Norovirus

Last updated July 14,2006

Agent
Pathogenesis
Epidemiology
Clinical Features
Differential Diagnosis forGastroenteritis
Laboratory Diagnosis
Treatment
Vaccines
Travel Implications
Disease Prevention and Control
References

Agent

Classification

Norovirus is a member of the Caliciviridae family that includes four viral genera: Lagovirus, Vesivirus, Sapovirus, and norovirus.
Sapoviruses and noroviruses cause gastroenteritis in humans; whereas, lagoviruses cause hemorrhagic diseases in rabbits and vesiviruses cause vesicular disease in swine, cats, and marine mammals (see References: CDC 2001, Treanor 2005, Petric 2003).
Norwalk virus was the first norovirus identified as a cause of acute gastroenteritis. Following an outbreak of "winter vomiting disease" in 1968 in Norwalk, Ohio, investigators found that they could transmit the illness to volunteers through organism-free filtrates of stool from affected individuals, suggesting that the illness was caused by a virus. In 1972, 27-nm viral particles were observed through electron microscopy in fecal filtrates used to induce illness in volunteers (see References: Atmar 2001).
No practical in vitro method exists for growing norovirus or sapovirus in cell culture, so until the advent of molecular biologic techniques, these viruses were grouped according to their physical properties as visualized with electron microscopy. Initially, they were referred to as small round-structured viruses (SRSVs). Further molecular characterization demonstrated that they were closely related to other caliciviruses.
Noroviruses currently are classified into five distinct genogroups designated GI to GV, and are further subclassified into more than 25 genetic clusters:

GI (five genetic clusters)
GII (>15 genetic clusters)
GIII (detected in pigs and cattle)
GIV
GV (recently detected in mice)

GI, GII, and GIV strains infect only humans and cause acute gastroenteritis. Examples of GI clusters include Norwalk virus (GI/1), Southampton virus (GI/2), and Desert Shield virus (GI/3); examples of GII clusters include Hawaii virus (GII/1), Snow Mountain agent (GII/2), and Toronto virus (GII/3); and an example of a GIV cluster is Ft. Lauderdale virus (GIV/1) (see References: Blanton 2006).
Molecular analysis of the distinct nucleic acid sequences for each strain can be used to further classify the strains into "sequivars."

Key Microbiologic Characteristics

Noroviruses have the followingcharacteristics:

Virions have a diameter between 26 and 34 nm.
They have a single-strand, positive-sense RNA genome with a polyadenylated 3' tail and a single capsid polypeptide of 59 to 62 kiloDaltons (kD).
The RNA is about 7.6 kilobases (kb) and has three open reading frames (ORFs):

ORF 1 encodes for the large polyprotein that breaks down into helicase, protease, and RNA polymerase after proteolytic cleavage.
ORF 2 encodes for the capsid protein (VP3).
ORF 3 encodes for a predicted 22.5 kD protein of unknown function.

Multiple genetic and antigenic types exist.
Particles have cubic symmetry with a somewhat indistinct, rough outer edge.
Particles are relatively heat and acid stable.
Less than 100 viral particles are required to cause infection.
Particles can survive 10 ppm (parts per million) chlorine, freezing, and heating to 60°C.
Noroviruses can reinfect previously infected hosts; immunity following infection generally is short-lived.
Infected hosts can shed virus in stool for up to 2 weeks.

Pathogenesis

Virulence Factors

Noroviruses bind to several histo-blood group antigens (complex carbohydrate structures expressed on many cell types, including gastrointestinal epithelial cells; three distinct antigens exist: A, B, and O).
Different viral genogroups have differing affinity for ABO antigens (see References: Huang 2003, Tan 2000):

GI noroviruses preferentially recognize blood group antigens A and O.
GII noroviruses preferentially recognize blood group antigens A and B.
The binding domain for these antigens centers on the P2 domain of the viral capsid.

