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Efficacy of a 4-Food Elimination Diet for Children With Eosinophilic Esophagitis

  • Amir F. Kagalwalla
    Correspondence
    Reprint requests Address requests for reprints to: Amir F. Kagalwalla, MBBS, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois 60611-2991. fax: 312-227-9645.
    Affiliations
    Northwestern University Feinberg School of Medicine, Chicago, Illinois

    Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois

    John H Stroger Hospital of Cook County, Chicago, Illinois
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  • Joshua B. Wechsler
    Affiliations
    Northwestern University Feinberg School of Medicine, Chicago, Illinois

    Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Katie Amsden
    Affiliations
    Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Sally Schwartz
    Affiliations
    Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Melanie Makhija
    Affiliations
    Northwestern University Feinberg School of Medicine, Chicago, Illinois

    Division of Allergy & Clinical Immunology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Anthony Olive
    Affiliations
    Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
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  • Carla M. Davis
    Affiliations
    Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
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  • Maria Manuel-Rubio
    Affiliations
    Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Seth Marcus
    Affiliations
    GI Care for Kids, Atlanta, Georgia
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  • Ronda Shaykin
    Affiliations
    Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Maureen Sulkowski
    Affiliations
    Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Kristen Johnson
    Affiliations
    Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Jessica N. Ross
    Affiliations
    Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Mary Ellen Riffle
    Affiliations
    Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York City, New York
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  • Marion Groetch
    Affiliations
    Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York City, New York
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  • Hector Melin-Aldana
    Affiliations
    Northwestern University Feinberg School of Medicine, Chicago, Illinois

    Department of Pathology and Laboratory Medicine, Ann & Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Deborah Schady
    Affiliations
    Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
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  • Hannah Palac
    Affiliations
    Department of Preventive Medicine, Feinberg School of Medicine, Chicago, Illinois
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  • Kwan-Youn A. Kim
    Affiliations
    Department of Preventive Medicine, Feinberg School of Medicine, Chicago, Illinois
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  • Barry K. Wershil
    Affiliations
    Northwestern University Feinberg School of Medicine, Chicago, Illinois

    Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
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  • Margaret H. Collins
    Affiliations
    Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio
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  • Mirna Chehade
    Affiliations
    Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York City, New York
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      Background & Aims

      A 6-food elimination diet induces remission in most children and adults with eosinophilic esophagitis (EoE). The effectiveness of empiric elimination of only 4 foods has not been studied in children. We performed a prospective observational outcome study in children with EoE treated with dietary exclusion of cow's milk, wheat, egg, and soy. The objective was to assess the clinical, endoscopic, and histologic efficacy of this treatment in EoE.

      Methods

      We recruited children (1–18 years old, diagnosed per consensus guidelines) from 4 medical centers. Study participants (n = 78) were given a proton pump inhibitor twice daily and underwent a baseline esophagogastroduodenoscopy. Subjects were instructed on dietary exclusion of cow's milk, wheat, egg, and soy. Clinical, endoscopic, and histologic assessments were made after 8 weeks. Responders had single foods reintroduced for 8 weeks, with repeat endoscopy to assess for recurrence of active disease. The primary endpoint was histologic remission (fewer than 15 eosinophils per high-powered field). Secondary endpoints included symptom and endoscopic improvements and identification of foods associated with active histologic disease.

      Results

      After 8 weeks on 4-food elimination diet, 50 subjects were in histologic remission (64%). The subjects' mean baseline clinical symptoms score was 4.5, which decreased to 2.3 after 8 weeks of 4-food elimination diet (P < .001). The mean endoscopic baseline score was 2.1, which decreased to 1.3 (P < .001). After food reintroduction, the most common food triggers that induced histologic inflammation were cow's milk (85%), egg (35%), wheat (33%), and soy (19%). One food trigger that induced recurrence of esophageal inflammation was identified in 62% of patients and cow's milk–induced EoE was present in 88% of these patients.

      Conclusions

      In a prospective study of children with EoE, 8 weeks of 4-food elimination diet induced clinical, endoscopic, and histologic remission in more than 60% of children with EoE. Although less restrictive than 6-food elimination diet, 4-food elimination diet was nearly as effective, and can be recommended as a treatment for children with EoE.

      Keywords

      Abbreviations used in this paper:

      BMI (body mass index), CI (confidence interval), EGD (esophagogastroduodenoscopy), EoE (eosinophilic esophagitis), eos/hpf (eosinophils per high power field), FFED (4-food elimination diet), OR (odds ratio), SFED (6-food elimination diet), sIgE (serum-specific IgE), SPT (skin prick test)
      See editorial on page 1668.
      Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory disease of the esophagus characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation.
      • Furuta G.T.
      • Katzka D.A.
      Eosinophilic esophagitis.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      Kelly et al
      • Kelly K.J.
      • Lazenby A.J.
      • Rowe P.C.
      • et al.
      Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.
      demonstrated clinical and histologic remission in children with isolated esophageal eosinophilia when treated with an exclusive amino-acid-based formulation. Reintroduction of incriminating foods resulted in recurrence, thereby establishing that EoE is triggered by food antigen. Six-food elimination diet (SFED) excluding cow's milk, wheat, egg, soy, peanut/tree nut, and fish/shell-fish demonstrated clinical and histologic remission in 74% of children.
      • Kagalwalla A.F.
      • Sentongo T.A.
      • Ritz S.
      • et al.
      Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.
      Other retrospective pediatric and prospective and retrospective adult studies showed remission in 58%–81% of children and adults treated with SFED.
      • Henderson C.J.
      • Abonia J.P.
      • King E.C.
      • et al.
      Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.
      • Spergel J.M.
      • Brown-Whitehorn T.F.
      • Cianferoni A.
      • et al.
      Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.
      • Gonsalves N.
      • Yang G.Y.
      • Doerfler B.
      • et al.
      Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
      • Lucendo A.J.
      • Arias A.
      • Gonzalez-Cervera J.
      • 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.
      • Wolf W.A.
      • Jerath M.R.
      • Sperry S.L.
      • et al.
      Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis.
      • Rodriguez-Sanchez J.
      • Gomez Torrijos E.
      • Lopez Viedma B.
      • et al.
      Efficacy of IgE-targeted vs empiric six-food elimination diets for adult eosinophilic oesophagitis.
      Cow's milk, wheat, egg, and soy were identified as the 4 foods most likely causing inflammation in EoE.
      • Henderson C.J.
      • Abonia J.P.
      • King E.C.
      • et al.
      Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.
      • Spergel J.M.
      • Brown-Whitehorn T.F.
      • Cianferoni A.
      • et al.
      Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.
      • Kagalwalla A.F.
      • Shah A.
      • Li B.U.
      • et al.
      Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
      A recently published 4 food group elimination diet study in Spanish subjects demonstrated remission in 54% adults.
      • Molina-Infante J.
      • Arias A.
      • Barrio J.
      • et al.
      Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
      We investigated whether excluding fewer foods is effective in inducing clinical, endoscopic, and histologic remission. We also wanted to identify the frequency of specific EoE trigger foods.

