low-dose (twice-daily 0.25 mg) OVB in in both the median-dose and high-dose groups compared with maintaining remission of quiescent EoE. Pre- and post-treatment placebo, with no age group differences. Furthermore, there was a disease activity was assessed clinically, endoscopically, and histo- significant dose-related histological improvement in the median- logically by high-resolution endosonography and by immunofluor- dose and high-dose groups compared with placebo. Symptoms escence. The authors reported that at the end of the study period, alone could not distinguish active treatment from placebo, high- 35.7% of the patients with OVB were in complete and 14.3% in lighting the dissociation between symptomatic and histological partial histological remission, whereas among patients who response. Low-dose OVB proved to have no/minimal effect on received placebo, none was in complete and 28.6% were in partial clinical and histological parameters. The authors reported no remission. The median time to relapse of symptoms was >125 days trends or significant dose-related increase in any adverse events in patients receiving OVB and 95 days in those receiving placebo Maintenance with OVB reduced the thickness of the super- Based on available evidence, the recommended starting ficial wall layers measured by high-resolution endosonography but dose of budesonide as a viscous suspension is 1 mg daily for had no significant effect on thickness of the deeper layers. No effect children younger than 10 years and 2 mg daily for older children was seen in patients receiving placebo. The authors concluded that and adults split into 2 divided doses In case of no response, low-dose OVB was more effective than placebo in maintaining the starting dose may be gradually increased to 2.8 and 4 mg, histological and clinical remission Systemic Corticosteroids Factors Influencing the Effectiveness of Treatment WithTopical Steroids.
It is unclear whether the inadequate response Despite oral corticosteroids being extremely effective at to topical steroids in some patients is a result of patient nonadherence, symptom control, they are infrequently used in patients with difficulty in accurately delivering an adequate dose of topical EoE because of their systemic adverse effects; however, systemic corticosteroids, or true drug resistance; however, the esophageal corticosteroids can be used for extremely severe symptoms, for wall thickening shown on endoscopic ultrasound along with example, when immediate relief of the patient's symptoms is subepithelial fibrosis and neural dysfunction occurring beneath the required (eg, severe dysphagia, food impaction, dehydration, epithelium, raises the question whether topical therapies can weight loss, esophageal strictures).
penetrate sufficiently deep to affect the disease process.
Liacouras et al reported improvement of clinical symp- To date, only 2 steroid preparations, FP and OVB, have been toms within 1 week in 19 of 20 children receiving systemic oral shown to have a therapeutic benefit in EoE. Ciclesonide is topical corticosteroids for EoE. There was resolution of histological steroid that has a 100-fold greater glucocorticoid receptor–binding abnormalities at biopsy 4 weeks after treatment onset. The Indiana capacity. It is nonhalogenated and converted by epithelial esterases University group compared oral prednisone with swallowed FP in a to desisobutyryl-ciclesonide. In a study by Schroeder et al, 4 randomized prospective trial. Both therapies proved effective in children with EoE (4–16 years of age) received 8 weeks of achieving clinical symptom resolution and histological remission at swallowed topical ciclesonide, and all experienced a clinical and week 4; however, neither of the treatments prevented symptom histological response without adverse effects These prelimi- relapse, which occurred in 45% of the patients by week 24 nary data need to be replicated in future studies in steroid-resistant Although these trials demonstrate the clear efficacy of patients with EoE.
systemic steroids, they are still only recommended for extremely As yet, there are no clear clinical predictors of steroid severe cases or where other formulations have been unsuccessful; responsiveness. Konikoff et al reported in a randomized however, the relative thickness of the esophageal epithelial barrier placebo-controlled trial in children with EoE that the resolution compared with that of the lung, together with the recruitment of mucosal eosinophilia after a 3-month treatment with swallowed pattern of eosinophils from the deeper, subepithelial layers, may FP was more pronounced in nonallergic patients and in those of mean that topical treatment alone may be less successful than in younger age, shorter height, and lower weight, suggesting a dose- asthma, and that courses of oral corticosteroids may be needed in response effect. Furthermore, a retrospective study in 20 pediatric selected cases with treatment-resistant exacerbations. Their dose is patients with EoE showed that the coexistence of allergy, based on similar to that used in patients with inflammatory bowel disease (ie, the results of SPT, influenced the therapeutic effect of swallowed 1–2 mg  kg1  day1 of prednisolone orally, with a maximum FP. All of the nonallergic patients responded to treatment, whereas 40 mg). This dose is then weaned down gradually. Intravenous only 20% of the allergic patients showed partial and 20% no methyl prednisolone may be considered initially if the patient improvement Other researchers suggested that steroid- cannot tolerate oral medication.
Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 58, Number 1, January 2014 Management Guidelines of EoE in Childhood Reslizumab was again able to reduce the esophageal eosinophilia, but the latter did not correlate with the clinical improvement that Swallowed FP or OVB for a minimum of 4 weeks and a was reported in both groups maximum of 12 weeks can be a treatment option either alone Omalizumab is a humanized anti-IgE monoclonal antibody or in combination with an elimination diet Systemic that binds IgE, thus preventing activation of mast cells and basophils.
oral corticosteroids are only recommended when rapid relief is A study of 9 patients with eosinophil-associated gastrointestinal required for symptoms such as severe dysphagia, dehydration, disorders treated with omalizumab for 16 weeks showed decreased weight loss, or esophageal strictures, or where the diagnosis is peripheral blood eosinophilia and eosinophilic tissue infiltration of certain and other treatments have failed. The efficacy of the stomach and duodenum, but not of the esophagus A recent case drug treatment should be monitored by assessment of symp- report of 2 children with EoE and multiple food allergies showed that toms and evaluation of endoscopic and histological response.
omalizumab was effective in improving food tolerance and symp- Histologic remission is followed by drug titration and discon- toms, but did not improve endoscopic or histological abnormalities tinuation of treatment. In case of symptoms persistence or A prospective randomized double-blind placebo-controlled recurrence, endoscopy and biopsies for the histological assess- trial in 30 adult patients (mean age 30 years), who received omali- ment of the esophagus are necessary. Long-term follow-up of zumab for 16 weeks, reported no improvement in the esophageal asymptomatic patients remains individualized and depends on eosinophil infiltration in either group, whereas dysphagia scores local practice.
improved in both treatment and placebo groups Tumor necrosis factor (TNF) is more highly expressed in esophageal epithelial cells of active EoE compared with control tissue This suggested a potential role for anti-TNF agents inpatients with more severe EoE; however, a recent report of 3 adults Sodium Cromoglycate and Leukotriene Receptor with severe, corticosteroid-dependent EoE, who were treated with 2 doses of infliximab, showed only mild improvement in symptoms in There is no evidence that cromolyn sodium is useful in EoE.
2 patients, whereas symptoms worsened in the third The A small trial in 14 patients reported that a 1-month administration of authors reported decreased eosinophil (but not mast cell) numbers cromolyn sodium (100 mg 4 times per day) was not associated with in the responders, whereas TNF-a expression decreased markedly clinical improvement Although the drug does not have any in the esophageal epithelial cells of only 1 of them.
significant adverse effects, present evidence does not support its use Future potential therapeutic options for EoE that still warrant in children with EoE investigation include anti-IL-5 receptor monoclonal antibodies.
Furthermore, there is inadequate evidence to recommend These have been reported to decrease peripheral eosinophil counts leukotriene receptor antagonists Gupta et al reported in patients with mild asthma Furthermore, local treatment, comparable leukotriene levels in children with EoE and healthy targeted at inhibition of IL-4 and -13 in the lung, substantially controls. Attwood et al reported clinical but not histological diminished the symptoms of asthma The latter was tested in 2 remission in 8 patients with EoE during 14 months of treatment with randomized double-blind placebo-controlled, parallel-group, phase montelukast at doses up to 40 mg daily, with recurrence of IIa clinical trials in patients with atopic asthma The drug was symptoms in 6 patients 3 weeks following discontinuation. A recent introduced to the patients via 2 routes (by subcutaneous injection in study in adults showed that montelukast was not effective at the first study; by nebulizer in the second). The second study maintaining either the clinical or the histological remission induced reported a significantly smaller decrease in forced expiratory by a 6-month treatment course with FP volume in 1 second following allergen challenge in the study groupcompared with placebo Neither cromolyn sodium nor leukotriene receptor antagonists are recommended as treatment for children with Neither currently available immunomodulators nor bio- logical agents can be recommended for treatment in childrenwith EoE.
