Rotaviruses, Caliciviruses, and Astroviruses

Etiology

Rotaviruses, astroviruses, caliciviruses such as the Norwalk agent, and enteric adenoviruses are the medically important pathogens of human viral gastroenteritis (see Chapter 366 ).

Rotaviruses are in the Reoviridae family and cause disease in virtually all mammals and birds. These viruses are wheel-like, triple-shelled icosahedrons containing 11 segments of double-stranded RNA. The diameter of the particles on electron microscopy is approximately 80 nm. Rotaviruses are classified by serogroup (A, B, C, D, E, F, and G) and subgroup (I or II). Rotavirus strains are species specific and do not cause disease in heterologous hosts. Group A includes the common human pathogens as well as a variety of animal viruses. Group B rotavirus is reported as a cause of severe disease in infants and adults in China only. Occasional human outbreaks of group C rotavirus are reported. The other serogroups infect only nonhumans.

Subgrouping of rotaviruses is determined by the antigenic structure of the inner capsid protein, VP6. Serotyping of rotaviruses, described for group A only, is determined by classic cross-neutralization testing and depends on the outer capsid glycoproteins, VP7 and VP4. The VP7 serotype is referred to as the G type (for glycoprotein). There are ten G serotypes, of which four cause most illness and vary in occurrence from year to year and region to region. The VP4 serotype is referred to as the P type. There are eleven P serotypes. Although both VP4 and VP7 elicit neutralizing immunoglobulin G antibodies, the relative role of these systemic antibodies compared with that of mucosal immunoglobulin A antibodies and cellular responses in protective immunity remains unclear.

Caliciviruses, which constitute the Caliciviridae family, are small, 27- to 35-nm viruses that are the most common cause of gastroenteritis outbreaks in older children and adults. Caliciviruses also cause a rotavirus-like illness in young infants. They are positive-sense, single-stranded RNA viruses with a single structural protein. Human caliciviruses are divided into two genera, the noroviruses and sapoviruses. Caliciviruses have been named for locations of initial outbreaks: Norwalk, Snow Mountain, Montgomery County, Sapporo, and others. Caliciviruses and astroviruses are sometimes referred to as small, round viruses on the basis of appearance on electron microscopy.

Astroviruses, which constitute the Astroviridae family, are important agents of viral gastroenteritis in young children, with a high incidence in both the developing and developed worlds. Astroviruses are positive-sense, single-stranded RNA viruses. They are small particles, approximately 30 nm in diameter, with a characteristic central five- or six-pointed star when viewed on electron microscopy. The capsid consists of three structural proteins. There are eight known human serotypes.

Enteric adenoviruses are a common cause of viral gastroenteritis in infants and children. Although many adenovirus serotypes exist and are found in human stool, especially during and after typical upper respiratory tract infections (see Chapter 289 ), only serotypes 40 and 41 cause gastroenteritis. These strains are very difficult to grow in tissue culture. The virus consists of an 80-nm–diameter icosahedral particle with a relatively complex double-stranded DNA genome.

Aichi virus is a picornavirus that is associated with gastroenteritis and was initially described in Asia. Several other viruses that may cause diarrheal disease in animals have been postulated but are not well established as human gastroenteritis viruses. These include coronaviruses, toroviruses, and pestiviruses. The picobirnaviruses are an unclassified group of small (30-nm), single-stranded RNA viruses that have been found in 10% of patients with HIV-associated diarrhea.

Epidemiology

Worldwide, rotavirus is estimated to cause more than 111 million cases of diarrhea annually in children younger than 5 yr of age. Of these, 18 million cases are considered at least moderately severe, with approximately 500,000 deaths per year. Rotavirus causes 3 million cases of diarrhea, 80,000 hospitalizations, and 20-40 deaths annually in the United States.

Rotavirus infection is most common in winter months in temperate climates. In the United States, the annual winter peak historically spread from west to east. Unlike the spread of other winter viruses, such as influenza, this wave of increased incidence was not caused by a single prevalent strain or serotype. Since widespread adoption of vaccine, this geographic phenomenon has vanished. Typically, several serotypes predominate in a given community for one or two seasons but nearby locations may harbor unrelated strains. Disease tends to be most severe in patients 3-24 mo of age, although 25% of the cases of severe disease occur in children older than 2 yr of age, with serologic evidence of infection developing in virtually all children by 4-5 yr of age. Infants younger than 3 mo are relatively protected by transplacental antibody and possibly breastfeeding. Infections in neonates and in adults in close contact with infected children are generally asymptomatic. Some rotavirus strains have stably colonized newborn nurseries for years, infecting virtually all newborns without causing any overt illness.

