Norovirus infection

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Noroviruses (Norwalk) infection is the most common cause of acute gastroenteritis. Norovirus is a single-stranded RNA, non-enveloped virus. Norovirus is a highly contagious virus. It is often transmitted via contaminated food or water, or by touching contaminated surfaces. Norovirus gastroenteritis results in abdominal pain (usually diffuse, stabbing pain), nausea, diarrhea (usually watery), and vomiting. There is no age or gender predisposition to the development of norovirus infection. Risk factors for norovirus infection include close contact with infected individuals, particularly those in the same household, poor food-handling hygiene, and consumption of contaminated shellfish and/or raw vegetables. Symptoms of norovirus infection start within 12 to 48 hours of exposure to the virus and usually last 24 to 72 hours. Patients usually recover completely without treatment (only hydration) and without any serious long-term sequalae. Young children, elderly, and immunocompromised patients are at a higher risk of complications. In rare cases, norovirus illness can be serious, especially for young children and older adults. Lab findings are usually non-specific and may only be remarkable for signs of dehydration, such as elevated BUN and creatinine, relative polycythemia, and metabolic alkalosis. Real-time PCR is the optimal method for the diagnosis of norovirus infection. Supportive care is the mainstay of therapy for norovirus infection. Treatment includes oral/IV fluid administration to replace fluids lost from vomiting and diarrhea and to electrolyte disturbances. Other pharmacologic agents, such as anti-motility and anti-emetic agents may be administered among adults only (controversial efficacy), whereas anti-diarrheal agents are usually not recommended. Preventive measures include avoidance of exposure, proper hand washing, and adequate handling of food products.

Originally called the “Norwalk agent” after Norwalk, Ohio, Norovirus was first discovered after an outbreak in an elementary school in 1968. The first documentation of the virus on electron microscopy was in 1972.

Norovirus constitutes a genus of genetically diverse single-stranded RNA, non-enveloped viruses belonging to the Caliciviridae family. The Norwalk virus is the only species belonging to that genus; however, several strains have been identified including: Hawaii virus, Mexico virus, and Desert Shield virus. These strains can genetically be classified into five different genogroups (GI, GII, GIII, GIV, and GV).

Noroviruses are highly contagious, given that as few as 10 particles are enough to cause the disease, transmission is via the fecal-oral route and peaks during the period when symptoms are most severe, and up to 3 days after recovery. As many strains of noroviruses exist, immunity is not gained following an infection. A non-functional fucosyltransferase FUT2 mutation has been associated with protection against the most common norovirus strains as FUT2 is required for viral transport in the small intestine.

Norovirus is the cause of norovirus infection. Noroviruses (genus Norovirus) are a group of related, single-stranded RNA, nonenveloped viruses that cause acute gastroenteritis in humans. Noroviruses belong to the family Caliciviridae.

Norovirus should be differentiated from other causes of infectious vomiting and diarrhea, including other causes of viral gastroenteritis (sapovirus, adenovirus, rotavirus), bacterial gastroenteritis (yersinia, vibrio, shigella, salmonella, escherichia coli), and parasitic infections (amoebiasis, cryptosporidiosis).

Norovirus is the leading cause of acute gastroenteritis and foodborne illness in all age groups in the United States. It causes approximately 21 million cases of gastroenteritis yearly. The genogroup II, genotype 4 strain is most commonly involved in large outbreaks of norovirus.

Risk factors for norovirus infection include close contact with infected individuals, particularly those in the same household, poor food-handling hygiene, and consumption of contaminated shellfish and/or raw vegetables.

Symptoms of norovirus infection start within 12 to 48 hours of exxposure to the virus and usually last 24 to 72 hours. Patients usually recover completely without treatment (only hydration) and without any serious long-term sequalae. Young children, elderly, and immunocompromised patients are at a higher risk of complications.

