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Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis

Published:April 30, 2012DOI:https://doi.org/10.1016/j.jaci.2012.03.023

      Background

      Eosinophilic esophagitis is a chronic, immune-mediated inflammatory disorder that responds to dietary therapy; however, data evaluating the effectiveness of dietary therapeutic strategies are limited.

      Objective

      This study compared the effectiveness of 3 frequently prescribed dietary therapies (elemental, 6-food elimination, and skin prick and atopy patch–directed elimination diets) and assessed the remission predictability of skin tests and their utility in directing dietary planning.

      Methods

      A retrospective cohort of proton-pump inhibitor–unresponsive, non–glucocorticoid-treated patients with eosinophilic esophagitis who had 2 consecutive endoscopic biopsy specimens associated with dietary intervention was identified. Biopsy histology and remissions (<15 eosinophils/high-power field) after dietary therapy and food reintroductions were evaluated.

      Results

      Ninety-eight of 513 patients met the eligibility criteria. Of these 98 patients, 50% (n = 49), 27% (n = 26), and 23% (n = 23) received elemental, 6-food elimination, and directed diets, respectively. Remission occurred in 96%, 81%, and 65% of patients on elemental, 6-food elimination, and directed diets, respectively. The odds of postdiet remission versus nonremission were 5.6-fold higher (P = .05) on elemental versus 6-food elimination diets and 12.5-fold higher (P = .003) on elemental versus directed diets and were not significantly different (P = .22) on 6-food elimination versus directed diets. After 116 single-food reintroductions, the negative predictive value of skin testing for remission was 40% to 67% (milk, 40%; egg, 56%; soy, 64%; and wheat, 67%).

      Conclusion

      All 3 dietary therapies are effective; however, an elemental diet is superior at inducing histologic remission compared with 6-food elimination and skin test–directed diets. Notably, an empiric 6-food elimination diet is as effective as a skin test–directed diet. The negative predictive values of foods most commonly reintroduced in single-food challenges are not sufficient to support the development of dietary advancement plans solely based on skin test results.

      Key words

      Abbreviations used:

      APT (Atopy patch test), CCED (Cincinnati Center for Eosinophilic Disorders), CCHMC (Cincinnati Children's Hospital Medical Center), EGID (Eosinophilic gastrointestinal disease), EGD (Esophagogastroduodenoscopy), EoE (Eosinophilic esophagitis), hpf (High-power field), NPV (Negative predictive value), SFED (Six-food elimination diet), SPT (Skin prick test)
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      Because EoE is thought to be primarily non–IgE mediated, skin testing based on delayed hypersensitivity to foods through atopy patch tests (APTs) has been advocated.
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      Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests.
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      Predictive values for skin prick test and atopy patch test for eosinophilic esophagitis.
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      • et al.
      Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.
      Liacouras et al
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      • Verma R.
      • Mascarenhas M.
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      • et al.
      Eosinophilic esophagitis: a 10-year experience in 381 children.
      and Spergel et al
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      • Brown-Whitehorn T.F.
      • Beausoleil J.L.
      • Liacouras C.A.
      Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests.
      demonstrated that 60% to 80% of patients with EoE respond to a directed elimination diet, which removes all of the patient's SPT- and APT-positive foods, but that disease reoccurs on food reintroduction.
      Recently, an alternative approach to food elimination has been recommended based on empiric avoidance of the 6 most common allergenic foods in the United States (milk, egg, soy, wheat, peanuts/tree nuts, and fish/shellfish).
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      • et al.
      Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.
      Using a response cutoff of 10 or fewer eosinophils/high-power field (hpf), Kagalwalla et al
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      • Ritz S.
      • Hess T.
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      • Emerick K.M.
      • et al.
      Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.
      initially reported a histologic response of 74% for this empiric 6-food elimination diet (SFED). Complete elimination of eosinophilic inflammation (≤1 eosinophil/hpf) was reported in 29% (10/35) of patients in the SFED group and in 56% (14/25) of patients in the elemental diet group.
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      • et al.
      Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.
      These findings are consistent with the original report by Kelly et al
      • 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.
      that 50% of patients with EoE have complete histologic resolution and 100% have partial resolution after an elemental diet. Uncovering whether dietary therapy based on skin testing (a directed diet) is better than empiric removal of foods (SFED) could have a significant affect on clinical practice, which is currently based on the common paradigm of skin testing before food elimination.
      Herein, we report comparison of remission rates among 3 dietary therapies frequently prescribed in pediatric EoE and implemented in a clinical setting: elemental diet, SFED, and a skin test–directed elimination diet. In addition, we evaluate the possibility of using skin tests for dietary planning and report the NPVs for single-food reintroductions.

      Methods

       Study design

      A retrospective convenience cohort study consisted of patients seen from January 1999 to October 2011 at the Cincinnati Center for Eosinophilic Disorders (CCED) (http://www.cincinnatichildrens.org/service/c/eosinophilic-disorders/default/), Cincinnati Children's Hospital Medical Center (CCHMC). Participants were recruited from the eosinophilic gastrointestinal disease (EGID) database, an institutional review board–approved repository of disease-related information from patients who have eosinophilic disorders. Written informed consent was obtained from parents, and written informed assent was obtained from children 11 years and older.

