In our study, one fifth of AGE among children within a large pediatric hospital was of viral origin and acquired within the healthcare setting. Furthermore, at least 1 virus was detected in >50% of HA-AGE patients, and in 28%, >1 virus was identified. HA viral gastroenteritis is a major infection control issue in hospital pediatric wards (19). Our study systematically detected each of the 5 established causes of viral gastroenteritis.

Rotavirus was the most common virus identified among children with CA- and HA-AGE (43% and 31%, respectively). It was also the virus most likely to occur alone and was the virus with which severe symptoms were most often associated. A recent review of European studies identified rotavirus in 31%–87% of all-cause HA-AGE, reflecting the differences in methods used in individual studies (4). HA rotavirus infections in our study accounted for 32% of all rotavirus infections identified. This finding is consistent with 2 recent retrospective studies showing that 21% (20) and 36% (21) of rotavirus gastroenteritis cases were HA and 2 reviews documenting that 14%–51% of rotavirus infections among hospitalized children were HA (3,5). Therefore, the impact of HA rotavirus gastroenteritis in major pediatric hospitals has not decreased since the first major study of this subject published nearly 20 years ago (22).

With the availability and application of molecular assays capable of detecting a broad range of norovirus genotypes, norovirus is now recognized as a major cause of sporadic CA-AGE in children (23–25). We document that norovirus was the second most common virus identified (after rotavirus) among children with HA-AGE (detected in 16% of HA-AGE patients and in 24% of HA-AGE patients in which a single virus was identified). Furthermore, norovirus was associated with severe illness in a substantial percentage (24%) of HA-AGE patients in whom it was identified as a sole infection, a percentage similar to that obtained for rotavirus (36%).

Previous studies have investigated adenovirus 40/41 in CA-AGE, and we systematically looked for it in children with HA-AGE. Adenovirus 40/41 was the third most commonly identified virus in our study among children with CA- and HA-AGE (detected in 14% and 15% of patients, respectively). Studies that have investigated for adenovirus 40/41 among children with CA-AGE by using antigen-based detection methods have generally reported detection rates of ≈5% (1). We used molecular methods, therefore suggesting a greater role for adenovirus 40/41 in CA-AGE than has been previously appreciated, and now indicating it also plays a prominent role in HA-AGE. Notably, adenovirus 40/41 was also the third most commonly identified enteric virus in a recent study in East Anglia, UK where it was detected by PCR in 9.6% of all children examined (10). Astroviruses and sapoviruses were much less frequently identified in our study, despite the application of molecular methods.

With the use of molecular methods to detect 5 established viral agents of gastroenteritis, we demonstrated that 15% of HA-AGE patients contained >1 virus, emphasizing the value of the simultaneous examination for multiple viruses. Thus, in a recent community-based study in the United Kingdom that examined for each of these 5 viruses using molecular assays, mixed virus infections were identified in 11.7% of case-patients (24). In almost 50% of the norovirus infections in our study, an additional virus was identified (most commonly rotavirus). Although we found no evidence of increased disease severity among rotavirus–norovirus co-infections (data not shown), our data clearly demonstrate the frequency with which both viruses cocirculate with the potential for nosocomial spread. Dual norovirus–rotavirus co-infections were also commonly recognized in a recent study of hospitalized children in Italy, in whom the severity of illness was higher than with norovirus infection alone (26). Similar to the observations made for norovirus, additional virus infections were commonly identified among case-patients excreting adenovirus 40/41, in whom more than half had additional viruses.

