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Dietary therapy for eosinophilic esophagitis

  • Javier Molina-Infante
    Correspondence
    Corresponding author: Javier Molina-Infante, MD, PhD, Department of Gastroenterology, Hospital Universitario San Pedro de Alcantara, C/Pablo Naranjo s/n 10003, Caceres, Spain.
    Affiliations
    Department of Gastroenterology, Hospital Universitario San Pedro de Alcantara, Caceres, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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  • Alfredo J. Lucendo
    Affiliations
    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain

    Department of Gastroenterology, Hospital General de Tomelloso (CIBEREHD), Tomelloso, Spain
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Published:March 06, 2018DOI:https://doi.org/10.1016/j.jaci.2018.02.028
      Eosinophilic esophagitis is a chronic, immune-mediated esophageal disease triggered predominantly, but not exclusively, by food antigens. Presently, available food allergy tests are suboptimal to predict food triggers for eosinophilic esophagitis, especially in adults. Elemental diets (exclusive feeding with amino acid–based formulas) and empiric 6-food elimination diets (withdrawing milk, wheat, egg, soy, nuts, and fish/seafood for 6 weeks) have consistently shown the best efficacy rates. However, their high level of restriction and need for multiple endoscopies have hampered their implementation in clinical practice. Currently, milk, wheat/gluten, and egg are the most common food triggers in children and adults from the United States, Spain, and Australia. Hence less restrictive empiric schemes, such as a 4-food elimination diet (dairy, gluten-containing cereals, egg, and legumes) or a 2-food elimination diet (dairy and gluten-containing cereals) have been lately developed with good efficacy rates (2-food elimination diet, 43%; 4-food elimination diet in adults, 54%; and 4-food elimination diet in children, 64%). A step-up approach (2-4-6) might result in prompt recognition of a majority of responders with few food triggers, reducing the number of endoscopies and costs and shortening the diagnostic process. Standardization of food reintroduction, novel food allergy testing, and studies evaluating a milk elimination diet in children and the long-term outcomes of dietary interventions are warranted.

      Key words

      Abbreviations used:

      EoE (Eosinophilic esophagitis), 2-FED (Two-food elimination diet), 4-FED (Four-food elimination diet), 6-FED (Six-food elimination diet)
      Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated disease isolated to the esophagus and characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • Atkins D.
      • Attwood S.E.
      • Bonis P.A.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      Since its initial description in the early 1990s,
      • Attwood S.E.
      • Smyrk T.C.
      • Demeester T.R.
      • Jones J.B.
      Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome.
      EoE has become an emerging cause of esophageal symptoms worldwide, mainly reflux-like symptoms, vomiting, abdominal pain, food refusal, and failure to thrive in infants and younger children and dysphagia/food impaction in older children and young adults across westernized countries.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • von Arnim U.
      • Bredenoord A.J.
      • Bussmann C.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      The concept of food allergens as the main antigenic trigger of EoE was introduced in a seminal report published in 1995.
      • Kelly K.J.
      • Lazenby A.J.
      • Rowe P.C.
      • Yardley J.H.
      • Perman J.A.
      • Sampson H.A.
      Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.
      In this study the authors showed complete reversal of refractory esophageal eosinophilia in 8 children attributed theoretically to gastrointestinal reflux disease after being fed exclusively with an amino acid–based formula for at least 6 weeks.
      • Kelly K.J.
      • Lazenby A.J.
      • Rowe P.C.
      • Yardley J.H.
      • Perman J.A.
      • Sampson H.A.
      Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.
      Since then, numerous series have replicated the effectiveness of a dietary elimination diet for EoE in children and adults.
      • Molina-Infante J.
      • Gonzalez-Cordero P.L.
      • Arias A.
      • Lucendo A.J.
      Update on dietary therapy for eosinophilic esophagitis in children and adults.
      Unlike drug therapy (eg, proton pump inhibitors, topical corticosteroids, or both) and/or endoscopic dilation, dietary elimination therapy potentially offers an effective nonpharmacologic treatment, with continued food avoidance targeted as a long-term, drug-free disease control option. In addition, dietary therapy is the only treatment targeting the cause of the disease.
      It is important to stress that initial diets are not permanent but rather a starting point. After documenting remission and subsequent individual food reintroduction, the final goal will be lifelong elimination of identified culprit foods, usually one to 3 food groups, including dairy, gluten-containing cereals, and/or eggs.
      • Molina-Infante J.
      • Gonzalez-Cordero P.L.
      • Arias A.
      • Lucendo A.J.
      Update on dietary therapy for eosinophilic esophagitis in children and adults.
      Therefore it is crucial to begin with the end in mind for both patients and physicians. This aspect should be carefully discussed between physicians, patients, and their relatives before implementing any dietary therapy in clinical practice. Likewise, the choice of dietary therapy should be negotiated with the patient or family, considering prior therapies, nutritional adequacy of baseline diet because of previous dietary restrictions related to IgE-mediated food allergy (increased risk for nutritional deprivation), patient age, family dynamics and financial resources, growth profile/rate, and potential diet-related psychological problems and patient/family preferences. Initial considerations and practical tips for elimination diets in clinical practice are summarized in Table I.
      Table IInitial considerations and practical information for empiric elimination diets in clinical practice
      • 1.
        Patients should begin with the end in mind. The final goal of diet will always be identifying which foods trigger esophageal inflammation to design an individualized diet with long-term avoidance of culprit food antigens, the most common being milk, wheat/gluten, and egg.
      • 2.
        Ponder cautiously any elimination diet in patients who are already experiencing multiple dietary restrictions because of IgE-mediated food allergies or celiac disease.
      • 3.
        Severe symptomatic patients can benefit best from topical corticosteroids. Dietary therapy can be further tested while not receiving topical steroid therapy.
      • 4.
        Compliance issues with diets often arise in older children, adolescents, and young adults.
      • 5.
        Provide comprehensive written information to ensure label reading is performed adequately.
      • 6.
        Efficacy rates for empiric elimination diets are consistent between children and adults. Cow's milk, wheat/gluten, and eggs are the most common food triggers of EoE in children and adults from the United States, Spain, and Australia.
      • 7.
        A step-up approach for empiric elimination diets might be cost-effective and improve patient uptake for dietary therapy. Therefore a 6-FED diet must be reserved for highly motivated patients unresponsive to a 2-FED or 4-FED.
      • 8.
        All elimination diets should be instituted for a minimum of 6 weeks and always followed by esophageal biopsies applied during an endoscopic procedure.
      • 9.
        On documented clinical and histologic remission by eliminating several foods or food groups, foods should be individually reintroduced while continuing on the diet (one at a time) for a minimum of 6 weeks, with an endoscopic procedure after each food reintroduction.
      • 10.
        Neither symptoms nor endoscopic features alone without histologic results can accurately guide the reintroduction process.
      • 11.
        The reintroduction process can take up to several months. The more foods eliminated, the longer it will be. Intermittent breaks during the process are strongly recommended.
      • 12.
        When available, dietary counselling by a dietitian trained in food allergies and elimination diets is advisable, especially for highly restrictive diets.
      EoE is a condition mediated by allergic sensitization to food antigens, which develops in genetically susceptible subjects with predisposing early-life environmental factors through a TH2 cell–mediated immune response involving eosinophils, mast cells, and the cytokines IL-5 and IL-13.
      • O'Shea K.M.
      • Aceves S.S.
      • Dellon E.S.
      • Gupta S.K.
      • Spergel J.M.
      • Furuta G.T.
      • et al.
      Pathophysiology of eosinophilic esophagitis.
      Even though IgE sensitization to food/airborne allergens and food allergy is greater in patients with EoE, disease induction, propagation, or both have not been shown to rely on IgE-mediated mechanisms.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • von Arnim U.
      • Bredenoord A.J.
      • Bussmann C.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      Therefore available blood and skin tests for food allergy are suboptimal to predict causative foods in patients with EoE, especially adults.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • von Arnim U.
      • Bredenoord A.J.
      • Bussmann C.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      • O'Shea K.M.
      • Aceves S.S.
      • Dellon E.S.
      • Gupta S.K.
      • Spergel J.M.
      • Furuta G.T.
      • et al.
      Pathophysiology of eosinophilic esophagitis.
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      Empiric elimination diets, which consist of eliminating the most common food groups known to trigger EoE, have become the standard in clinical practice when dietary therapy is chosen. This review aims to update and summarize the most relevant data information on dietary therapy for pediatric and adult patients with EoE.