       Subjects

      Subjects recruited for the EGID database were only those seen at the CCED by one of 2 gastroenterologists. Patient records were selected for review if they met the following eligibility criteria: (1) diagnosis of EoE
      • 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.
      • Furuta G.T.
      • Liacouras C.A.
      • Collins M.H.
      • Gupta S.K.
      • Justinich C.
      • Putnam P.E.
      • et al.
      Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.
      (diagnostic criteria consisted of having ≥15 eosinophils/hpf in ≥1 esophageal biopsy specimen, having no response to a proton-pump inhibitor prescribed in varying doses [up to 2 mg/kg/d] for at least 6 weeks, or having normal results on multichannel intraluminal impedance pH or pH probe and the exclusion of other causes of esophageal eosinophilia); (2) having at least 2 consecutive esophagogastroduodenoscopies (EGDs) to monitor dietary therapy; (3) not having received oral or topical glucocorticoids for at least 2 months before and during the duration of the study; and (4) being 21 years of age or less throughout the study's duration. Patients were excluded if they were given a diagnosis of other diseases or conditions associated with eosinophilia (eg, celiac disease, Crohn disease, and hypereosinophilic syndrome), were given a diagnosis of a mitochondrial disorder,
      • Miles M.V.
      • Putnam P.E.
      • Miles L.
      • Tang P.H.
      • DeGrauw A.J.
      • Wong B.L.
      • et al.
      Acquired coenzyme Q10 deficiency in children with recurrent food intolerance and allergies.
      were enrolled in a concomitant drug trial, were not following any of the 3 dietary therapies under study, or were identified as noncompliant with dietary therapy (ie, documentation by a physician that the diet was not followed as prescribed). Medications not known to affect esophageal eosinophilia, as well as asthma medications (including nasal and inhaled glucocorticoids), were permitted. A clinical history of allergic disease (ie, asthma, allergic rhinitis, or atopic dermatitis) was recorded. Evaluation of food reintroductions occurred only in patients who had both SPTs and APTs performed at the CCED. Patients' demographic and disease characteristics were evaluated. Duration of follow-up at the CCED was defined as the number of years patients were followed at the CCED since their first CCED EGD. Patients were categorized as being local if their home zip code was included in CCHMC's designated regional catchment area.

       Dietary therapy

      Three commonly prescribed diet therapies, the elemental diet, the SFED, and the allergy test–directed elimination diet, were evaluated in this study. Patients were treated with one of 3 food-elimination therapies as the sole intervention, except for acid-suppression therapy between 2 endoscopic assessments. The initial dietary therapy chosen for each patient was not randomly assigned but was negotiated between physicians and patients based on multiple factors after comprehensive medical history (including social history) and physical examination. Medical history factors included a patient's response to any dietary therapies implemented before evaluation at our institution that might have precluded the use of one of the dietary therapy options under study and the assessment of the child and family's ability and willingness to implement a dietary therapy.
      The 3 dietary therapy interventions evaluated in this study were defined in the following manner. First, an elemental diet was defined as eliminating all foods and providing complete nutrition by the exclusive use of formula that contained crystalline amino acids, such as Neocate or E028 Splash (Nutricia North America, Rockville, Md) or EleCare (Abbott Laboratories, Columbus, Ohio).
      Second, the SFED encompasses 2 variations: the classical SFED, during which 42% (11/26) of patients empirically avoided the 6 most common allergenic foods (ie, milk, soy, wheat, egg, peanuts/tree nuts, and fish/shellfish) regardless of allergy test results, and the modified SFED, during which 58% (15/26) of patients avoided foods eliciting positive SPT and APT results in combination with the avoidance of the 6 most common allergenic foods. The median numbers of foods eliminated in the SFED, the modified SFED, and the directed diets were 7 (interquartile range, 6-11), 8 (interquartile range, 7-9), and 5 (interquartile range, 3-11), respectively. No significant differences were detected between demographic or disease-related variables or remission (<15 eosinophils/hpf) among those undergoing the classical and modified SFED (data not shown); therefore, these data were combined and were referred to as SFED data.
      Third, a skin test–directed elimination (directed) diet was defined as the avoidance of only those foods that elicited positive SPT results, APT results, or both; resulted in anaphylaxis; or were avoided because of known oral allergy syndrome.
      The duration of dietary therapy was defined as the number of months that patients received initial dietary therapy intervention.

       Esophageal histology

      Esophageal biopsy specimens were fixed in formalin and embedded in paraffin; 5-μm sections were stained with hematoxylin and eosin. The peak eosinophil count per hpf was defined as the highest eosinophil count in either the distal or proximal esophagus. The peak eosinophil count in biopsy specimens was determined at ×400 magnification (area, 0.3 mm2) by CCHMC board-certified pathologists. For patients who had begun dietary therapy before their initial CCED visit, the peak eosinophil count from biopsy slides provided from the outside institutions was determined by a board-certified pathologist (M.H.C.) at the CCHMC.

       Remission status

      Because of the departure from symmetry, the median prediet and postdiet peak eosinophil counts were calculated. Remission status was determined by using the postdiet peak eosinophil count and was initially defined in 4 categories: complete remission, 1 or fewer eosinophils/hpf; partial remission, 2 to 5 eosinophils/hpf; partial resolution, 6 to 14 eosinophils/hpf; and nonremission or active disease, 15 or more eosinophils/hpf. For greater simplicity, remission status after dietary therapy and food reintroduction was dichotomized, with remission being defined as less than 15 eosinophils/hpf and nonremission being defined as 15 or more eosinophils/hpf. Complete elimination of eosinophilic inflammation, previously defined as 1 or fewer eosinophils/hpf,
      • Markowitz J.E.
      • Spergel J.M.
      • Ruchelli E.
      • Liacouras C.A.
      Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents.
      was referred to as complete remission and was compared among dietary therapies. The odds of postdiet remission versus nonremission were calculated among dietary therapies.