Immunomodulators and Biologics Because corticosteroids fail to induce a long-lasting remis- sion in patients with EoE, immunomodulation has been consideredas a potential means of providing some maintenance efficacy.
ESOPHAGEAL DILATATION A trial of thiopurines in 3 patients with EoE, who were Esophageal dilatation can be helpful in acutely symptomatic resistant to corticosteroids, proved effective in achieving symptom patients who present with severe esophageal narrowing in whom resolution. Their use however has not been further studied and medical treatment has failed to improve symptoms. Most of the hence they cannot yet be recommended as maintenance therapy in studies report data from adult patients patients with EoE A recent database review of the effectiveness, safety, and Studies in animal models have shown that antibodies against tolerability of esophageal dilatation in EoE has been published in IL-5 induce eosinophil trafficking to the esophagus A double- adults Two hundred seven patients were examined, of whom blind randomized trial compared mepolizumab with placebo in 11 63 were treated with dilatation and 144 with dilatation and drug adults. There was a decrease in number of eosinophils in the therapy. Dilatation proved to be effective and safe, although it esophagus compared with the control group, but this was not caused postprocedural pain in 74% of patients and did not alter the associated with symptom control Reslizumab, a humanized underlying inflammatory process In a recent review of 13 monoclonal antibody with potent IL-5-neutralizing effects, was also pediatric patients, dilatations were performed in 4 cases with good evaluated in a double-blind randomized placebo-controlled trial results Esophageal dilatation can provide relief of dysphagia in involving 226 pediatric patients receiving 4 doses of treatment.
highly selected children with a significant esophageal stricture Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
ESPGHAN EoE Working Group/GI Committee JPGN  Volume 58, Number 1, January 2014 because of EoE, where there has been no response to drug therapy. It should be noted, however, that in the absence of severe esophageal 1. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis stenosis, it is mandatory to try medical or dietary therapy before in children and adults: a systematic review and consensus recommen- performing esophageal dilatation.
dations for diagnosis and treatment. Gastroenterology 2007;133:1342–63.
2. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J AllergyClin Immunol Esophageal dilatation is only recommended in highly selected cases with severe esophageal narrowing that persists 3. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis.
N Engl J Med 2004;351:940–1.
despite other forms of treatment. In all of the cases, esophageal 4. Cherian S, Smith NM, Forbes DA. Rapidly increasing prevalence of dilatation must be accompanied by medical treatment of EoE.
eosinophilic oesophagitis in Western Australia. Arch Dis Child2006;91:1000–4.
Future Directions 5. Dalby K, Nielsen RG, Kruse-Andersen S, et al. Eosinophilic oeso- phagitis in infants and children in the region of southern Denmark: a The lack of appropriate biomarkers to evaluate response to prospective study of prevalence and clinical presentation. J PediatrGastroenterol Nutr 2010;51:280–2.
treatment and detect early relapse may require repeat endoscopy and 6. DeBrosse CW, Buckmeier Butz BK, Allen CL, et al. Identification, biopsy during the course of the disease. Such biomarkers are presently epidemiology, and chronicity of pediatric esophageal eosinophilia.
under investigation A better understanding of the disease J Allergy Clin Immunol 2010;126:112–9.
phenotype and mechanisms governing treatment response should 7. van Rhijn BD, VJ, Smout AJ, Bredenoord AJ. Rapidly increasing lead to more effective short- and long-term interventions. As this incidence of eosinophilic esophagitis in a large cohort. Neurogas- population grows in number and is followed up for longer periods, troenterol Motil 2013;25:47–52.
robust long-term outcomes should become available. Only this will 8. Ronkainen J, Talley NJ, Aro P, et al. Prevalence of oesophageal truly inform us as to how persistently we must reassess the mucosa to eosinophils and eosinophilic oesophagitis in adults: the population- achieve histologic normality, while minimizing the effect on the child based Kalixanda study. Gut 2007;56:615–20.
and family, hence leading to a favorable long-term outcome.
9. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, et al. 14 Years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr 2009;48:30–6.
10. Spergel JM, Brown-Whitehorn TF, Cianferoni A, et al. Identification EoE is a chronic, relapsing inflammatory disease of the of causative foods in children with eosinophilic esophagitis treated esophagus, which often requires prolonged therapy. In recent years, with an elimination diet. J Allergy Clin Immunol 2012;130:461–7.
there has been a significant increase in the number of publications 11. Dellon ES, Gibbs WB, Fritchie KJ, et al. Clinical, endoscopic, and on its treatment; however, many unresolved questions on treatment histologic findings distinguish eosinophilic esophagitis from gastro- choice and duration remain Interpreting the results of esophageal reflux disease. Clin Gastroenterol Hepatol 2009;7:1305– these publications is difficult because of the variability of dosing regimens, durations of treatment, and study endpoints. The disease 12. Sant'Anna AM, Rolland S, Fournet JC, et al. Eosinophilic esophagitis course is unpredictable and long-term complications are unknown.
in children: symptoms, histology and pH probe results. J Pediatr Furthermore, there is poor correlation between clinical symptoms Gastroenterol Nutr 2004;39:373–7.
and histological measures, making absolute recommendations for 13. Erwin EA, James HR, Gutekunst HM, et al. Serum IgE measurement monitoring impossible. These factors mean that clinicians need to and detection of food allergy in pediatric patients with eosinophilicesophagitis. Ann Allergy Asthma Immunol 2010;104:496–502.
be particularly aware that investigations and treatment should be 14. Shah A, Kagalwalla AF, Gonsalves N, et al. Histopathologic variability individualized and must not create more morbidity for the patient in children with eosinophilic esophagitis. Am J Gastroenterol and family than the disease itself. This guidance provides a practical framework for the choices available in managing EoE in children.
15. Gonsalves N, Policarpio-Nicolas M, Zhang Q, et al. Histopathologic variability and endoscopic correlates in adults with eosinophilicesophagitis. Gastrointest Endosc 2006;64:313–9.
TABLE 1. Unresolved questions and areas for further research in child- 16. DeBrosse CW, Collins MH, Buckmeier Butz BK, et al. Identification, epidemiology, and chronicity of pediatric esophageal eosinophilia.
J Allergy Clin Immunol 2010;126:112–9.
1. Definition of disease phenotypes (eg, stricturing/GERD-like/ 17. Hogan SP, Mishra A, Brandt EB, et al. A pathological function for dysmotility) and correlation with treatment response and eotaxin and eosinophils in eosinophilic gastrointestinal inflammation.
Nat Immunol 2001;2:353–60.
2. Natural history of the disease, specifically potential progression to 18. Butt AM, MS, Ng CL, et al. Upregulated eotaxin expression and T cell fibrosis in nonstricturing or asymptomatic disease infiltration in the basal and papillary epithelium in cows' milk asso- 3. Role of food antigens and GERD in clinical and histological ciated reflux oesophagitis. Arch Dis Child 2002;87:124–30.
disease phenotypes 19. Fox VL, Nurko S, Teitelbaum JE, et al. High-resolution EUS in 4. Further development of methodology to identify potentially children with eosinophilic ‘‘allergic'' esophagitis. Gastrointest Endosc significant food or aeroantigens 5. Development of biomarkers for disease diagnosis, monitoring, 20. Korsapati H, Babaei A, Bhargava V, et al. Dysfunction of the long- itudinal muscles of the oesophagus in eosinophilic oesophagitis. Gut 6. Effect of treatment duration on outcome 7. Role of maintenance treatment on long-term prognosis 21. Dahms BB. Reflux esophagitis: sequelae and differential diagnosis in 8. Role of novel treatments in long-standing, treatment-resistant EoE infants and children including eosinophilic esophagitis. Pediatr Dev 9. Need and importance of treatment and follow-up in asymptomatic patients with EoE 22. Batres LA, Liacouras C, Schnaufer L, et al. Eosinophilic esophagitis associated with anastomotic strictures after esophageal atresia repair.
