Rotaviruses

Description of the Pathogens

Rotaviruses were first discovered in humans in 1973 when researchers identified wheel-shaped particles on electron microscopy of duodenal mucosa biopsies from infants with severe gastroenteritis ( Fig. 216.1 ). ^, Rotaviruses are 100-nm, nonenveloped RNA viruses belonging to the family Reoviridae. ^, Viral particles contain a triple-layered capsid surrounding a viral genome of 11 segments of double-stranded RNA. These RNA segments code for six structural proteins (VP1–VP4, VP6, and VP7) and six nonstructural proteins (NSP1–NSP6). The VP7 protein (a glycoprotein, or G-type protein) and VP4 protein (a protease-activated protein, or P-type protein) constitutes the outer layer of the capsid. These proteins are the principal targets of neutralizing antibodies and are critical to vaccine development. The VP6 protein makes up the middle layer of the capsid and is the protein to which common stool immunoassays are directed. The other three structural proteins make up the inner core of the capsid (VP2) or are associated with viral RNA (VP1 and VP3). The NSP4 protein is an enterotoxin that mediates some of the early symptoms and signs of disease and may be a protein to which antibodies are developed in the immune response to infection. ^,

Rotaviruses most commonly are classified according to group and serotype. Nine groups have been described (A–I) and are based on genetic and antigenic differences in the VP6 protein. Only viruses in groups A, B, and C are known to cause disease in humans. Group A rotaviruses are the principal cause of human disease worldwide and the subject of this chapter. Group B rotaviruses have been associated with epidemic gastroenteritis in Asia, and group C rotaviruses have been associated with sporadic mild gastroenteritis. Several animal species are susceptible to rotavirus infection (e.g., primates and cows). However, the rotavirus strains that infect animals differ from those that infect humans, and animal-to-human transmission appears to be uncommon. ^,

Group A rotaviruses are further classified by serotype based on their VP7 (G-type) and VP4 (P-type) proteins which was replaced by a binomial genotyping system (Gx-P[x]) based on the genes for these two proteins. This latter system is being replaced with a genotyping system for all 11 genes. At least 27 G serotypes and 37 P genotypes have been described. Although the genes that code for VP7 and VP4 segregate independently, five combinations of these common types generally accounted for 80%–90% of circulating viruses globally in the pre-vaccine period: G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]. ^, In the US, G12[8] has recently become the most prevalent genotype. Of note, certain histo-blood group antigens on enterocytes have been proposed as receptors or ligands for the P protein of rotaviruses and associations between a population’s frequency of particular histo-blood group antigens and disease (or lack of disease) from particular P genotypes have been made.

Epidemiology

Rotaviruses are the most common cause of severe, dehydrating gastroenteritis among children worldwide. ^, However, the epidemiology of infection in different settings can be distinct. Before the availability of rotavirus vaccines, an estimated 527,000 children aged <5 years died each year from rotavirus disease worldwide, accounting for about 40% of all diarrheal deaths and 5% of all deaths in this age group. More than 85% of these deaths occurred in low-income countries ( Fig. 216.2 ). Although rotavirus-associated deaths were rare in high-income countries, hospitalizations were common in both developed and economically developing countries. ^, In the US, before rotavirus vaccine introduction in 2006, rotavirus gastroenteritis accounted for 55,000–70,000 hospitalizations, 205,000–272,000 emergency department visits, and 410,000 physician visits annually, with total annual direct and indirect costs of about $1 billion. Rotavirus continued to be the leading cause of moderate to severe gastroenteritis in young children in an in-depth study conducted from 2007 to 2011 at African and Asian sites that had not yet introduced vaccine. ^, Similarly, data from a vast global network of surveillance sites during 2008–2016 found that in locations without vaccine, a mean proportion of 38% of children hospitalized for acute gastroenteritis had laboratory evidence of rotavirus infection.

In temperate climates, with no vaccine use, rotavirus disease occurs in distinct winter seasonal peaks. ^, Before introduction of vaccine in the US, rotavirus activity usually began in early winter in the Southwest and moved across the country, ending in northeastern states in the spring. In tropical settings, rotavirus can circulate year-round, but often has seasonal peaks during the cool or dry months. ^, Rotaviruses are spread through fecal-oral contamination, predominantly by close person-to-person contact. Transmission also likely occurs through contaminated fomites, especially in out-of-homecare settings and hospitals. Very few infectious virions are needed to cause disease in susceptible hosts. Although probable waterborne transmission has been described, spread through food and water is likely to be rare. Transmission through airborne droplets has been hypothesized because of rapid seasonal transmission through populations, but is not proved. ^,

