See “Identification of Specific Foods Responsible for Inflammation in Children With Eosinophilic Esophagitis Successfully Treated With Empiric Elimination Diet” by Kagalwalla et al on page 145.
During the last decade, the increasing prevalence of eosinophilic esophagitis (EoE) has been recognized in both pediatric and adult populations. Initially, case series described the clinical, endoscopic, and histologic manifestations of the condition (1,2). In 2007, a major effort was launched by a multidisciplinary group of experts that resulted in the first consensus recommendations for diagnosis and treatment of EoE (3), which was recently updated (4). These documents provide detailed information on diagnosis and therapeutic options for management, but they do not provide an algorithm for long-term management of individuals.
The present diagnostic concept is that EoE is a chronic, immune-mediated inflammatory process, isolated to the esophagus, which is most often triggered by exposure to food antigens (4). Exclusion of offending food antigens results in disease remission, and reexposure leads to recurrence. Because the number and nature of dietary triggers greatly vary between individuals, no “one-size-fits-all” diet has been devised that can at once eliminate the offending antigens while ensuring complete nutrition for all ages. Replacement of the diet by a nonallergenic, amino acid–based formula accomplishes the task, but cost, palatability, psychosocial difficulties, prolonged process for antigen reintroduction, and the frequent need for tube feeding pose great challenges for families (5).
One alternative to an elemental diet trial in the initial management of EoE is the 6-food elimination diet (SFED). Kagalwalla et al (6) have studied the impact of this diet, which simultaneously eliminates milk, egg, wheat, soy, fish/shellfish, and nuts without regard to results of traditional allergy testing. Approximately 75% of children experience remission of the esophageal eosinophilia while avoiding these antigens. The obvious advantage over an elemental diet is the retention of a substantial portion of the diet, which can be nutritionally complete when managed by a dietician. When successful, the offending food(s) are assumed to come from this group of antigens. Which of the antigens truly promote inflammation is then determined by individual reintroduction followed by endoscopic biopsies (unless obvious recurrence of symptoms requires its withdrawal). As such, a relatively small number of endoscopies would be required to complete the process from initial withdrawal to the final acceptable diet, in contrast to the number of endoscopic biopsies needed if the entire diet were withdrawn during an elemental diet trial.
In the present study, the frequency with which the individual antigens were responsible for eosinophilic inflammation upon reintroduction was established (7). Milk was the most frequent (75%), but each of the antigens was an offender for some individuals, and some individuals adversely reacted to 2 or more of the foods. The latter phenomenon is the basis for removing all 6 foods simultaneously at the outset. If foods were removed individually, then none of the children who are intolerant of >1 antigen would show resolution because of the constant, although changing, presence of at least 1 offending food in their diet.
In an ideal world, EoE would be diagnosed without biopsy, for example, by using biomarkers such as eotaxin-3 or eosinophil-derived neurotoxin, currently under investigation (8), and the penultimate effective diet would be identified at presentation by some form of immune response testing. Antigen-avoidance diets based on allergy testing at presentation achieve a similar rate of disease remission to the SFED (9). Because most children who have EoE have adverse reactions to multiple foods, withdrawal of individual foods while leaving other offenders in the diet simply perpetuates the inflammation. At the same time, false-positive and false-negative allergy testing results in the failure of some elimination diets because either some offending foods remain or nonoffenders are removed unnecessarily. In either case, repeated food trials and endoscopies are required to complete the process of establishing the least restrictive diet. Data published by Spergel et al (10) would suggest that attempting to optimize the SFED by current allergy testing is likely to fail, because the positive predictive value of milk testing in EoE is low at 37%.
Because symptoms do not necessarily return in the early phase of antigen reintroduction, endoscopic biopsy has been performed to ascertain the impact of the antigen on the mucosa. This is a standard practice and has been viewed as a necessary evil in the absence of a perfect biomarker that would indicate the presence of eosinophilic inflammation. To date, no clinical or laboratory factor correlates well enough to replace biopsy in this process, although the search is ongoing.
It is well established that EoE can result in lamina propria fibrosis, loss of compliance of the esophageal wall, or stricture, manifest as chronic dysphagia (the most common symptom in adolescents and adults) (4). The observation that symptoms and histology correlate poorly raises the concern that undertreatment of individuals who have ongoing inflammation may lead to these complications, whether or not they are acutely symptomatic. It is not clear whether all patients who have EoE are at equal risk for this complication, but because the remodeling of the lamina propria is reversible with therapy, the consensus is to treat eosinophil-predominant inflammation compulsively to cause mucosal healing and prevent complications.
The present study provides more data to support an empiric SFED in the initial management of children who have EoE. To be clear, it should be offered only to children for whom the diagnosis of EoE has been carefully established by biopsy and after exclusion of other causes of esophageal eosinophilia. Patient and parent education by an experienced dietician is crucial in maintaining adequate nutrition when major food antigens are eliminated.
An algorithm is clearly needed to guide the optimal management of children who have EoE. Dietary antigen avoidance and off-label use of topical steroids are the mainstays of therapy and seem to be durable therapies over time, although the lack of truly long-term continuous pharmacologic management studies still generates some uncertainty for its safety. At the same time, none of the available therapies are universally effective, likely because of phenotypic variation within the population. No formal definitions of the phenotypes exist, but, for example, we recognize that some individuals are clearly atopic, whereas others are not. Similarly, some develop fibrostenotic complications (strictures, narrow caliber esophagus), whereas others do not. Perhaps matching therapy to phenotype would increase the likelihood of initial remission.
Successful therapy of EoE clearly has many components. Patient education is crucial, and targeting therapy to disease phenotype and patient lifestyle may be important. Comprehensive review of pros and cons of the available therapeutic options with the patients and families may identify individuals for whom a diet trial would not be desirable or successful because of a predicted lack of adherence, for example. Ongoing research should allow more precise directed initial therapy and guide long-term management of this chronic condition.
1. Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology
2. Orenstein SR, Shalaby TM, Di Lorenzo C, et al. The spectrum of pediatric eosinophilic esophagitis beyond infancy: a clinical series of 30 children. Am J Gastroenterol
3. Furuta GT, Liacouras CA, Collins MH, et al. First International Gastrointestinal Eosinophil Research Symposium (FIGURES) Subcommittees. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology
4. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol
2011. [Epub ahead of print April 6]
5. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, et al. 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr
6. Kagalwalla AF, Sentongo TA, Ritz S, et al. Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin Gastroenterol Hepatol
7. Kagalwalla AF, Shah A, Li BUK, et al. Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet. J Pediatr Gastroenterol Nutr
8. Konikoff MR, Blanchard C, Kirby C, et al. Potential of blood eosinophils, eosinophil-derived neurotoxin, and eotaxin-3 as biomarkers of eosinophilic esophagitis. Clin Gastroenterol Hepatol
9. Spergel JM, Andrews T, Brown-Whitehorn TF, et al. Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests. Ann Allergy Asthma Immunol
10. Spergel JM, Brown-Whitehorn T, Beausoleil JL, et al. Predictive values for skin prick test and atopy patch test for eosinophilic esophagitis. J Allergy Clin Immunol