Rotaviruses are a major cause of diarrheal illness in human infants and young animals, including calves and piglets. Infections in adult humans and animals are also common. Among the rotaviruses are the agents of human infantile diarrhea, Nebraska calf diarrhea, epizootic diarrhea of infant mice, and SA11 virus of monkeys.
Rotaviruses resemble reoviruses in terms of morphology and strategy of replication.
Classification and Antigenic Properties
Rotaviruses have been classified into seven species (A–G) plus one tentative species (H) based on antigenic epitopes on the internal structural protein VP6. These can be detected by immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and immune electron microscopy (IEM). Group A rotaviruses are the most frequent human pathogens. Outer capsid proteins VP4 and VP7 carry epitopes important in neutralizing activity, with VP7 glycoprotein being the predominant antigen. These type-specific antigens differentiate among rotaviruses and are demonstrable by neutralization tests. Five predominant serotype strains of rotavirus species A (G1-G4, G9) are responsible for the majority of human disease. Serotype distributions differ geographically. Multiple serotypes have been identified among human and animal rotaviruses. Some animal and human rotaviruses share serotype specificity. For example, monkey virus SA11 is antigenically very similar to human serotype 3. The gene-coding assignments responsible for the structural and antigenic specificities of rotavirus proteins are shown in Figure 37-4.
Rotavirus structure. A: Gel diagram showing the 11 segments of the genome. The structural (VP) and nonstructural (NSP) proteins encoded by these segments are indicated. B: Surface representation of the rotavirus structure from cryoelectron microscopic analysis. The two outer layer proteins are VP4, which forms the spikes, and VP7, which forms the capsid layer. C: Cut-away view showing the triple-layered organization of the virion, with the intermediate VP6 layer and the innermost VP2 layer indicated. The enzymes required for endogenous transcription (VP1) and capping (VP3) are attached as heterodimeric complexes to the inner surface of the VP2 layer. D: Proposed organization of the double-stranded RNA genome inside the VP2 layer along with transcription enzyme complexes (VP1/3) depicted as balls. E: Exit of transcripts from the channels at the fivefold vertices of actively transcribing double-layered particles. F: Close-up view of one of the exit channels. (Courtesy of BVV Prasad.)
Molecular epidemiologic studies have analyzed isolates based on differences in the migration of the 11 genome segments after electrophoresis of the RNA in polyacrylamide gels (Figure 37-5). These differences in electropherotypes can be used to differentiate species A viruses from other groups, but they cannot be used to determine serotypes.
Electrophoretic profiles of rotavirus RNA segments. Viral RNAs were electrophoresed in 10% polyacrylamide gels and visualized by silver stain. Different rotavirus groups and RNA patterns are illustrated: a group A monkey virus (SA11; lane A), a group A human rotavirus (lane B), a group B human adult diarrhea virus (lane C), and a group A rabbit virus that exhibits a “short” RNA pattern (lane D). Rotaviruses contain 11 genome RNA segments, but sometimes two or three segments migrate closely together and are difficult to separate. (Photograph provided by T Tanaka and MK Estes.)
Rotaviruses have a wide host range. Most isolates have been recovered from newborn animals with diarrhea. Cross-species infections can occur in experimental inoculations, but it is not clear if they occur in nature. Swine rotavirus infects both newborn and weanling piglets. Newborns often exhibit subclinical infection, perhaps reflecting the presence of maternal antibody; overt disease is more common in weanling animals.
Propagation in Cell Culture
Rotaviruses are fastidious agents to culture. Most group A human rotaviruses can be cultivated if pretreated with the proteolytic enzyme trypsin and if low levels of trypsin are included in the tissue culture medium. This cleaves an outer capsid protein and facilitates uncoating. Very few non–group A rotavirus strains have been cultivated.
Rotaviruses infect cells in the villi of the small intestine (gastric and colonic mucosa are spared). They multiply in the cytoplasm of enterocytes and damage their transport mechanisms. One of the rotavirus-encoded proteins, NSP4, is a viral enterotoxin and induces secretion by triggering a calcium-dependent signal transduction pathway. Damaged cells may slough into the lumen of the intestine and release large quantities of virus, which appear in the stool (up to 1012 particles per gram of feces). Viral excretion usually lasts from 2 to 12 days in otherwise healthy patients but may be prolonged in those with poor nutrition and immunocompromised patients. Diarrhea caused by rotaviruses may also be due to impaired sodium and glucose absorption as damaged cells on villi are replaced by nonabsorbing immature crypt cells. It may take from 3 to 8 weeks for normal function to be restored.
Clinical Findings and Laboratory Diagnosis
Rotaviruses cause the major portion of diarrheal illness in infants and children worldwide but not in adults (Table 37-2). There is an incubation period of 1–3 days. Typical symptoms include watery diarrhea, fever, abdominal pain, and vomiting, leading to dehydration.