Although each of the enteric viruses detected in this study is firmly established as a gastroenteritis pathogen, the detection of a virus in a child with AGE does not necessarily imply causation. This is most clearly relevant in the context of co-infections including mixed virus infections, where >1 detected organisms may not be primarily responsible for diarrhea. Although we did not exhaustively and systematically search for other potential infective causes of diarrhea, we identified enteropathogenic bacteria and parasites in <2% of specimens examined, which suggests that they were not major causes of diarrhea in our study population (data not shown). Additionally, although detection of a virus by a sensitive molecular method may be more likely than a less sensitive antigen-based assay to indicate subclinical infection (27), prolonged rotavirus shedding demonstrated by RT-PCR was associated with symptoms of diarrhea in a longitudinal study of children recovering from severe rotavirus infection (28). Because molecular-based assays are widely accepted as the preferred detection method for norovirus, but not for other gastroenteritis viruses, application in this study of molecular methods that likely have similar (high) levels of sensitivity for detection of all 5 gastroenteritis viruses allowed more appropriate recognition of the extent of virus circulation within the hospital. Finally, although a stool sample obtained from a patient at hospital admission would be required to conclusively categorize a viral gastroenteritis episode as CA or HA, two thirds of these infections occurred >1 weeks after admission, and a 48-hour symptom-based definition has been used extensively in previous studies (3–5).

The entry and spread of enteric viruses into and within pediatric healthcare settings is not completely understood. Several studies have indicated that multiple rotavirus introductions from the community into the hospital and subsequent spread between patients accounts for most HA rotavirus infections because of the diversity among strains recovered from hospitalized children and similarity at the genotype level between viruses circulating within the community and hospital (20,29,30). Similarly, a recent study that described frequent, brief clusters of norovirus gastroenteritis among pediatric inpatients attributed these findings to frequent introduction of noroviruses into the hospital from the community (31). For both rotaviruses and noroviruses, however, previous studies have not provided direct evidence that strains detected among hospitalized children originated in the community. In this respect, our study provides strong molecular epidemiologic support, at the nucleotide level, for the hypothesis that rotaviruses and noroviruses in the community are the sources of HA infection. Thus, rotaviruses (judged by VP7 sequence), and noroviruses (examined by sequence of the capsid region) detected among HA-AGE cases were similar or identical to corresponding viruses detected in children with CA-AGE.

In contrast to CA-AGE cases, the highest rates of HA- viral enteric infections did not occur on the acute medical and surgical wards but instead in the critical care areas, neurologic, cardiac, and long stay wards where chronically ill children are patients. We observed this trend for each of the 3 major viruses identified (rotavirus, norovirus, and adenovirus 40/41). Although we noticed differences in the hospital distribution of HA-AGE cases, the ages of children with HA-AGE did not differ significantly from children with CA-AGE. We did, however, find evidence for severe disease among 28% of children with HA viral gastroenteritis in our study; 22% of such children had an underlying medical condition (data not shown). Given that CA viruses are likely to be the source of HA viral gastroenteritis, standard hospital infection prevention measures (e.g., isolation of children with AGE) should be emphasized (32). Hand washing by staff before patient contact may be particularly important because asymptomatic staff members could be a source of HA rotavirus infection (33) and hand washing has been shown to reduce the rate for nosocomial rotavirus infection (34). However, because HA rotavirus infection remains a substantial clinical problem ≈20 years after publication of a seminal study on the subject (22), even stringent infection control precautions are likely to be insufficient to greatly reduce the problem. In the context of rotavirus, the major pathogen responsible for CA- and HA-AGE, rotavirus vaccines offer a further opportunity to reduce the impact of HA-AGE. Routine rotavirus vaccination of children in the community is expected to greatly reduce the number of CA, rotavirus-associated hospitalizations (35,36), thereby reducing the hospital rotavirus reservoir and HA rotavirus gastroenteritis. The prevention of HA rotavirus gastroenteritis should represent an important secondary goal of rotavirus vaccines (3,6).

In conclusion, we have demonstrated that viruses accounted for more than half the cases of HA-AGE in a large pediatric hospital and resulted from the frequent introduction of gastroenteritis viruses from the community. Because rotavirus is the single most common pathogen, introduction of a rotavirus vaccine into childhood immunization programs is expected to substantially reduce the incidence of CA and HA rotavirus gastroenteritis in hospitals.