Eosinophilic gastroenteritis (EOG) is an uncommon disease characterized by eosinophilic infiltration of the gastrointestinal tract, usually associated with eosinophilia in the peripheral blood (1). Its origin remains unknown, but several studies of adult cases indicate that eosinophil accumulation and release of eosinophil granule proteins such as major basic protein lead to damage of the gastrointestinal mucosa (2,3). Viral infection has been detected in a small number of patients with EOG (4), but there have been no reports of patients with Epstein-Barr virus (EBV) infection. We previously reported the immunohistopathologic findings of massive major basic protein deposition in the gastroduodenal mucosa of a child with EOG (5). We further examined the gastroduodenal biopsy specimens and found that the gastroduodenal damage observed in this case was associated with EBV infection.
A 6-year-old boy was admitted to Yamaguchi University Hospital in June 1999. He had attacks of bronchial asthma several times a year and was hospitalized twice, at age 7 months and again at 20 months. Nine days before the current hospitalization, he experienced vomiting, loss of appetite, and generalized edema. Notable physical findings upon admission were blood pressure of 125/56 mm Hg, dry and partially atopic skin, pitting edema in all dependent areas of the body, soft abdomen with normal bowel sounds, and normal brown stool.
Significant laboratory findings on admission were total leukocytes count, 13.1 × 10 9 /L; neutrophils, 1.83 × 10 9 /L; eosinophils, 1.18 × 10 9 /L; lymphocytes, 9.43 × 10 9 /L; monocytes, 0.66 × 10 9 /L; total protein, 3.6 g/dL; and albumin, 1.6 g/dL, suggesting protein-losing enteropathy. Results of liver function tests and urinalysis were normal, as were blood electrolyte, urea nitrogen, and creatinine levels. Serum immunoglobulin levels were IgG, 337.0 mg/dL; IgA, 41.7 mg/dL; IgM, 28.2 mg/dL; and IgE, 580 IU/mL. Serum specific IgE antibodies were found against milk, egg, house dust, and house dust mite. Results of enzyme-linked immunosorbent assay (ELISA) for antibodies were VCA-IgM, 1.1; VCA-IgG, 3.6; EBNA, 9.0 (positive is >1.0). Serum serology demonstrated low titers against cytomegalovirus (IgM and IgG). Upper gastrointestinal endoscopy revealed broad geographic erosion with areas of attached necrotic tissue in the gastric body and antrum (Fig. 1A). The patient was treated with albumin infusion and an H2-blocker. All clinical and laboratory parameters normalized within 1 month. The patient was still in remission when he visited our clinic in February 2000.
Gastric and duodenal biopsy specimens were obtained during the upper gastrointestinal endoscopy. Sections were formalin-fixed, paraffin-embedded, and stained with hematoxylin and eosin and with Giemsa (to detect Helicobacter pylori). Immunohistochemical studies were performed on paraffin-embedded sections by the streptavidin–biotin method with a labeled streptavidin– biotin kit (DAKO, Kyoto, Japan). The monoclonal antibodies used were anti-CD20 (pan B-cell marker; DAKO), anti-CD4 (helper/inducer T-cell marker; Novocastra, Newcastle upon Tyne, UK), anti-CD8 (cytotoxic/suppressor T-cell marker; Novocastra), anti-CD16 (natural killer cell marker; Novocastra), and antibody reagent for cytomegalovirus (Novocastra). In situ hybridization for EBV was performed with a fluorescein-conjugated EBV-encoded small RNA peptide nucleic acid probe (DAKO; Glostrup, Denmark) and peptide nucleic acid in situ hybridization detection kit (DAKO). Gastroduodenal biopsy specimens obtained from a 4-year-old girl with psychogenic vomiting were used for negative control.
Microscopic examination of with hematoxylin and eosin–stained tissue sections revealed eosinophil and lymphocyte infiltrations in the lamina propria of the gastric mucosa (Fig. 1B). Eosinophil and lymphocyte infiltrations were also observed in the duodenal mucosa, which had appeared normal at gastroscopy. We adopted the criteria shown in Table 1 for evaluating tissue eosinophilia, and moderate eosinophilia (25 eosinophils/×400 field) was demonstrated in the gastric and duodenal mucosae. Helicobacter pylori was not detected in the Giemsa stain preparations. The infiltrating lymphocytes were almost all CD8 + T lymphocytes (Fig. 1C), but a small number of B lymphocytes were also present. No CD4 + T lymphocytes or CD16 + cells were seen. Staining for cytomegalovirus was negative in the gastric and duodenal mucosae.
The in situ hybridization with EBV-encoded small RNA probe produced a positive signal in the nuclei of a small number of lymphocytes (Fig. 1D) but not in control specimens.
Increased tissue eosinophils must be demonstrated to establish a diagnosis of EOG. Whitington et al. (4) evaluated the tissue specimens from children with EOG with respect to the criteria for grading histologic severity of eosinophilia (Table 1) and reported that moderate to extremely severe eosinophilia should be demonstrated for a definitive diagnosis of EOG. In our study, moderate eosinophilia was seen in the gastric and duodenal mucosae, so we were able to diagnose histologically. Eosinophilic gastroenteritis has recently been subdivided into two types: IgE-mediated and non–IgE-mediated EOG (6). Up to 50% of patients with EOG are atopic. However, food allergen–induced reactions are implicated in a minority of patients (6). Although we did not exclude food allergens and we gave neither cromolyn sodium nor steroid, which are usually effective for the treatment of EOG (4), the clinical course for our patient was favorable. Our patient had an obvious history of atopy, but it is questionable whether the gastroduodenal mucosal damage in our patient was related to reactions to food allergens.
On the basis of serum EBV assays and in situ hybridization findings, the gastroduodenal mucosal damage in our patient was mostly likely caused by EBV infection. To our knowledge, there have been no reports of EOG in which EBV infection has been demonstrated in serum and gastrointestinal tissue. This report appears to be the first.
The usual acute EBV infection is likely to occur in epithelial cells of the oropharynx, and the clinical features of infectious mononucleosis are fever, sore throat, and malaise, accompanied by signs of tonsillopharyngitis and lymphadenopathy (7). However, our patient did not manifest these symptoms. In previous reports, evidence of EBV infection has been found in gastric tissue specimens from patients with chronic atrophic gastritis (8); the gastric epithelium is frequently infected with EBV. The initial infection in our patient may have occurred in the gastroduodenal epithelium, not the oropharynx. We think this is the reason our patient did not show the usual clinical manifestations of acute EBV infection.
Microscopic examination of with hematoxylin and eosin–stained tissue sections revealed that eosinophils and lymphocytes, almost all CD8 + T lymphocytes, infiltrated the gastroduodenal mucosa. We previously reported massive major basic protein deposition in the gastroduodenal mucosa of this patient (5). We speculate that CD8 + T lymphocytes induced by EBV infection may produce cytokines that stimulate eosinophil infiltration and release of cytotoxic proteins such as major basic protein. The CD8 + T lymphocytes may play a key role in damage to the gastroduodenal mucosa. Further investigation in other cases is required to clarify the relation between EBV infection and the occurrence of EOG.
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