TABLE 37-2Viruses Associated With Acute Gastroenteritis in Humansa |Favorite Table|Download (.pdf) TABLE 37-2 Viruses Associated With Acute Gastroenteritis in Humansa
|Virus ||Size (nm) ||Epidemiology ||Important as a Cause of Hospitalization |
| Group A ||60–80 ||Single most important cause (viral or bacterial) of endemic severe diarrheal illness in infants and young children worldwide (in cooler months in temperate climates) ||Yes |
| Group B ||60–80 ||Outbreaks of diarrheal illness in adults and children in China and SE Asia ||No |
| Group C ||60–80 ||Sporadic cases and occasional outbreaks of diarrheal illness in children ||No |
|Enteric adenovirus ||70–90 ||Second most important viral agent of endemic diarrheal illness of infants and young children worldwide ||Yes |
| Noroviruses ||27–40 ||Important cause of outbreaks of vomiting and diarrheal illness in older children and adults in families, communities, and institutions; frequently associated with ingestion of food ||No |
| Sapoviruses ||27–40 ||Sporadic cases and occasional outbreaks of diarrheal illness in infants, young children, and elderly adults ||No |
|Astroviruses ||28–30 ||Sporadic cases and occasional outbreaks of diarrheal illness in infants, young children, and elderly adults ||No |
In infants and children, severe loss of electrolytes and fluids may be fatal unless treated. Patients with milder cases have symptoms for 3–8 days and then recover completely. However, viral excretion in the stool may persist up to 50 days after onset of diarrhea. Asymptomatic infections with seroconversion occur. In children with immunodeficiencies, rotavirus can cause severe and prolonged disease.
Adult contacts may be infected, as evidenced by seroconversion, but they rarely exhibit symptoms, and virus is infrequently detected in their stools. A common source of infection is contact with pediatric cases. However, epidemics of severe disease have occurred in adults, especially in closed populations, as in a geriatric ward. Group B rotaviruses have been implicated in large outbreaks of severe gastroenteritis in adults in China and southeastern Asia (Table 37-2).
Laboratory diagnosis rests on demonstration of virus in stool collected early in the illness and on a rise in antibody titer. Virus in stool is demonstrated by enzyme immunoassays (EIAs) or IEM. The EIA test is more sensitive than the IEM. Genotyping of rotavirus nucleic acid from stool specimens by the polymerase chain reaction (PCR) is the most sensitive detection method. Serologic tests can be used to detect an antibody titer rise, particularly ELISA.
Epidemiology and Immunity
Rotaviruses are the single most important worldwide cause of gastroenteritis in young children. Estimates range from 3 to 5 billion for annual diarrheal episodes in children younger than 5 years of age in Africa, Asia, and Latin America, resulting in as many as 1 million deaths. Developed countries have a high morbidity rate but a low mortality rate. Typically, up to 50% of cases of acute gastroenteritis of hospitalized children throughout the world are caused by rotaviruses.
Rotavirus infections usually predominate during the winter season. Symptomatic infections are most common in children between ages 6 months and 2 years, and transmission appears to be by the fecal–oral route. Nosocomial infections are frequent.
Rotaviruses are ubiquitous. By age 3 years, 90% of children have serum antibodies to one or more types. This high prevalence of rotavirus antibodies is maintained in adults, suggesting subclinical reinfections by the virus. Rotavirus reinfections are common; it has been shown that young children can suffer up to five reinfections by 2 years of age. Asymptomatic infections are more common with successive reinfections. Local immune factors, such as secretory immunoglobulin A (IgA) or interferon, may be important in protection against rotavirus infection. Asymptomatic infections are common in infants before age 6 months, the time during which protective maternal antibody acquired passively by newborns should be present. Such neonatal infection does not prevent reinfection, but it does protect against the development of severe disease during reinfection.
Treatment of gastroenteritis is supportive to correct the loss of water and electrolytes that may lead to dehydration, acidosis, shock, and death. Management consists of replacement of fluids and restoration of electrolyte balance either intravenously or orally as feasible. The infrequent mortality from infantile diarrhea in developed countries is the result of the routine use of effective replacement therapy.
In view of the fecal–oral route of transmission, wastewater treatment and sanitation are significant control measures.
An oral live attenuated rotavirus vaccine was licensed in the United States in 1998 for vaccination of infants. It was withdrawn a year later because of reports of intussusception (bowel blockages) as an uncommon but serious side effect associated with the vaccine. In 2006, an oral live attenuated pentavalent human–bovine reassortant rotavirus vaccine was licensed in the United States, followed by licensing of an oral live attenuated monovalent human rotavirus vaccine in 2008. Both vaccines are safe and effective, and neither is associated with intussusception. Similar to other live attenuated vaccines, immunization of immunocompromised individuals or their family members should be avoided as vaccine strains can cause disease in these patients. A safe and effective vaccine remains the best hope for reducing the worldwide burden of rotavirus disease.