To the Editor.

We read with interest the article by Sepulveda and Patil.1 Other than cytomegalovirus gastritis, viral infections of the stomach were not discussed in the article. Although enteroviruses were thought to be common causes of acute gastritis, few patients had endoscopies and biopsies to confirm the diagnosis.2 Enteroviruses do not form intracellular inclusion bodies and could be easily missed by routine examination without special immunohistochemical stain. A lack of neutrophilic response may not rule out an acute enterovirus infection of the stomach because acute enterovirus meningitis is usually associated with lymphocyte-predominant pleocytosis. Immunoperoxidase staining for enteroviral capsid protein 1 (VP 1) allowed us to identify enterovirus infection in 82% of the stomach biopsies taken from 165 patients with chronic fatigue syndrome and chronic upper gastrointestinal symptoms, as compared with 20% of the control subjects.3 Most of the biopsy specimens had minimal chronic inflammation by pathologic examination, and Helicobacter pylori was only demonstrated in 5% of the specimens.

We investigated the role of acute enterovirus infection in stomach biopsies taken from 20 immunocompetent patients (age 50 ± 22 years, 14 women, 6 men) who were hospitalized for severe vomiting and epigastric pain without known etiology after extensive laboratory and radiographic studies. Endoscopic examinations demonstrated minimal erythema or subepithelial hemorrhage in the antrum in 20 of 20 patients, and the pathologic examination showed mild, nonspecific, chronic inflammatory changes in 20 of 20 biopsies. Six of 20 (30%) had 1+ stainable enterovirus protein in the antrum3; 13 of 20 (65%) had extensive staining (2+) of the specimens with only minimal chronic inflammation (Figure, A through D). Helicobacter pylori was seen in 2 of 20 samples (10%), but both patients also had positive enterovirus staining. All 20 specimens failed to stain with anti-cytomegalovirus monoclonal antibody of the same isotype. Two of 3 biopsy specimens grew enterovirus in cell culture, and 2 of 4 other specimens tested positive for viral RNA by reverse transcriptase-polymerase chain reaction, using previously described procedures.3 Two of 8 perirectal swabs tested positive for enterovirus RNA. Stool cultures and examinations for ova and parasites were negative for all 20 patients. In contrast, 2 of 10 volunteers and 0 of 7 patients who had antrum biopsies for anemia, or gastropathy related to nonsteroidal antiinflammatory drug and alcohol, showed 2+ enterovirus staining. Interestingly, of the 2 volunteers who stained positive, one had recent history of cyclical vomiting and the other had chronic symptoms of gastroesophageal reflux. The difference between the patients and control group was statistically significant (P < .01, χ2 test with Yate correction).

Enterovirus-specific immunoperoxidase staining of antrum biopsy taken from patients with acute gastritis. A, 1+ staining with enterovirus-specific monoclonal antibody (5D8/1 at 1∶2000 dilution, Dako Automation, Carpenteria, California, original magnification x100). B, No staining of the same sample with cytomegalovirus-specific mAb (at 1∶1000 dilution, Chemicon, Temecula, California, original magnification x100). C and D, Another patient specimen with extensive staining (2+) with 5D8/1 of the antrum biopsy (original magnifications x100 [C] and x400 [D]).

Enterovirus-specific immunoperoxidase staining of antrum biopsy taken from patients with acute gastritis. A, 1+ staining with enterovirus-specific monoclonal antibody (5D8/1 at 1∶2000 dilution, Dako Automation, Carpenteria, California, original magnification x100). B, No staining of the same sample with cytomegalovirus-specific mAb (at 1∶1000 dilution, Chemicon, Temecula, California, original magnification x100). C and D, Another patient specimen with extensive staining (2+) with 5D8/1 of the antrum biopsy (original magnifications x100 [C] and x400 [D]).

On follow-up, 17 of 19 patients had chronic, recurrent symptoms of epigastric pain, dyspepsia, nausea, anorexia, reflux, and bloating that lasted 3 months to more than 12 months. Five patients had cyclical vomiting; 1 patient was treated with parenteral hyperalimentation for at least 1 month after the hospitalization.

In the United States, at least 30 million people develop symptomatic enterovirus infection per year.4 The most common route of transmission is oral fecal. Stomach is likely one of the first sites of viral replication because our previous study demonstrated chronic persistent infection in the stomach,3 and enterovirus infection of animal stomach has been well documented by a recent study.5 Although most cases of acute infection may be mild and self-limited, a significant number of patients develop severe, localized symptoms in the gastrointestinal tract requiring hospitalizations or outpatient evaluations. Proper diagnosis of acute enterovirus infection of the stomach may not only define one of the common etiologies of acute gastritis but also help us approach chronic diseases that developed as the result of viral persistence. The findings of this article may provide the impetus for further studies on the role of enteroviruses in acute upper gastrointestinal illness.

1
Sepulveda
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A.
and
M.
Patil
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Practical approach to the pathologic diagnosis of gastritis.
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2008
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Dixon
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Genta
,
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Yardley
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Correa
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Classification and grading of gastritis: the updated Sydney system: international workshop on the histopathology of gastritis, Houston 1994.
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1996
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Chia
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J. K.
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A. Y.
Chia
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Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach.
J Clin Pathol
2008
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4
Oberste
,
M. S.
and
M.
Pallansch
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Establishing evidence for enterovirus infection in chronic diseases.
Ann N Y Acad Sci
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5
Kuss
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S.
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Etheredge
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Pfeiffer
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2008
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EV Med Research, LLC, holds a patent (US patent 7,579,144 B2) for diagnosing chronic fatigue syndrome using the procedure described herein.