      Dietary treatment options

      Currently, the 3 primary choices for initial dietary therapy for EoE are an elemental diet, an empiric elimination diet, and a food allergy testing–guided elimination diet. Overall, an elemental diet remains the most effective approach (90%) for both children and adults but seems unfeasible in clinical practice.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • von Arnim U.
      • Bredenoord A.J.
      • Bussmann C.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      A food allergy testing–guided elimination diet has shown poor consistent results in adult studies and has met success in 2 pediatric retrospective series, which have not been replicated elsewhere.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • von Arnim U.
      • Bredenoord A.J.
      • Bussmann C.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      Finally, empiric 6-food elimination diets (6-FEDs; withdrawing milk, wheat/gluten, egg, soy, nuts, and fish/seafood) have demonstrated a consistent 72% effectiveness overall for pediatric and adult patients.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • von Arnim U.
      • Bredenoord A.J.
      • Bussmann C.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      More recently, less restrictive dietary schemes, such as a 4-food elimination diet (4-FED; dairy, gluten-containing cereals, egg, and legumes) or a 2-food elimination diet (2-FED; dairy and gluten-containing cereals), have been developed lately with good efficacy rates. Effectiveness rates for all 3 dietary interventions in children and adults are summarized in Fig 1.
      Figure thumbnail gr1
      Fig 1Histologic remission rates broken down by age group and shown by different modalities of dietary therapy (elemental diet, empiric elimination diet, and allergy testing–guided elimination diet) for EoE. *Indirect data from prospective studies on 4-FEDs and 2-FEDs. Efficacy of milk elimination diets in children ranges from 33% to 56%.

       Elemental diet

      As mentioned previously, an elemental diet paved the way 25 years ago for dietary interventions in patients with EoE.
      • Kelly K.J.
      • Lazenby A.J.
      • Rowe P.C.
      • Yardley J.H.
      • Perman J.A.
      • Sampson H.A.
      Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.
      Ten children with refractory symptomatic EoE were exclusively fed an elemental formula for a minimum of 6 weeks, in which all proteins are eliminated and the nitrogen source is exclusively provided by single amino acids, thus being devoid of antigenic capacity. All patients had normalized esophageal histology, and 8 in 10 exhibited complete clinic remission as well. Since then, numerous studies, mostly retrospective in pediatric populations, corroborated these initial promising data.
      Overall effectiveness was estimated in a recent meta-analysis to be around 90% in both children and adults.
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      However, this dietary strategy seems unfeasible in clinical practice for a variety of reasons, including its poor palatability (requiring nasogastric tubes in most children and lack of adherence in up to one third of patients recruited in recent adult prospective studies with a diet duration of 2-4 weeks
      • Peterson K.A.
      • Byrne K.R.
      • Vinson L.A.
      • Ying J.
      • Boynton K.K.
      • Fang J.C.
      • et al.
      Elemental diet induces histologic response in adult eosinophilic esophagitis.
      • Warners M.J.
      • Vlieg-Boerstra B.J.
      • Verheij J.
      • van Hamersveld P.H.P.
      • van Rhijn B.D.
      • Van Ampting M.T.J.
      • et al.
      Elemental diet decreases inflammation and improves symptoms in adult eosinophilic oesophagitis patients.
      ); social, psychologic, and quality-of-life impairment related to complete avoidance of all kinds of table food; and high cost and lack of universal coverage by health systems or insurance providers.
      A potential role for an elemental diet has been proposed after failure of conventional and optimally performed therapy, either topical steroids or empiric elimination diets, in patients who wish to remain in remission while investigating the casual role of unusual foods and aeroallergens in their disease, but this approach has yet to be evaluated.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • von Arnim U.
      • Bredenoord A.J.
      • Bussmann C.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      Of note, maintaining and promoting oral skills should be a priority for the duration of the elemental diet, especially in children less than 2 years of age or older children with known feeding dysfunction. When all kinds of solid foods are removed from the diet, infants and toddlers can be at risk for delayed oral-motor skill development.
      • Delaney A.L.
      • Arvedson J.C.
      Development of swallowing and feeding: prenatal through first year of life.