       Evaluation of atopic sensitization

       SPTs

      For consistency of the allergen extract and the interpretation, only SPTs performed at the CCED were included. Foods tested were individually selected by the allergist based on clinical history and dietary intake. Patients had SPTs to as many as 62 foods and 11 environmental allergen extracts. The types, concentrations, and manufacturers of the allergen extracts and grading system used have been published previously.
      • Assa'ad A.H.
      • Putnam P.E.
      • Collins M.H.
      • Akers R.M.
      • Jameson S.C.
      • Kirby C.L.
      • et al.
      Pediatric patients with eosinophilic esophagitis: an 8-year follow-up.
      Histamine (1 mg/mL) and albumin in saline were used as positive and negative controls, respectively. Tests were read after 15 minutes and interpreted as follows: 0, negative control; 1+, very small induration and erythema present; 2+, 50% of histamine control; 3+, histamine control; and 4+, ≥ histamine control or presence of pseudopodia. Test results graded as 2+ or higher were considered positive, as were tests in which the largest wheal diameter measured was at least 3 mm larger than that elicited by the negative control. It is generally accepted that a mean wheal size of at least 3 mm larger than that elicited by the negative control is suggestive of food allergy.
      • Eigenmann P.A.
      • Sampson H.A.
      Interpreting skin prick tests in the evaluation of food allergy in children.

       APTs

      Only patch tests performed at the CCED were included in the analysis. All available foods were tested by using APTs, except for foods to which the patient had a history of allergic reaction or a positive SPT response. Details related to APT allergen manufacturers, preparations, and placements have been reported previously.
      • Assa'ad A.H.
      • Putnam P.E.
      • Collins M.H.
      • Akers R.M.
      • Jameson S.C.
      • Kirby C.L.
      • et al.
      Pediatric patients with eosinophilic esophagitis: an 8-year follow-up.
      The patches were removed after 48 hours and scored at 72 hours as follows: 0, no visible findings; 1, erythema but no induration; 2, erythematous with generalized induration, a few scattered papules, or both; 3, erythematous, marked induration/papules; and 4, erythematous papules and vesicular eruption. A score of 2 or greater was considered positive.

       Atopy

      Patients were considered atopic if they had a history of asthma, allergic rhinitis, or atopic dermatitis and a positive SPT response.

       Food reintroduction

      Investigation of single-, multiple-, and combined (both single and multiple)–food reintroductions are reported only for patients who underwent an allergy evaluation and underwent both SPTs and APTs at the CCED. A multiple-food reintroduction was defined as more than 1 food being reintroduced within 1 histologic evaluation interval. Food reintroductions were initiated only when the peak eosinophilic count after diet therapy was less than 15 eosinophils/hpf. If symptoms occurred after reintroduction of a food, patients were instructed to discontinue that food, wait approximately 10 to 14 days, and then reintroduce another food. The frequency and type of food reintroductions performed were identified. Remissions occurring as a result of initial dietary therapy (food elimination) and esophageal eosinophilia or symptoms recurring after food reintroduction were documented. A food reintroduction was considered successful if no symptoms were reported and the postpeak eosinophil count was less than 15 eosinophils/hpf and considered unsuccessful if symptoms returned or if the postpeak eosinophil count was 15 eosinophils/hpf or greater. Because of the paucity of dual SPT/APT-positive results (1/116), NPVs were calculated by using only SPT responses to assess the utility of the SPT in dietary planning.

       Statistical analysis

      Prediet and postdiet therapy peak eosinophil counts per hpf and percentages of patients in remission (<15 eosinophils/hpf) were compared among each dietary therapy by using the Kruskal-Wallis and χ2 tests, respectively. If significant differences (P < .05) were detected, pairwise comparisons were performed. Adjusted P values were reported for significant pairwise comparisons by using the Dwass, Steel, Critchlow, Fligner correction for continuous variables and the Hochberg correction for discrete variables. This approach was repeated by using each remission category: complete remission (≤1 eosinophil/hpf), partial remission (2-5 eosinophils/hpf), partial resolution (6-14 eosinophils/hpf), and nonremission (≥15 eosinophils/hpf). Comparisons of demographic and disease-related variables among dietary therapies were performed by using the Kruskal-Wallis or Mann-Whitney U tests for continuous variables and the χ2 and Fisher exact tests for discrete variables. The odds ratios and their CIs for postdiet remission versus nonremission among dietary therapies were calculated by using logistic regression. The Wilcoxon paired signed-rank test was used to determine statistical significance between prediet and postdiet therapy median peak eosinophil counts per hpf among each dietary therapy. Statistical analyses were performed with PASW Statistics 18.0 software (SPSS, Inc, Chicago, Ill) and SAS version 9.3 software (SAS Institute, Inc, Cary, NC).

      Results

       Enrollment

      A flow diagram of participant recruitment is shown in Fig 1. A total of 513 patients were assessed for eligibility, of whom 81% (n = 415) were excluded and 19% (n = 98) were enrolled in the study. Reasons for exclusion are as follows: not meeting the consensus disease criteria (n = 181), not having 2 consecutive EGDs separated by dietary intervention therapy (n = 16), having received oral or topical glucocorticoids (n = 122), patient age greater than 21 years (n = 23), presence of another eosinophilia-associated condition or disorder (n = 52), enrollment in a concomitant drug trial (n = 4), on a diet that was not under study (n = 14), and obvious noncompliance with dietary intervention therapy (n = 3).
      Figure thumbnail gr1
      Fig 1Flow diagram of the study participants.