      Materials and Methods

      The institutional review board approved this study at each of the following participating institutions: Lurie Children's Hospital of Chicago, Chicago, Illinois; Mount Sinai Medical Center, New York, New York; Texas Children's Hospital, Houston, Texas; and GI Care for Kids, Atlanta, Georgia. Parents or legal guardians provided written informed consent for participation. All investigators followed the same protocol detailing the study's design, inclusion criteria, endoscopic grading, allergy testing, and treatment endpoints. A manual of operations and 4-food elimination diet (FFED) patient handouts were developed and shared by all the centers. Subjects were recruited from outpatient gastroenterology clinics at the participating institutions. EoE cases, aged 1–18 years, were diagnosed per consensus guidelines,
      • Furuta G.T.
      • Katzka D.A.
      Eosinophilic esophagitis.
      which included symptoms of esophageal dysfunction, and the presence of ≥15 eosinophils per high power field (eos/hpf) in esophageal biopsies. Subjects were treated with twice-daily proton pump inhibitor for 8 weeks followed by baseline diagnostic esophagogastroduodenoscopy (EGD), and only those who demonstrated persistent esophageal eosinophilia were included in the study. Subjects previously treated with topical steroids underwent a baseline EGD off steroids for 3 months and were included on demonstrating esophageal eosinophilia. After diagnostic EGD, all subjects continued proton pump inhibitor once daily for the remainder of the study to treat comorbid gastroesophageal reflux disease and limit proton pump inhibitor as a confounder between patients throughout the study. All EGD were performed under general anesthesia. Other medications for the treatment of asthma and allergic rhinitis including nasal steroids were continued unchanged throughout the study. Patients on systemic or topical steroids or those with eosinophilic gastroenteritis and eosinophilic colitis were excluded from the study, as were patients with celiac disease, and inflammatory bowel disease.

       Study Endpoints

      The primary study treatment endpoint was histologic remission with eosinophil count <15 eos/hpf. Secondary endpoints included symptomatic and endoscopic improvement and identification of specific food triggers.

       Allergy Testing

      Food-specific serum-specific IgE (sIgE) ImmunoCAP testing and skin prick testing (SPT) to cow's milk, wheat, egg, and soy was performed. Positive tests were defined as sIgE >0.35 KU/L and SPT >3 mm maximal wheal diameter.

       Study Design

      A dietitian instructed both parents and patients on proper food elimination, food label reading, appropriate food substitution, and avoiding cross contact with eliminated foods per protocol as shown in Supplementary Tables 1 and 2. The dietitian's contact information was provided to address concerns about implementing the elimination diet. The dietitian also reviewed a 3-day pretreatment diet log to assess the pretreatment diet to provide guidance about food substitutions when the 4 foods were excluded. Identification of contamination resulted in removing the contamination and delaying the posttreatment EGD by an additional 4 weeks.
      Four foods were eliminated and endoscopic biopsies were performed 8 weeks after the elimination diet to assess histologic response. In responders defined as those who achieved <15 eos/hpf, eliminated foods were reintroduced. Single foods were introduced sequentially in the same order starting with soy, then egg, followed by wheat, and finally milk, with EGD performed at least 8 weeks after every new food reintroduction. Immediate hypersensitivity-inducing food was not introduced, moving instead to the next food in the protocol. If the reintroduced food did not result in the recurrence of eosinophilia (<15 eos/hpf) it was kept in the diet and the next food was reintroduced. A trigger food was identified by the recurrence of inflammation (≥15 eos/hpf) with food reintroduction. The identified trigger food was again removed from the diet. Eight weeks after eliminating the trigger food repeat normal (<15 eos/hpf) baseline EGD (defined as washout period) was performed. The next food was introduced after the washout EGD, and this study design is illustrated in Figure 1.
      Figure thumbnail gr1
      Figure 1Diagram outlining the order of food reintroduction in responders. Single foods reintroduced every 8 weeks in 4-FED responders starting with soy, egg, wheat, and milk. Inflammation-inducing trigger foods removed followed by a normal baseline EGD demonstrating remission of inflammation before the next food reintroduction. 4-FED, 4-food elimination diet.
      Demographics and atopic medical history was collected at the time of recruitment. The presence of IgE-mediated food allergy was determined from history of immediate reaction to specific foods confirmed with food-specific allergy testing (IgE or SPT).

       Symptom Data Collection

      Parents and subjects completed nonvalidated 17-question symptom instrument at the time of study entry (baseline) and at the time of each subsequent EGD. The 17 symptoms in the instrument are listed in Table 1. Each symptom was scored absent (0) or present (+1). The total symptom score was determined by adding the individual patient symptom scores.
      Table 1Baseline Demographic, Clinical, and Histologic Characteristics of All Subjects Who Underwent FFED
      VariableN (%)P value
      Patients completing the FFED