EoE ¼ eosinophilic esophagitis; GERD ¼ gastroesophageal reflux disease.
J Pediatr Gastroenterol Nutr 2002;35:224–6.
Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 58, Number 1, January 2014 Management Guidelines of EoE in Childhood 23. Oliveira C, Zamakhshary M, Marcon P, et al. Eosinophilic esophagitis 45. Henderson CJ, Abonia JP, King EC, et al. Comparative dietary therapy and intermediate esophagitis after tracheoesophageal fistula repair: a effectiveness in remission of pediatric eosinophilic esophagitis.
case series. J Pediatr Surg 2008;43:810–4.
J Allergy ClinImmunol 2012;129:1570–8.
24. Gorter RR, Heij HA, van der Voorn JP, et al. Eosinophilic esophagitis 46. Markowitz JE, Spergel JM, Ruchelli E, et al. Elemental diet is an after esophageal atresia: is there an association? Case presentation and effective treatment for eosinophilic esophagitis in children and ado- literature review. J Pediatr Surg 2012;47:e9–13.
lescents. Am J Gastroenterol 2003;98:777–82.
25. Mulder DJ, Hurlbut DJ, Noble AJ, et al. Clinical features distinguish 47. Peterson K, Clayton F, Vinson LA, et al. Utility of an elemental diet in eosinophilic and reflux-induced esophagitis: an age-matched, case- adult eosinophilic esophagitis. Gastroenterology 2011;140:2011;suppl controlled study and a novel scoring system. J Pediatr Gastroenterol 48. Lamba R, Feuling MB, Levy MB, et al. Allergy testing in pediatric 26. Kirsch R, Bokhary R, Marcon MA, et al. Activated mucosal mast cells eosinophilic esophagitis - identification of IgE and delayed hypersen- differentiate eosinophilic (allergic) esophagitis from gastroesophageal sitivity food reactions and its impact on management. Gastroenterol- reflux disease. J Pediatr Gastroenterol Nutr 2007;44:20–6.
ogy 2011;140:S243.
27. Furuta GT, Kagalwalla AF, Lee JJ, et al. The oesophageal string test: a 49. Teitelbaum JE, Fox VL, Twarog FJ, et al. Eosinophilic esophagitis in novel, minimally invasive method measures mucosal inflammation in children: immunopathological analysis and response to fluticasone eosinophilic oesophagitis. Gut 2013;62:1395–405.
50. Spergel JM, Brown-Whitehorn T, Beausoleil JL, et al. Predictive 28. Dranove JE, Horn DS, Davis MA, et al. Predictors of response to values for skin prick test and atopy patch test for eosinophilic proton pump inhibitor therapy among children with significant eso- esophagitis. J Allergy Clin Immunol 2007;119:509–11.
phageal eosinophilia. J Pediatr 2009;154:96–100.
51. Mehl A, Niggemann B, Keil T, et al. Skin prick test and specific serum 29. Krarup AL, Villadsen GE, Mejlgaard E, et al. Acid hypersensitivity in IgE in the diagnostic evaluation of suspected cow's milk and hen's egg patients with eosinophilic oesophagitis. Scand J Gastroenterol 2010; allergy in children: does one replace the other? Clin Exp Allergy 30. Yoshida N, Uchiyama K, Kuroda M, et al. Interleukin-8 expression in 52. Eggesbo M, Botten G, Halvorsen R, et al. The prevalence of CMA/ the esophageal mucosa of patients with gastroesophageal reflux dis- CMPI in young children: the validity of parentally perceived reactions ease. Scand J Gastroenterol 2004;39:816–22.
in a population-based study. Allergy 2001;56:393–402.
31. Yoshida N, Yoshikawa T, Tanaka Y, et al. A new mechanism for anti- 53. Klemola T, Vanto T, Juntunen-Backman K, et al. Allergy to soy inflammatory actions of proton pump inhibitors–inhibitory effects on formula and to extensively hydrolyzed whey formula in infants with neutrophil-endothelial cell interactions. Aliment Pharmacol Ther cow's milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. J Pediatr 2002;140:219–24.