       Dietary therapy

      Of the 98 patients who met the eligibility criteria, 50% (n = 49), 27% (n = 26), and 23% (n = 23) were assigned to an elemental diet, SFED, and directed elimination diet at enrollment, respectively.

       Subjects

      Of the 98 enrolled patients, 50% were given a diagnosis of EoE before the age of 3.5 years. The mean ± SD ages at EoE diagnosis and on the first patient visit at the CCED were 5.1 ± 4.2 and 5.9 ± 4.4 years, respectively; neither differed significantly among dietary therapies. Demographic and disease characteristics for each dietary therapy are outlined in Table I. An approximate 3:1 male/female ratio was identified. On average, patients had 8.5 ± 6.3 EGDs (range, 1-24 EGDs) performed at the CCED, with the number of EGDs being significantly greater among patients on the elemental diet compared with those on the SFED (P = .017) or the directed diet (P = .039). Seventy-six percent (n = 74) of patients had at least 1 EGD performed at an outside site before their first visit to the CCED. Seven percent (n = 7) of patients were seen at the CCED only once for an initial evaluation. The mean ± SD number of EGDs performed per year in the 91 patients who returned to the CCED after their initial visit was 3.8 ± 1.8, and no statistical differences were detected among dietary therapies (P = .26). The duration of CCED follow-up (mean ± SD) was 2.5 ± 2.2 years (range, 0-8.5 years), with there being a significantly longer interval for the elemental diet compared with the SFED (P = .01). A total of 68% of patients (n = 67) were atopic; this percentage did not differ significantly among the examined dietary therapies. Approximately 67% (n = 66) of patients lived outside the CCHMC's regional catchment area; this percentage did not differ significantly among the examined dietary therapies. Of the 49 patients on an elemental diet, 55% (n = 27) ingested formula by mouth, and the remainder received tube feedings. Supplemental elemental formula for nutritional support was used in 27% (n = 7) of the patients on the SFED and 35% (n = 8) of the patients on the directed diet.
      Table IPatients' demographic and disease-related characteristics among 3 EoE dietary therapies (n = 98)
      Elemental diet (n = 49), mean (range)SFED (n = 26), mean (range)Directed diet (n = 23), mean (range)P value
      Diet therapies were compared statistically by using the Kruskal-Wallis test for continuous variables and the χ2 or Fisher exact tests for discrete variables. If significant differences were detected, pairwise comparisons were performed. Adjusted P values using the Dwass, Steel, Critchlow, Fligner correction for multiple pairwise comparisons that were significantly different.
      Age at study (y)5.6 (0.9-19.7)6.6 (2.2-20.8)5.2 (0.9-15.0).32
      Age at first EGD (y)4.3 (0.7-16.2)5.5 (0.6-20.3)4.6 (0.1-13.6).25
      Duration between first EGD and EoE diagnosis (y)0.5 (0-4.3)0.4 (0-2.9)0.2 (0-1.6).73
      Dietary therapy duration
      Duration of dietary therapy was defined as the number of months patients received initial dietary therapy intervention.
      (mo)
      4.5 (0.8-23.2)4.4 (2.3-10.5)3.9 (2.4-7.3).79
      Total no. of EGDs11.1
      Elemental versus SFED, P = .004.
      (2-26)
      6.2
      Elemental versus SFED, P = .004.
      (3-12)
      8.4 (3-22).005
      No. of EGDs at the CCED8.5
      Elemental versus SFED, P = .017.
      ,
      Elemental versus directed, P = .039.
      (1.0-24.0)
      4.0
      Elemental versus SFED, P = .017.
      (1.0-8.0)
      5.2
      Elemental versus directed, P = .039.
      (1.0-19.0)
      .006
      Duration of follow-up at the CCED
      Duration of follow-up at the CCED was defined as the number of years patients were followed at the CCED since their first CCED EGD.
      (y)
      2.9
      Elemental versus SFED, P = .01.
      (0-8.5)
      1.1
      Elemental versus SFED, P = .01.
      (0-2.6)
      2.1 (0-6.8).009
      Atopy,
      Atopy was defined as having a history of asthma, allergic rhinitis, or atopic dermatitis and having a positive SPT response.
      no. (%)
       Yes32 (65.3)20 (76.9)15 (65.2).55
      Sex, no. (%)
       Male36 (73.5)19 (73.1)19 (82.6).66
      Race, no. (%)
       White44 (89.8)25 (96.2)22 (95.7).54
       African American2 (4.1)1 (3.8)1 (4.3)
       Other3 (6.1)00
      Ethnicity, no. (%)
       Non-Hispanic48 (98.0)25 (96.2)22 (95.7).84
      Residence, no. (%)
       Nonlocal34 (69.4)16 (61.5)16 (69.6).76
      Diet therapies were compared statistically by using the Kruskal-Wallis test for continuous variables and the χ2 or Fisher exact tests for discrete variables. If significant differences were detected, pairwise comparisons were performed. Adjusted P values using the Dwass, Steel, Critchlow, Fligner correction for multiple pairwise comparisons that were significantly different.
      Elemental versus SFED, P = .004.
      Elemental versus SFED, P = .017.
      § Elemental versus directed, P = .039.
      Elemental versus SFED, P = .01.
      Duration of dietary therapy was defined as the number of months patients received initial dietary therapy intervention.
      # Duration of follow-up at the CCED was defined as the number of years patients were followed at the CCED since their first CCED EGD.
      ∗∗ Atopy was defined as having a history of asthma, allergic rhinitis, or atopic dermatitis and having a positive SPT response.