Blood group antigens likely serve as receptors for noroviruses or some other function critical for infection, because human blood group type is closely linked to susceptibility to norovirus gastroenteritis (see References: Rockx 2005).
In a study that examined histo-blood group antigens and norovirus susceptibility following a waterborne outbreak caused by a GI norovirus (see References: Rockx 2005), the authors made the following observations:

Binding of recombinant norovirus capsids to panels of saliva of patients with ABO, secretor, and Lewis phenotypes showed that among secretors:

Blood group B was poorly recognized by capsids and was significantly correlated with protection from infection.
Binding to blood group O was greater than that of B.
Binding to blood group A was the highest.
Lewis phenotype had no effect on capsid binding.

Althoughnot significant, there wasa trend showing thatnonsecretors were less likelyto become infected with the outbreak strain.
In a group of adults not associated with the outbreak, those of blood group B weresignificantly less likely tohave antibodies to norovirus GI and, therefore, to presumably have been protected against past infection with this genogroup. This finding is consistent with blood group B being a protective attribute in the outbreak investigation. However, those of blood group B were not less likely to have antibodies to GII norovirus (indicating presence of past infection), suggesting that blood group B does not protect against viruses of the GII genogroup.

These findings are supported by an earlier study which also showed that individuals expressing histo-blood group B antigen were less susceptible to infection with Norwalk virus (which is also in the GI group) when challenged in volunteer studies (see References: Hutson 2002).
Another study showed that patients who are ABO nonsecretors are very resistant to infection, even when challenged with large amounts of norovirus (see References: Gary 1987).

Major Mechanisms of Pathogenesis

The following information isdrawn from Treanor 2005 (see References).

Convenient animal models of norovirus-induced gastroenteritis are not available, but conclusions regarding pathogenesis have been obtained from studies of experimentally induced disease among human volunteers.
Acute infection with norovirus results in reversible histopathologic lesions in the jejunum but not the stomach or rectum and manifests with vomiting and diarrhea.
Changes appear within 24 hours of viral challenge, remain through the height of the illness, and persist for a variable time after the illness.
Intestinal villi appear blunted, but the mucosa remains intact. On electron microscopy, epithelial cells are intact, but microvilli are shortened and have widened intercellular spaces.
Histopathic changes clear within 2 weeks, but some jejunal changes may remain for as long as 6 weeks.
Diarrhea is associated with a transient malabsorption of D-xylose and fat, and brush-border enzymes (eg, alkaline phosphatase, trehalase) show reduced activity. Levels return to normal within 2 weeks.
During acute illness, intestinal fluid is produced, but this has not been associated with enterotoxin production.
The precise mechanism of virus-induced diarrhea and vomiting are currently unknown.

Epidemiology

Reservoir

Humans are the only known reservoir for noroviruses and other caliciviruses that cause gastroenteritis in humans.
Some noroviruses are present in swine, cattle, and mice, but these genogroups do not infect humans.

Modes of Transmission

The major mode of transmission is fecal-oral spread, usually through consumption of a fecally contaminated vehicle (either food or water).

Because the infectious dose is as low as 100 viral particles, low-level contamination of food and water can lead to outbreaks.
A food vehicle may be fecally contaminated at its source (such as oysters harvested from contaminated waters or fruits and vegetables grown in contaminated environments). Outbreaks related to oysters appear to be relatively common because norovirus can be concentrated by filter-feeding mollusks and steaming does not kill all viral particles. Oysters from various regions of the world have been shown to be contaminated with norovirus (see References: Cheng 2005).
Food handlers who are shedding virus in their stool can contaminate food items during preparation. Viral shedding in stool can persist for up to 2 weeks after experimental administration of virus to volunteers, and anecdotal evidence from outbreak investigations supports viral shedding beyond the period of active illness (see References: CDC 2000, Lo 1994, Okhuysen 1995).
Waterborne infections may occur as a result of drinking water from a contaminated water supply or through exposure to contaminated recreational water sources (such as contaminated swimming pools, water parks, or lakes). Swimming pools can serve as vehicles for transmission because relatively high levels of chlorine do not kill the virus and water may be contaminated by swimmers who are shedding virus (see References: CDC 2004; Maunula 2005).