      n = 78
      Responders

      n = 50 (64%)
      Nonresponders

      n = 28 (36%)
      Age, y, mean ± SD9.01 ± 4.889.21 ± 4.98.66 ± 4.92.6376
      Gender, n (%)
       Male52 (66.67)29 (58)23 (82.14).0300
      P values < .05 were considered statistically significant.
       Female26 (33.33)21 (42)5 (17.86)
      White, n (%)65 (83.33)39 (78)26 (92.86).1194
      Presenting symptoms, n (%)
       Abdominal pain39 (50)25 (50)14 (50).9999
       Slow eating33 (42.31)21 (42)12 (42.86).9414
       Early satiety32 (41.03)21 (42)11 (39.29).8152
       Dysphagia27 (34.62)15 (30)12 (42.86).2522
       Vomiting24 (30.77)15 (30)9 (32.14).8441
       Poor appetite25 (32.05)16 (32)9 (32.14).9897
       Feeding difficulties21 (26.92)12 (24)9 (32.14).4367
       Regurgitation20 (25.64)12 (24)8 (28.57).6574
       Poor weight gain18 (23.08)12 (24)6 (21.43).7960
       Food impaction19 (24.36)14 (28)5 (17.86).3168
       Nausea18 (23.08)9 (18)9 (32.14).1550
       Pocketing food/spitting after chewing18 (23.08)12 (24)6 (21.43).7960
       Gagging/choking18 (23.08)13 (26)5 (17.86).4129
       Heartburn10 (12.82)5 (10)5 (17.86).4814
       Chest pain12 (15.38)6 (12)6 (21.43).3319
       Odynophagia8 (10.26)4 (8)4 (14.29).4478
       Nocturnal awakening caused by symptoms8 (10.26)5 (10)3 (10.71).9999
      Atopy, n (%)
       Eczema32 (41.03)20 (40)12 (42.86).8056
       IgE-mediated food allergy (n = 77)24 (31.17)12 (24.49)12 (42.86).0942
       Asthma22 (28.21)18 (36)4 (14.29).0409
      P values < .05 were considered statistically significant.
       Allergic conjunctivitis14 (17.95)10 (20)4 (14.29).5281
       Allergic rhinitis46 (58.97)29 (58)17 (60.71).8152
      Family history (n = 77) , n (%)
       Rhinitis55 (71.43)32 (65.31)23 (82.14).1157
       Asthma40 (51.95)22 (44.9)18 (64.29).1014
       GERD41 (53.25)26 (53.06)15 (53.57).9656
       Food allergy34 (44.16)15 (30.61)19 (67.86).0015
      P values < .05 were considered statistically significant.
       Eczema31 (40.26)18 (36.73)13 (46.43).4041
       Hiatal hernia17 (22.08)9 (18.37)8 (28.57).2990
       EoE11 (14.29)6 (12.24)5 (17.86).5157
       Stricture9 (11.69)6 (12.24)3 (10.71).9999
       Celiac4 (5.19)4 (8.16)0 (0).2903
       Recurrent vomiting4 (5.19)1 (2.04)3 (10.71).1337
      Common food allergens on skin prick test, n (%)
       Egg (n = 54)18 (33.33)10 (27.03)8 (47.06).1470
       Milk (n = 55)13 (23.64)9 (24.32)4 (22.22).9999
       Soy (n = 54)21 (38.89)12 (33.33)9 (50).2363
       Wheat (n = 53)11 (20.75)8 (22.22)3 (17.65).9999
      Food sensitization on serum-specific IgE test, n (%)
       Egg (n = 53)24 (45.28)11 (29.73)13 (81.25).0005
      P values < .05 were considered statistically significant.
       Milk (n = 56)31 (55.36)18 (47.37)13 (72.22).0806
       Soy (n = 55)21 (38.18)10 (26.32)11 (64.71).0068
      P values < .05 were considered statistically significant.
       Wheat (n = 53)24 (45.28)13 (34.21)11 (73.33).0100
      P values < .05 were considered statistically significant.
      Endoscopy visual findings, n (%)
       Furrows (n = 76)56 (73.68)34 (70.83)22 (78.57).4599
       Edema (n = 75)53 (70.67)32 (66.67)21 (77.78).3104
       Exudates (n = 76)41 (53.95)24 (50)17 (60.71).3660
       Rings (n = 76)9 (11.84)5 (10.42)4 (14.29).7178
       Strictures (n = 76)1 (1.32)0 (0)1 (3.57).3684
      Baseline peak eosinophil count, median (IQR)60 (40–100)52.5 (40–85)80 (48–100).1211
      Posttreatment peak eosinophil count, median (IQR)8 (3–40)5 (1–8)51 (35.5–90)<.0001
      P values < .05 were considered statistically significant.
      NOTE. Chi-square and Fisher exact tests were used to assess differences in response groups for categorical variables. A 2-sample t-test was used to compare age between groups, and the nonparametric Wilcoxon rank sum test was used to compare baseline peak EOS and posttreatment EOS.
      EoE, eosinophilic esophagitis; FFED, 4-food elimination diet; GERD, gastroesophageal reflux disease; IQR, interquartile range.
      a P values < .05 were considered statistically significant.

       Endoscopic Findings

      Endoscopic features including edema, rings, white plaques, linear furrows, and strictures were scored absent (0) or present (+1). The total (composite) endoscopic score was derived by adding the component scores for individual findings. The total scores ranged from 0 to 5.

       Histologic Analysis

      Four biopsy samples for histologic assessment were obtained from 2 different levels of the esophagus. Eosinophils were reported as peak eosinophil counts/hpf from the densest areas of the esophagus. Presence of basal cell hyperplasia was also described. Gastric and duodenal biopsies were also obtained. Pathologists reviewed the biopsies at each of the participating institutions, and their assessment was used to define remission or identify trigger foods. The study's central pathologist (MHC) provided oversight by reviewing random biopsies from participating institutions. There was no interobserver variability, and interobserver consistency was identified between the participating pathologists and the central pathologist. Eosinophil count was assessed at high power magnification ×400 hpf (0.23 mm2). The cutoff value of 15 eos/hpf was used to evaluate remission.

       Anthropometric Measurements

      The z scores for weight, height, and body mass index (BMI) at baseline and each subsequent EGD were determined using the SAS program for CDC 2000 growth charts (SAS Institute, Cary, NC) (2 to <20 years).

       Statistical Analysis

      Changes in peak eos/hpf before and after FFED were evaluated using a 2-sided paired t-test. Differences in baseline characteristics between treatment responders and nonresponders were assessed using a 2-sample Student t test, the Wilcoxon rank sum test, or the chi-square/Fisher exact tests. Association between demographic and clinical characteristics of interest and treatment response was tested with logistic regression. The area under the curve of the receiver operating characteristic curve was calculated to assess the predictive value for the final model. Pairwise comparisons for each pair of geographic regions explored for significant omnibus test using 2-sample Student t tests, Wilcoxon rank sum tests, chi-square, or Fisher exact tests as appropriate using Bonferroni corrections. Sensitivity, specificity, negative predictive value, and positive predictive value were calculated for each food to evaluate the validity of SPT and serum sIgE allergy test compared with FFED-identified trigger foods. Changes in standardized height, weight, and BMI z scores was assessed between responders and nonresponders using 2-sample Student t tests. All statistical analyses were performed using SAS version 9.4 (SAS Institute). Unless otherwise specified, alpha = 0.05 was used to determine statistical significance.

      Results

       Patients

      Between 2011 and 2016, a total of 96 children consented to participate and of these 18 were excluded: 5 left prior to starting the diet, 8 found the diet too difficult, 1 dropped out for insurance reasons, 1 was lost to follow up and 3 did not meet the inclusion criteria (Figure 2). All 78 subjects (67% male, mean age 9.01, 83% white, 90% atopic) who met inclusion criteria were incident cases, except for 3 who had been previously treated with topical steroids, and are the basis of this study Table 1.
      Figure thumbnail gr2
      Figure 2Diagram of patient flow. Ninety-six patients were screened for the study; 18 were excluded and 78 underwent upper endoscopy with biopsies after 4-FED. Fifty demonstrated histologic remission. 4-FED, 4-food elimination diet.

       Histologic, Clinical, and Endoscopic Responses

      Histologic remission was achieved in 50 of 78 (64%) subjects. The peak eosinophil count in the proximal esophagus decreased from 43 ± 32 and 3 ± 3 per hpf and in the distal esophagus decreased from 55 ± 34 to 4 ± 4 per hpf with FFED treatment. Basal cell hyperplasia resolved in 36% of the responders (P < .001) and persisted in all the nonresponders. Food contamination was not identified in any patients before the scheduled post-4-food elimination EGD.
      All symptoms resolved in 36% of respondents and symptom score decreased in 91%. The mean baseline symptom score decreased from 4.5 to 2.3 in responders (P < .001). Table 2 shows specific symptoms that resolved in a significant number of FFED treatment responders: abdominal pain (P < .05), poor appetite (P = .01), vomiting (P = .01), food impaction (P < .05), choking/gagging (P = .01), regurgitation (P = .01), pocket/spit out food (P = .01). Interestingly nonresponders had resolution of chest pain (P < .05) and atypical symptoms, such as early satiety (P < .05), and nausea (P = .5).
      Table 2Histologic, Endoscopic, and Symptomatic Response to FFED in Responders and Nonresponders
      HistologyResponders (n = 50)Nonresponders (n = 28)
      Pre