       Postdiet therapy esophageal histology

      Comparison of the prediet and postdiet therapy peak eosinophil counts per hpf for each dietary therapy is shown in Fig 2. For each dietary therapy, the median prediet therapy eosinophil count per hpf was significantly higher than the median postdiet therapy eosinophil count per hpf (elemental diet, P < .0001; SFED, P = .005; and directed diet, P = .003).
      Figure thumbnail gr2
      Fig 2Comparisons of prediet and postdiet therapy peak eosinophil counts per hpf for diet therapies using the Kruskal-Wallis test. Data points between the dashed horizontal lines represent remission (0 to <15 eosinophils/hpf), and data points above the upper dashed line represent nonremission (≥15 eosinophils/hpf). The Wilcoxon paired signed-rank test was used to compare prediet and postdiet therapy median peak eosinophil counts per hpf. The solid horizontal lines represent median values. ϕAdjusted P value using the Dwass, Steel, Critchlow, Fligner correction for pairwise comparison between the postdiet therapy peak eosinophil counts per hpf for the elemental and directed diets (P = .01).
      Table II compares the median prediet and postdiet therapy peak eosinophil count per hpf among dietary therapies and presents the interquartile range for each diet therapy. Pairwise comparison revealed a significantly higher median prediet therapy peak eosinophil count per hpf in the SFED compared with the directed diet (P = .036). No significant differences in prediet therapy peak eosinophil counts per hpf were detected in those on the elemental diet compared with those on the SFED (P = .34) or those on directed diet (P = .41).
      Table IIComparison of prediet and postdiet therapy peak eosinophil counts per hpf and remission status among diet therapies (n = 98)
      Diet therapy
      Elemental (n = 49)SFED (n = 26)Directed (n = 23)
      Prediet therapy:
       Peak eosinophil count/hpf
      Median51.076.5
      SFED versus directed, P = .036.
      38.0
      SFED versus directed, P = .036.
      Interquartile range28.0-90.048.0-101.023.0-87.0
      Postdiet therapy:
       Peak eosinophil count/hpf
      Median1.0
      Elemental versus directed, P = .01.
      2.57.0
      Elemental versus directed, P = .01.
      Interquartile range0-3.50-10.30-25.0
      Remission types
      Remission types were defined as follows: remission, <15 eosinophils/hpf; complete remission, ≤1 eosinophil/hpf; partial remission, 2-5 eosinophils/hpf; partial resolution, 6-14 eosinophils/hpf; and nonremission, ≥15 eosinophils/hpf.
       Remission, no. (%)47 (96)
      Elemental versus directed, P = .001.
      21 (81)15 (65)
      Elemental versus directed, P = .001.
      Complete remission, no. (%)29 (59)
      Elemental versus directed, P = .04.
      10 (39)7 (30)
      Elemental versus directed, P = .04.
      Partial remission, no. (%)13 (27)6 (23)2 (9)
      Partial resolution, no. (%)5 (10)5 (19)6 (26)
       Nonremission, no. (%)2 (4)
      Elemental versus directed, P = .001.
      5 (19)8 (35)
      Elemental versus directed, P = .001.
      Remission types were compared statistically by using the Kruskal-Wallis test. If significant differences were detected, pairwise comparisons were performed. Adjusted P values with the Hochberg correction for multiple pairwise comparisons that were significantly different.
      SFED versus directed, P = .036.
      Elemental versus directed, P = .01.
      Elemental versus directed, P = .001.
      § Elemental versus directed, P = .04.
      Remission types were defined as follows: remission, <15 eosinophils/hpf; complete remission, ≤1 eosinophil/hpf; partial remission, 2-5 eosinophils/hpf; partial resolution, 6-14 eosinophils/hpf; and nonremission, ≥15 eosinophils/hpf.
      Pairwise comparison demonstrated a significantly lower median posttherapy peak eosinophil count per hpf in those on the elemental diet compared with those on the directed diet (P = .01). The postdiet therapy peak eosinophil counts per hpf did not differ significantly between the those on the elemental diet and the SFED (P = .26) or between those on the SFED and the directed diet (P = .35).

       Remission status

      Table II compares the remission status among dietary therapies. Remission (<15 eosinophils/hpf) was attained in 96% (47/49) of patients on the elemental diet, 81% (21/26) of patients on the SFED (82% [9/11] of patients on the classical SFED and 80% [12/15] of patients on the modified SFED), and 65% (15/23) of patients on the directed diet. Pairwise comparison revealed a significantly higher complete remission rate (≤1 eosinophil/hpf, P = .04) and significantly lower nonremission rate (≥15 eosinophils/hpf, P = .001) for the elemental diet compared with the directed diet. There were no significant differences in any type of remission between those on the elemental diet and the SFED or between those on the SFED and the directed diet.
      The odds of postdiet remission (<15 eosinophils/hpf) versus nonremission (≥15 eosinophils/hpf) were 5.6-fold (95% CI, 1.0-31.2; P = .05) greater on the elemental diet compared with the SFED, 12.5-fold (95% CI, 2.3-65.6; P = .003) greater on the elemental diet compared with the directed diet, and not significantly different (2.2-fold; 95% CI, 0.12-1.64; P = .22) greater on the SFED compared with the directed diet.