Following a common source exposure to contaminated food or water, secondary and tertiary cases among contacts of primary cases result from person-to-person transmission (see References: Becker 2000).
Airborne transmission has been suspected in large outbreaks in closed settings (eg, cruise ships) but has not been reproduced experimentally (see References: Marks 2000, Marks 2003).
Transmission through contact with environmental surfaces has been shown to perpetuate some outbreaks in institutional settings or aboard cruise ships (see References: CDC 2002: Outbreaks of gastroenteritis associated with noroviruses on cruise ships—United States, 2002; Wu 2005).
Outbreaks can be difficult to control because the virus is relatively hardy, multiple modes of transmission may be involved, the infectious dose is low, and decontaminating affected environmental surfaces may be difficult.

Incidence (United States)

Caliciviruses are the most common etiologic agent of acute gastroenteritis and are estimated to cause 23 million illnesses each year in the United States (see References: Mead 1999).
Antibodies to the virus are noted initially in young children (ages 3 to 4), and antibody prevalence exceeds 50% by the fifth decade of life (see References: Treanor 2005).
Transmission of noroviruses occurs year-round, but higher disease incidences occur in the winter months in temperate climates (see References: CDC 2001).
The Centers for Disease Control (CDC) performed a molecular (reverse transcription-polymerase chain reaction [RT-PCR]) and epidemiologic study of trends of caliciviruses associated with outbreaks of acute gastroenteritis suspected to be of viral origin in the United States from 2000 to 2004 (see References: Blanton 2006). Major findings include the following.

Caliciviruses accounted for 81% (181/226) of suspected viral outbreaks; 24% (44) of outbreaks were associated with multiple calicivirus strains:

Multiple GII stains were involved in 28 outbreaks.
Multiple GI strains were involved in three outbreaks.
Both GI and GII noroviruses were involved in 10 outbreaks.

Outbreaks revealed a winter seasonality, but outbreaks also occurred at other times of the year.

The peak was between December and March, although no distinct peak was seen in the 2001-2002 season.
GI and GII noroviruses occurred throughout each season, but GII strains accounted for 86% of all confirmed outbreaks between July 2002 and June 2004, compared with 69% between July 2000 and June 2002.

Outbreaks from 2002 to 2004 had several distinguishing characteristics:

GII/4 strains were detected more often in outbreaks confirmed in closed or semiclosed settings (nursing homes, retirement centers, hospitals, schools, daycare centers).
58% of outbreaks occurred in vacation settings, including cruise ships.
GII/4 strains were significantly more common in confirmed outbreaks involving person-to-person transmission than those involving foodborne transmission (55% vs 18%).
Remaining outbreaks were associated with a wide distribution of GI and GII strains

In 2002, the number of norovirus outbreaks was sharply increased on cruise ships and on land and one sequivar (GII/4-Farmington Hills) predominated. Patients in these outbreaks were more likely to be ill with diarrhea than patients in other outbreaks, but no difference was observed in the frequency of vomiting.
This survey builds on data from earlier surveys (see References: Fankhauser 2002, Fankhauser 1998) which also showed the emergence of strains related to the GII/4 sequivar.

Incidence (Global)

Noroviruses occur around the globe and are a common cause of acute gastroenteritis, although data on the annual incidence of disease generally are not available.

A study conducted in the Netherlands demonstrated that the incidence of gastroenteritis was 79.7 per 10,000 person years and Norwalk-like viruses were isolated from 5% of patients who participated in the study (see References: de Wit 2001).
In a study conducted in England, small round structured viruses were found in 6% to 7% of stools from patients with gastrointestinal illness (see References: Tompkins 1999).