       Food allergy testing–based elimination diet

      In this specific dietary approach, skin prick tests and atopy patch tests are performed to test for food allergies, with subsequent elimination of foods eliciting positive test results. A first report on the effectiveness of this strategy showed clinical and histologic remission in 49% of pediatric patients.
      • Spergel J.M.
      • Beausoleil J.L.
      • Mascarenhas M.
      • Liacouras C.A.
      The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis.
      Mean age of patients was 5 years, and on average, 5 food groups were eliminated per patient. The main criticism to this study is that food triggers were not identified by histologic remission but rather by symptom relapse reported by parents after individual food reintroduction.
      • Spergel J.M.
      • Beausoleil J.L.
      • Mascarenhas M.
      • Liacouras C.A.
      The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis.
      The same research group updated their results in 2012, with an overall effectiveness of 53%.
      • Spergel J.M.
      • Brown-Whitehorn T.F.
      • Cianferoni A.
      • Shuker M.
      • Wang M.L.
      • Verma R.
      • et al.
      Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.
      When cow's milk (the main food trigger in patients with EoE) was eliminated systematically, regardless of skin prick test/atopy patch test results, and an elemental diet was instituted in patients with diets believed to be too restrictive, the effectiveness increased up to 77%.
      • Spergel J.M.
      • Brown-Whitehorn T.F.
      • Cianferoni A.
      • Shuker M.
      • Wang M.L.
      • Verma R.
      • et al.
      Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.
      These results have been replicated (65% histologic remission) in just 1 retrospective study,
      • Henderson C.J.
      • Abonia J.P.
      • King E.C.
      • Putnam P.E.
      • Collins M.H.
      • Franciosi J.P.
      • et al.
      Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.
      with much more disappointing findings in numerous pediatric studies.
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      As for adult patients, poor histologic remission rates (22%
      • Molina-Infante J.
      • Martin-Noguerol E.
      • Alvarado-Arenas M.
      • Porcel-Carreño S.L.
      • Jimenez-Timon S.
      • Hernandez-Arbeiza F.J.
      Selective elimination diet based on skin testing has suboptimal efficacy for adult eosinophilic esophagitis.
      and 35%
      • Wolf W.A.
      • Jerath M.R.
      • Sperry S.L.W.
      • Shaheen N.J.
      • Dellon E.S.
      Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis.
      ) were reported initially with an allergy testing–based elimination diet. Beyond skin testing, a pilot study evaluated the effectiveness of a serum IgE microarray–guided elimination diet, but the study was interrupted early because of poor efficacy (7% histologic remission rate).
      • van Rhijn B.D.
      • Vlieg-Boerstra B.J.
      • Versteeg S.A.
      • Akkerdaas J.H.
      • van Ree R.
      • Terreehorst I.
      • et al.
      Evaluation of allergen-microarray-guided dietary intervention as treatment of eosinophilic esophagitis.
      More recently, a comprehensive study from Australia assessed the accuracy of combining 5 different skin and blood food allergy tests to detect causative foods in adults with EoE.
      • Philpott H.
      • Nandurkar S.
      • Royce S.G.
      • Thien F.
      • Gibson P.R.
      Allergy tests do not predict food triggers in adult patients with eosinophilic oesophagitis. A comprehensive prospective study using five modalities.
      None of the evaluated food allergy tests measuring IgE and non-IgE hypersensitivity to foods could accurately predict food triggers identified through food challenge with histologic reassessment in responders to a 6-FED.
      • Philpott H.
      • Nandurkar S.
      • Royce S.G.
      • Thien F.
      • Gibson P.R.
      Allergy tests do not predict food triggers in adult patients with eosinophilic oesophagitis. A comprehensive prospective study using five modalities.
      Overall, a recent meta-analysis revealed that this dietary approach led to histologic remission in 45.5% of patients, with wide heterogeneity (I2 = 75%) indicating low reproducibility.
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      It is noteworthy that its effectiveness was significantly less in adults when compared with that found in children (32.2% vs 47.9%).
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.

       Novel allergy testing

      Overall, cumulative data support the current thought that EoE is primarily non-IgE mediated.
      • Clayton F.
      • Fang J.C.
      • Gleich G.J.
      • Lucendo A.J.
      • Olalla J.M.
      • Vinson L.A.
      • et al.
      Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE.
      • Simon D.
      • Cianferoni A.
      • Spergel J.M.
      • Aceves S.
      • Holbreich M.
      • Venter C.
      • et al.
      Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity.
      Aside from methodological issues, discrepancies between children and adults hint at the possibility of EoE switching from an IgE-type allergy to an IgG4-type allergy as patients become adults, but this remains to be elucidated. More recently, food-specific IgG4 in esophageal tissue has been evaluated recently in a small exploratory study.
      • Wright B.L.
      • Kulis M.
      • Guo R.
      • Orgel K.A.
      • Wolf W.A.
      • Burks A.W.
      • et al.
      Food-specific IgG4 is associated with eosinophilic esophagitis.
      Food-specific IgG4 was significantly overexpressed in 20 patients with EoE compared with control subjects, confirming that an antigen-specific IgG4 response can contribute to the pathogenesis of EoE. These differences were not observed in blood samples. However, no differences in food-specific IgG4 levels were observed between diet responders (n = 11) and nonresponders, likely related to the small sample size.
      • Wright B.L.
      • Kulis M.
      • Guo R.
      • Orgel K.A.
      • Wolf W.A.
      • Burks A.W.
      • et al.
      Food-specific IgG4 is associated with eosinophilic esophagitis.
      Further studies evaluating this hypothesis are underway.
      A novel esophageal prick test that directly challenges the esophagus with local injection of allergen extracts has been reported.
      • Warners M.J.
      • Terreehorst I.
      • van den Wijngaard R.M.
      • Akkerdaas J.
      • van Esch B.C.A.M.
      • van Ree R.
      • et al.
      Abnormal responses to local esophageal food allergen injections in adult patients with eosinophilic esophagitis.
      Among 8 patients with EoE, 5 showed immediate mucosal blanching and/or total luminal obstruction after mucosal injection of soy (n = 2), banana, apple, oats, and hazelnut. In all patients luminal obstruction improved, allowing passage of the endoscopy around 10 minutes later, and was completely gone the next day.
      • Warners M.J.
      • Terreehorst I.
      • van den Wijngaard R.M.
      • Akkerdaas J.
      • van Esch B.C.A.M.
      • van Ree R.
      • et al.
      Abnormal responses to local esophageal food allergen injections in adult patients with eosinophilic esophagitis.
      No patient had a reaction to milk, wheat, or egg, the most common food triggers in patients with EoE. Although this study first proves the ability of the esophagus for immediate reactions after local food allergen injection, both its usefulness to guide dietary therapy and safety should be further evaluated.