      Mean (SD)
      Post

      Mean (SD)
      P valuePre

      Mean (SD)
      Post

      Mean (SD)
      P value
      Peak eos/hpf62.0 (33.7)5.0 (4.1)< .001
      P < .05.
      74.4 (36.4)62.1 (31.6).15
      Distal eos/hpf55.9 (33.9)4.1 (3.9)< .001
      P < .05.
      58.3 (37.6)51.5 (30.1).48
      Proximal eos/hpf43.9 (32.4)2.6 (3.3)< .001
      P < .05.
      63.7 (36.7)44.8 (33.1).03
      P < .05.
      Visual findingsCount (%)Count (%)P valueCount (%)Count (%)P value
      Furrow34 (71)17 (35)< .001
      P < .05.
      22 (79)23 (82)1.00
      Edema32 (67)12 (25)< .001
      P < .05.
      21 (75)20 (74)1.00
      Exudate24 (50)1 (2)< .001
      P < .05.
      17 (61)17 (61)1.00
      Rings5 (10)6 (12)1.004 (14)4 (14)1.00
      Stricture0 (0)0 (0)1 (4)0 (0)
      SymptomsCount (%)Count (%)P valueCount (%)Count (%)P value
      Abdominal pain25 (50)15 (30).03
      P < .05.
      14 (50)11 (39).58
      Slow eating21 (42)18 (36).5512 (43)6 (21).08
      Early satiety21 (42)13 (26).0611 (39)5 (18).04
      P < .05.
      Poor appetite16 (32)5 (10).01
      P < .05.
      9 (32)5 (18).34
      Dysphagia15 (30)11 (22).4512 (43)9 (32).58
      Vomiting15 (30)4 (8).01
      P < .05.
      9 (32)6 (21).55
      Food impaction14 (28)5 (10).04
      P < .05.
      5 (18)3 (11).68
      Gagging/choking13 (26)3 (6).01
      P < .05.
      5 (18)4 (14)1.00
      Regurgitation12 (24)2 (4).01
      P < .05.
      8 (29)2 (7).08
      Poor weight gain12 (24)5 (10).076 (21)2 (7).13
      Pockets/spits after chewing12 (24)1 (2).01
      P < .05.
      6 (21)2 (7).13
      Feeding difficulties12 (24)5 (10).129 (32)5 (18).29
      Nausea9 (18)7 (14).779 (32)2 (7).05
      P < .05.
      Chest pain6 (12)4 (8).686 (21)0 (0).04
      P < .05.
      Heartburn5 (10)5 (10)1.005 (18)3 (11).68
      Nocturnal awakening5 (10)1 (2).133 (11)1 (4).48
      Odynophagia4 (8)5 (10)1.004 (14)1 (4).37
      FFED, 4-food elimination diet.
      a P < .05.
      The mean endoscopic baseline score decreased from 2.1 to 1.3 (P < .001) in the responders. The changes in specific endoscopic findings are shown in Table 2. Exudates resolved in 96% respondents (P < .001). Edema resolved in 66% (P < .001) and furrows in 62% (P < .001). Rings persisted in all subjects who had them at baseline.
      Mean weight and BMI z scores in responders decreased 0.2 ± 0.43 and 0.31 ± −0.56, respectively, from baseline values. On completion of food reintroduction process weight and BMI z scores showed increase from baseline scores.
      Baseline characteristics of patients showed no differences between responders and nonresponders regarding demographics, symptoms, endoscopic findings, and eosinophilic density in biopsies but there were more female responders (P = .003); more responders with asthma (P = .041); higher proportion with family history of allergy in nonresponders (P = .002); and higher proportion of nonresponders with food-specific IgE sensitization to wheat (P = .010), egg (P = .001), and soy (P = .007). At baseline all included subjects consumed all 4 foods except 5 subjects with anaphylactic food allergies who avoided milk (1), egg (3), and/or soy (1). These foods were not reintroduced during the reintroduction phase.
      Forty-seven subjects reintroduced between 1 and 4 foods, and the distribution of the trigger foods in these subjects is shown in Figure 3A. Twenty-five of the 47 subjects were challenged with all foods except foods avoided at baseline (2 egg, 1 soy). Distribution of specific food triggers in these 25 subjects is shown in Figure 3B. In this group of 25 the distribution of the number of identified food triggers is shown in Figure 3C. From responders who introduced all foods single food trigger was identified in 16 patients and included 14 (88%) to cow's milk, and 1 each to soy (6%) and wheat (6%). Two patients reintroduced all 4 foods without reactivity.
      Figure thumbnail gr3
      Figure 3Food triggers identified in subjects reintroducing between 1 and 4 foods in the diet and in those who reintroduced all foods back. (A) Food triggers in patients who reintroduced 1–4 foods. (B) Food triggers in 25 patients who completed reintroduction of all foods. This included 3 subjects with anaphylaxis to egg (2) and soy (1) who did not reintroduce these foods in their diet. (C) Distribution by number of food triggers in 25 who reintroduced all foods.
      Because histologic, symptom, and endoscopic scores decreased after treatment the correlation between histology, symptoms, and endoscopic and weight z scores was analyzed at multiple time points that included baseline, after FFED, and after each food reintroduction as shown in Figure 4.
      Figure thumbnail gr4
      Figure 4Comparison of histology with symptom response, endoscopic findings, and weight z scores. (A) Eosinophil counts at 6 different time points: baseline; post-4-FED; and after introduction of soy, wheat, egg, and milk. (B) Symptom scores at 6 different time points: baseline; post-4-FED; and after introduction of soy, wheat, egg, and milk. (C) Endoscopic scores at 6 different time points: baseline; post-4-FED; and after soy, wheat, egg, and milk. (D) Weight z scores at 6 different time points: baseline; post-4-FED; and after soy, wheat, egg, and milk. 4-FED, 4-food elimination diet; EREFS, Edema Rings Exudate Furrowing Stricture.
      The utility of specific sIgE and SPT testing to identify EoE food triggers was assessed in treatment responders. Sensitivity, specificity, negative predictive value, and positive predictive value were calculated to cow's milk, wheat, egg, and soy, and the results suggest that serum sIgE and SPT are not useful in identifying EoE food triggers (Supplementary Table 3). More responders had posttreatment EGD performed during the pollen season than the nonresponders (70% vs 50%; P = .09). Thus, pollen season did not influence the responses.
      Family history of food allergy (odds ratio [OR], 0.21; 95% confidence interval [CI], 0.05–0.90) and positive serum sIgE test to any of the 4 foods (OR, 0.15; 95% CI, 0.03–0.90) were significantly associated with treatment nonresponse. Gender (OR, 1.64; 95% CI, 0.31–8.73) and asthma (OR, 4.89; 95% CI, 0.88–27.23) were not statistically associated with treatment response in the multivariable model. The area under the curve of the final model, which included asthma, family history of food allergy, and positive serum sIgE to any of the 4 foods, was 0.80 (95% CI, 0.67–0.93), shown in Supplementary Figure 1.
      Demographic, clinical, allergy testing, endoscopic, and histologic characteristics in the 3 different regions is shown in Supplementary Table 4. A higher proportion of subjects from the East Coast had IgE-mediated food allergy (P = .027), exudates (P = .001), and a strong family history of eczema (P = .014) compared with the Midwest or South.