Norovirus has been shown to be a common cause of travelers' diarrhea. In an evaluation of 124 travelers to Mexico who had acute diarrhea, noroviruses were the second most commonly identified pathogen in diarrheal stool samples (21/124, 17%), exceeded only by enterotoxigenic Escherichia coli (50/106, 47%) (see References: Ko 2005).
The increase in the incidence of norovirus GII/4 strains during the period from July 2002 to June 2004 in the United States is similar to what occurred in England, Wales, Germany, and the Netherlands in 2002 (see References: Lopman 2004).
Other countries, including Ireland, Hungary, Japan, New Zealand, and Australia experienced a similar surge in norovirus of the GII group (See References: Buesa 2002, Bull 2006, Foley 2001, Greening 2001, Kageyama 2004, Reuter 2002). In these countries, molecular subtyping demonstrated a preponderance of GII strains, although the specific sequivars varied somewhat.
The Virus Reference Department at the Health Protection Agency's Centre for Infections in the United Kingdom recently reported that an increasing proportion of norovirus outbreaks have been caused by a new variant of the genogroup II.4 (Bristol/1993/UK [Grimsby]) strain (see References: HPA 2006). Sequencing of capsids revealed conserved amino acid changes compared with other strains of this genotype:

The Hunter 284 strain had been the predominant strain until the end of 2005. The new variant was detected in December 2005 and has also been reported in the Netherlands, France, and Denmark. Strains from two outbreaks on cruise ships have been identified as the new variant.
In April 2006, 29% of all genotype II.4 strains were identified as new variant, and in May 2006 the percentage had risen to 57%. The incidence of infections from the new strain has increased every month since January 2006. Such a seasonal pattern is unusual because norovirus outbreaks normally decline by summer. Unusual seasonal patterns have previously coincided with the emergence of novel strains (see References: HPA 2006).

Risk Factors for Infection

All age groups can be affected.
The elderly, immunocompromised patients, and infants may be severely affected.
Infection among the elderly, the immunocompromised, or others with serious underlying medical conditions may rarely be fatal.
Some patients may be genetically more susceptible to infection, but these factors have not yet been completely studied and may be related to genetic factors such as ABO blood type and secretor status (see References: Rockx 2005; Marionneau 2005).

Examples of Key Outbreaks

The most commonsettings/circumstances for norovirus outbreaks are:

Restaurants and events with catered meals (usually foodborne transmission; the most commonly implicated food items include salads, sandwiches, and produce [see References: Widdowson 2005])
Military troops (foodborne or person-to-person transmission)
Recreational camps (foodborne, waterborne, and/or person-to-person transmission)
Athletic teams (person-to-person transmission [see References: Becker 2000])
Swimming pools or other recreational water supplies (waterborne transmission)
Cruise ships (foodborne, waterborne, person-to-person, and environmental transmission)
Nosocomial outbreaks (involving nursing homes or hospitals) and other institutional settings (person-to-person and environmental transmission)

Outbreaks that illustrate thesekey general themes are outlined below.

A large community outbreak occurred in Minneapolis, Minnesota in 1982 (see References: Kuritsky 1984). Illness was associated with consuming frosted bakery items; a single ill food handler had prepared the frosting. Outbreaks that occurred at four social events demonstrated an attack rate of 60% among those who consumed the bakery items. When this was extrapolated to the total volume of contaminated bakery items sold in the community, the authors estimated that 3,000 outbreak-associated cases occurred. This investigation illustrated that reported discrete outbreaks were only the "tip of the iceberg" of norovirus activity related to a common commercial source in the community.
The largest recent outbreak reported in the literature occurred among Hurricane Katrina evacuees in Houston in September 2005 (see References: CDC 2005: Norovirus outbreak among evacuees from Hurricane Katrina—Houston, Texas, September 2005).

1,169 evacuees out of 6,500 who visited the Reliant Park Medical Clinic did so because of symptoms of acute gastroenteritis.
Most of the patients were adults older than age 18 and resided in three facilities in Reliant Park or in smaller shelters and hotels in Houston.
Of the patients reporting acute gastroenteritis, 511 reported diarrhea only, 342 reported vomiting, and 316 reported both.
Stool samples were analyzed for bacterial, parasitic, and viral enteropathogens, and 44 samples were tested by RT-PCR for norovirus.
Norovirus was confirmed in 50% (22/44) samples and no other enteropathogen was identified.