In areas without rotavirus vaccine, almost all children are infected at least once with rotavirus by the age of 5 years. ^, The highest rates of rotavirus gastroenteritis occur among children aged 4–23 months, who also are more likely to experience severe, dehydrating rotavirus gastroenteritis. Infants aged <3 months have lower rates of infection, and full-term neonates are more likely to be asymptomatic when infected, possibly owing to protection from passively transferred maternal antibody. ^, Data from a cohort of children in Mexico found that after one previous natural infection, 77% were protected against subsequent rotavirus gastroenteritis, and 87% were protected against severe rotavirus gastroenteritis; second and third infections conferred progressively greater protection. Lower levels of protection from previous episodes was observed in a cohort from India. Because natural infection confers protection against subsequent infection and disease, symptomatic illness is less common among those aged >5 years. ^, Even so, rotavirus can cause gastroenteritis among older children and adults, often in households with young children, or among adults who care for young children with rotavirus. ^, Rotavirus outbreaks have been reported among elderly adults in residential facilities.

Clinical Manifestations

Rotavirus infects the villus enterocytes of the proximal small intestine, leading to destruction of the absorptive enterocytes, downregulation of the expression of absorptive enzymes, functional changes in tight junctions between enterocytes, and production of an enterotoxin. ^, This leads to symptoms of gastroenteritis after an incubation period of 1–3 days. The initial manifestations of illness are often fever and abrupt onset of vomiting. Most children have profuse, frequent diarrhea that can occur 8–20 times per day. Vomiting often resolves in 1–3 days, whereas diarrhea can persist for 5–8 days. Some children initially have fever without gastrointestinal tract symptoms. Complications and fatalities are related almost exclusively to the adverse effects of dehydration, electrolyte imbalance, and acidosis. Symptoms and asymptomatic viral shedding can be prolonged in immunocompromised patients, such as those with primary immunodeficiencies and those who have undergone bone marrow or solid-organ transplantation. Rotavirus infection does not appear to cause more severe disease in children infected with HIV. Rotavirus is associated with more severe gastroenteritis than other enteric pathogens and is more likely to result in dehydration.

Rare cases of meningoencephalitis possibly due to rotavirus have been reported. Other extraintestinal rotavirus manifestations have been described, including acute myositis, hepatitis, hemophagocytic lymphohistiocytosis, and polio-like paralysis, but their relationship to rotavirus infection remains unclear. Rotavirus antigenemia and viremia have been identified in children with rotavirus disease, but the clinical significance of these findings is unclear. Rotavirus has been detected in some surveys of children with intussusception, although the studies usually are uncontrolled and the results variable. Two large case-control studies did not find an association between rotavirus infection and intussusception. ^, Rotavirus is not thought to be a principal cause of intussusception.

Laboratory Findings and Diagnostic Tests

Stool examination from patients infected with rotavirus reveals watery or soft stools, which rarely contain gross blood and usually are guaiac-test negative. Fecal leukocytes generally are not observed. Patients can demonstrate electrolyte abnormalities associated with accompanying dehydration. Additionally, rotavirus causes a transient rise in serum hepatic enzyme levels in about two-thirds of children hospitalized for rotavirus gastroenteritis.

The diagnosis of rotavirus is primarily made by testing of fresh, whole stool sample. Many commercial kits are available that detect group A rotavirus antigen by EIA or immunochromatography. However, in countries such as the US that have had marked reduction in rotavirus disease because of vaccination, the positive-predictive value of these tests is expected to be lower (and negative-predictive value to be higher) compared with the pre-vaccine era. Multi-pathogen PCR-based assays for stool samples are increasingly being used in clinical laboratories. As with other pathogens, detection of rotavirus nucleic acid in a stool sample may be due to a more remote infection and may not indicate the cause of a current illness; hence, clinical interpretation of a positive result can be challenging. Rotavirus can be detected in stool using EIA tests during the symptomatic period and immediately before onset and for days after resolution of symptoms. ^, Virus also can be identified in stool by electron microscopy, electrophoresis and silver staining, and viral culture in some research and reference laboratories.

Treatment

No specific therapies exist for rotavirus infection. Care requires assessment of hydration status, appropriate correction of fluid loss and electrolyte disturbances, and maintenance of adequate hydration and nutrition. Oral rehydration using appropriate solutions is sufficient for most patients. Intravenous rehydration is required for some patients. Continuation or early reintroduction of oral feeding according to management guidelines should be a priority. Breastfed infants should continue to nurse on demand. Infants fed with formula should continue their usual formula immediately upon rehydration. Children receiving semisolid or solid foods should continue to receive their usual diet during episodes of diarrhea, although it may be useful to avoid substantial amounts of foods high in simple sugars (e.g., carbonated soft drinks, juice, gelatin desserts) because the osmotic content might worsen diarrhea. For children in low-income settings with diarrhea, daily zinc supplementation is recommended by the World Health Organization. Human or bovine colostrum and human serum immunoglobulin contain antibodies to rotavirus and may be beneficial in decreasing or preventing rotavirus diarrhea, but these are not used in routine practice. ^{, ,}