      Discussion

      This study demonstrates that exclusion of milk, wheat, egg, and soy for 8 weeks induces clinical, endoscopic, and histologic remission in most children with EoE. This is the largest prospective, multicentered outcome study to date evaluating the efficacy of an empiric elimination diet for the treatment of EoE in children or adults. It is additionally the first prospective elimination diet study conducted in children with EoE.
      Cow’s milk was the most common food trigger identified in 85% of patients, followed by egg (in 35% of patients), wheat (in 33% of patients), and soy (in 19% of patients) with the frequency of trigger foods that is identical to the SFED study.
      • Kagalwalla A.F.
      • Shah A.
      • Li B.U.
      • et al.
      Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
      The number of subjects in whom milk was a food trigger is even higher in our study than previously reported,
      • Kagalwalla A.F.
      • Shah A.
      • Li B.U.
      • et al.
      Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
      thereby making cow’s milk elimination the most significant component of any elimination diet therapy and providing the basis for milk-only elimination diet approach. Thirty-six percent of responders had more than 1 food trigger, and this finding supports single food reintroduction process to accurately identify food triggers.
      Symptom scores decreased in 91% of the histologic responders, with complete symptom resolution in 36% of the histologic remitters. Symptom response, however, is an unreliable marker of mucosal healing, as has been previously documented, and histology remains the only reliable modality to assess treatment response.
      • Kagalwalla A.F.
      • Sentongo T.A.
      • Ritz S.
      • et al.
      Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.
      • Gonsalves N.
      • Yang G.Y.
      • Doerfler B.
      • et al.
      Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
      • Lucendo A.J.
      • Arias A.
      • Gonzalez-Cervera J.
      • 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.
      • Safroneeva E.
      • Straumann A.
      • Coslovsky M.
      • et al.
      Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis.
      One or more abnormal endoscopic findings persisted in more than 50% of histologic responders, demonstrating as previously reported that endoscopic findings are not a reliable biomarker for histologic disease activity.
      • van Rhijn B.D.
      • Verheij J.
      • Smout A.J.
      • et al.
      The Endoscopic Reference Score shows modest accuracy to predict histologic remission in adult patients with eosinophilic esophagitis.
      Elimination of multiple foods from the diet increases the risk for malnutrition and nutritional deficiencies.
      • Christie L.
      • Hine R.J.
      • Parker J.G.
      • et al.
      Food allergies in children affect nutrient intake and growth.
      • Liu T.
      • Howard R.M.
      • Mancini A.J.
      • et al.
      Kwashiorkor in the United States: fad diets, perceived and true milk allergy, and nutritional ignorance.
      Nutritional guidance regarding proper food substitution and vitamin and mineral replacement to prevent malnutrition and nutritional deficiencies was provided at the outset. Despite this, responders demonstrated temporary weight loss with subsequent catch up weight gain once reintroduction of foods was completed.
      SFED is first-line nonpharmacologic treatment for EoE in children and adults.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      Excluding 68 foods simultaneously, the long reintroduction process, and costs associated with lost work/school and of multiple EGD are limitations of this approach. The present study by being less restrictive, requiring less time to complete food reintroduction, and fewer EGD is likely to be accepted by patients and their families.
      Female gender was identified as one of the statistically significant predictors of response in our subjects. This observation differs from adults, where a higher likelihood of response was reported in males.
      • Gonsalves N.
      • Yang G.Y.
      • Doerfler B.
      • et al.
      Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
      History of asthma was another positive predictor of response. Family history of food allergies was a predictor of poor response as was the presence of food sensitization to FFED foods based on serum sIgE testing with abnormal serum sIgE levels predicting lower response. This last finding has also been previously reported by Erwin et al,
      • Erwin E.A.
      • Kruszewski P.G.
      • Russo J.M.
      • et al.
      IgE antibodies and response to cow's milk elimination diet in pediatric eosinophilic esophagitis.
      and supports the concept that EoE patients with IgE-mediated food allergy represent a unique EoE phenotype, as we have previously reported.
      • Pelz B.J.
      • Wechsler J.B.
      • Amsden K.
      • et al.
      IgE-associated food allergy alters the presentation of paediatric eosinophilic esophagitis.
      Food sensitization seems to be a marker for a more broadly food-allergic phenotype that does not respond to FFED.
      The large cohort size and the multicenter design with children recruited from 4 large metropolitan areas in 3 different geographic regions of the country is the major strength of this study and reinforce the external validity of our results. Other strengths of this study include single food reintroduction and washout period when the trigger food is identified. This added step removes the likelihood of recurrence of inflammation being ascribed to factors other than true allergy to the trigger food. The identical order of food reintroduction removes bias about the relative incidence of each antigen-triggering inflammation.
      Limitations of this study include nonrandomization and the absence of a control group. There is potential selection bias by recruiting nonconsecutive patients and families motivated by elimination diet, although this mirrors clinical practice. A nonvalidated symptom instrument was used because at the time of this study's inception a validated symptom instrument was not available and this is another potential limitation of the study. Another potential limitation of the study is the applicability of this dietary approach to children in countries with dietary habits that are different and unique from those in United States.
      Twenty-four subjects who responded to FFED dropped out before completing the reintroduction process identifying all possible trigger foods. This is emblematic of the difficulties of even temporarily excluding 4 foods and undergoing multiple EGD. It highlights the fact that dietary therapy is not suited for every patient. Careful patient selection, based on detailed and realistic explanation of the constraints of the diet, the number of EGDs required, and the length of time to complete the reintroduction process are essential for the success of this approach.
      In summary, this prospective multicenter empiric FFED diet study achieved clinical remission in 9 out of 10 histologic respondents. Histologic remission was achieved in more than 6 out of 10 children, which is nearly identical to remission with SFED but with a diet that is less stringent. Subsequent systematic food reintroduction identified cow’s milk as the most frequently identified trigger followed by wheat, egg, and soy. Thus, 4-food empiric elimination diet has nearly comparable efficacy to SFED but is less restrictive and requires less time to complete the reintroduction. Our results provide evidence that FFED can be offered to children in preference to SFED and as an alternative to topical corticosteroid–refractory patients for the treatment of EoE.