In July 2005, a syndromic sentinel surveillance system monitored disease and injury at a 10-day camping event attended by about 43,000 youths and adults. The system detected an outbreak of gastrointestinal illness among the campers (see References: CDC 2006).

Among four groups of campers, attack rates were 40% (16 of 40) for group A, 48% (38 of 80) for group B, 38% (15 of 40) for group C, and eight (20%) of 40 for group (D). The overall incidence of gastroenteritis for the entire camp throughout the event was 22.2 cases per 1,000 persons.
Stool specimens from all affected groups were analyzed by RT-PCR, and nucleic acid sequencing was done on three of the four groups.
The norovirus identified in two of the groups was similar, differing by only a single nucleotide; one group had a genetically distinct norovirus.

During 2002, CDC received reports of 21 outbreaks of acute gastroenteritis on 17 cruise ships (see References: CDC 2002: Outbreaks of gastroenteritis associated with noroviruses on cruise ships—United States, 2002). Of the 21 outbreaks, nine (43%) were confirmed by laboratory analysis of stool specimens from affected persons to be associated with noroviruses.
A swimming pool was identified as the source of an outbreak of norovirus in Vermont in 2004 (see References: CDC 2004: An outbreak of norovirus gastroenteritis at a swimming club—Vermont, 2004).

Acute gastroenteritis was detected among children whose only common exposure was attendance at a swimming club the previous weekend.
Of the 189 persons for whom information was collected, 53 reported an illness consistent with norovirus (vomiting, 89%; diarrhea, 50%; nausea, 77%).
Analysis by RT-PCR revealed norovirus in 5 of 10 stool specimens tested.

A recent review of waterborne outbreaks in Finland noted that norovirus caused 18 of 28 outbreaks (64%) during the period 1998-2003. Norovirus was identified by RT-PCR testing (see References: Maunula 2005).
Outbreaks also were recently reported among combat troops in Afghanistan (see References: CDC 2002: Outbreak of acute gastroenteritis associated with Norwalk-like viruses among British military personnel—Afghanistan).
Japanese researchers have characterized a norovirus strain among patients of an infant home as a naturally occurring recombinant norovirus (between Hawaii- and Mexico-type viruses). The illness in these cases was more severe than that in previously reported in outbreaks or in sporadic cases (see References: Tsugawa 2006).
Three outbreaks and a series of community cases in Michigan were linked to a single ill food handler who prepared submarine sandwiches for a franchise restaurant (see References: CDC 2006). Outbreaks involved the following settings: a staff luncheon at a school, a staff luncheon at a publishing company, and a luncheon for a social services organization. The ill food handler returned to work several hours after experiencing an illness characterized by vomiting and diarrhea. A stool specimen from the food handler that was obtained 8 days after the illness was positive for norovirus.

Clinical Features

The table below outlines theclinical features of norovirus infection.

Clinical Features of Norovirus Acute Gastroenteritis
Incubation period	12-72 hr after ingestion of contaminated food or water
Presenting features	—Onset of symptoms may be gradual or abrupt; nausea and cramping are often first symptoms —Nausea, vomiting, abdominal cramps, diarrhea —Vomiting relatively more common in children —Low-grade fever in 50% of cases —Diarrhea moderate, with 4-8 nonbloody stools over 24 hr —Other constitutional symptoms frequent (eg, chills, malaise, headache, myalgias)
Laboratory features	—Specific diagnosis requires laboratory confirmation —Routine laboratory tests not helpful in making diagnosis —Decreased activity of brush-border enzymes, including alkaline phosphatase and trehalase —Liver function tests, blood urea nitrogen, creatinine determinations, and urinalysis usually within normal limits —Peripheral white blood cell counts slightly elevated, with relative polymorphonuclear leukocytosis and lymphopenia, but otherwise unremarkable —Absence of leukocytes in feces is a useful tool for excluding enteroinvasive pathogens such as Shigella
Duration of illness	—Usually 1-2 days —After gastroenteritis resolves, patients can excrete the virus for 5 to 7 days and, in some cases for as long as 13 days —Immunocompromised patients can excrete the virus for longer periods
Complications	Severe dehydration or electrolyte imbalance can be fatal in the elderly or those with debilitating conditions; severe vomiting and diarrhea may require parenteral intravenous therapy
Case-fatality rate	Most patients recover without incident, and fatal illnesses are rare; however, illness among the elderly and immunocompromised patients may be severe enough to cause death

DifferentialDiagnosis of Norovirus Infection

Conditions that should beconsidered as causes of symptoms in patients with suspected norovirus infectionare listed below.

