Norovirus

Norwalk virus was officially renamed norovirus by the International Committee on Taxonomy of Viruses in 2002. The virions contain a single-stranded RNA molecule in round to hexagonal capsids that are 35-39 nm in diameter, with icosahedral symmetry. The surface structure of the capsid is a regular pattern with distinctive features and 32 cup-shaped depressions.[5, 6]

Norovirus was first recognized as a cause of gastroenteritis in 1972, when it was detected in stool samples collected from infected elementary school students and contacts during an outbreak in Norwalk, Ohio, in 1968. It was declared a member of the Caliciviridae family of viruses in 1993.[7] It is now considered the most common cause of epidemic nonbacterial gastroenteritis in the world.

In the 1970s and 1980s, typing of Norwalk-like virus (NLV) relied solely on immunologic methods involving human clinical samples as the source of antigens and antibodies. These methods had serious limitations in accuracy and reproducibility and never provided a reliable scheme for antigenic classification of strains. In the 1990s, however, newer molecular techniques to amplify, sequence, and express the genome of NLV strains allowed researchers to genetically and antigenically characterize NLV strains.[8]

The Norovirus genus contains more than 40 different strains that are divided into 5 genogroups based on sequence similarity. Viruses in genogroups I, II, and IV are primarily human pathogens, although genogroup II contains a porcine-specific virus. Viruses in genogroup III and V infect bovine and murine species, respectively. Each genogroup is further subdivided into genoclusters based on sequence similarity.[9]

The genome consists of single-stranded RNA of 7.3-7.7 kilobases. It encodes 3 open reading frames (ORFs). ORF 1 is the largest (approximately 1700 amino acids) and expressed as a nonstructural polyprotein precursor that is cleaved by the viral 3C-like protease. ORF 2 encodes the viral capsid (550 amino acids) and contains the shell and protruding domains. ORF 3 encodes a small basic protein of unknown function. See the image below.

The norovirus genomic structure and capsid domains.

Noroviruses are transmitted person to person via direct contact, exposure to aerosols, or fecal–oral routes. Noroviruses are highly contagious, with infection requiring fever than 10 virions (ID50 = 10 virions), leading to disease in 50% of inoculated individuals. The virus is extremely stable in the environment and resists freezing temperatures, heat (up to 60°C), disinfection with chlorine, acidic conditions, vinegar, alcohol, antiseptic hand solutions, and high sugar concentrations. The incubation period is approximately 1-2 days, and symptoms typically last 1-3 days (or longer in immunocompromised individuals). Viral shedding occurs for up to 3 weeks following infection.[10]

Noroviruses bind polymorphic histoblood group antigens (HBGAs) that putatively serve as receptors or cofactors for infection. Strains from different genoclusters bind various HBGAs: Genogroup I viruses preferentially bind blood group A and O antigens, while genogroup II viruses predominantly bind A and B antigens.[11] Individual norovirus strains may be capable of infecting only a subset of the human population, although the diverse binding profiles found within genogroup I and genogroup II viruses likely collectively make nearly all individuals susceptible to norovirus infection.[10] Recurrent infections can occur throughout life because of the great diversity of norovirus strains and the lack of cross-strain or long-term immunity.

Infection is characterized by damage to the microvilli in the small intestine. Upon microscopic investigation, villi are found to be blunted, although the mucosa and epithelium remain intact.[12] A recent study demonstrated increased epithelial cell apoptosis and damage to tight junction proteins.[13] Diarrhea is induced by D-xylose and fat malabsorption, with enzymatic dysfunction observed at the brush border, along with leak flux and anion secretion.[14, 13] Vomiting is related to virus-mediated changes in gastric motility and delayed gastric emptying. Notably, no histopathologic lesions can be identified in the gastric mucosa of infected patients.[15] Noroviruses do not invade the colon, so fecal leukocytes are typically absent, and hematochezia is rare.

Frequency

United States

According to a Centers for Disease Control and Prevention (CDC) report updated in December 2014, each year on average in the United States, norovirus causes 19-21 million cases of acute gastroenteritis (inflammation of the stomach or intestines or both), leads to 1.7-1.9 million outpatient visits and 400,000 emergency department visits (primarily in young children), and contributes to about 56,000-71,000 hospitalizations and 570-800 deaths (mostly among young children and elderly persons).[16]

Norovirus illness can be acquired at any time during the year, but it is most common in winter. In addition, there can be 50% more norovirus illness cases in years when a new strain of the virus is being circulated.