      Supplementary Material

      Figure thumbnail fx1
      Supplementary Figure 1ROC curve identifying factors associated with response with an area under the curve of 0.8. ROC curve for final multivariable model identified asthma, family history of food allergy, and positive serum sIgE test to any of the 4 foods as significantly associated with treatment nonresponse. The area under the curve of the final model was 0.8. ROC curve, receiver operating characteristic curve.
      Supplementary Table 1Handout Provided to Families Before Starting FFED
      Four-Food Elimination Diet
      This diet is free of milk, soy, egg, and wheat.
      Any or all of these restricted foods on the elimination diet may be an ingredient in many processed foods. They may be also used as preservatives or flavors.
      There is no substitute to careful reading of food labels in order to make certain that none of the four food allergens is contained in a given food.
      Ingredients in a given food can change without warning. So read labels carefully on all foods every time you shop and even for foods that you have bought before.
      Avoid buying foods from bulk bins there is highly likelihood of mislabeling the foods. There is also a high probability of cross contamination of foods sold in bulk bins.
      Foods served in a restaurant or fast food establishments may be cross contaminated with above restricted foods, and many foods contain hidden sources of antigens and thus caution should be exercised when eating out.
      Cross-contamination occurs when one food comes into contact with another food & their proteins mix. Each food then contains small amounts of the other food that we often can’t see.
      Even a trace amount of food from cross-contamination can cause an allergic reaction.
      When cooking at home, cook the allergy-free meal first, cover, and cook/prepare the rest of the meal. Make sure utensils and cookware are clean prior to use (thoroughly washed with soap and water).
      Make sure you wash your hands when preparing foods.
      When calling food manufacturers regarding possible cross-contamination, ask about dedicated lines vs. shared equipment. Shared equipment = cross contamination, avoid.
      Vitamins
      Always check labels for allowed ingredients with vitamins
      Phlexy-Vits - www.shsna.com
      Kirkman® Children’s Multivitamin and Mineral Hypoallergenic Capsule - www.kirkmanlabs.com
      Tums® Calcium Supplement (does contain cornstarch for corn allergies)
      Nano VM (has a hypoallergenic vitamin for 1-3years, and 4-8 years) - www.solacenutrition.com
      Freeda Vitamins Vitalets - www.freedavitamins.com
      Hero Nutritionals®: Yummy Bears Multivitamin & minerals - www.heronutritionals.com
      Carlson for Kids vitamins: Chewable Vitamins and Minerals - www.carlsonlabs.com
      Nature’s Plus: Animal Parade Vitamins - www.naturesplus.com
      Elemental Formulas
      Can be ordered through your local pharmacy/home health care agency with a prescription or directly through manufacturer.
      Tabled 1Diet free of Milk, Wheat, Egg, and Soy
      Type of FoodFoods Allowed
      Milk & DairyEnriched rice milk, hemp, coconut, quinoa, cashew, almond, pea or oat milk

      In recipes: substitute fruit or vegetable juice, homemade soup stock, potato water

      Instead of butter on toast, use pure jelly, jam, honey or herb flavored olive oil

      Allowed margarines (milk/soy free*)

      Cheese: rice/pea protein based

      Yogurt: coconut milk and almond yogurt

      *may contain soy oil/soy lecithin
      Breads & cerealsGrains & flours

       Amaranth & amaranth flour Barley & barley flour Buckwheat & buckwheat flour

       Chickpea or garbanzo flour Millet & millet flour Oats & oat flour

       Potato starch & flour Quinoa & quinoa flour Rice & rice flour

       Rye flour Sago flour Tapioca starch & flour

       Wild rice & wild rice flour

      Breads & baked goods – check freezer section for ready-made breads with allowed ingredients

       Baked goods & specialty baking mixes containing allowed foods from specialty shops.

       (Rice, brown rice, millet or tapioca)

       Homemade baked goods with allowed foods

       Pure corn tortillas, wheat free tortillas

      Crackers and snacks

       Plain potato chips, corn chips, rice chips

       Pure rye crisp crackers

       Rice cakes, rice crackers

       Plain popcorn

      Cereals

       Cream of Rice Oatmeal and oat bran (plain) Puffed rice

       Rolled Oats/grits Corn/buckwheat based cereal Homemade granola with allowed grains

      Pasta

       Brown rice pasta wild rice pasta corn pasta

       Rice noodles & pasta bean pasta quinoa pasta
      VegetablesAll plain, fresh, & frozen vegetables and their juices except: soy bean sprouts & mixed sprouts. Tomato sauce: check labels for milk, soy or wheat
      FruitAll plain, fresh & frozen fruits & their juices (avoid pie filling fruits, may contain wheat)
      Meat & poultryAll fresh or frozen, plain meat or poultry

      Avoid all deli meats, luncheon meats with allowed ingredients
      Fish & ShellfishAll, check breading, sauces and marinades for allowed ingredients
      EggsEner-G® Egg Replacer / egg substitute recipes (see handout on cooking guidelines)
      LegumesAll plain bean or legumes and bean or legume dishes prepared with allowed foods, except soy.
      NutsAll, check nuts for wheat flour; avoid nuts from bulk bins
      SeedsAll, including sunflower, sesame, cumin, poppy, pumpkin, flax, caraway, anise
      Fats & oilsOils: olive, soybean oil (not cold pressed, expeller pressed, or extruded oil), canola, sunflower, safflower, coconut, corn or peanut