       Empiric elimination diets

       6-FEDs

      The rationale for the development of this dietary strategy was based on the concept that the empiric avoidance of foods that most commonly cause immediate food hypersensitivity would also potentially resolve EoE. This diet was first tested in 2006 in pediatric patients from Chicago, in which 6 food groups that account for the majority of IgE-mediated food reactions (milk, wheat, egg, soy, nuts, and fish/seafood) were eliminated for 6 weeks.
      • Kagalwalla A.F.
      • Sentongo T.A.
      • Ritz S.
      • Hess T.
      • Nelson S.P.
      • Emerick K.M.
      • et al.
      Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.
      The 6-FED led to clinical and histologic remission in 74% of children in this first seminal study, with no inferiority compared with an elemental diet. Quite similar results have been replicated further in pediatric
      • Henderson C.J.
      • Abonia J.P.
      • King E.C.
      • Putnam P.E.
      • Collins M.H.
      • Franciosi J.P.
      • et al.
      Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.
      • Kagalwalla A.F.
      • Shah A.
      • Li B.U.
      • Sentongo T.A.
      • Ritz S.
      • Manuel-Rubio M.
      • et al.
      Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
      and adult
      • Wolf W.A.
      • Jerath M.R.
      • Sperry S.L.W.
      • Shaheen N.J.
      • Dellon E.S.
      Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis.
      • Gonsalves N.
      • Yang G.Y.
      • Doerfler B.
      • Ritz S.
      • Ditto A.M.
      • Hirano I.
      Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
      • Lucendo A.J.
      • Arias A.
      • Gonzalez-Cervera J.
      • Yagüe-Compadre J.L.
      • Guagnozzi D.
      • Angueira T.
      • et al.
      Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease.
      • Rodríguez-Sánchez J.
      • Gómez Torrijos E.
      • López Viedma B.
      • de la Santa Belda E.
      • Martín Dávila F.
      • García Rodríguez C.
      • et al.
      Efficacy of IgE-targeted vs empiric six-food elimination diets for adult eosinophilic oesophagitis.
      • Philpott H.
      • Nandurkar S.
      • Royce S.G.
      • Thien F.
      • Gibson P.R.
      A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis.
      • Molina-Infante J.
      • Arias A.
      • Barrio J.
      • Rodríguez-Sánchez J.
      • Sanchez-Cazalilla M.
      • Lucendo A.J.
      Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
      • Kagalwalla A.F.
      • Wechsler J.B.
      • Amsden K.
      • Schwartz S.
      • Makhija M.
      • Olive A.
      • et al.
      Efficacy of a 4-food elimination diet for children with eosinophilic esophagitis.
      populations. A detailed summary of prospective studies evaluating the efficacy of a 6-FED is shown in Table II.
      • Kagalwalla A.F.
      • Shah A.
      • Li B.U.
      • Sentongo T.A.
      • Ritz S.
      • Manuel-Rubio M.
      • et al.
      Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
      • Gonsalves N.
      • Yang G.Y.
      • Doerfler B.
      • Ritz S.
      • Ditto A.M.
      • Hirano I.
      Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
      • Lucendo A.J.
      • Arias A.
      • Gonzalez-Cervera J.
      • Yagüe-Compadre J.L.
      • Guagnozzi D.
      • Angueira T.
      • et al.
      Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease.
      • Rodríguez-Sánchez J.
      • Gómez Torrijos E.
      • López Viedma B.
      • de la Santa Belda E.
      • Martín Dávila F.
      • García Rodríguez C.
      • et al.
      Efficacy of IgE-targeted vs empiric six-food elimination diets for adult eosinophilic oesophagitis.
      • Philpott H.
      • Nandurkar S.
      • Royce S.G.
      • Thien F.
      • Gibson P.R.
      A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis.
      • Molina-Infante J.
      • Arias A.
      • Barrio J.
      • Rodríguez-Sánchez J.
      • Sanchez-Cazalilla M.
      • Lucendo A.J.
      Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
      • Kagalwalla A.F.
      • Wechsler J.B.
      • Amsden K.
      • Schwartz S.
      • Makhija M.
      • Olive A.
      • et al.
      Efficacy of a 4-food elimination diet for children with eosinophilic esophagitis.
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      A meta-analysis revealed that this dietary approach provided an extremely homogenous (I2 statistic = 0) 72% histologic remission in both children and adults.
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      Table IIComprehensive information in prospective studies evaluating the efficacy of the empiric 6-FED, 4-FED, and 2-FED
      First author, year of publication, countryDiet/population/designHistologic remissionNo. of culprit foods identified through individual reintroduction of either 6, 4, or 2 food groupsMost common food triggers identified through individual food reintroduction
      12>2
      Kagalwallaet al, 2011, United States
      • Kagalwalla A.F.
      • Shah A.
      • Li B.U.
      • Sentongo T.A.
      • Ritz S.
      • Manuel-Rubio M.
      • et al.
      Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
      6-FED/children/unicenter74%72%8%
      Not every dietary responder patient underwent complete food reintroduction.
      8%
      Not every dietary responder patient underwent complete food reintroduction.
      Milk = 74%

      Wheat = 26%

      Eggs = 17%
      Gonsalves et al, 2012, United States
      • Gonsalves N.
      • Yang G.Y.
      • Doerfler B.
      • Ritz S.
      • Ditto A.M.
      • Hirano I.
      Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
      6-FED/adults/unicenter70%85%15%
      Not every dietary responder patient underwent complete food reintroduction.
      Wheat = 60%

      Milk = 50%
      Lucendo et al, 2013, Spain
      • Lucendo A.J.
      • Arias A.
      • Gonzalez-Cervera J.
      • Yagüe-Compadre J.L.
      • Guagnozzi D.
      • Angueira T.
      • et al.
      Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease.
      6-FED/adults/unicenter72%36%31%33%Milk = 62%

      Wheat = 29%

      Egg = 26%

      Legumes = 24%
      Rodriguez-Sanchez et al, 2014, Spain
      • Rodríguez-Sánchez J.
      • Gómez Torrijos E.
      • López Viedma B.
      • de la Santa Belda E.
      • Martín Dávila F.
      • García Rodríguez C.
      • et al.
      Efficacy of IgE-targeted vs empiric six-food elimination diets for adult eosinophilic oesophagitis.
      6-FED/adults/unicenter53%Milk = 64%

      Wheat = 28%

      Egg = 21%

      Legumes = 7%
      Philpott et al, 2016, Australia
      • Philpott H.
      • Nandurkar S.
      • Royce S.G.
      • Thien F.
      • Gibson P.R.
      A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis.
      6-FED/adults/unicenter52%56%17%13%Milk = 43%

      Wheat = 43%

      Egg = 34%
      Molina-Infante et al, 2014, Spain
      • Molina-Infante J.
      • Arias A.
      • Barrio J.
      • Rodríguez-Sánchez J.
      • Sanchez-Cazalilla M.
      • Lucendo A.J.
      Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
      4-FED/adults/multicenter54%45%45%Milk = 50%

      Egg = 36%

      Wheat = 31%

      Legumes = 18%
      Kagalwalla et al, 2017, United States
      • Kagalwalla A.F.
      • Wechsler J.B.
      • Amsden K.
      • Schwartz S.
      • Makhija M.
      • Olive A.
      • et al.
      Efficacy of a 4-food elimination diet for children with eosinophilic esophagitis.
      4-FED/children/multicenter64%64%
      Percentages referred to the subgroup of 25 children who completed all foods.
      20%
      Percentages referred to the subgroup of 25 children who completed all foods.
      16%
      Percentages referred to the subgroup of 25 children who completed all foods.
      Milk = 85%

      Egg = 35%

      Wheat = 33%
      Molina-Infante et al, 2017, Spain
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      2-FED/children and adults/multicenter43%68%28%0%Milk = 52%

      Milk and wheat = 28%

      Wheat = 16%
      Molina-Infante et al, 2017, Spain
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      Combined effective 2-FED plus 4-FED/nonresponders/multicenter60%10%60%30%Milk = 90%