       Food reintroduction

      Approximately 70% (69/98) of patients underwent both SPTs and APTs at the CCED. Table III shows the following variables by dietary therapy: the number of patients who underwent food reintroductions, the duration of the food reintroduction phase, and the total number of single-, multiple-, and combined-food reintroductions performed. Seventy-five percent (51/69) of patients underwent food reintroductions. No significant difference in the distribution of patients who underwent any type of food reintroduction (single, multiple, or combined) was detected among the 3 dietary therapies (P = .10). Forty-eight percent (25/51) of food reintroductions were performed in patients on the elemental diet, 29% (15/51) in patients on the SFED, and 21% (11/51) in patients on the directed diet. No significant difference in the percentage of patients with atopy was detected among dietary therapies (P = .24). A total of 33 foods were reintroduced in 116 single-food challenges conducted in a total of 42 patients (21 patients who underwent single food–only reintroductions plus 21 patients who underwent combination reintroductions that included single-food challenges). Twelve percent (14/116) of single-food reintroductions resulted in positive SPT responses; only 1 single-food reintroduction resulted in positive test results on both the SPT and the APT because the APTs were not performed for the other 13 foods eliciting positive SPT responses. Of the 42 patients (Table III) who underwent single-food reintroductions, 5% (2/42) had positive findings to more than 1 food. A total of 285 foods were reintroduced in 99 multiple-food challenges in 30 patients. On average, 2.9 foods were reintroduced in each multiple-food challenge.
      Table IIIFood reintroduction
      Food reintroductions were conducted in 75% of the 69 patients who had both SPTs and APTs performed at the CCED.
      characteristics among dietary therapies
      Diet therapyP value
      Diet therapies were compared statistically by using the χ2 or Fisher exact tests for discrete variables and the Kruskal-Wallis test for continuous variables. No significant differences for pairwise comparisons were detected.
      Elemental (n = 49)SFED (n = 26)Directed (n = 23)
      SPT and APT performed at the CCED, no. (%)28 (57.1)22 (84.6)19 (83.3)NA
      Atopy, no. (%)17/28 (60.7)18/22 (81.8)15/19 (78.9).24
      Food reintroduction(s),
      Food reintroductions were conducted in 75% of the 69 patients who had both SPTs and APTs performed at the CCED.
      no. (%)
      25/28 (89.3)15/22 (68.1)11/19 (57.9).78
      No. of patients who underwent food reintroduction(s), no. (%)
       Single only6/25 (24.0)9/15 (60.0)6/11 (54.6)
       Multiple only5/25 (20.0)3/15 (20.0)1/11 (9.0)
       Combination (single and multiple)14/25 (56.0)3/15 (20.0)4/11 (36.4).10
      Duration of food reintroduction phase (y)
       Mean ± SD2.1 ± 1.80.9 ± 0.51.6 ± 1.7.11
       Range0.2-6.40.2-2.00.2-5.9NA
      NA, Not applicable.
      Food reintroductions were conducted in 75% of the 69 patients who had both SPTs and APTs performed at the CCED.
      Diet therapies were compared statistically by using the χ2 or Fisher exact tests for discrete variables and the Kruskal-Wallis test for continuous variables. No significant differences for pairwise comparisons were detected.
      Of the 50% (58/116) of single-food reintroductions that failed, 12% (7/58) failed as a result of symptoms. The remaining 88% (51/58) failed single-food reintroductions based on histologic results. Thirty-seven percent (104/285) of the foods that were reintroduced during multiple-food challenges failed histologically. Table IV outlines the single- and multiple-food reintroduction results. The percentage of food reintroductions that passed histologic evaluation (peak count <15 eosinophils/hpf) ranged from 35% to 63%, and the NPVs for the foods most often reintroduced during single-food challenges ranged from 40% to 67%. These 4 foods (milk, egg, soy, and wheat; Table IV) represent 48% (56/116) of all single-food reintroductions. For the foods most often reintroduced during multiple-food challenges, the percentage of food reintroductions that passed histologic evaluation appears in Table IV. The 15 foods listed under multiple reintroductions in Table IV represent 53% (150/285) of all of the foods reintroduced in multiple-food challenges.
      Table IVSingle- and multiple-food reintroduction results
      Food (no.)Type of food reintroduction
      Single (n = 116)Multiple
      A multiple-food reintroduction was defined as more than 1 food being challenged within 1 histologic evaluation interval.
      (n = 99)
      Pass (%)
      Reintroductions that passed were based on a postpeak count of less than 15 eosinophils/hpf.
      NPV (%)Food (no.)Pass (%)
      Reintroductions that passed were based on a postpeak count of less than 15 eosinophils/hpf.
      Wheat (16)6367Cocoa (9)78
      Soy (13)6264Pork (12)75
      Egg (10)6056Grapes (11)73
      Milk (17)3540Oats (10)70
      Sweet potatoes (10)70
      Rice (11)64
      Apple (13)62
      Chicken (12)58
      Carrot (9)55
      Banana (10)50
      Broccoli (7)43
      Tomato (7)43
      Beef (12)42
      Corn (10)40
      Strawberry (7)29
      NPV, Negative predictive value for SPT responses.
      A multiple-food reintroduction was defined as more than 1 food being challenged within 1 histologic evaluation interval.
      Reintroductions that passed were based on a postpeak count of less than 15 eosinophils/hpf.

