Caliciviruses

Pathogens and Pathogenesis

The first calicivirus was discovered in 1972 by electron microscopic examination of stool samples from children affected by an outbreak of gastroenteritis in a school in Norwalk, Ohio, several years previously. This discovery of the subsequently named Norwalk virus marked the first identification of a virus as a cause of gastroenteritis. Norwalk virus and other viruses with similar morphologic features are now classified in the genus Norovirus of the family Caliciviridae Caliciviruses are small, nonenveloped, single-stranded RNA viruses that can be divided into at least 5 genera: Norovirus , Sapovirus , Nebovirus , Lagovirus , and Vesivirus . The main characteristics of noroviruses and sapoviruses, also referred to as human caliciviruses, are summarized in Table 239.1 . Neboviruses, lagoviruses, and vesiviruses are strictly animal pathogens and have not been detected in naturally occurring human illnesses.

Noroviruses are classified into 10 genogroups (G): viruses of GI, GII, GIV, GVIII, and GIX cause human disease, whereas GIII, GV, GVI, GVII, and GX contain viruses only found in animals. These genogroups are further subdivided into 49 genotypes, among which GII.4 viruses have emerged as the leading cause of norovirus outbreaks worldwide. Sapoviruses similarly are divided into 7 genogroups, 4 of which (I, II, IV, and V) contain viruses causing disease in humans. Humans are considered the primary reservoirs for human caliciviruses, but serologic evidence of human infection with bovine and canine noroviruses suggests the potential for rare zoonotic transmission. ^, Additionally, some evidence suggests possible infection of dogs and cats with human strains of norovirus and sapovirus. ^,

Noroviruses and sapoviruses infect villi of the small intestine and likely cause diarrhea by a variety of mechanisms, including disruption of the epithelial barrier and active anion secretion. Mechanisms of immunity to norovirus infection remain unclear. Immunity to an infecting strain might only be temporary and does not appear to confer broad cross-protection. In experimental challenge studies using high doses of Norwalk (GI.1) virus, people became susceptible to reinfection with the same strain after 6 months or less. ^, However, modeling of community transmission based on observed disease incidence rates suggests that immunity can last 4 to 8 years. Early studies found preexisting antibody does not seem to be associated with protective immunity, but rather a marker for susceptibility and prior infection, with some people entirely refractory to infection with a particular strain. This apparent paradox has been explained in part by studies demonstrating genetic factors related to susceptibility and resistance to norovirus infection. Innate resistance has been associated with mutations in the genes for the secretor enzyme, 1,2-fucosyltransferase (FUT2), leading to lack of expression of histo−blood group antigens. These antigens are expressed on the surface of intestinal cells and in body fluids such as saliva and serve as binding ligands for norovirus. People who express histo−blood group antigens (i.e., secretors) are susceptible to most, but not all, norovirus genotypes and typically have higher antibody levels. ^{, ,}

Epidemiology

Caliciviruses, specifically noroviruses, are the most common infectious causes of acute gastroenteritis in people of all ages worldwide and are second only to rotavirus among children aged <5 years. In a systematic review and meta-analysis of 175 studies conducted in 48 different countries, noroviruses were detected in 18% of acute gastroenteritis cases. In the US, noroviruses are estimated to cause on average 19 million to 21 million illnesses, 110,000 hospitalizations, and 900 deaths annually. Following the implementation of universal rotavirus vaccination in the US, norovirus has surpassed rotavirus to become the leading cause of severe pediatric gastroenteritis. With the introduction of rotavirus immunization in many other countries and the consequent reduction of the burden of rotavirus disease, the relative importance of noroviruses in severe pediatric gastroenteritis is similarly expected to increase in these settings.