      Meat drippings and poultry fat Homemade gravy made with allowed foods

      Tahini Lard
      Spices & herbsAll pure fresh or dried herbs & spices
      The information included in this document is for informational purposes only and is not intended to substitute in any way for medical education, training, treatment, advice, or diagnosis by a healthcare professional. A qualified healthcare professional should always be consulted before making any healthcare-related decision.
      Supplementary Table 2Provided to Families at the Time FFED is Discussed
      Shopping Guide (4-FED)**ALWAYS CHECK LABELS AS INGREDIENTS CAN CHANGE**
      Whole GrainsProteinsVegetables - unlimited (canned, fresh, or frozen)Fruits - unlimited (canned, fresh, or frozen)Dairy Substitutes
      • Amaranth and amaranth flour
      • Bagels/breads (Wheat, soy, egg, milk free)
      • Brown or white rice
      • Corn
      • Cornmeal/polenta
      • Corn Tortilla
      • Corn Chips
      • Millet & millet flour
      • Quinoa
      • Teff
      • Peas
      • Potatoes (w/skin)
      • Sweet potatoes (w/skin)
      • Plantains
      • Pasta:
        • Corn
        • Rice
        • Lentil
        • Legume
        • Quinoa pasta
      • Yucca
      • Cereals:
        • -
          Oatmeal/Oats (wheat free)
        • -
          Puffed rice
        • -
          Wheat Free Granola
        • -
          Cream of Rice
        • -
          Brown rice cereal
        • -
          Rice
        • -
          Corn
        • -
          Quinoa
        • -
          Buckwheat
      • Canned beans:
        • -
          Azuki
        • -
          Black
        • -
          Garbanzo
        • -
          Kidney
        • -
          Pinto
        • -
          White
      • Bean/lentil soups
      • Hummus
      • Fish
      • Shellfish
      • Nut butters:
        • -
          Sunflower butter
        • -
          Peanuts & peanut butter
        • -
          Tree nuts/nut butters
      • Seeds:
        • -
          Flax
        • -
          Sesame
        • -
          Pumpkin
        • -
          Sunflower
        • -
          Poppyseed
        • -
          Chia
      • Tahini (Soy-free)
      • Bratwurst, hotdogs, sausage (meat/turkey)
      • Lean Meats:
        • -
          Poultry
        • -
          Pork
        • -
          Lamb
        • -
          Veal
        • -
          Beef
        • -
          Poultry
      • Deli Meat (packaged)
      • (not from deli counter)
      • Artichoke hearts
      • Asparagus
      • Beets
      • Bok choy
      • Broccoli
      • Brussels sprouts
      • Cabbage
      • Carrots
      • Cauliflower
      • Celery
      • Collard greens
      • Cucumber
      • Daikon
      • Eggplant
      • Endive
      • Green beans
      • Green onions
      • Hearts of palm
      • Jicama slices
      • Kale
      • Kohlrabi
      • Leeks
      • Mushrooms
      • Mustard greens
      • Okra
      • Onions
      • Pea pods
      • Peppers (all varieties)
      • Radishes
      • Romaine
      • Salsa
      • Salad greens
      • Scallions
      • Spaghetti sauce
      • Spinach
      • Summer squash
      • Swiss chard
      • Tomato
      • Tomato sauce
      • Tomatillos
      • Grape tomatoes
      • Turnips
      • Water chestnuts
      • Watercress
      • Zucchini
      • Apples
      • Applesauce (no sugar added)
      • Apricots
      • Bananas
      • Blackberries
      • Blueberries
      • Cantaloupe
      • Cherries
      • Grapefruit
      • Grapes
      • Honeydew
      • Kiwi
      • Mandarin oranges
      • Mango
      • Nectarine
      • Orange
      • Papaya
      • Persimmons
      • Peach
      • Pear
      • Pineapple
      • Plum
      • Pomegranate
      • Prunes
      • Raspberries
      • Strawberries
      • Tangerines
      • Watermelon
      • Individual fruit cups (in own juice)
      • Dried fruit
      • Freeze Dried Vegetables/Fruits
      • Fortified Milks:
        • -
          Almond
        • -
          Coconut
        • -
          Hemp
        • -
          Oat
        • -
          Rice
        • -
          Cashew
        • -
          Quinoa
        • (under 3 years old: recommend elemental formulas to replace milk in diet)
      • Margarines/spreads
      • Yogurts:
        • -
          Almond
        • -
          Coconut
      • Cheese:
        • -
          Rice based
        • -
          Pea based
      Frozen FoodsSnacks/ DessertsMiscellaneous
      • Allergy free kids foods
      • (chicken nuggets, fish nuggets, tator tots, French fries, macaroni and cheese)
      • Allergy free pizzas
      • Wheat free Breads
      • Sweets/Treats:
      • Allowed Carob Chips, cookies, cereal bars
      • 100% fruit sorbet
      • 100% all fruit bars
      • Hard candy
      • Plain potato chips
      • Rice crackers (plain)
      • Rice cakes (plain)
      • Popcorn (air popped or stovetop),plain
      • Potato (sweet potato) chips, plain
      • Corn chips
      • Wheat free pretzel chips, pretzels
      • Avocado
      • Garlic
      • Herbs and spices, fresh or dried –
      • McCormick Brand spices
      • Lemon/lime juice
      • Mustard
      • Fats/Oil:
        • -
          Canola
        • -
          Grape seed
        • -
          Olive
        • -
          Safflower
        • -
          Sesame
        • -
          Avocado
        • -
          coconut
      • Vinegars
      • Beverages:
        • -
          Sparkling water
        • -
          Juice spritzers
        • -
          Tea, hot/iced
        • -
          Diet/regular pop
        • -
          Sports drinks-electrolytes only, protein free
        • -
          Vitamin water
        • -
          100% fruit juice
        • (8floz/day limit)
      • Sweeteners:
        • -
          Sugar
        • -
          Equal
        • -
          Splenda®
        • -
          Honey
        • -
          Jam/jelly
      • Tupperware/baggies
        • -
          Sports bottle w/straw
      Supplementary Table 3Final Multivariable Logistic Regression Model for Treatment Response Based on History of Asthma, Family History of Food Allergy, Positive Serum sIgE, and Gender
      Allergy testFFED trigger foodP value (95% CI)
      NNPVPPVSensitivitySpecificity
      Skin prickMilk18.14 (0–0.33).75 (0.33–1).20 (0–0.4).67 (0.13–1)
      Wheat32.76 (0.56–0.97).25 (0–0.67).20 (0–0.55).81 (0.62–1)
      Egg27.77 (0.6–0.95).60 (0.17–1).38 (0.04–0.71).89 (0.76–1)
      Soy21.81 (0.64–0.98).18 (0–0.41).33 (0–0.71).65 (0.47–0.84)
      Serum sIgEMilk18.10 (0–0.29).75 (0.45–1).40 (0.15–0.65).33 (0–0.87)
      Wheat33.73 (0.51–0.96).38 (0.04–0.71).43 (0.06–0.8).69 (0.46–0.91)
      Egg27.70 (0.51–0.88).75 (0.33–1).30 (0.02–0.58).94 (0.83–1)
      Soy23.84 (0.7–0.98).25 (0–0.55).33 (0–0.71).78 (0.62–0.93)
      NPV, negative predictive value; PPV, positive predictive value.
      Supplementary Table 4Demographic, Clinical, Allergy Testing, Endoscopic, and Histologic Characteristics Compared in the Three Different Regions
      VariableN (%)P value
      Midwest

