No patient was evaluated for gastroesophageal reflux using pH probe testing. Rather, patients were treated presumptively for reflux with a proton pump inhibitor. A lack of response to aggressive therapy was used as the clinical indication to perform endoscopy. Most of our patients were treated with a proton pump inhibitor at a dose of 1 to 2 mg/kg/day for 4 to 6 weeks before endoscopy. We thought this approach would improve histologic changes that may have resulted from mild to moderate reflux, which could have confounded the clinicopathologic diagnosis.
At the time of writing, 6 of 13 children had been treated with an elimination diet. RAST was performed for the most common antigens implicated in food allergies (cow's milk, soy, egg white, peanut, and wheat), along with any other foods identified by the parents as related to symptoms. Four of the children's elimination diets were directed by RAST, and the remaining two were based on the five most common antigens. Three of these children had both symptomatic and histologic improvement of their EE. New foods were methodically reintroduced, starting with the least allergenic. Initially rice; yellow, green, and orange vegetables; and selected fruits (apples, pears, bananas) were tried. Next, meats and fish (excluding shellfish) and grain, and finally the foods with high allergic potential, such as eggs, tomatoes, and dairy were introduced. New foods were tried for 5 days before introduction of another food. Foods identified on RAST as allergic were eliminated completely. In three patients, the elimination diet failed, and the patients were switched to an elemental diet. Four children were initially started on an elemental diet. Three had complete resolution of clinical and histologic symptoms, and the other is awaiting follow-up. Three children are currently being considered for elimination diets. Table 4 provides the details of each patient's treatment plan and clinical course.
We report 13 pediatric patients with adherent white plaques in the esophagus associated with the diagnosis of EE. Eight of these patients also had eosinophilic microabscesses on histopathologic analysis. All children seen in follow-up have had clinical improvement on either elimination or elemental diets. In addition, patients who have had follow-up biopsies after treatment have shown disappearance of the adherent white plaques and histologic improvement.
The histologic criteria that define EE have not been established. Kelly et al. (2) described a group of patients with 15 to 100 eosinophils/hpf (median, 41) in the distal esophagus who improved on elemental diets. Liacouras et al. (3) found patients with gastroesophageal reflux have 2.3 ± 1.2 eosinophils/hpf compared with 34.2 ± 9.6 eosinophils/hpf in patients with EE. Orenstein et al. (4) reported a group of children with at least 20 eosinophils/hpf and indicated that those with 5 to 20 eosinophils/hpf should be considered in the EE category. Finally, Walsh et al. (7) described two groups of patients with 31 ± 19.5 eosinophils/hpf and 28 ± 23.7 eosinophils/hpf, as having EE if they also had incomplete response to antireflux therapy and clinical improvement with antiallergy therapy. All of our patients meet the most stringent criteria for EE proposed by these authors.
A variety of visual findings may be observed in patients with EE. Some children meeting the histopathologic criteria of EE have a grossly normal appearing esophagus. Some have nonspecific erythema, friability, or ulcerations. More characteristically, the mucosa may appear granular, occasionally with circumferential creases, rather than its normal smooth, shiny appearance (4). Fox et al. (5) describe longitudinal furrowed lines in the distal esophageal mucosa in patients with moderate to severe EE. Rings, webs, and a corrugated appearance attributable to repetitive rings or webs, also have been reported (6). Several previous reports of patients with EE, without specifically describing white plaques, do note a negative or inadequate evaluation for candidal infections, thus implying that white plaques may have been present (8–10). Ahmed (11) and Lim et al. (12) described adherent white plaques in the esophageal mucosa of patients with EE. The adherent white plaques seen in our patients may be present in a few discrete areas or more diffusely. Most of our patients had eosinophilic micro-abscesses of the esophageal mucosa on histologic analysis (Fig. 2B). We speculate that the adherent white plaques may represent the visual correlate of eosinophilic abscesses.
It is crucial that the adherent white plaques of EE not be confused with candidal esophagitis. The absence of yeast must be demonstrated, either by a brushed potassium hydroxide preparation or by specific histologic staining. Brito and Barbosa (13) described a patient with intermittent dysphagia and partial stenosis of the gastroesophageal junction who had esophageal candidiasis and an associated heavy infiltration of the esophagus with eosinophils. This patient's symptoms resolved after antifungal therapy, but the eosinophilic infiltration remained. (13). This example underscores the importance of excluding a superimposed or primary fungal infection. In each of our patients, fungal infection was systematically excluded by negative fungal histologic findings and often supported by the addition of a negative potassium hydroxide preparation.
EE has been classified as a mixed IgE and non-IgE mediated disorder. Total serum IgE levels may be normal or slightly elevated, but peripheral eosinophilia is uncommon (14). All of our patients in whom serum IgE was measured had elevated levels, but only a few had peripheral eosinophilia. Similar to other reports, we found an association between the eosinophilic gastrointestinal disorder and other allergic conditions, such as eczema and asthma (15). The presumption is that eosinophilic infiltration of the esophageal mucosa represents an adverse immunologic response. Eosinophils may serve as links between the immune system and inflammatory effector cells. IL-5, a cytokine secreted by lymphocytes, attracts and activates eosinophils (15). T cells from patients with eosinophilic gastroenteritis secrete more IL-5 than those of control subjects (16), although the exact immunopathogenesis is poorly understood.
Many patients with EE are initially thought to have gastroesophageal reflux disease. Because of the variability in clinical presentation, the diagnosis of EE often is not suspected before EGD. Although white exudate has been described in association with severe reflux, this report did not consider the possibility of EE. Thus, an evaluation of allergic gastrointestinal disorders, including eosinophil count, was not performed (17). Our patients were treated presumptively with a proton pump inhibitor before endoscopy. Lack of response to therapy was used as a clinical indication to evaluate endoscopically for refractory gastroesophageal reflux or allergic EE. After the diagnosis of EE was made, if precipitating foods could be identified, patients began an elimination diet. If precipitants could not be identified or an elimination diet failed, an elemental diet, such as EO-28 or Neocate One + (Scientific Hospital Supplies, Inc.) (2), was begun. These amino acid-based formulas were used to remove all potential food antigens and induced prompt remission of disease. Once symptoms improved, typically after 6 weeks, another EGD was done to assess visual and histologic changes. In our series, RAST testing proved useful in several patients in designing an elimination diet that excluded identified allergens. Many patients were allergic to common antigens (milk, soy, eggs, and wheat), whereas a few manifested unusual food allergies. None of our patients were treated with topical or systemic steroid therapy.
In summary, we have described an under-recognized endoscopic finding in EE, adherent white plaques in the esophagus, that resembles candidal esophagitis. This visual finding should prompt clinicians and pathologists to seriously consider EE and evaluate for fungal infections. Eosinophilic abscesses or collections may account for this visual finding. The prognostic implications of this finding require further investigation.
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