Rotaviruses, Noroviruses, and Other Gastrointestinal Viruses

Definition

Viruses are a principal cause of acute infectious gastroenteritis, a syndrome of vomiting, watery diarrhea, or both that begins abruptly in otherwise healthy persons. Two distinct viruses account for much of these cases. Before rotavirus vaccines were widely introduced over the last 15 years, rotaviruses accounted for over 400,000 deaths annually. Rotaviruses remain the most frequent cause of sporadic, severe gastroenteritis in young children worldwide, causing about 130,000 annual deaths in children younger than age 5 years, mainly in developing countries that have not yet implemented widespread rotavirus vaccination. Noroviruses are the primary cause of epidemic infectious gastroenteritis in both infants and adults in developed countries. For example, outbreaks of gastroenteritis in closed settings, such as cruise ships and nursing homes, are a typical manifestation of epidemic norovirus infections. However, noroviruses are also an increasingly common cause of sporadic, mild to moderately severe gastroenteritis, especially in young children and adolescents, and they are the leading cause of acute diarrhea in families with children in the Netherlands, even though it does not have a rotavirus vaccine program. By comparison, in a birth cohort study from eight sites in South America, Africa, and Asia, rotavirus had the highest attributable burdens for sites without rotavirus vaccination.

The Pathogens

Noroviruses

Noroviruses, which are one of the five genera of the Caliciviridae family, are nonenveloped, icosahedral viruses with a relatively small, positive-sense, single-stranded RNA genome. The norovirus genus is further classified into 10 genogroups. Viruses in each genogroup are further divided into genotypes (more than 48 have been described), and a dual-typing nomenclature (genotype and P-type, depending on serology) has been proposed. Norwalk virus is a prototype genogroup I genotype 1 (GI.1) virus. The norovirus genome is approximately 7.7 kilobases in size and consists of three open reading frames, the first of which encodes the nonstructural proteins that are essential for virus replication. The second open reading frame encodes the major capsid protein, viral protein 1 (VP1). When VP1 is expressed as a recombinant protein, 180 molecules can autoassemble into virus-like particles (VLPs) that closely resemble authentic virions. These VLPs have proven to be critical to the study of noroviral epidemiology and immunity. Human noroviruses have only recently been reproducibly cultured in vitro in human enteroids, so diagnosis generally depends on amplification of viral genes by polymerase chain reaction (PCR; see later) or use of VLPs as recombinant antigens for serologic analysis.

Rotavirus

Rotaviruses, which belong to the family Reoviridae, are large, icosahedral, nonenveloped viruses with a segmented, double-stranded RNA genome and a triple-layered protein coat. Rotaviruses are classified into nine species, A through I, on the basis of the presence of cross-reactive antigenic epitopes and their overall genetic relatedness. Species A rotaviruses are the most commonly encountered viral enteric pathogens of young humans and many other mammalian species. Species B viruses have been identified sporadically in outbreaks of adult diarrheal illness in China and more recently in studies of children with sporadic gastroenteritis, principally in India. Species C rotaviruses are primarily veterinary pathogens and are infrequently associated with diarrheal disease in humans and animals around the world when compared with species A. Species D through G rotaviruses have been isolated only from animals, primarily avian species. Rotaviruses are 100-nm particles that have three concentric layers of proteins: the core is composed of VP1, VP2, and VP3 and the segmented, double-stranded RNA genome; the intermediate layer is formed by VP6, the most abundant and antigenic viral protein; and the external layer is composed of VP7 and VP4. The genome, which is composed of 11 segments of double-stranded RNA that together are approximately 18 kilobases in length, encodes six structural and six nonstructural proteins. As is the case among virtually all other RNA viruses, the rotavirus RNA polymerase is error prone and, along with selective pressure such as the evolution of immunity, drives viral diversity. For rotaviruses, gene reassortment, which is the mixing of gene segments from different parental viruses in cells coinfected by two or more strains, and rearrangement of the viral genome also contributes to genetic diversity. Reassortment of gene segments between animal and human rotavirus strains also occurs in natural settings, especially in less developed countries. Recently an efficient and practical helper virus–free method was developed to recover recombinant rotaviruses, and this method will certainly lead to improved understanding of rotavirus biology as well as enhance the possibility of developing improved vaccines.