According to surveillance reports prepared by CDC's OutbreakNet team, in 2006, 1,270 reported foodborne outbreaks resulted in 27,634 illnesses and 11 deaths. Among these 1,270 outbreaks, 621 had a single confirmed cause that was most often norovirus (54% of outbreaks), followed by Salmonella species (18% of outbreaks).[17]

Outbreaks have been reported in restaurants, health care facilities, schools, resorts, cruise ships, military ships, and barracks. Viral transmission occurs year-round, with a higher incidence of disease in winter months in temperate climates.[18]

International

Data regarding outbreaks in developing nations are not well quantified, but the outbreak rate in other industrial nations is similar to that of the United States.

Mortality/Morbidity

Norovirus gastroenteritis typically lasts 24-72 hours, with remission occurring without sequelae. Death is extremely rare, except in individuals particularly vulnerable to profound volume depletion.

Age

Norovirus gastroenteritis can occur in individuals of all ages. Studies using norovirus recombinant antigen have suggested an increase in antibody prevalence with advancing age. In one study, the prevalence of norovirus immunoglobulin G (IgG) rose during school-aged years, reaching a peak of 70% in persons aged 11-16 years.[19] It should be noted, however, that not all infected individuals sustain detectable antibody responses.

Norovirus gastroenteritis is a self-limiting disease with an excellent prognosis in otherwise healthy individuals.

Patients with norovirus infection should be educated on personal and environmental hygiene, including avoiding/eliminating contaminated foods and water. Ill individuals should refrain from attending school or work.

Symptomatic gastroenteritis typically develops 24-48 hours after ingestion of contaminated food or water or after contact with an infected individual. Each episode is short-lived, lasting only 24-72 hours. The onset can be abrupt or gradual.

Symptoms include the following:

• Nausea and vomiting (profuse, nonbloody, nonbilious)

• Watery diarrhea (nonbloody)

• Abdominal cramps

• Headaches

• Low-grade fever is common (but temperatures may be higher as well)

• Myalgias and malaise

Vital signs include low-grade fever, tachycardia, and possible hypotension with volume depletion.

Abdominal examination reveals the absence of focal tenderness and peritoneal signs.

Vectors for norovirus infection include the following:

• Water sources include both potable water and lake or swimming pool water (when ingested); noroviruses are relatively resistant to inactivation by chlorine.

• Food sources include shellfish (eg, oysters, clams), salads, cake frosting, and meats. Spread can occur through undercooked contaminated foods or improper hand washing by an infected food handler.

• Body fluid sources include vomitus and feces from infected individuals. Maximal viral shedding occurs during the first 48 hours of illness; however, viruses can be detected in stool up to 3 weeks after illness resolves.[20]

Significant electrolyte and blood chemistry abnormalities such as hypokalemia, hyponatremia, metabolic alkalosis, and elevated creatinine phosphokinase can occur in patients with pre-existing conditions such as inflammatory bowel disease, renal failure, immunocompromising conditions, and cardiovascular disease. Severe clinical features, including acute renal failure, arrhythmia, and signs of acute organ rejection in renal transplant patients were observed in a university hospital outbreak.[21]

One case of norovirus encephalopathy was reported in a 23-month-old child.[22]

Hemolytic uremic syndrome has been reported in association with norovirus gastroenteritis in a patient with chronic renal failure.[23]

Generally, routine laboratory studies are not helpful in suspected cases of norovirus gastroenteritis. In severe cases of gastroenteritis with volume depletion, electrolytes and blood urea nitrogen and creatinine should be monitored.

The peripheral white blood cell count is usually normal. There may be slight polymorphonuclear leucocytosis and lymphopenia.

The absence of fecal leucocytes and occult blood in stool is helpful in ruling out other enteroinvasive infectious diarrhea processes. Stool culture should be performed to exclude infection with bacterial organisms such as Yersinia, Shigella, Salmonella, and Campylobacter species.[24]

Detection methods include the following:

• Immune electron microscopy: Immune serum is used to aggregate virus in stool samples to aid detection.