Symptoms of norovirus infection include malaise, fever, stabbing diffuse abdominal pain, diarrhea, vomiting, and anorexia. Parents of infected children may often report easy irritability and oliguria/anuria.

Physical examination of patients with norovirus infection may be remarkable for low-grade fever, tachycardia, abdominal tenderness, and signs of dehydration (reduced skin turgor, sunken fontanelles, sunken eyes, dry mucous membranes). Physical examination in severe cases may be remarkable for hypotension and altered mental status.

Laboratory findings of norovirus infection include elevated concentration of inflammatory markers, hypokalemia, and chloride-sensitive metabolic alkalosis. Signs of dehydration may be present, such as relative polycythemia, elevated BUN, and elevated creatinine (pre-renal acute kidney injury). RT-qPCR assay is the optimal test for the diagnosis of norovirus infection. Enzyme immunoassays to detect norovirus have been developed but are less useful due to low sensitivity. Norovirus is not usually grown on culture.

Supportive care is the mainstay of therapy for norovirus infection. Treatment includes oral/IV fluid administration to replace fluids lost from vomiting and diarrhea and to electrolyte disturbances. Over the counter oral rehydration solutions (ORS) are usually available, but home-made ORS may be prepared by mixing 1 liter of clean drinking water, 0.5 teaspoon of salt, and 6 teaspoons of sugar. Anti-motility and anti-emetic agents may be administered for symptomatic relief among adults only (controversial efficacy). Antimicrobial agents, including antiviral agents, are generally not recommended to treat norovirus infection.

There is no vaccine to prevent norovirus infection. Prevention of foodborne norovirus disease is based on the provision of safe food and water. Noroviruses are relatively resistant to temperature changes and have been associated with illness after eating steamed shellfish. Moreover, noroviruses can survive in up to 10 ppm chlorine, well in excess of levels routinely present in public water systems. Despite these features, it is likely that relatively simple measures, such as correct handling of cold foods, strict hand washing after using the bathroom and before handling food items, and paid sick leave, may substantially reduce foodborne transmission of noroviruses. Prevention of norovirus disease spread via droplets from vomitus (person to person transmission) should focus on methods that limit transmission including: isolation precautions (e.g. isolating sick patients in a healthcare facility) and environmental disinfection.

The CDC currently does not conduct active surveillance to monitor outbreaks of gastroenteritis caused by noroviruses. The National Outbreak Reporting System (NORS) is a web-based system that was launched by the CDC in 2009 to collect information on outbreaks of foodborne, waterborne, and enteric diseases that spread from person-to-person, animals, environmental surfaces, and other or unknown ways. Public health agencies can report all outbreaks of gastroenteritis, including norovirus illness. The CDC also developed CaliciNet in 2009. It is a network of public health and food regulatory laboratories that submit norovirus sequences identified from outbreaks into a national database.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Originally called the “Norwalk agent” after Norwalk, Ohio, Norovirus was first discovered after an outbreak in an elementary school in 1968. The first documentation of the virus on electron microscopy was in 1972.

