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HOUSTON, April 17 -- Rotavirus infection, the most common cause of severe pediatric diarrhea, spreads beyond the intestines into the blood stream, researchers here reported.

While previous studies had found rotavirus RNA and antibodies in the blood of infected children, the study offers the first definitive proof of viremia, said Margaret E. Conner, of Baylor here, and colleagues.

Nearly all the children with rotavirus infection by stool or antibody analysis also tested positive for viremia (90% and 100%, respectively), the investigators reported online in Public Library of Science Medicine.

"The finding of infectious rotavirus in the blood suggests extraintestinal involvement in rotavirus pathogenesis," they wrote. "However, the impact of rotavirus viremia on clinical manifestations of infection is unknown."

Further study will be needed to confirm whether rotavirus could be responsible for respiratory and other symptoms that have occasionally been reported among children with rotavirus infection, according to an editorial by David C.A. Candy, M.D., of the Royal West Sussex National Health Service Trust in Chichester, England.

"One possibility -- which needs further investigation -- is that the extra-intestinal manifestations of rotavirus infection, such as respiratory symptoms and seizures, are in fact due to the infection being systemic rather than localized to the jejunal mucosa," he wrote.

In the study, the researchers examined blood samples obtained from a range of patients for rotavirus antigen testing. They included children with gastroenteritis (57 stool rotavirus-positive, 41 negative), children with bronchiolitis (58 known, 17 unknown viral etiology), children with noninfectious, nonchronic conditions (17), and healthy adults (28).

Among those with blood-borne rotavirus detected, the researchers reported:

• 90% of children with rotavirus-positive stools (51 of 57).

• 89% of children with rotavirus-positive stools but no diarrhea (eight of nine).

• 12% of children with gastroenteritis but rotavirus-negative stools (five of 41, two of the five tested positive for rotavirus antibodies).

• 12% of children with bronchiolitis of unknown etiology but no gastroenteritis (two of 17).

• None of the children with noninfectious, nonchronic conditions, children with bronchiolitis of known etiology without gastroenteritis, or healthy adults.

• 100% of serum antigen-positive (11 of 11) and 22% of serum antigen-negative children (two of nine both of whom were stool rotavirus-positive, P=0.002).

Neither patient age (P=0.83) nor timing of blood sample collection within eight days after onset of gastroenteritis (P=0.09) significantly affected levels of rotavirus found in the blood. There was no correlation between viral detection in the blood and viral genotype (P=0.96 for G type and P=0.78 for P type).

However, rotavirus antibodies appeared to impair detection of the virus in the blood. Serum rotavirus antigen was negatively correlated with acute rotavirus-specific serum IgA (P=0.025) and IgG (P=0.01) titers.

Explanations may be that "serum antibody prevents antigenemia or serum antibody is bound to rotavirus antigens present in the blood, preventing detection of the antigens" by the assay used, the investigators said.

A previous study found that up to 66% of rotavirus-infected children exhibit both gastroenteritis and upper respiratory tract symptoms, but it is unknown whether rotavirus infection can cause respiratory or other disease without gastroenteritis.

"Our findings suggest that rotavirus infection may be underdiagnosed and highlight a possible etiologic role for rotavirus in respiratory illness in some children," they wrote.

Furthermore, they said they suspect that nearly all rotavirus infections cause bloodstream infection early on with the rate then declining as acute antibody titers or other immune factors rise.

The findings suggest that the association between rotavirus and nonintestinal diseases should be re-evaluated, the researchers said.

"Because the number of children infected with rotavirus each year is over 114 million, even a small percentage of these children experiencing serious clinical extraintestinal disease would mean a relatively large number of children could be affected," they wrote.

"The discovery that rotavirus causes viremia in children changes the way we view rotavirus pathogenesis, and future work will need to focus upon the impact of rotavirus viremia upon disease burden," they concluded.

The study was supported by grants from the National Institutes of Health, the Department of Veterans Affairs, the Gulf Coast Digestive Disease Center, the Public Health Service, and Wyeth-Lederle Vaccines and Pediatrics and a Glaser Pediatric Research Network Fellowship Award. One of the authors is a member of the advisory boards of GlaxoSmithKline and Merck. Dr. Candy reported no specific funding or competing interests related to his editorial.

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