32. Handa O, Yoshida N, Fujita N, et al. Molecular mechanisms involved 54. Koletzko S, NB, Arato A, Dias JA, et al. Diagnostic approach and in anti-inflammatory effects of proton pump inhibitors. Inflamm Res management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroen- 33. Zhang X, Cheng E, Huo X, et al. Omeprazole blocks STAT6 binding to terol Nutr 2012;55:221–9.
the eotaxin-3 promoter in eosinophilic esophagitis cells. PLoS One 55. Sicherer S. Epidemiology of food allergy. J Allergy Clin Immunol 34. Sayej WN, Patel R, Baker RD, et al. Treatment with high-dose proton 56. Rona RJ, Keil T, Summers C, et al. The prevalence of food allergy: a pump inhibitors helps distinguish eosinophilic esophagitis from none- meta-analysis. J Allergy Clin Immunol 2007;120:638–46.
osinophilic esophagitis. J Pediatr Gastroenterol Nutr 2009;49:393–9.
57. Gonsalves N, Doerfler B, Hirano I. Long term maintenance therapy 35. Dohil R, Newbury RO, Aceves S. Transient PPI responsive esophageal with dietary restriction in adults with eosinophilic esophagitis. Gas- eosinophilia may be a clinical sub-phenotype of pediatric eosinophilic esophagitis. Dig Dis Sci 2012;57:1413–9.
58. Spergel JM, Rothenberg ME, Collins MH, et al. Reslizumab in 36. Molina-Infante J, Ferrando-Lamana L, Ripoll C, et al. Esophageal children and adolescents with eosinophilic esophagitis:results of a eosinophilic infiltration responds to proton pump inhibition in most double-blind, randomised placebo controlled trial. J Allergy Clin adults. Clin Gastroenterol Hepatol 2011;9:110–7.
37. Dohil R, Newbury RO, Fox L, et al. Oral viscous budesonide is 59. Rea B, Akhtar N, Jacques K, et al. Epithelial mesenchymal transition effective in children with eosinophilic esophagitis in a randomized, induced esophageal remodeling in eosinophilic esophagitis reverses placebo-controlled trial. Gastroenterology 2010;139:418–29.
with treatment. Gastroenterology 2011;140:S180.
60. Hackett T. Epithelial-mesenchymal transition in the pathophysiology 38. Untersmayr E, Bakos N, Scho¨ll I, et al. Anti-ulcer drugs promote IgE of airway remodelling in asthma. Curr Opin Allergy Clin Immunol formation toward dietary antigens in adult patients. FASEB J 2005; 61. Gonsalves N, Yang G, Doerfler B, et al. Elimination diet effectively 39. Rothenberg ME, Aceves S, Bonis PA, et al. Working with the US Food treats eosinophilic esophagitis in adults; food reintroduction identifies and Drug Administration: progress and timelines in understanding and causative factors. Gastroenterology 2012;42:1451–9.
treating patients with eosinophilic esophagitis. J Allergy Clin Immunol 62. Moawad FJ, Veerappan GR, Lake JM, et al. Correlation between eosinophilic oesophagitis and aeroallergens. Aliment Pharmacol Ther 40. Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino 63. Scichilone N, Arrigo R, Paterno A, et al. The effect of intranasal acid-based formula. Gastroenterology 1995;109:1503–12.
corticosteroids on asthma control and quality of life in allergic rhinitis 41. Spergel JM, Shuker M. Nutritional management of eosinophilic with mild asthma. J Asthma 2011;48:41–7.
esophagitis. Gastrointest Endosc Clin N Am 2008;18:179–94.