      Egg = 60%

      Legumes = 40%

      Wheat = 30%
      Molina-Infante et al, 2017, Spain
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      Combined effective 2-FED and 4-FED plus 6-FED/nonresponders/multicenter79%0%0%100%Egg = 100%

      Fish-seafood = 100%

      Milk = 75%

      Wheat = 75%

      Legumes = 50%

      Nuts = 25%
      Not every dietary responder patient underwent complete food reintroduction.
      Percentages referred to the subgroup of 25 children who completed all foods.
      The most common causative foods identified after response to a 6-FED have been by far cow's milk, followed by wheat/gluten, egg, and, to a lesser extent, soy/legumes (with the exception of studies conducted in Spain, where legumes, such as lentils, chickpeas, or peas, are consumed regularly).
      • Lucendo A.J.
      • Arias A.
      • Gonzalez-Cervera J.
      • Yagüe-Compadre J.L.
      • Guagnozzi D.
      • Angueira T.
      • et al.
      Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease.
      • Molina-Infante J.
      • Arias A.
      • Barrio J.
      • Rodríguez-Sánchez J.
      • Sanchez-Cazalilla M.
      • Lucendo A.J.
      Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      On the contrary, all studies have consistently shown that nuts and fish/seafood rarely trigger EoE (Table II). Thus studies on 6-FEDs have been instrumental to decipher the most common food triggers in patients with EoE, but on the other hand, the high level of dietary restriction and numerous endoscopies required have been the best deterrent for patients and physicians to engage with dietary therapy. Interestingly, up to three quarters of responders in 6-FED studies were found to have just 1 or 2 causative foods after 6-food challenges and 6 endoscopic procedures (Table II). As such, it was predictable that less restrictive dietary schemes, eliminating the most common food triggers and reducing the number endoscopic procedures, could provide efficacy rates closer to those observed with a 6-FED.

       Four-food elimination diet

      On the aforementioned basis intended to optimize dietary restrictions and endoscopic procedures for dietary therapy, the 4-food elimination diet (4-FED) was developed, avoiding the most common food triggers in patients with EoE (animal milk, gluten-containing cereals, eggs, and legumes).
      • Philpott H.
      • Nandurkar S.
      • Royce S.G.
      • Thien F.
      • Gibson P.R.
      A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis.
      A first prospective multicenter study conducted in 52 Spanish adults with EoE showed a 54% remission.
      • Molina-Infante J.
      • Arias A.
      • Barrio J.
      • Rodríguez-Sánchez J.
      • Sanchez-Cazalilla M.
      • Lucendo A.J.
      Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
      Half of adult responders to 4-FEDs were found to have milk, gluten, or both as food triggers, and therefore theoretically, they could have been identified with a 2-FED by eliminating milk and gluten without egg or legume restriction. As for children, a first multicenter study in 78 patients from the United States has been reported recently.
      • Kagalwalla A.F.
      • Wechsler J.B.
      • Amsden K.
      • Schwartz S.
      • Makhija M.
      • Olive A.
      • et al.
      Efficacy of a 4-food elimination diet for children with eosinophilic esophagitis.
      The histologic remission rate was even greater than in adults (64%). The most common food triggers were cow's milk (85%), egg (35%), wheat (33%), and soy (19%). It is noteworthy that 55% of pediatric responders to a 4-FGED had cow's milk as the only food trigger after individual food reintroduction. Detailed information about both studies is displayed in Table II.

       Step-up approach: 2-4-6

      If among responders to a 4-FED half of adults could have been identified with a simplified 2-FED (milk and gluten)
      • Molina-Infante J.
      • Arias A.
      • Barrio J.
      • Rodríguez-Sánchez J.
      • Sanchez-Cazalilla M.
      • Lucendo A.J.
      Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
      and 56% children with an even simpler 1-food elimination diet (milk),
      • Kagalwalla A.F.
      • Wechsler J.B.
      • Amsden K.
      • Schwartz S.
      • Makhija M.
      • Olive A.
      • et al.
      Efficacy of a 4-food elimination diet for children with eosinophilic esophagitis.
      a step-up approach for dietary therapy in patients with EoE (ie, eliminating at first the 1 or 2 most common food triggers and subsequently increasing the level of restriction in nonresponders) could result in notable advantages, such as reducing dietary restrictions, endoscopic procedures, costs, and shortening the diagnostic process. This approach has been first assessed in a multicenter study conducted in 14 centers, mostly from Spain, gathering 130 consecutive patients, of whom 25 were children.
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      In this study all patients underwent a 2-FED (milk and gluten), and nonresponders were offered to escalate to a 4-FED and eventually to a 6-FED if no response was observed. A 2-FED achieved EoE remission in 43% of patients, without differences between pediatric and adult patients. In nonresponders to a 2-FED, stepping up to a 4-FED (60%) and a 6-FED (79%) led to similar remission rates previously reported. Compared with starting with a 6-FED, this step-up strategy allowed reduction of endoscopic procedures and shortening of the diagnostic process time by 20%.
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      Moreover, dietary restrictions for patients were notably optimized because 43% of included patients with EoE could know their triggering foods without eliminating egg, legumes, nuts, and fish/seafood, up to 60% while consuming nuts and fish/seafood. Additionally, 90% of responders to a 2-FED or 4-FED had 1 or 2 causative food groups, thus identifying responders with few food triggers without need of a 6-FED. These responders with few food triggers for EoE are definitively the best candidates for maintenance dietary therapy. It is interesting to note that responders to a 6-FED with previous failure of a 2-FED and 4-FED had 3 or more food triggers, including nuts and fish/seafood. By using this step-up approach, it has been shown that the higher the level of restriction, the higher likelihood of having more food triggers.
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      Taking these results into consideration, a 6-FED might be reserved currently for motivated patients unresponsive to less restrictive empiric elimination diet schemes who are still willing to elucidate their food triggers. Last but not least, the results obtained with this step-up approach study might definitely improve patient acceptance of dietary therapy, which makes it much more easier and doable compared with a 6-FED. Overall, the most common food triggers identified in all prospective empiric elimination diet studies (either 6-, 4-, or 2-FEDs) are shown in Table II.

