Rotavirus Antigenemia in Children Is Associated with Viremia

Abstract

Background

Antigenemia is commonly detected in rotavirus-infected children. Although rotavirus RNA has been detected in serum, definitive proof of rotavirus viremia has not been shown. We aimed to analyze a defined patient population to determine if infectious virus could be detected in sera from children with rotavirus antigenemia.

Methods and Findings

Serum samples obtained upon hospitalization from children with gastroenteritis (57 stool rotavirus-positive and 41 rotavirus-negative), children with diagnosed bronchiolitis of known ( n = 58) or unknown ( n = 17) viral etiology, children with noninfectious, nonchronic conditions ( n = 17), and healthy adults ( n = 28) were tested for rotavirus antigen by enzyme immunoassay (EIA). Results of serum antigen testing were assessed for association with clinical and immunological attributes of the children. Rotavirus antigenemia was detected in 90% (51/57) of children with rotavirus-positive stools, in 89% (8/9) of children without diarrhea but with rotavirus-positive stools, in 12% (2/17) of children with bronchiolitis of unknown etiology without gastroenteritis, and in 12% (5/41) of children with gastroenteritis but with rotavirus-negative stools. Antigenemia was not detected in sera from children with noninfectious nonchronic conditions, children with bronchiolitis of known etiology and no gastroenteritis, or healthy adults. Neither age nor timing of serum collection within eight days after onset of gastroenteritis significantly affected levels of antigenemia, and there was no correlation between antigenemia and viral genotype. However, there was a negative correlation between serum rotavirus antigen and acute rotavirus-specific serum IgA ( r = −0.44, p = 0.025) and IgG ( r = −0.40, p = 0.01) titers. We examined 11 antigen-positive and nine antigen-negative sera for infectious virus after three blind serial passages in HT-29 cells using immunofluorescence staining for rotavirus structural and nonstructural proteins. Infectious virus was detected in 11/11 (100%) sera from serum antigen-positive children and in two out of nine (22%) sera samples from antigen-negative children ( p = 0.002).

Conclusions

Most children infected with rotavirus are viremic. The presence of viremia is directly related to the detection of antigenemia and is independent of the presence of diarrhea. Antigenemia load is inversely related to the titer of antirotavirus antibody in the serum. The finding of infectious rotavirus in the blood suggests extraintestinal involvement in rotavirus pathogenesis; however, the impact of rotavirus viremia on clinical manifestations of infection is unknown.

Abstract

A study of 57 children with rotavirus-positive stools found that most were viremic, and that the presence of viremia was directly related to antigenemia and independent of the presence of diarrhea.

Editors' Summary

Background.

Rotavirus is a type of virus that is the commonest cause of severe diarrhea among children worldwide. It is passed from one person to another when virus present in the stool of an infected person is swallowed by another individual. The infection causes vomiting, watery diarrhea, and fever; many children need to be hospitalized as a result and globally more than 600,000 children are thought to die as a result of rotavirus infections per year. Evidence from single case descriptions of infected children have suggested that rotavirus might also cause symptoms outside of the gut—for example, in the lungs or brain. Previous studies have found fragments of rotavirus, for example RNA or parts of virus protein, in tissues outside of the gut such as liver, kidney, blood, and heart. However, simply finding fragments such as RNA or protein does not necessarily mean that rotavirus infects these tissues.

Why Was This Study Done?

These researchers wanted to find out whether rotavirus was present in the blood of infected children. If evidence of rotavirus in the blood was found, this might help explain why some children infected with rotavirus have symptoms affecting organs other than the gut.

What Did the Researchers Do and Find?

In this study, five groups of patients were recruited and tests were done on each to find out whether infectious rotavirus was present in their bloodstream, and also whether the researchers could detect rotavirus components in blood using antibodies against particular parts of the rotavirus particle. The five groups of patients that were compared included children hospitalized with gastroenteritis; children hospitalized with noninfectious conditions; healthy adult laboratory workers; children with lung infections from known viruses; and finally children with lung infections of unknown cause. The researchers found that among the children with gastroenteritis who had rotavirus in their stool, 90% also had evidence of rotavirus particles in their bloodstream. By contrast, control individuals (either children who were hospitalized with noninfectious conditions or healthy adults) did not have rotavirus particles in blood. A small proportion of children with gastroenteritis but no rotavirus in their stool did have rotavirus particles in blood. Interestingly, a small proportion of the children who had lung infections (but in whom no known virus had been identified as the cause) showed evidence of rotavirus in their bloodstreams. Finally, in a group of 11 children with evidence of rotavirus particles in their bloodstreams, all were found to also have infectious virus present in the blood.

What Do These Findings Mean?

These results show that rotavirus is able to spread beyond the gut and into the bloodstream. The finding that rotavirus can spread into the bloodstream may explain some earlier suggestions that rotavirus is responsible for symptoms outside of the gut. However, it is not yet clear how commonly children with rotavirus have other symptoms resulting from the virus spreading into their bloodstream.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040121.

• Read the related PLoS Medicine Perspective article by David Candy

• Information from the World Health Organization Initiative for Vaccine Research on rotavirus disease burden; see also the Rotavirus Vaccine Program, a partnership that aims to develop rotavirus vaccines appropriate for use in developing countries

• Information from the US Centers for Disease Control and Prevention about rotavirus

• Health Encyclopedia entry from the UK's NHS Direct on Rotavirus