      Discussion

      Herein we report the first comparative study to determine the effectiveness of 3 different dietary therapies for EoE. We demonstrate that dietary therapy is highly effective at inducing disease remission in patients with EoE and that the elemental diet is superior to restricted dietary therapies. These findings are consistent with a dose-response relationship between the number of immunologically reactive foods and the presence of active allergic inflammation in the esophagus. Furthermore, we demonstrate that the empiric removal of the most common allergens from the diet (SFED) is notably no less successful than the directed diet that is based on results of skin (prick and patch) testing alone. Consistent with the unreliability of skin testing at guiding dietary management for disease remission, the predictive value of SPTs for the maintenance of disease remission after food reintroduction remained low (≤67%). Taken together, our data substantiate an immune cause for EoE and yet undermine the value of skin test–directed dietary management. The failure of skin testing to identify causative specific food hypersensitivities might be explained by the local generation of immunoglobulins (including IgE) in the esophagus, suggesting that the skin is not a good surrogate for tissue-specific responses.
      • Vicario M.
      • Blanchard C.
      • Stringer K.F.
      • Collins M.H.
      • Mingler M.K.
      • Ahrens A.
      • et al.
      Local B cells and IgE production in the oesophageal mucosa in eosinophilic oesophagitis.
      Our findings might also be reconciled by a disease mechanism that does not depend on IgE-mediated responses, which is consistent with studies in mice that have elicited experimental EoE in B cell–deficient mice
      • Mishra A.
      • Schlotman J.
      • Wang M.
      • Rothenberg M.E.
      Critical role for adaptive T cell immunity in experimental eosinophilic esophagitis in mice.
      and a recent preliminary report that anti-IgE therapy is unsuccessful for EoE.
      • Rocha R.
      • Vitor A.B.
      • Trindade E.
      • Lima R.
      • Tavares M.
      • Lopes J.
      • et al.
      Omalizumab in the treatment of eosinophilic esophagitis and food allergy.
      The objectives of this study were to evaluate remission rates among 3 dietary therapies implemented in a focused population of children who have EoE and to assess the utility of skin testing in directing dietary planning. Access to our EGID data repository permitted comprehensive longitudinal evaluation of histologic remission associated with dietary therapies and subsequent food reintroduction. These data reflect the evolution of dietary-based treatment options offered to patients with EoE over the past decade. No patients received topical or systemic steroids for a minimum of 2 months before and during the duration of the study to avoid the confounding influence of glucocorticoid treatment on remission. This allowed comparison of remission response among dietary therapies but not other mainstays of treatment, such as topical steroids. Notably, there are not yet formal standards for defining histologic remission in response to therapy; thus the standards used vary widely among published studies.
      Results from this retrospective observational study identified the superiority of inducing histologic remission with the elemental diet compared with the SFED and the directed diet. No statistical difference in remission (overall, complete remission, partial remission, or partial resolution) was detected among those on the SFED and those on the directed diet in our study. Although we suspect that differences in secondary clinical outcomes might exist among dietary therapies, such as more rapid individual diet optimization (symptomatic and histologic tolerance of desired foods) in patients on the SFED compared with that seen in patients on the elemental diet (who underwent more EGDs) or differences in quality of life and dietary adherence,
      • Franciosi J.P.
      • Hommel K.A.
      • Debrosse C.W.
      • Greenberg A.B.
      • Greenler A.J.
      • Abonia J.P.
      • et al.
      Quality of life in paediatric eosinophilic oesophagitis: what is important to patients?.
      these secondary clinical outcomes and associated costs were not measured in this study. Multiple studies indicate that adherence is inversely related to the number of foods eliminated.
      • Hong S.
      Food allergy and eosinophilic esophagitis: learning what to avoid.
      • Hommel K.A.
      • Franciosi J.P.
      • Hente E.A.
      • Ahrens A.
      • Rothenberg M.E.
      Treatment adherence in pediatric eosinophilic gastrointestinal disorders.
      Ensuring a nutritionally adequate dietary intake is more difficult for patients on a restrictive diet that eliminates the most common allergenic foods compared with the elemental diet,
      • Feuling M.B.
      • Noel R.J.
      Medical and nutrition management of eosinophilic esophagitis in children.
      but intensive education by a registered dietitian and interval monitoring of growth makes the diet manageable for most families. Interestingly, complete remission (≤1 eosinophil/hpf) occurred in only 30% to 60% of patients, with a higher percentage occurring in patients on an elemental diet and a lower percentage in patients on a directed elimination diet. These results differ from a previous study that demonstrated a significant improvement in esophageal eosinophilia (mean ± SD, 1.1 ± 0.6 eosinophils/hpf) in 97% (160/164) of patients on an elemental diet.
      • Liacouras C.A.
      • Spergel J.M.
      • Ruchelli E.
      • Verma R.
      • Mascarenhas M.
      • Semeao E.
      • et al.
      Eosinophilic esophagitis: a 10-year experience in 381 children.
      In this same study 57% (75/132) of patients demonstrated significant improvement in esophageal eosinophilia (mean ± SD, 5.3 ± 2.7 eosinophils/hpf) in patients on a directed elimination diet.
      • Liacouras C.A.
      • Spergel J.M.
      • Ruchelli E.
      • Verma R.
      • Mascarenhas M.
      • Semeao E.
      • et al.
      Eosinophilic esophagitis: a 10-year experience in 381 children.
      In our study the odds of postdiet remission versus nonremission were 5.6-fold greater on an elemental diet compared with the SFED, 12.5-fold greater on an elemental diet compared with the directed diet, and not significantly different on the SFED compared with the directed diet.
      A single-food reintroduction followed by histologic evaluation is the gold standard method for determining whether a food is tolerated.
      • 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.
      Only food reintroductions conducted in patients who underwent both SPTs and APTs at the CCED were included to reduce variation when interpreting results. A total of 116 single-food reintroductions were evaluated. The use of combined SPT and APT results has been advocated when identifying foods as a causative agent in patients with EoE.