       Cow's milk elimination diet

      Because cow's milk has been reported to be the most common food trigger, especially in children, a cow's milk elimination diet would be an easier way to check the efficacy of dietary intervention. A cow's milk elimination diet in children has been reported recently in 2 studies.
      • Kagalwalla A.F.
      • Amsden K.
      • Shah A.
      • Ritz S.
      • Manuel-Rubio M.
      • Dunne K.
      • et al.
      Cow's milk elimination: a novel dietary approach to treat eosinophilic esophagitis.
      • Kruszewski P.G.
      • Russo J.M.
      • Franciosi J.P.
      • Varni J.W.
      • Platts-Mills T.A.
      • Erwin E.A.
      Prospective, comparative effectiveness trial of cow's milk elimination and swallowed fluticasone for pediatric eosinophilic esophagitis.
      Despite encouraging histologic remission rates (65%
      • Kagalwalla A.F.
      • Amsden K.
      • Shah A.
      • Ritz S.
      • Manuel-Rubio M.
      • Dunne K.
      • et al.
      Cow's milk elimination: a novel dietary approach to treat eosinophilic esophagitis.
      and 61%
      • Kruszewski P.G.
      • Russo J.M.
      • Franciosi J.P.
      • Varni J.W.
      • Platts-Mills T.A.
      • Erwin E.A.
      Prospective, comparative effectiveness trial of cow's milk elimination and swallowed fluticasone for pediatric eosinophilic esophagitis.
      ), both studies might be flawed by methodological issues.
      For the first study, patients included were children with IgE-mediated cow's milk food allergy after cow's milk oral desensitization.
      • Kagalwalla A.F.
      • Amsden K.
      • Shah A.
      • Ritz S.
      • Manuel-Rubio M.
      • Dunne K.
      • et al.
      Cow's milk elimination: a novel dietary approach to treat eosinophilic esophagitis.
      Aside from not being representative of a standard population of pediatric EoE, cow's milk oral immunotherapy–induced EoE is always responsive to a cow's milk elimination diet.
      • Lucendo A.J.
      • Arias A.
      • Tenias J.M.
      Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis.
      Regarding the second study, proton pump inhibitors were given concomitantly with dietary therapy, which might have overestimated histologic remission rates. Up to 50% of pediatric and adult patients can achieve EoE remission with proton pump inhibitor monotherapy.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • von Arnim U.
      • Bredenoord A.J.
      • Bussmann C.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      Indirect estimations from 4-FEDs and 2-FEDs have shown that histologic remission with a milk elimination diet can be accomplished in 18%
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      and 25%
      • Molina-Infante J.
      • Arias A.
      • Barrio J.
      • Rodríguez-Sánchez J.
      • Sanchez-Cazalilla M.
      • Lucendo A.J.
      Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
      of adult patients, whereas these figures seem to be greater in children (33%,
      • Molina-Infante J.
      • Arias Á Alcedo J.
      • Garcia-Romero R.
      • Casabona-Frances S.
      • Prieto-Garcia A.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      56%
      • Kagalwalla A.F.
      • Wechsler J.B.
      • Amsden K.
      • Schwartz S.
      • Makhija M.
      • Olive A.
      • et al.
      Efficacy of a 4-food elimination diet for children with eosinophilic esophagitis.
      ). Prospective studies specifically designed to assess the efficacy of a milk elimination diet in children and adults are definitely warranted.

      Long-term efficacy and safety of dietary therapy

      Once food triggers responsible for EoE have been identified in each patient, long-term avoidance is advisable to maintain drug-free disease remission. Presently, we have only few short-term data on this matter. A first study in children demonstrated that after effective long-term avoidance of food triggers (of up to 4 years), all cases relapsed on rechallenge with food triggers.
      • Kagalwalla A.F.
      • Shah A.
      • Li B.U.
      • Sentongo T.A.
      • Ritz S.
      • Manuel-Rubio M.
      • et al.
      Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
      Two studies in adults have consistently reported that all compliant patients who strictly avoided a food or foods known to trigger the disease continued with clinical and histologic remission for a period of up to 3 years.
      • Gonsalves N.
      • Yang G.Y.
      • Doerfler B.
      • Ritz S.
      • Ditto A.M.
      • Hirano I.
      Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
      • Lucendo A.J.
      • Arias A.
      • Gonzalez-Cervera J.
      • Yagüe-Compadre J.L.
      • Guagnozzi D.
      • Angueira T.
      • et al.
      Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease.
      Two more recent studies in adults have confirmed that all patients who remain compliant with avoidance of the identified food triggers after an elimination diet maintain histologic remission after 1 year.
      • Philpott H.
      • Nandurkar S.
      • Royce S.G.
      • Thien F.
      • Gibson P.R.
      A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis.
      • Reed C.C.
      • Fan C.
      • Koutlas N.T.
      • Shaheen N.J.
      • Dellon E.S.
      Food elimination diets are effective for long-term treatment of adults with eosinophilic oesophagitis.
      Studies with longer follow-up of diet responders are required to clarify the role of maintenance dietary therapy in patients with EoE.
      As for safety, there are controversial data in the literature regarding the effect of elimination diets on anthropometric profiles and growth in children and adults with EoE.
      • Kliewer K.L.
      • Cassin A.M.
      • Venter C.
      Dietary therapy for eosinophilic esophagitis: elimination and reintroduction.
      It is important to stress that children with IgE-mediated food allergies, a common comorbid condition in pediatric EoE, and avoiding more than 3 food groups might be at high risk of impaired growth.
      • Kliewer K.L.
      • Cassin A.M.
      • Venter C.
      Dietary therapy for eosinophilic esophagitis: elimination and reintroduction.
      Weight loss and growth rates should be assessed before initiating any therapeutic elimination diet and closely monitored afterward. Although there are no studies available on this issue, low macronutrient (especially fats in milk- and egg- free diets and carbohydrates in milk- and wheat-free diets), low fiber (in cereal- and legume-free diets), and low micronutrient (calcium, vitamin D, B vitamins, and iodine in milk-, wheat-, and egg-free diets) intake should be assessed regularly during follow-up.
      • Kliewer K.L.
      • Cassin A.M.
      • Venter C.
      Dietary therapy for eosinophilic esophagitis: elimination and reintroduction.
      Similar to the FODMAP diet,
      • Halmos E.P.
      • Christophersen C.T.
      • Bird A.R.
      • Shepherd S.J.
      • Gibson P.R.
      • Muir J.G.
      Diets that differ in their FODMAP content alter the colonic luminal microenvironment.
      the effect of milk, wheat, and legume avoidance on intestinal microbiota as a result of reducing sources of prebiotic carbohydrates to the gut also deserves further consideration. When available, the involvement of a dietitian trained in food allergies and elimination diets used in the management of EoE should be considered an invaluable asset to manage dietary therapy.
      • Groetch M.
      • Venter C.
      • Skypala I.
      • Vlieg-Boerstra B.
      • Grimshaw K.
      • Durban R.
      • et al.
      Dietary therapy and nutrition management of eosinophilic esophagitis: a work group report of the American Academy of Allergy, Asthma, and Immunology.