64. Elliott EJ, Thomas D, Markowitz JE. Non-surgical interventions for 42. Spergel JM, Andrews T, Brown-Whitehorn TF, et al. Treatment of eosinophilic esophagitis. Cochrane Database Syst Rev 2010;3: eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests. Ann Allergy Asthma 65. Konikoff MR, Noel RJ, Blanchard C, et al. A randomized, double- blind, placebo-controlled trial of fluticasone propionate for pediatric 43. Mosel MA, Schultz LS, Silverman AH, et al. Family psychosocial eosinophilic esophagitis. Gastroenterology 2006;131:1381–91.
dysfunction is a prominent feature in eosinophilic esophagitis pre- 66. Aceves SS, Dohil R, Newbury RO, et al. Topical viscous budesonide senting as pediatric feeding disorder. Gastroenterology 2011; suspension for treatment of eosinophilic esophagitis. J Allergy Clin 44. Kagalwalla AF, Sentongo TA, Ritz S, et al. Effect of six-food elim- 67. Alexander JA, Jung KW, Arora AS, et al. Swallowed fluticasone ination diet on clinical and histologic outcomes in eosinophilic eso- improves histologic but not symptomatic response of adults with phagitis. Clin Gastroenterol Hepatol 2006;4:1097–102.
eosinophilic esophagitis. Clin Gastroenterol Hepatol 2012;10:742–9.
Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
ESPGHAN EoE Working Group/GI Committee JPGN  Volume 58, Number 1, January 2014 68. Schaefer ET, Fitzgerald JF, Molleston JP, et al. Comparison of oral 87. Foroughi S, Foster B, Kim N, et al. Anti-IgE treatment of eosinophil- prednisone and topical fluticasone in the treatment of eosinophilic associated gastrointestinal disorders. J Allergy Clin Immunol esophagitis: a randomized trial in children. Clin Gastroenterol Hepatol 88. Rocha R, Vitor AB, Trindade E, et al. Omalizumab in the treatment of 69. Arora AS, Perrault J, Smyrk TC. Topical corticosteroid treatment of eosinophilic esophagitis and food allergy. Eur J Pediatr 2011;170: dysphagia due to eosinophilic esophagitis in adults. Mayo Clin Proc 89. Fang JC, Hilden K, Gleich GJ, et al. A pilot study of the treatment of 70. Remedios M, Campbell C, Jones DM, et al. Eosinophilic esophagitis in eosinophilic esophagitis with omalizumab. Gastroenterology 2011; adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointest Endosc 2006;63:3–12.
90. Straumann A, Bauer M, Fischer B, et al. Idiopathic eosinophilic 71. Noel RJ, Putnam PE, Collins MH, et al. Clinical and immunopatho- esophagitis is associated with a T(H)2-type allergic inflammatory logic effects of swallowed fluticasone for eosinophilic esophagitis.
response. J Allergy Clin Immunol 2001;108:954–61.
Clin Gastroenterol Hepatol 2004;2:568–75.
91. Straumann A, Bussmann C, Conus S, et al. Anti-TNF-alpha (inflix- 72. Aceves SS, Bastian JF, Newbury RO, et al. Oral viscous budesonide: a imab) therapy for severe adult eosinophilic esophagitis. J Allergy Clin potential new therapy for eosinophilic esophagitis in children. Am J 92. Busse WW, Katial R, Gossage D, et al. Safety profile, pharmacoki- 73. Netzer P, Gschossmann JM, Straumann A, et al. Corticosteroid-de- netics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha pendent eosinophilic oesophagitis: azathioprine and 6-mercaptopurine antibody, in a phase I study of subjects with mild asthma. J Allergy Clin can induce and maintain long-term remission. Eur J Gastroenterol 93. Wenzel S, Wilbraham D, Fuller R, et al. Effect of an interleukin-4 74. Straumann A, Conus S, Degen L, et al. Budesonide is effective in variant on late phase asthmatic response to allergen challenge in adolescent and adult patients with active eosinophilic esophagitis.
asthmatic patients: results of two phase 2a studies. Lancet 2007; 75. Gupta SK, Collins MH, Lewis JD, et al. Efficacy and safety of oral budesonide suspension (OBS) in pediatric subjects with eosinophilic 94. Schoepfer AM, Gschossmann J, Scheurer U, et al. Esophageal stric- esophagitis (EoE): results from the double-blind, placebo-controlled tures in adult eosinophilic esophagitis: dilation is an effective and safe PEER study. Gastroenterology 2011;140:S179.