Other Agents

Other viral agents that cause human acute infectious gastroenteritis that is difficult to distinguish from disease caused by rotaviruses and noroviruses include the sapovirus (like norovirus, a member of the Caliciviridae family), enteric adenoviruses ( Chapter 333 ) belonging to types 40 and 41, and astroviruses ( Table 350-1 ). The frequency of detection (by PCR assays) of these viruses in individuals with acute gastroenteritis depends on the setting, but they are almost always detected much less frequently than either rotaviruses or noroviruses. Coronaviruses ( Chapter 334 ), toroviruses, picobirnaviruses, picornavirus ( Chapter 349 ), bocavirus, parechoviruses, and pestiviruses have also been isolated occasionally from persons with acute gastroenteritis, but their roles as causative agents of enteric disease remain unproven. Among patients with acute gastroenteritis, no etiologic agent is found in approximately 25 to 50% of cases.

TABLE 350-1

EPIDEMIOLOGIC AND CLINICAL FEATURES OF NOROVIRUS AND ROTAVIRUS

	NOROVIRUS	ROTAVIRUS	ASTROVIRUS
Epidemics	Occurs year-round; outbreaks tend to peak in cold weather	Year-round in equatorial countries; winter peak in others	Winter epidemics in children and endemic year-round
Key driver of epidemics	Antigenic drift strains promoted by population-based immunologic pressure	Size of the susceptible birth cohort	Unknown
Transmission	Fecal-oral, water, and food-borne outbreaks	Fecal-oral	Fecal-oral
Severity of diarrhea in children	Mild to moderate but can be severe	Moderate to severe	Milder than rotavirus or norovirus
Reservoir	Humans are the only known reservoir of noroviruses that infect humans	Mostly humans, but rotaviruses from farm animals and pets (especially in developing countries) can rarely infect humans and very rarely spread	Humans are the only known reservoir of astroviruses that infect humans
Prevention	Viral protein 1–based vaccine in development	Several live attenuated vaccines available	No vaccine in development
Age predisposition	All ages	Primarily children <5 years; disease transmission in older family contacts is relatively low (<25%)	Generally children, but adults may also get disease

Epidemiology

Norovirus

Over time, noroviruses appear to undergo antigenic drift in response to the acquisition of immunity in the general population. At present, gastroenteritis cases around the world are most frequently caused by strains of GII.4 norovirus, with new pandemic GII.4 strains generally appearing every 2 to 4 years. However, pandemic strains seem to circulate for years prior to their worldwide distribution and do not develop from previous pandemic strains, thereby suggesting that these pandemics are driven by an interplay between pre-circulating antigenic diversity and temporal changes in host immunity. Outbreaks of gastroenteritis frequently take place in settings of close human contact, such as military establishments, cruise ships, nursing homes, and schools, especially in cold and dry weather (see Table 350-1 ). Viral spread is enhanced by the very high level of infectivity of noroviruses, as data suggest that 1 to 10 particles constitute an infectious dose, as well as by the shedding of norovirus in the stool for a month or more.

Noroviruses of genotypes GII.4 and GII.3 also are currently responsible for about 12 to 20% of sporadic gastroenteritis in children younger than 5 years in both developed and developing countries. In the United States, where rotavirus vaccination is now widespread, noroviruses have surpassed rotavirus as the principal cause of medically attended visits for gastroenteritis in children younger than 5 years. Among U.S. adults, norovirus may be second only to Clostridioides difficile ( Chapter 271 ) as the cause of severe acute diarrhea, with hospitalizations especially in individuals over age 80 years. Of note is that the prevalence of asymptomatic carriage of norovirus in adults is about 2 to 3%.

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