Noroviruses are highly infectious and are transmitted primarily through the fecal-oral route, either directly from person to person or indirectly by contaminated food and water ( Fig. 239.1 ). Droplet spread from vomitus can infect others in the vicinity or contaminate environmental surfaces, where norovirus can persist and remain infectious for several days. These characteristics help make noroviruses the leading causes of acute gastroenteritis outbreaks in the US and Europe, responsible for approximately 50% of all reported outbreaks. ^, Although outbreaks occur year round, they are more common in colder months. ^, Periodic increases in norovirus outbreaks also have occurred in association with the emergence of new viral strains, particularly those within GII.4, resulting in seasons with increased norovirus activity. ^, Although the emergence of new GII.4 strains typically results in replacement of the previously predominant strain, it does not always result in an increased number of outbreaks, as observed with the most recent GII.4 New Orleans and GII.4 Sydney strains. ^, Of 3709 suspected or confirmed norovirus outbreaks reported to the Centers for Disease Control and Prevention during 2009 through 2016, the most common setting was long term care facilities, in which the predominant transmission route is direct person-to-person contact. ( Fig. 239.2 ).

Noroviruses also are the leading causes of foodborne disease outbreaks in the US. In 2017, norovirus was the most common cause of confirmed, single-etiology foodborne disease outbreaks reported to the Centers for Disease Control and Prevention, responsible for 35% of all outbreaks and 46% of illnesses. Outbreaks have been associated with consumption of oysters, which concentrate viruses from contaminated waters, raspberries presumed to be contaminated in fields, and delicatessen meat contaminated during processing; however, outbreaks are usually linked to prepared foods (e.g., salads, sandwiches) contaminated during final preparation by an infected food worker.

The epidemiology of sapoviruses is less well studied. A US study estimated 9 community sapovirus cases and 1 sapovirus-associated outpatient visit each year per 1000 population, representing 2% of all cases of acute gastroenteritis across the age spectrum. A prospective study in the UK found similar results of 26 community cases and 2 cases in patients presenting to general practice per 1000 person-years attributable to sapovirus. Although sapoviruses are a common causes of infection of infants, with seroprevalence similar to that of GII noroviruses, infections are often mild or asymptomatic. Outbreaks of sapovirus illness are much less common than are outbreaks of norovirus, but they have been reported in schools, childcare facilities, adult long term care facilities, and hospitals, as well as occasional foodborne outbreaks. The broad age range of people affected in these outbreaks suggests that sapovirus infection may not be restricted to young children. Furthermore, an emergent genotype of sapovirus (GI.2) has been associated with an increased number of outbreaks in Europe that primarily affected older adults.

Clinical Manifestations

Norovirus and sapovirus infections usually manifest as acute-onset vomiting with watery, nonbloody diarrhea, after an incubation period of 12–48 hours. Other symptoms include abdominal cramps, nausea, and occasionally low-grade fever. The term “stomach flu” is therefore commonly used to describe these illnesses, although these infections are not related to influenza. Although illness is generally self-limiting and full recovery can usually be expected in 1–4 days, symptoms can be debilitating and lead to dehydration and its sequelae requiring medical attention, especially in children aged <5 years and adults aged ≥65 years. ^, Norovirus outbreaks in nursing homes also have been associated with increased rates of all-cause hospitalization and death, thus underscoring the severe impacts that norovirus infection can have in these populations. Norovirus infections do not appear to result in long term sequelae, although secondary features that have been reported include necrotizing enterocolitis in neonates, chronic diarrhea in immunosuppressed patients, postinfectious irritable bowel syndrome, and neurologic manifestations such as infantile seizures and encephalopathy. More epidemiologic data are needed to confirm these observations and determine their relative frequency.

Generally, norovirus illness is less severe than is rotavirus disease, although medically attended pediatric cases of acute gastroenteritis associated with either virus have similar severity scores. Clinical sapovirus infection manifests with similar but milder symptoms than does norovirus infection and with less vomiting. ^, Volunteer studies suggested that 30% of norovirus infections can be asymptomatic. Importantly, norovirus and sapovirus can be shed in stools for 2–4 weeks after infection, although peak shedding occurs 2–5 days after infection. ^{, ,} Children and people with suppressed immune systems have been reported to shed virus for longer periods. The point at which an infected person ceases to represent a significant risk of contagion is unclear.