alternative after failure of topical corticosteroids. Endoscopy 2008; 76. Schroeder SS, Fleischer DM, Masterson JC, et al. Successful treatment of eosinophilic esophagitis with ciclesonide. J Allergy Clin Immunol 95. Pasha SF, Sharma VK, Crowell MD. Current concepts and treatment options in eosinophilic esophagitis. Curr Opin Investig Drugs 77. Dellon ES, Bower JJ, TKeku TO, et al. Markers of tyrosine kinase activity for diagnosis and treatment response in eosinophilic esopha- 96. Cantu P, Velio P, Prada A, et al. Ringed oesophagus and idiopathic gitis: a pilot study of pERK 1/2 and pSTAT5. Gastroenterology eosinophilic oesophagitis in adults: an association in two cases. Dig Liver Dis 2005;37:129–34.
78. Helou EF, Simonson J, Arora AS. 3-yr-follow-up of topical corticos- 97. Zimmerman SL, Levine MS, Rubesin SE, et al. Idiopathic eosinophilic teroid treatment for eosinophilic esophagitis in adults. Am J Gastro- esophagitis in adults: the ringed esophagus. Radiology 2005;236:159– 79. Straumann A, Conus S, Degen L, et al. Long-term budesonide main- tenance treatment is partially effective for patients with eosinophilic 98. Schoepfer AM, Gonsalves N, Bussmann C, et al. Esophageal dilation esophagitis. Clin Gastroenterol Hepatol 2011;9:400–9.
in eosinophilic esophagitis: effectiveness, safety, and impact on the 80. Liacouras CA, Wenner WJ, Brown K, et al. Primary eosinophilic underlying inflammation. Am J Gastroenterol 2010;105:1062–70.
esophagitis in children: successful treatment with oral corticosteroids.
99. Robles-Medranda C, Villard F, le Gall C, et al. Severe dysphagia in J Pediatr Gastroenterol Nutr 1998;26:380–5.
children with eosinophilic esophagitis and esophageal stricture: an 81. Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: indication for balloon dilation? J Pediatr Gastroenterol Nutr a 10-year experience in 381 children. Clin Gastroenterol Hepatol 100. Konikoff MR, Blanchard C, Kirby C, et al. Potential of blood eosi- 82. Gupta SK, Peters-Golden M, Fitzgerald JF, et al. Cysteinyl leukotriene nophils, eosinophil-derived neurotoxin, and eotaxin-3 as biomarkers of levels in esophageal mucosal biopsies of children with eosinophilic eosinophilic esophagitis. Clin Gastroenterol Hepatol 2006;4:1328– inflammation: are they all the same? Am J Gastroenterol 2006;101: 83. Attwood SE, Lewis CJ, Bronder CS, et al. Eosinophilic oesophagitis: a novel treatment using Montelukast. Gut 2003;52:181–5.
84. Lucendo AJ, De Rezende LC, Jimenez-Contreras S, et al. Montelukast Additional members of the ESPGHAN Eosinophilic was inefficient in maintaining steroid-induced remission in adult Esophagitis Working Group (in alphabetical order): H. Antunes eosinophilic esophagitis. Dig Dis Sci 2011;56:3551–8.
(Portugal), M. Auth (UK), C. Dupont (France), M. Fotoulaki 85. Mishra A, Hogan SP, Brandt EB, et al. IL-5 promotes eosinophil trafficking to the esophagus. J Immunol 2002;168:2464–9.
(Greece), M. Furman (UK), R. Garcia-Puig (Spain), C. Gutie´rrez 86. Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody Junquera (Spain), C.M.F. Kneepkens (Netherlands), A. Kostovski treatment (mepolizumab) in active eosinophilic oesophagitis: a rando- (FYROM), R. Orel (Slovenia), Ch. Spray (UK), M. Thomson (UK), mised, placebo-controlled, double-blind trial. Gut 2010;59:21–30.
V. Urbonas (Lithuania), N. Zevit (Israel).
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    Microsoft word - 081007 guidelines for the administration of drugs through enteral feeding tubes anon

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