      Unmet issues with dietary therapy in patients with EoE

      Numerous unsolved issues yet related to elimination diets in patients with EoE have been summarized in Table III.
      • Lucendo A.J.
      • Arias A.
      • Tenias J.M.
      Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis.
      The precise correct duration of the initial elimination diet remains unknown, but 6 weeks seems to be a minimum. Because of cross-reactivity between cow's milk and other mammalian milks or wheat and other gluten-containing grains, whether just cow's milk and wheat should be eliminated or also all potential cross-reactive foods remains debatable.
      • Kliewer K.L.
      • Venter C.
      • Cassin A.M.
      • Abonia J.P.
      • Aceves S.S.
      • Bonis P.A.
      • et al.
      Should wheat, barley, rye, and/or gluten be avoided in a 6-food elimination diet?.
      Once remission of eosinophilic inflammation is achieved with an elimination diet, individual reintroduction of food or food groups 1 at a time should be undertaken for a minimum of 6 weeks. The accurate duration of the food challenge remains unknown. Similarly, the frequency and serving size of the challenged food per week remains to be elucidated. Losing IgE tolerance to foods after elimination diets and subsequent allergic IgE-mediated reaction is a potential concern. Isolated symptoms or endoscopic signs should not guide the reintroduction process because of the poor correlation of both with histologic remission.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • von Arnim U.
      • Bredenoord A.J.
      • Bussmann C.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      Because of the lack of noninvasive biomarkers that can adequately predict the presence or absence of esophageal eosinophilic inflammation, multiple endoscopies with systematic biopsy specimens are currently mandatory to accurately identify food triggers. Acceptance of this strategy and reuptake of patients is largely conditioned by providing systematic sedation for endoscopic procedures, along with flexibility to schedule and reschedule endoscopic appointments, depending on histologic results. The long-term safety of repeated procedural sedation remains unknown.
      Table IIIUnsolved issues in dietary therapy for EoE
      Related to eliminated foods
       Cross-reactivity issuesCow's milk vs mammalian milk
      Wheat vs gluten-containing grains
      Soy vs all legumes (Mediterranean countries)
      Cross-reactivity between foods and airborne allergens
       Elimination diet durationSix, 8, 12 weeks, or beyond?
       Milk elimination dietProspective studies in children and adults are warranted
       Dependence on different patterns of food consumption across the worldShould different diets be applied according to local food consumption patterns? Will EoE food triggers be different in nonwesternized countries?
      Related to individual food reintroduction
       Need for standardization
      • Lucendo A.J.
      • Arias A.
      • Tenias J.M.
      Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis.
      Individual reintroduction one at a time
      Reintroduce all eliminated foods
      Order of reintroduction?
      Duration: 6, 8, 12 weeks, or beyond?
      A shorter timeframe if symptoms develop on food challenge?
      Washout periods after positive challenge result? For how long?
       Loss of tolerance to eliminated antigens showing high baseline IgE titersRisk of IgE-mediated allergic reactions
      Related to repeat endoscopic proceduresSafety of repeat propofol sedation
      Validation of minimally invasive procedures (String Test, Cytosponge) for food reintroduction
      Related to the development of novel food allergy testing for EoEEsophageal prick test?
      IgG4-based local methods?
      Genetic profiling?
      Related to long-term efficacyLong-term response in adherent patient
      Loss of response because of airborne allergens
      Spontaneous development of tolerance to culprit food antigens?
      Tolerance induction with baked foods?
      Related to EoE development after oral immunotherapyIndividual risk factors for having de novo EoE after oral immunotherapy
      Best option to solve EoE: eliminating the responsible food (and assuming the risk of further IgE-mediated reactions) or managing EoE with drugs?