Rotavirus and the other gastrointestinal viruses spread efficiently via a fecal-oral route, and outbreaks are common in children's hospitals and childcare centers. The virus is shed in stool at a very high concentration before and for days after the clinical illness. Very few infectious virions are needed to cause disease in a susceptible host.

The epidemiology of astroviruses is not as thoroughly studied as that of rotavirus, but these viruses are a common cause of mild to moderate watery winter diarrhea in children and infants and an uncommon pathogen in adults. Hospital outbreaks are common. Enteric adenovirus gastroenteritis occurs year-round, mostly in children younger than 2 yr of age. Nosocomial outbreaks occur but are less common than with rotavirus and astrovirus. Calicivirus is best known for causing large, explosive outbreaks among older children and adults, particularly in settings such as schools, cruise ships, and hospitals. Often a single food, such as shellfish or water used in food preparation, is identified as a source. Like astrovirus and rotavirus, caliciviruses are also commonly found in winter infantile gastroenteritis.

Pathogenesis

Viruses that cause human diarrhea selectively infect and destroy villus tip cells in the small intestine. Biopsies of the small intestines show variable degrees of villus blunting and round cell infiltrate in the lamina propria. Pathologic changes may not correlate with the severity of clinical symptoms and usually resolve before the clinical resolution of diarrhea. The gastric mucosa is not affected despite the commonly used term gastroenteritis, although delayed gastric emptying has been documented during Norwalk virus infection.

In the small intestine, the upper villus enterocytes are differentiated cells, which have both digestive functions, such as hydrolysis of disaccharides, and absorptive functions, such as the transport of water and electrolytes via glucose and amino acid cotransporters. Crypt enterocytes are undifferentiated cells that lack the brush-border hydrolytic enzymes and are net secretors of water and electrolytes. Selective viral infection of intestinal villus tip cells thus leads to (1) decreased absorption of salt and water and an imbalance in the ratio of intestinal fluid absorption to secretion, and (2) diminished disaccharidase activity and malabsorption of complex carbohydrates, particularly lactose. Most evidence supports altered absorption as the more important factor in the genesis of viral diarrhea. It has been proposed that a rotavirus nonstructural protein (NSP4) functions as an enterotoxin.

Viremia may occur often in severe, primary infections, but symptomatic extraintestinal infection is extremely rare in immunocompetent persons—although immunocompromised patients may rarely experience central nervous system, hepatic, and renal involvement. The increased vulnerability of infants (compared with older children and adults) to severe morbidity and mortality from gastroenteritis viruses may relate to a number of factors, including decreased intestinal reserve function, lack of specific immunity, and decreased nonspecific host defense mechanisms such as gastric acid and mucus. Viral enteritis greatly enhances intestinal permeability to luminal macromolecules and has been postulated to increase the risk for food allergies.

Clinical Manifestations

Rotavirus infection typically begins after an incubation period of < 48 hr (range: 1-7 days) with mild to moderate fever as well as vomiting, followed by the onset of frequent, watery stools. All three symptoms are present in about 50–60% of cases. Vomiting and fever typically abate during the second day of illness, but diarrhea often continues for 5-7 days. The stool is without gross blood or white blood cells. Dehydration may develop and progress rapidly, particularly in infants. The most severe disease typically occurs among children 4-36 mo of age. Malnourished children and children with underlying intestinal disease, such as short-bowel syndrome, are particularly likely to acquire severe rotavirus diarrhea. Rarely, immunodeficient children experience severe and prolonged illness. Rotavirus has rarely been associated with mild encephalopathy with reversible splenium lesions; this may progress to cerebellitis. Although most newborns infected with rotavirus are asymptomatic, some outbreaks of necrotizing enterocolitis have been associated with the appearance of a new rotavirus strain in the affected nurseries.

The clinical course of astrovirus infection appears to be similar to that of rotavirus gastroenteritis, with the notable exception that the disease tends to be milder, with less significant dehydration. Adenovirus enteritis tends to cause diarrhea of longer duration, often 10-14 days. The Norwalk virus has a short (12-hr) incubation period. Vomiting and nausea tend to predominate in an illness associated with the Norwalk virus, and the duration is brief, usually consisting of 1-3 days of symptoms. The clinical and epidemiologic picture of Norwalk virus often closely resembles so-called food poisoning from preformed toxins such as Staphylococcus aureus and Bacillus cereus.