      n = 52 (66.7%)
      East Coast

      n = 15 (19.2%)
      South

      n = 11 (14.1%)
      Age (y), mean ± SD9.11 ± 4.938.84 ± 5.078.79 ± 4.87.9700
      Gender, n (%)
       Male35 (67.31)11 (73.33)6 (54.55).5954
       Female17 (32.69)4 (26.67)5 (45.45)
      White, n (%)40 (76.92)15 (100)10 (90.91).0717
      Presenting symptoms, n (%)
       Abdominal pain29 (55.77)4 (26.67)6 (54.55).1320
       Slow eating21 (40.38)9 (60)3 (27.27).2208
       Early satiety20 (38.46)8 (53.33)4 (36.36).5545
       Dysphagia18 (34.62)7 (46.67)2 (18.18).3206
       Vomiting17 (32.69)3 (20)4 (36.36).6647
       Poor appetite17 (32.69)5 (33.33)3 (27.27).9999
       Feeding difficulties14 (26.92)5 (33.33)2 (18.18).7466
       Regurgitation13 (25)4 (26.67)3 (27.27).9999
       Poor weight gain9 (17.31)6 (40)3 (27.27).1574
       Food impaction13 (25)4 (26.67)2 (18.18).9999
       Nausea11 (21.15)5 (33.33)2 (18.18).6156
       Pocketing food/spitting after chewing13 (25)3 (20)2 (18.18).9999
       Gagging/choking15 (28.85)1 (6.67)2 (18.18).2380
       Heartburn8 (15.38)1 (6.67)1 (9.09).8772
       Chest pain11 (21.15)1 (6.67)0 (0).1950
       Odynophagia3 (5.77)3 (20)2 (18.18).1144
       Nocturnal awakening caused by symptoms7 (13.46)1 (6.67)0 (0).5461
      Atopy, n (%)
       Eczema18 (34.62)10 (66.67)4 (36.36).0797
       IgE-mediated food allergy (n=77)12 (23.08)9 (60)3 (30).0269
      P values <.05 were considered statistically significant.
       Asthma16 (30.77)1 (6.67)5 (45.45).0669
       Allergic conjunctivitis9 (17.31)5 (33.33)0 (0).1102
       Allergic rhinitis31 (59.62)10 (66.67)5 (45.45).5470
      Family history (n=77) , n (%)
       Rhinitis38 (74.51)13 (86.67)4 (36.36).0187
      P values <.05 were considered statistically significant.
       Asthma26 (50.98)8 (53.33)6 (54.55).9703
       GERD27 (52.94)7 (46.67)7 (63.64).6908
       Food allergy21 (41.18)8 (53.33)5 (45.45).7035
       Eczema16 (31.37)11 (73.33)4 (36.36).0138
      P values <.05 were considered statistically significant.
       Hiatal hernia11 (21.57)2 (13.33)4 (36.36).4341
       EoE6 (11.76)2 (13.33)3 (27.27).4231
       Stricture7 (13.73)2 (13.33)0 (0).5765
       Celiac1 (1.96)0 (0)3 (27.27).0173
      P values <.05 were considered statistically significant.
       Recurrent vomiting2 (3.92)1 (6.67)1 (9.09).4152
      Common food allergens on skin prick test, n (%)
       Egg (n = 54)9 (25)4 (44.44)5 (55.56).1617
       Milk (n = 55)9 (24.32)2 (22.22)2 (22.22).9999
       Soy (n = 54)12 (34.29)4 (44.44)5 (50).6559
       Wheat (n = 53)6 (17.14)2 (22.22)3 (33.33).4772
      Food sensitization on serum sIgE test, n (%)
       Egg (n = 53)14 (40)8 (66.67)2 (33.33).2392
       Milk (n = 56)19 (51.35)7 (58.33)5 (71.43).6176
       Soy (n = 55)11 (31.43)7 (53.85)3 (42.86).3661
       Wheat (n = 53)15 (42.86)6 (50)3 (50).9175
      Endoscopy findings, n (%)
       Furrows (n = 76)38 (73.08)13 (92.86)5 (50).0606
       Edema (n = 75)36 (69.23)12 (92.31)5 (50).0881
       Exudates (n = 76)26 (50)13 (92.86)2 (20).0012
      P values <.05 were considered statistically significant.
       Rings (n = 76)9 (17.31)0 (0)0 (0).1391
       Strictures (n = 76)1 (1.92)0 (0)0 (0).9999
      Baseline peak eosinophil count, median (IQR)70 (42.5–100)65 (29–100)40 (25–60).0347
      P values <.05 were considered statistically significant.
      Posttreatment peak eosinophil count, median (IQR)8 (2–22.5)35 (7–85)6 (0–52).0728
      NOTE. Chi-square and Fisher exact tests were used to assess differences by region for categorical variables. A two-sample Student t test was used to compare age between regions and the nonparametric Wilcoxon rank sum test was used to compare baseline peak EOS and posttreatment EOS.
      GERD, gastroesophageal reflux disease; IQR, interquartile range.
      a P values <.05 were considered statistically significant.

      References

        • Furuta G.T.
        • Katzka D.A.
        Eosinophilic esophagitis.
        N Engl J Med. 2015; 373: 1640-1648
        • Liacouras C.A.
        • Furuta G.T.
        • Hirano I.
        • et al.
        Eosinophilic esophagitis: updated consensus recommendations for children and adults.
        J Allergy Clin Immunol. 2011; 128 (quiz 21–22): 3-20
        • Kelly K.J.
        • Lazenby A.J.
        • Rowe P.C.
        • et al.
        Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.
        Gastroenterology. 1995; 109: 1503-1512
        • Kagalwalla A.F.
        • Sentongo T.A.
        • Ritz S.
        • et al.
        Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2006; 4: 1097-1102
        • Henderson C.J.
        • Abonia J.P.
        • King E.C.
        • et al.
        Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.
        J Allergy Clin Immunol. 2012; 129: 1570-1578
        • Spergel J.M.
        • Brown-Whitehorn T.F.
        • Cianferoni A.
        • et al.
        Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.
        J Allergy Clin Immunol. 2012; 130: 461-467
        • Gonsalves N.
        • Yang G.Y.
        • Doerfler B.
        • et al.
        Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
        Gastroenterology. 2012; 142 (quiz e14–5): 1451-1459
        • Lucendo A.J.
        • Arias A.
        • Gonzalez-Cervera J.
        • 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
        • Wolf W.A.
        • Jerath M.R.
        • Sperry S.L.
        • et al.
        Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2014; 12: 1272-1279
        • Rodriguez-Sanchez J.
        • Gomez Torrijos E.
        • Lopez Viedma B.
        • et al.
        Efficacy of IgE-targeted vs empiric six-food elimination diets for adult eosinophilic oesophagitis.
        Allergy. 2014; 69: 936-942
        • Kagalwalla A.F.
        • Shah A.
        • Li B.U.
        • 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
        • Molina-Infante J.
        • Arias A.
        • Barrio J.
        • et al.
        Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study.
        J Allergy Clin Immunol. 2014; 134: 1093-1099
        • Safroneeva E.
        • Straumann A.
        • Coslovsky M.
        • et al.
        Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis.
        Gastroenterology. 2016; 150: 581-590
        • van Rhijn B.D.
        • Verheij J.
        • Smout A.J.
        • et al.
        The Endoscopic Reference Score shows modest accuracy to predict histologic remission in adult patients with eosinophilic esophagitis.
        Neurogastroenterol Motil. 2016; 28: 1714-1722
        • Christie L.
        • Hine R.J.
        • Parker J.G.
        • et al.
        Food allergies in children affect nutrient intake and growth.
        J Am Diet Assoc. 2002; 102: 1648-1651
        • Liu T.
        • Howard R.M.
        • Mancini A.J.
        • et al.
        Kwashiorkor in the United States: fad diets, perceived and true milk allergy, and nutritional ignorance.
        Arch Dermatol. 2001; 137: 630-636
        • Erwin E.A.
        • Kruszewski P.G.
        • Russo J.M.
        • et al.
        IgE antibodies and response to cow's milk elimination diet in pediatric eosinophilic esophagitis.
        J Allergy Clin Immunol. 2016; 138: 625-628
        • Pelz B.J.
        • Wechsler J.B.
        • Amsden K.
        • et al.
        IgE-associated food allergy alters the presentation of paediatric eosinophilic esophagitis.
        Clin Exp Allergy. 2016; 46: 1431-1440

      Linked Article

      • Issue Highlights
        Clinical Gastroenterology and HepatologyVol. 15Issue 11
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          Eosinophilic esophagitis (EoE) is an immune-mediated condition that affects children and adults, and is believed to be triggered by food antigens. Use of a 6-food elimination diet (SFED) that excludes cow’s milk, wheat, egg, soy, peanut/tree nuts, and fish/shellfish has been shown to induce clinical as well as histologic remission in most children and adults with EoE, with cow’s milk, wheat, egg and soy identified as the four most common trigger foods. In this issue of Clinical Gastroenterology and Hepatology, Kagalwalla and colleagues analyzed the results of a prospective multicenter study of pediatric patients with EoE to determine if exclusion of only 4 foods (4-FED: cow’s milk, wheat, egg, and soy) was effective in inducing clinical, endoscopic, and histologic remission.
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