• The norovirus was originally named the “Norwalk agent” after Norwalk, Ohio, in the United States, where an outbreak of acute gastroenteritis occurred among children at Bronson Elementary School in November 1968.
• In 1972, electron microscopy on stored human stool samples identified a virus, which was given the name “Norwalk virus.” Numerous outbreaks with similar symptoms have been reported since.
• The cloning and sequencing of the Norwalk virus genome showed these viruses have a genomic organization consistent with viruses belonging to the family Caliciviridae.^[1]
• The name was shortened to “norovirus” after being identified in a number of outbreaks on cruise ships and receiving attention throughout the United States. The name “norovirus” (Norovirus for the genus) was approved by the International Committee on Taxonomy of Viruses (ICTV) in 2002.^[2] In 2011, however, a press release and a newsletter^[3] were published by ICTV, which strongly encourage the media, national health authorities and the scientific community to use the virus name Norwalk virus, rather than the genus name Norovirus, when referring to outbreaks of the disease.
• In addition to “Norwalk agent” and “Norwalk virus,” the virus previously has been called “Norwalk-like virus,” “small, round-structured viruses” (SRSVs), and “Snow Mountain virus.”^[4]
• Common names of the illness caused by noroviruses still in use include “winter vomiting disease,”^[5] “winter vomiting bug,”^[6][7] “viral gastroenteritis,” and “acute nonbacterial gastroenteritis.” It also colloquially is known as “stomach flu,” but this actually is a broad name that refers to gastric inflammation caused by a range of viruses and bacteria.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Norovirus constitutes a genus of genetically diverse single-stranded RNA, non-enveloped viruses belonging to the Caliciviridae family. The Norwalk virus is the only species belonging to that genus; however, several strains have been identified including: Hawaii virus, Mexico virus, and Desert Shield virus. These strains can genetically be classified into five different genogroups (GI, GII, GIII, GIV, and GV).

• Noroviruses (NoV) are a group of the Caliciviridae family with diverse genetic variations. They are non-enveloped viruses with single-stranded RNA.^[1] According to the International Committee on Taxonomy of Viruses, the genus Norovirus has one species, which is called Norwalk virus.^[2] Serotypes, strains and isolates include:^[3]

• Norwalk virus
• Hawaii virus
• Snow Mountain virus
• Mexico virus
• Desert Shield virus
• Southampton virus
• Lordsdale virus
• Wilkinson Virus^[4]

• Noroviruses can genetically be classified into five different genogroups (GI, GII, GIII, GIV, and GV), which can be further divided into different genetic clusters or genotypes. For example, genogroup II, the most prevalent human genogroup, presently contains 19 genotypes. Genogroups I, II and IV infect humans, whereas genogroup III infects bovine species, and genogroup V has recently been isolated in mice^[4].Genogroup I (GI) including Norwalk virus, Desert Shield virus and Southampton virus and genogroup II (GII), which includes Bristol virus, Lordsdale virus, Toronto virus, Mexico virus, Hawaii virus and Snow Mountain virus are mostly isolated in cases of acute gastroenteritis ^[1].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Noroviruses are highly contagious, given that as few as 10 particles are enough to cause the disease, transmission is via the fecal-oral route and peaks during the period when symptoms are most severe, and up to 3 days after recovery. As many strains of noroviruses exist, immunity is not gained following an infection. A non-functional fucosyltransferase FUT2 mutation has been associated with protection against the most common norovirus strains as FUT2 is required for viral transport in the small intestine.

• Norovirus genome structure and protein coding regions: the genome is positive-sense single stranded RNA encoding three open reading frames (ORF). ORF1 encodes the nonstructural proteins. ORF2 and ORF3 encode the major capsid (VP1) and minor structural protein (VP2), respectively.^[1]
• Structural proteins: Norovirus consists of 90 dimers of VP1 and one or two copies of the VP2.
  • VP1: This major structural protein encoded by ORF2, consists of 530–555 amino acids with calculated molecular weights of 58–60 kDa. The protein has two conserved domains and a central variable domain with antigenic characteristics defining the specificity of the strain. VP1 assembles into virus-like particles^[2]. VP1 has two major domains; 1) the shell domain (S) and 2) the protruding domain (P). The S domain is on the N-terminal (225 amino acids), containing the elements for icosahedron formation^[3]. The P domain is comprised of the remaining amino acids and has two subdomains of P1 and P2. The P domain contributes to the stability of the capsid and formation of protrusions on the virion. P2 has a hypervariable region which is thought to play a role in receptor binding, immune reaction and interactions of ABO blood group antigens associated with susceptibility to the viral infection.^[4][1]
  • VP2: This minor structural protein encoded by ORF3, ranges from 208–268 amino acids with calculated molecular weights of 22–29 kDa. VP2 shows high sequence diversity among strains. The exact function of this protein in the virus is not yet known. It is suggested that VP2 might contribute in RNA genome packaging. VP2 is not necessary for viral particles assembly but it is necessary for the formation of an infection virus. ^[1]
• Nonstructural proteins^[1]
  • p48 (p37)
  • p22 (p20)
  • VPg
  • 3CLpro
  • RdRp