• Antigen detection immune assay: This has high sensitivity but low specificity because of reactivity with antigenic variants and homologous viruses.

• Nucleic acid amplification: This technique is highly sensitive and specific. The sensitivity of real-time polymerase chain reaction (RT-PCR) is more than 1000 times greater than that of standard enzyme-linked immunosorbent assays and approximately 10-fold greater than reverse-transcription PCR in detection of norovirus capsid proteins in stool and food samples.[1]

• Serum antibody titers can be detected within 2 weeks of illness. During norovirus infection, immunoglobulin M (IgM) to norovirus has been found to be more specific than IgG.[2]

Imaging for isolated uncomplicated gastroenteritis is not required.

In patients with severe symptoms in whom acute abdomen is suspected and in those with pre-existing diseases such as inflammatory bowel disease or other comorbidities, abdominal radiography or CT scanning should be performed.

If the patient is an international traveler, stool testing for ova and parasites and stool culture should be considered.

If the patient is severely immunocompromised (eg, with AIDS), stool tests for Cyclospora, cytomegalovirus (CMV), Isospora, and Cryptosporidium may be considered.

The surface area of the villus is reduced (villus blunting), along with the appearance of a dense intraepithelial infiltrate of CD8+ T lymphocytes. An increase in polymononuclear cells in the lamina propria of the small intestine is also observed.

In one study, electrophysiological analyses of duodenal biopsies from patients with norovirus infected showed increased epithelial apoptosis and a reduction in tight junctional protein expression, leading to epithelial barrier dysfunction. This likely contributes to diarrhea during norovirus infection by a leak flux mechanism (ie, ions and water leak from subepithelial capillaries into the intestinal lumen by paracellular diffusion due to increased permeability of tight junctions). Increased anion secretion was another finding in the study.[13] See the image below.

Hematoxylin and eosin stain of duodenal epithelium.

Oral fluid and electrolyte replacement is generally adequate for the treatment of norovirus infections.

In cases of severe volume depletion, intravenous fluid and electrolyte resuscitation may be necessary.

Symptomatic relief can be achieved using antiemetics for nausea and vomiting and analgesics for myalgias and headache.

Antiperistaltic agents should generally be avoided in cases of infectious diarrhea but could be considered in patients with severe diarrhea.

In all epidemic outbreaks (2 or more people who shared a common meal), the local and/or state health department should be contacted for investigation of potential sources.

For questions, the gastroenteritis section of the CDC can be reached at 404-639-3607. Frequently asked questions are addressed at the CDC’s Viral Gastroenteritis Web site.

See the list below:

• Electrolyte replacement liquids such as Pedialyte or Gatorade

• Regular diet as tolerated

Activity may be performed as tolerated.

In cases of norovirus outbreaks, several measures should be taken to prevent further transmission, as follows:

• Contaminated sources should be identified and eliminated.

• Strict hand hygiene is necessary. Food handlers should be thoroughly educated on the infectivity of norovirus, and updated hygienic codes should be maintained.[25]  Although virucidal efficacy of alcohol against feline calicivirus is inferior to that of povidone-iodine, it is greatly variable depending on different formulations, concentrations, and contact times. In one study, only a 0.5-1 log10 reduction in virus titer was achieved after exposure to ethanol (62%-99.5%) for 30 seconds. Another study showed a 2 and 3 log10 reduction in virus titer when 80% ethanol was used for 30 seconds and 1 minute, respectively. Successful control of a norovirus outbreak using 80% alcohol-based hand rubs was reported in an infirmary.[26]  Hand washing with soap and water is necessary for hands that are visibly soiled.[27]

• Environmental sanitization and disinfection should be performed.

• Instruct individuals with viral gastroenteritis to self-quarantine.

Symptoms of norovirus infection are usually self-limited and resolve spontaneously within 24-48 hours. Antidiarrheal agents may be used with caution but should be avoided in children. Over-the-counter analgesics (eg, ibuprofen, acetaminophen) and antiemetics, if prescribed by physician, can be used for symptomatic relief (drug-specific product labeling should be consulted). Fluid intake is recommended to maintain hydration.