      References

        • Liacouras C.A.
        • Furuta G.T.
        • Hirano I.
        • Atkins D.
        • Attwood S.E.
        • Bonis P.A.
        • et al.
        Eosinophilic esophagitis: updated consensus recommendations for children and adults.
        J Allergy Clin Immunol. 2011; 128: 3-20
        • Attwood S.E.
        • Smyrk T.C.
        • Demeester T.R.
        • Jones J.B.
        Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome.
        Dig Dis Sci. 1993; 38: 109-116
        • Lucendo A.J.
        • Molina-Infante J.
        • Arias Á.
        • von Arnim U.
        • Bredenoord A.J.
        • Bussmann C.
        • et al.
        Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
        Gastroenterol J. 2017; 5: 335-358
        • Kelly K.J.
        • Lazenby A.J.
        • Rowe P.C.
        • Yardley J.H.
        • Perman J.A.
        • Sampson H.A.
        Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.
        Gastroenterology. 1995; 109: 1503-1512
        • Molina-Infante J.
        • Gonzalez-Cordero P.L.
        • Arias A.
        • Lucendo A.J.
        Update on dietary therapy for eosinophilic esophagitis in children and adults.
        Expert Rev Gastroenterol Hepatol. 2017; 11: 115-123
        • O'Shea K.M.
        • Aceves S.S.
        • Dellon E.S.
        • Gupta S.K.
        • Spergel J.M.
        • Furuta G.T.
        • et al.
        Pathophysiology of eosinophilic esophagitis.
        Gastroenterology. 2018; 154: 333-345
        • Arias A.
        • Gonzalez-Cervera J.
        • Tenias J.M.
        • Lucendo A.J.
        Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
        Gastroenterology. 2014; 146: 1639-1648
        • Peterson K.A.
        • Byrne K.R.
        • Vinson L.A.
        • Ying J.
        • Boynton K.K.
        • Fang J.C.
        • et al.
        Elemental diet induces histologic response in adult eosinophilic esophagitis.
        Am J Gastroenterol. 2013; 108: 759-766
        • Warners M.J.
        • Vlieg-Boerstra B.J.
        • Verheij J.
        • van Hamersveld P.H.P.
        • van Rhijn B.D.
        • Van Ampting M.T.J.
        • et al.
        Elemental diet decreases inflammation and improves symptoms in adult eosinophilic oesophagitis patients.
        Aliment Pharmacol Ther. 2017; 45: 777-787
        • Delaney A.L.
        • Arvedson J.C.
        Development of swallowing and feeding: prenatal through first year of life.
        Dev Disabil Res Rev. 2008; 14: 105-117
        • Spergel J.M.
        • Beausoleil J.L.
        • Mascarenhas M.
        • Liacouras C.A.
        The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis.
        J Allergy Clin Immunol. 2002; 109: 363-368
        • Spergel J.M.
        • Brown-Whitehorn T.F.
        • Cianferoni A.
        • Shuker M.
        • Wang M.L.
        • Verma R.
        • et al.
        Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.
        J Allergy Clin Immunol. 2012; 130: 461-467
        • Henderson C.J.
        • Abonia J.P.
        • King E.C.
        • Putnam P.E.
        • Collins M.H.
        • Franciosi J.P.
        • et al.
        Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.
        J Allergy Clin Immunol. 2012; 129: 1570-1578
        • Molina-Infante J.
        • Martin-Noguerol E.
        • Alvarado-Arenas M.
        • Porcel-Carreño S.L.
        • Jimenez-Timon S.
        • Hernandez-Arbeiza F.J.
        Selective elimination diet based on skin testing has suboptimal efficacy for adult eosinophilic esophagitis.
        J Allergy Clin Immunol. 2012; 130: 1200-1202
        • Wolf W.A.
        • Jerath M.R.
        • Sperry S.L.W.
        • Shaheen N.J.
        • Dellon E.S.
        Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2014; 12: 1272-1279
        • van Rhijn B.D.
        • Vlieg-Boerstra B.J.
        • Versteeg S.A.
        • Akkerdaas J.H.
        • van Ree R.
        • Terreehorst I.
        • et al.
        Evaluation of allergen-microarray-guided dietary intervention as treatment of eosinophilic esophagitis.
        J Allergy Clin Immunol. 2015; 136: 1095-1097
        • Philpott H.
        • Nandurkar S.
        • Royce S.G.
        • Thien F.
        • Gibson P.R.
        Allergy tests do not predict food triggers in adult patients with eosinophilic oesophagitis. A comprehensive prospective study using five modalities.
        Aliment Pharmacol Ther. 2016; 44: 223-233
        • Clayton F.
        • Fang J.C.
        • Gleich G.J.
        • Lucendo A.J.
        • Olalla J.M.
        • Vinson L.A.
        • et al.
        Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE.
        Gastroenterology. 2014; 147: 602-609
        • Simon D.
        • Cianferoni A.
        • Spergel J.M.
        • Aceves S.
        • Holbreich M.
        • Venter C.
        • et al.
        Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity.
        Allergy. 2016; 71: 611-620
        • Wright B.L.
        • Kulis M.
        • Guo R.
        • Orgel K.A.
        • Wolf W.A.
        • Burks A.W.
        • et al.
        Food-specific IgG4 is associated with eosinophilic esophagitis.
        J Allergy Clin Immunol. 2016; 138: 1190-1192
        • Warners M.J.
        • Terreehorst I.
        • van den Wijngaard R.M.
        • Akkerdaas J.
        • van Esch B.C.A.M.
        • van Ree R.
        • et al.
        Abnormal responses to local esophageal food allergen injections in adult patients with eosinophilic esophagitis.
        Gastroenterology. 2018; 154: 57-60.e2
        • Kagalwalla A.F.
        • Sentongo T.A.
        • Ritz S.
        • Hess T.
        • Nelson S.P.
        • Emerick K.M.
        • et al.
        Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2006; 4: 1097-1102
        • Kagalwalla A.F.
        • Shah A.
        • Li B.U.
        • Sentongo T.A.
        • Ritz S.
        • Manuel-Rubio M.
        • et al.
        Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
        J Pediatr Gastroenterol Nutr. 2011; 53: 145-149
        • Gonsalves N.
        • Yang G.Y.
        • Doerfler B.
        • Ritz S.
        • Ditto A.M.
        • Hirano I.
        Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
        Gastroenterology. 2012; 142: 1451-1455
        • Lucendo A.J.
        • Arias A.
        • Gonzalez-Cervera J.
        • Yagüe-Compadre J.L.
        • Guagnozzi D.
        • Angueira T.
        • et al.
        Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease.
        J Allergy Clin Immunol. 2013; 131: 797-804
        • Rodríguez-Sánchez J.
        • Gómez Torrijos E.
        • López Viedma B.
        • de la Santa Belda E.
        • Martín Dávila F.
        • García Rodríguez C.
        • et al.
        Efficacy of IgE-targeted vs empiric six-food elimination diets for adult eosinophilic oesophagitis.
        Allergy. 2014; 69: 936-942
        • Philpott H.
        • Nandurkar S.
        • Royce S.G.
        • Thien F.
        • Gibson P.R.
        A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis.
        Aliment Pharmacol Ther. 2016; 43: 985-993
        • Molina-Infante J.
        • Arias A.
        • Barrio J.
        • Rodríguez-Sánchez J.
        • Sanchez-Cazalilla M.
        • Lucendo A.J.
        Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
        J Allergy Clin Immunol. 2014; 134: 1093-1099.e1
        • Kagalwalla A.F.
        • Wechsler J.B.
        • Amsden K.
        • Schwartz S.
        • Makhija M.
        • Olive A.
        • et al.
        Efficacy of a 4-food elimination diet for children with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2017; 15: 1698-1707
        • Molina-Infante J.
        • Arias Á Alcedo J.
        • Garcia-Romero R.
        • Casabona-Frances S.
        • Prieto-Garcia A.
        • et al.
        Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
        J Allergy Clin Immunol. 2017; ([Epub ahead of print])
        • Kagalwalla A.F.
        • Amsden K.
        • Shah A.
        • Ritz S.
        • Manuel-Rubio M.
        • Dunne K.
        • et al.
        Cow's milk elimination: a novel dietary approach to treat eosinophilic esophagitis.
        J Pediatr Gastroenterol Nutr. 2012; 55: 711-716
        • Kruszewski P.G.
        • Russo J.M.
        • Franciosi J.P.
        • Varni J.W.
        • Platts-Mills T.A.
        • Erwin E.A.
        Prospective, comparative effectiveness trial of cow's milk elimination and swallowed fluticasone for pediatric eosinophilic esophagitis.
        Dis Esophagus. 2016; 29: 377-384
        • Lucendo A.J.
        • Arias A.
        • Tenias J.M.
        Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis.
        Ann Allergy Asthma Immunol. 2014; 113: 624-629
        • Reed C.C.
        • Fan C.
        • Koutlas N.T.
        • Shaheen N.J.
        • Dellon E.S.
        Food elimination diets are effective for long-term treatment of adults with eosinophilic oesophagitis.
        Aliment Pharmacol Ther. 2017; 46: 836-844
        • Kliewer K.L.
        • Cassin A.M.
        • Venter C.
        Dietary therapy for eosinophilic esophagitis: elimination and reintroduction.
        Clin Rev Allergy Immunol. 2017; ([Epub ahead of print])
        • Halmos E.P.
        • Christophersen C.T.
        • Bird A.R.
        • Shepherd S.J.
        • Gibson P.R.
        • Muir J.G.
        Diets that differ in their FODMAP content alter the colonic luminal microenvironment.
        Gut. 2015; 64: 93-100
        • Groetch M.
        • Venter C.
        • Skypala I.
        • Vlieg-Boerstra B.
        • Grimshaw K.
        • Durban R.
        • et al.
        Dietary therapy and nutrition management of eosinophilic esophagitis: a work group report of the American Academy of Allergy, Asthma, and Immunology.
        J Allergy Clin Immunol Pract. 2017; 5: 312-324.e29
        • Kliewer K.L.
        • Venter C.
        • Cassin A.M.
        • Abonia J.P.
        • Aceves S.S.
        • Bonis P.A.
        • et al.
        Should wheat, barley, rye, and/or gluten be avoided in a 6-food elimination diet?.
        J Allergy Clin Immunol. 2016; 137: 1011-1014