Norovirus has a cytoplasmic replication. It attaches to the host receptors and enters the cell through endocytosis. Since, it is a positive sense virus, replication and transcription follows the corresponding models for positive stranded RNA viruses. Translation occurs by leaky scanning, and RNA termination-reinitiation.^[5]

Noroviruses are highly transmissible since only 10 virions (ID50 = 10 virions) per individual is required to infect half proportion of those individuals. Norovirus is transmitted via aerosols, direct contact and fecal-oral routes. The virus is highly resistant to extremely low and/or high temperatures, high sugar concentrations, acidic environments, exposure to chlorine, antiseptic solutions and alcohol. The virus has an incubation period of about 1-2 days with symptoms lasting for about 1-3 days. It could remain contagious for up to 3 weeks.^[6] Histoblood group antigens (HBGAs) are polymorphic receptors or cofactors of norovirus. Different genoclusters bind various HBGAs: Genogroup I viruses bind A and O antigens; genogroup II viruses mostly bind A and B antigens. Great diversity of norovirus strains and the lack of cross-strain or long-term immunity are the causes of recurrent infections.^[7] The virus primarily damages the microvilli of the cells of the small intestine.^[8] It affects the motility of stomach leading to delayed gastric emptying and eventually nausea and vomiting.^[9]The virus is responsible for the enzymatic disorder, leak flux, anion secretion and fat malabsorption at the brush border leading to diarrhea in infected individuals. Colon is intact in this infection so hematochezia is rare.^[10][11]

• A non-functional fucosyltransferase FUT2 provides high protection from the most common norovirus GII.4.^[12]
• Functional FUT2 fucosyltransferase transferes a fucose sugar to the end of the Histo-blood group ABO(H) precursor in gastrointestinal cells as well as saliva glands. The ABH antigen produced is thought to act as receptors for human norovirus. Homozygous carriers of any nonsense mutation in the FUT2 gene are called non-secretors as no ABH antigen is produced.
• Approximately 20% of Caucasians are non-secretors due to the G428A and C571T nonsense mutations in FUT2 and therefore have strong although not absolute protection from the norovirus GII.4.^[13]
• Non-secretors can still produce ABH antigens in erythrocytes as the precursor is formed by FUT1.^[14] Some norovirus genotypes (GI.3) can infect non-secretors.^[15]
• Of individuals who are secretor positive, those with blood type O were more likely to be infected and B less likely.^[16][17][18]
• Reports have shown a link between the expression of human histo-blood group antigens (HBGAs) and the susceptibility to norovirus infection. Studies have suggested the viral capsid of noroviruses may have evolved from selective pressure of human HBGAs.^[19]
• A 2008 study suggests the protein MDA-5 may be the primary immune sensor that detects the presence of noroviruses in the body.^[20] Interestingly, some people have common variations of the MDA-5 gene that could make them more susceptible to norovirus infection.^[21]
• A 2010 study suggested a specific genetic version of norovirus (which would not be distinguishable from other types of the virus using standard viral antibody tests) interacts with a specific mutation in the ATG16L1 gene to help trigger symptomatic Crohn’s disease in mice that have been subjected to a chemical that causes intestinal injury similar to the process in humans (there are other similar ways for such diseases to happen like this, and this study in itself does not prove norovirus causes Crohn’s in humans).

Conditions associated with Norovirus infection include:^[22]

• Immunocompromise
• Encephalopathy^[23]
• convulsions^[24]
• Hematopoietic stem cell transplant recipients
• solid organ transplant recipients

On gross pathology, there are no characteristic features of norovirus.