Differential Diagnosis of Norovirus Infection

Differential Diagnosis if the main symptom is vomiting
Other calicivirus infection (ie, sapoviruses, particularly in children younger than age 5)
Staphylococcus aureus (ingestion of preformed enterotoxin)
Bacillus cereus (ingestion of preformed enterotoxin)
Heavy metal poisoning (copper, tin, cadmium, zinc)
Ostrich fern (ie, fiddlehead fern) poisoning

Differential Diagnosis if the main symptom is watery diarrhea
Bacillus cereus (preformed diarrheal toxin)
Campylobacter species
Clostridium perfringens
Enterotoxigenic Escherichia coli (ETEC)
Other enteric viruses (astroviruses, other caliciviruses, enteric adenovirus, rotavirus)
Plesiomonas shigelloides
Shigella species
Vibrio cholerae
Vibrio parahemolyticus

LaboratoryDiagnosis

Specimen Collection and Transport

The following information is drawn from CDC 2001; CDC 2004:Diagnosis and management of foodborne illnesses; and Forman 2003 (see References).

Collection

Stool is the preferred sample and should be collected during active diarrhea, preferably as soon as possible after onset of illness.
Vomiting is the predominant symptom among children; therefore, specimens of vomitus can be collected to supplement the diagnostic yield from stool specimens during an investigation.
Stool (and vomitus) samples are collected (10 to 50 mL) in sterile leak-proof, wide-mouth containers (eg, urine cups). Smaller specimens and more formed samples will provide lower diagnostic yields.
Samples may be obtained from suspected food handlers later, since patients continue to excrete virus after being ill.
Rectal swabs are not used because of insufficient yield, but stool samples may be obtained from diaper scrapings.

Transport

Samples should be refrigerated in at 4ºC before testing. Samples can be stored refrigerated for 2 to 3 weeks without compromising diagnostic yield.
Specimens to be transported for testing should be bagged, sealed, and kept on ice or frozen refrigerant packed in an insulated, waterproof container.
If facilities are not available for testing in this time frame, samples can be frozen for antigen or RT-PCR testing. Freezing can destroy viral morphology for electron microscopic diagnosis, but viral nucleic acids can be purified from frozen samples.
Transport and storage for vomitus is the same as for stool.

Standard Diagnostic Tests

Techniques for identification ofclinical, outbreak, and epidemiologic studies are reviewed in Atmar 2001 (see References).

Norovirus-related illness can be suspected on the basis of clinical presentation, epidemiologic information, and failure to detect other pathogens, but specific diagnosis requires laboratory confirmation through one of the following:

Identification of viral RNA in stool or vomitus by RT-PCR assays
Enzyme linked immunoassays (EIA) to detect virus in fecal specimens
Visualization of small, round, structured viruses that react with convalescent sera by immune electron microscopy
Greater than four-fold rise in antibody titer to norovirus in acute and convalescent sera

A commercial EIA has been developed for detection of viral antigen in feces, but the sensitivity is only 55% when RT-PCR is the reference assay (see References: Moe 2004).
Electron microscopy can confirm diagnosis but requires 106 to 107 virus particles per milliliter of stool for visualization.
Immune electron microscopy (precipitation of virus with antibody before electron microscopy) can improve sensitivity by 1 to 2 orders of magnitude, but the technique is highly dependent on individual microscopists and virus can be masked if excess antibody is used (see References: CDC 2001). The technique is not used for routine screening.
RT-PCR assays have become one of the principal means of diagnosing human noroviruses. RT-PCR technology is available at the CDC and most state public health laboratories. The following steps are involved:

Clinical stool (or vomitus) suspensions (10% to 50%) are made and extracted to purify nucleic acid and remove potential RT-PCR inhibitors.
Viral nucleic acid is purified.
Viral nucleic acid is reverse transcribed and amplified using viral specific primers.
Amplified DNA can be analyzed by gel electrophoresis, hybridization, or DNA sequencing to confirm the sequence.