      • 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.
      • Spergel J.M.
      • Andrews T.
      • Brown-Whitehorn T.F.
      • Beausoleil J.L.
      • Liacouras C.A.
      Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests.
      • Spergel J.M.
      • Brown-Whitehorn T.
      • Beausoleil J.L.
      • Shuker M.
      • Liacouras C.A.
      Predictive values for skin prick test and atopy patch test for eosinophilic esophagitis.
      It was our original intent to use combined SPT and APT results to calculate both NPVs and positive predictive values for foods reintroduced. However, because of the paucity of dual SPT/APT-positive results (1/116), the NPVs were calculated by using only SPT results to assess the utility of the SPT in dietary planning. Moreover, because we implemented a clinical practice–based retrospective study design that did not require reintroduction of foods eliciting positive skin test results, very few patients elected to reintroduce food that elicited positive skin test results. As a result, the true- and false-positive rates for foods reintroduced are unknown; thus only the NPVs based on SPTs alone could be reliably calculated. This differs from studies conducted by Spergel et al,
      • Spergel J.M.
      • Andrews T.
      • Brown-Whitehorn T.F.
      • Beausoleil J.L.
      • Liacouras C.A.
      Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests.
      • Spergel J.M.
      • Brown-Whitehorn T.
      • Beausoleil J.L.
      • Shuker M.
      • Liacouras C.A.
      Predictive values for skin prick test and atopy patch test for eosinophilic esophagitis.
      which required reintroduction of foods eliciting positive skin test results followed by histologic evaluation. This permitted their assessment of the diagnostic accuracy of skin testing by using sensitivity, specificity, positive predictive values, and NPVs based on single and combined SPT and APT results.
      The limitations of this study are linked to the use of a retrospective study design. Patients were not randomly assigned to dietary therapies. Therefore bias related to dietary therapy selection is unknown and might not be equal among dietary therapies, even though demographic and disease-related characteristics measured were not significantly different, except the number of EGDs obtained and the duration of follow-up at the CCED. The evaluation of additional secondary clinical outcomes that could identify potential selection bias, such as a measure of disease severity, were not available or have not been developed at this time. Inferences made related to remission outcomes are based on a mutual agreement made between patients and their CCED gastroenterologist regarding dietary therapy selection. In addition, because of the stringent inclusion/exclusion criteria applied, the external validity is limited to identifiable populations that meet this study's eligibility criteria.
      The 4 foods most often reintroduced in a single-food challenge were milk, wheat, soy, and egg. The NPV for each of these foods was low, ranging from 40% (milk) to 67% (wheat). A low NPV indicates that using skin testing to predict the absence of adverse food reactions is not diagnostically adequate and risks recurrent esophagitis despite a negative SPT response to a particular food. Therefore, it does not seem plausible to design a successful dietary plan that is only based on SPT results. This finding is aligned with the 2010 National Institute of Allergy and Infectious Diseases–sponsored guidelines for managing food allergies, which state that skin test results (either alone or in combination) are not diagnostic of food allergies.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • Jones S.M.
      • Sampson H.A.
      • Wood R.A.
      • et al.
      Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored Expert Panel Report.
      Spergel et al's SPT-only NPVs
      • Spergel J.M.
      • Andrews T.
      • Brown-Whitehorn T.F.
      • Beausoleil J.L.
      • Liacouras C.A.
      Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests.
      • Spergel J.M.
      • Brown-Whitehorn T.
      • Beausoleil J.L.
      • Shuker M.
      • Liacouras C.A.
      Predictive values for skin prick test and atopy patch test for eosinophilic esophagitis.
      were generally higher than the NPVs of our study, with the exception of wheat: milk, 58% versus 40%; wheat, 65% versus 67%; soy, 69% versus 64%; and egg, 75% versus 56%. Perhaps these differences are due in part to our adherence to more stringent cut points for defining whether a food reintroduction passed (<15 compared with 20 eosinophils/hpf) and our higher threshold for considering an APT result as positive (a score of 2+ compared with Spergel et al's 1+).
      It is not uncommon for parents of children with EoE to prefer nonpharmacologic treatment to pharmacologic therapies; thus comparative analysis of histologic remission rates in 3 frequently prescribed dietary therapies is clinically relevant. As evidenced by our data, the implementation of the elemental diet is highly effective compared with the SFED and the directed elimination diet in attaining histologic remission. Further prospective study is warranted to elucidate the limitations and strengths of each dietary therapy, to optimize the initial diet in such a way as to obviate the need for food reintroductions, and to determine which patients require an elemental diet at presentation. Taken together, our study does not substantiate a reliable role for skin testing in dietary therapy for EoE.
      Key messages
      • Skin test (prick and patch)–directed elimination diets show no superiority compared with empiric SFEDs for the treatment of pediatric EoE.
      • Both of these diet plans are inferior at inducing remission compared with an elemental diet.
      • Skin testing has limited usefulness in directing dietary planning for remission and food reintroduction.
      We thank Shawna K. B. Hottinger, Scientific Writer in the Division of Allergy and Immunology, for her valuable and much appreciated editorial assistance.

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      Linked Article

      • A role for food allergy testing in eosinophilic esophagitis
        Journal of Allergy and Clinical ImmunologyVol. 131Issue 1
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          We read with interest the article by Henderson et al1 comparing the effectiveness of diet therapies in the treatment of eosinophilic esophagitis (EoE). As the first reported head-to-head comparison of multiple approaches to dietary therapy for EoE, this article will undoubtedly garner much attention. As such, we would like to raise some points that bear mentioning.
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