In microscopic pathology, blunted villi are seen. The mucosa and epithelium are often intact.^[8]Increased apoptosis and damage to tight junction proteins of the epithelial cells may be evident.^[10]Gastric mucosa of the infected patients remains histopathologically intact.^[9]

• 
  Electron micrograph of the Norovirus. From Public Health Image Library (PHIL). ^[25]
• 
  Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. From Public Health Image Library (PHIL). ^[25]
• 
  Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. From Public Health Image Library (PHIL). ^[25]
• 
  Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. From Public Health Image Library (PHIL). ^[25]
• 
  Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. From Public Health Image Library (PHIL). ^[25]
• 
  Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. From Public Health Image Library (PHIL). ^[25]
• 
  Transmission electron micrograph (TEM) revealed some of the ultrastructural morphology displayed by Norovirus virions. From Public Health Image Library (PHIL). ^[25]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Norovirus is the cause of norovirus infection. Noroviruses (genus Norovirus) are a group of related, single-stranded RNA, nonenveloped viruses that cause acute gastroenteritis in humans. Noroviruses belong to the family Caliciviridae.

Norovirus is transmitted through person-to-person contact, food and water. Genotype GII.4 is mostly contact transmitted. Non-GII.4 genotypes such as GI.3, GI.6, GI.7, GII.3, GII.6 and GII.12 are mostly food-borne. Genogroup GI strains are more often transmitted through water. This is due to their higher stability in water compared to other strains of the virus.^[1][2]

Norovirus is among top ranks of food-borne viruses, globally^[3]. Transmission could occur in different stages of pre- and post-production of the food products. For instance, shellfish can be contaminated with fecal discharge in the water^[4], fresh and frozen berries could be contaminated through water contaminated by sewage or contact during harvesting. Viral outbreaks through food-borne transmission can lead to a mixture of the viral strain and increased risk of genetic recombination. Studies show that about 7% of the foodborne outbreaks have a common source^[5].

Norovirus also has a nosocomial transition, causing a major burden for health care services^[6]. Immunocompromised patients may develop numerous norovirus variations due to the chronic infection. This intra-host viral variation may lead to the appearance of variants not similar to any of the ones of previous outbreaks, thus can escape the herd immunity.^[7][1]

To date, animal norovirus strains have not been reported to infect human population, but there has been evidence of intra-species transmission. Human norovirus has been detected in the stools of pigs, cattle and dogs.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Norovirus should be differentiated from other causes of infectious vomiting and diarrhea, including other causes of viral gastroenteritis (sapovirus, adenovirus, rotavirus), bacterial gastroenteritis (yersinia, vibrio, shigella, salmonella, escherichia coli), and parasitic infections (amoebiasis, cryptosporidiosis).

Norovirus should be differentiated from other causes of infectious vomiting and diarrhea, including:

• Rotavirus infection
• Sapovirus infection
• Adenovirus infection
• Astrovirus infection
• Enterovirus infection
• Vibrio cholerae infection
• Escherichia coli Infection
• Salmonellosis
• Shigellosis
• Yersiniosis
• Campylobacter infection
• Clostridium difficile Colitis
• Bacterial Overgrowth Syndrome
• Amebiasis
• Cryptosporidiosis
• Cyclosporiasis

Norovirus infection must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis.

∞Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field

Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient’s immunity system.

The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea^{[1][2][3][4][4]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Norovirus is the leading cause of acute gastroenteritis and foodborne illness in all age groups in the United States. It causes approximately 21 million cases of gastroenteritis yearly. The genogroup II, genotype 4 strain is most commonly involved in large outbreaks of norovirus.