Additional or Specialized Diagnostic Tests

Recently, an EIA that employs salivary antibody assays has been shown to confirm that infections among school children had greater than four-fold rises in anti-norovirus IgA when an antigen in the same cluster was used. This technique is the first documented mucosal antibody response to norovirus in children and it may provide a useful approach for diagnosing outbreaks (see References: Moe 2004).
Production of recombinant capsid antigens has allowed generation of high-titer animal hyperimmune sera for diagnostic purposes and may lead to development of commercial EIA assays for antigen detection in stool. EIAs using monoclonal antibodies also have been studied (see References: Atmar 2001).

Serologic Testing

Norovirus capsid genes can be expressed in baculovirus for development of EIA serologic tests. EIA tests have been used to characterize IgA, IgG, and IgM serologic responses following experimental human infection with norovirus infection (see References: Atmar 2001).
Since some persons have pre-existing IgG antibody to norovirus, a single elevated serologic titer cannot be used to indicate recent infection; a 4-fold or great rise in titer between acute and convalescent sera must be demonstrated (see References: CDC 2001).
Titers begin to rise the fifth day after symptom onset, peak approximately the third week, and then begin to decline after 6 weeks; therefore, acute-phase specimens should be drawn within the first 5 days and convalescent-phase specimens should be drawn at 3 to 6 weeks (see References: CDC 2001).
If more rapid diagnosis is needed, a single specimen for IgA antibody testing may be drawn 7 to 14 days after exposure (see References: CDC 2001).
Serologic testing is generally not used to clinically diagnose norovirus infection and has been applied primarily in outbreak investigations.

Treatment

No antiviral therapies exist to treat norovirus infection.
Oral rehydration with isotonic liquid is the usual treatment.
Patients who have severe vomiting and diarrhea may require intravenous parenteral therapy.
Symptomatic treatment of headache, myalgias, and nausea with analgesics and antiemetics may be useful for some patients.
Bismuth subsalicylate can reduce gastrointestinal symptoms but has no effect on the number or character of stools or virus shedding.
Antiperistaltic agents have been prescribed to control diarrhea, but their effects on disease course and on excretion of the virus have not been rigorously investigated.

Vaccines

No vaccines are currently available for norovirus, but recombinant and transgenic methodologies offer the potential for development of vaccines.
Recombinant vaccines: Expression of the major capsid protein in insect cells using baculovirus recombinants yields virus-like particles that fold spontaneously and lack nucleic acid. Such naked particles are immunogenic when given orally to volunteers and are a potential vaccine candidate (see References: Ball 1999; Tacket 2003).
Plant based vaccines: Expression of norovirus capsid protein in tobacco and potatoes has produced recombinant norovirus particles identical to those derived from insect cell culture, allowing the potential for an edible vaccine. In a small study, when volunteers ingested three doses (150 g) of transgenic potatoes, they experienced significant increases in numbers of IgA antibody-secreting cells, and about 20% had serum IgG antibodies to Norwalk virus capsid protein (NVCP). Stool IgA anti-NVCP was detected in 30% of volunteers (see References: Tacket 2000).

TravelImplications

Diarrhea is the most common illness in travelers to the developing world (see References: Freedman 2005, Freedman 2006) and is ranked among the top three illnesses in a recent survey of 30 GeoSentinel sites (see References: Freedman 2006).
Certain foods are implicated more often than others (see below), so travelers might wish to avoid them (see References: CDC 2001) and take precautions when eating or drinking abroad.
Norovirus outbreaks on cruise ships are a well-documented occurrence. Cruise ships may dock in countries in which levels of sanitation may be inadequate and present a risk of food and water contamination. The close quarters provide additional opportunities for person-to-person transmission and present problems for ship decontamination and may result in multiple outbreaks (see References: Ho 1989).
A recent study of ill students who had a short term stay in Guadalajara, Mexico, revealed that norovirus was the second most common illness after enterotoxigenic Escherichia coli (see References: Ko 2005).
Because of the possibility of multiple infections, presence of norovirus infection may explain the high rate of antibacterial drug failure among travelers (see References: Ko 2005).

DiseasePrevention and Control

Infection Control Recommendations

The following recommendations are taken from CDC 2005:Norovirus in healthcare facilities (see References).

Isolation precautions

Patients with suspected norovirus infection should be managed with Standard Precautions.
Contact Precautions should be added when caring for diapered or incontinent patients, during outbreaks in facilities, and in situations where there is a potential for splashes that might contaminate clothing. Contact Precautions include the following:

Place the patient in a private room, or if a private room is not available, place the patient in a room with a patient who has an active infection with the same pathogen (ie, cohort). When a private room is not available and cohorting is not possible, a spatial separation of at least 3 ft should be maintained between the infected patient and other patients and visitors.
Gloves should be worn when entering the room and removed before leaving the room; hands should be washed with an antimicrobial agent or a waterless handwashing agent immediately after removing gloves, and clean hands should not touch potentially contaminated items or environmental surfaces.
Gowns should be worn when entering the room if it is anticipated that clothing will have substantial contact with the patient, environmental surfaces, or items in the room; the gown should be removed before leaving the patient's environment.
Patient transport should be limited to essential purposes only; if the patient is transported out of the room, precautions should be maintained.
Noncritical patient-care equipment should be dedicated whenever possible. If equipment cannot be dedicated, then it should be adequately cleaned and disinfected between patients.

Persons cleaning areas heavily contaminated with feces or vomitus should wear surgical masks.

Environmental disinfection

CDC recommends that chlorine bleach be applied to hard, non-porous surfaces in the event of a norovirus outbreak. A minimum concentration of 1000 ppm of chlorine bleach should be used (generally a dilution of 1 part household bleach solution to 50 parts water).
Heat disinfection (ie, pasteurization) has been suggested for items that cannot be subjected to chemical disinfectants. A temperature >60°C (140°F) should be used.

Public Health Prevention Measures

Improper food handling and production can provoke outbreaks, but standard hygiene and control measures can help avoid infection and control spread.
Rigorous food handling procedures, including appropriate time-temperature standards, should be followed.
Ill food handlers should be excluded from handling food for 48 to 72 hours after resolution of illness.
Food handlers should be required to maintain strict personal hygiene, including frequent and proper handwashing with soap and water, at all times.
Surfaces that have been soiled should be cleaned with a germicidal product. A minimum concentration of 1000 ppm of chlorine bleach should be used (generally a dilution of 1 part household bleach solution to 50 parts water) (see References: CDC 2005: Norovirus in healthcare facilities).
When traveling to areas where sanitation standards are low, individuals may wish to avoid certain foods that pose a greater risk of infection, including:

Ice and drinks containing ice
Ready-to-eat foods that require handling but no subsequent cooking (eg, salad and deli sandwiches)
Food from street vendors

Individuals also may chose to avoid certain shellfish (such as oysters or clams) and fish caught in polluted waters, which are at increased risk of being contaminated with norovirus.
If drinking water or recreational water is suspected as an outbreak source, high-level chlorination (10 ppm or 10 mg/mL for more than 30 minutes) may be needed for disinfection; however, this method is not always be adequate (see References: CDC 2001).
New techniques for detection of norovirus in water may allow testing of water and prevention of outbreaks (see References: Parshionikar 2004).
In situations in which outbreaks can be extended by influx of new susceptible individuals, such as a cruise ship or camp, the facility or institution should be closed until it is cleaned properly. Environmental surfaces in such settings should be thoroughly disinfected using chlorine bleach as specified above.
Suspected outbreaks should be reported promptly to local or state public health authorities so that an epidemiologic investigation can be initiated.

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