Noroviruses causes about 900 deaths, mostly among adults aged 65 and older; 109,000 hospitalizations; 465,000 emergency department visits, mostly in young children; 2,270,000 outpatient clinic visits annually, mostly in young children and 19 to 21 million cases of vomiting and diarrhea illnesses norovirus causes about 21 million cases of acute gastroenteritis yearly. Norovirus accounts for 58% of foodborne illnesses in the United States. Norovirus outbreaks may be observed any time during the year, but it is most common in the winter months. The cost of norovirus illnesses is approximately $60 billion worldwide considering the lost productivity and healthcare costs.^[1][2]

• Norovirus is the leading cause of acute gastroenteritis and foodborne illness in all age groups in the United States.

• Norovirus shows no gender predilection.

• Norovirus is common across all races.

• Most noroviruses that infect humans belong to genogroups GI and GII.^[3]
• Noroviruses from Genogroup II, genotype 4 (abbreviated as GII.4) account for the majority of adult outbreaks of gastroenteritis and often sweep across the globe.^[4]
• Recent examples include US95/96-US strain, associated with global outbreaks in the mid- to late-1990s, Farmington Hills virus associated with outbreaks in Europe and the United States in 2002 and in 2004, and Hunter virus was associated with outbreaks in Europe, Japan and Australasia. In 2006, there was another large increase in NoV infection around the globe.^[5]
• Nearly two-thirds of all norovirus outbreaks reported in the United States occur in long-term care facilities. Outbreaks of norovirus illness have also occurred in restaurants, cruise ships, schools, banquet halls, summer camps, and even at family dinners. These are all places where people often eat food handled or prepared by others. In fact, norovirus is the leading cause of illness from contaminated food in the United States. About 50% of all outbreaks of food-related illness are caused by norovirus. Foods that are commonly involved in outbreaks of norovirus illness are:
• Leafy greens (such as lettuce)
• Fresh fruits
• Shellfish (such as oysters)

• Epidemiological data from developing countries about the importance of norovirus in pediatric diarrhea are limited. Recently, in Nicaragua, it has been observed that norovirus is responsible for 11% of the diarrhea cases occurring in children less than five years of age at community level and 15% of the moderate to severe cases requiring intravenous rehydration.^[6]

• In the Guangdong province of the People’s Republic of China, the Provincial Health Department said on December 17, 2010, that it had confirmed 429 cases of norovirus infection in the November 2010 outbreak in Conghua, Guangzhou, but no one died from it.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Risk factors for norovirus infection include close contact with infected individuals, particularly those in the same household, poor food-handling hygiene, and consumption of contaminated shellfish and/or raw vegetables.

The following factors increase the risk of contracting norovirus, particularly during outbreaks:^[1][2]

• Poor food-handling hygiene
• Poor hand hygiene
• Shared food
• Close contact with person with recent or current history of norovirus infection.
• Ingestion of raw or insufficiently steamed shellfish and raw vegetables (Shellfish and salad ingredients are the foods most often implicated in outbreaks)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Symptoms of norovirus infection start within 12 to 48 hours of exposure to the virus and usually last 24 to 72 hours. Patients usually recover completely without treatment (only hydration) and without any serious long-term sequalae. Young children, elderly, and immunocompromised patients are at a higher risk of complications.

• The incubation period for norovirus-associated gastroenteritis in humans is usually between 24 and 48 hours (median in outbreaks 33 to 36 hours), but cases can occur within 12 hours of exposure.
• Symptoms of gastroenteritis usually last 24 to 72 hours.
• Patients usually recover completely without treatment (only hydration) and without any serious long-term problems.
• Patients continue to shed the virus up to at least 3 days after their recovery.^[1]

• Norovirus is rarely associated with serious complications especially in an immunocompetent host.
• Among young children, the elderly, and those who are immunocompromised, norovirus required close monitoring and aggressive supportive therapy to prevent severe dehydration and electrolyte imbalances that may lead to death.^[1][2]

• The prognosis of norovirus infection is excellent. Almost all patients recover completely without any long-term sequalae.
• Young children, elderly, and immunocompromised patients are at a higher risk of complications.^[2]

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