Norovirus

Norovirus is a nonenveloped, single-stranded, positive-sense RNA virus belonging to the Caliciviridae family. Norovirus infections are transmitted via the fecal-oral route or by aerosols from vomiting. The virus is one of the most common causes of non-bacterial gastroenteritis epidemic worldwide. Symptoms include watery and nonbloody diarrhea, nausea, vomiting, and low-grade fever. Although the infection is self-limiting, severe dehydration can occur. The diagnosis is usually presumptive, and viral detection using PCR or enzyme immunoassay may be used for patients with severe disease or immunocompromised status. Management is supportive and may include rehydration therapy.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

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General Characteristics and Epidemiology

Basic features of human norovirus

Also known as Norwalk virus

  • Taxonomy:
    • Family: Caliciviridae
    • Genus: Norovirus
  • RNA virus:
    • Single stranded
    • Positive sense
    • Linear
    • Nonsegmented
  • Structure:
    • Icosahedral symmetry
    • Nonenveloped 
    • Protein capsid
  • Highly stable in the environment and resistant to:
    • Freezing
    • Heat up to 60°C (140°F)
    • Alcohol
    • Acid
    • Chlorine

Clinically relevant species

Genogroups I and II cause the majority of human norovirus cases.

Associated diseases

Norovirus is a major cause of gastroenteritis.

Epidemiology

  • Responsible for 60% of the cases of acute gastroenteritis in the United States
  • Incidence:
    • United States: 21 million cases annually
    • Worldwide: 685 million cases annually
  • More prevalent in developing countries
  • Demographics:
    • Occurs in all age groups
    • No sex predilection
    • No race predilection
  • Mortality:
    • United States: 800 deaths annually (mostly young children and the elderly)
    • Worldwide: approximately 50,000 deaths annually (primarily in developing countries)
  • Outbreaks are common in: 
    • Hospitals
    • Cruise ships
    • Schools
    • Nursing homes
    • Military bases

Pathogenesis

Reservoir

Humans are the only known reservoir for human norovirus.

Transmission

This highly virulent disease is transmitted by:

  • Fecal-oral route (contaminated food, water, or surfaces/fomites)
  • Aerosols (often from vomiting)

Host risk factors

The following groups have higher rates of infection and/or serious complications:

  • Neonates
  • Elderly
  • Immunocompromised patients

Pathophysiology

  • The mechanism is not entirely understood.
  • The virus may enter a human host through:
    • Enterocytes
    • M cells
  • The virus replicates in macrophages, dendritic cells, and B cells.
  • The disease is associated with:
    • Delayed gastric acid emptying → nausea and vomiting
    • ↓ Brush border enzyme activity → malabsorptive diarrhea
  • Virions are shed in the stool.
Pathogenesis of norovirus infection

Pathogenesis of norovirus infection

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Pathology

Norovirus gastroenteritis is associated with the following reversible findings:

  • Jejunal biopsy shows blunting of the microvilli, but the mucosa is otherwise intact.
  • Cytoplasmic vacuolization is seen along with mononuclear infiltrates of tissue.
Recombinant porcine norovirus identified from piglet with diarrhea

Hematoxylin and eosin staining:
A: Normal-appearing long villi of the duodenum
B: Villi of the duodenum showing mild villous atrophy from a norovirus infection
C: Normal-appearing long villi of the jejunum
D: Villi of the jejunum showing mild villous atrophy from a norovirus infection

Image: “F3” by Key laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai JiaoTong University, 800 Dongchuan Road, Shanghai, People’s Republic of China. License: CC BY 2.0

Clinical Presentation

Timeline:

  • Incubation period: 12‒60 hours
  • Duration of symptoms: 1‒3 days

Common symptoms include:

  • Nausea and vomiting (more prominent than the other causes of gastroenteritis)
  • Diarrhea
    • Watery
    • Nonbloody
  • Abdominal cramping
  • Fever
  • Malaise
  • Myalgias
  • Headache

Severe manifestations:

  • Dehydration
    • Tachycardia
    • Orthostatic hypotension
    • Dry mucous membranes
    • ↓ Skin turgor
  • Neurologic symptoms (more common in young children)
    • Seizure
    • Encephalopathy

Diagnosis and Management

Diagnosis

The diagnosis is usually presumptive and diagnostic testing is not usually necessary. However, confirmatory testing may be pursued for immunocompromised individuals or those with severe symptoms:

  • Stool PCR for viral RNA
    • Method of choice
    • May be limited by a low viral load
  • Enzyme immunoassay antigen detection
    • Limited utility
    • Lower sensitivity and specificity than PCR

Management

  • Treatment is supportive.
  • Oral or IV hydration

Prevention

  • Wash hands (soap and water, not alcohol-based sanitizers).
  • Clean surfaces.
  • Wear personal protective equipment when handling stool or emesis from infected individuals.
  • Symptomatic individuals should: 
    • Stay home from work, school, or daycares
    • Not handle or prepare food for others

Comparison of Similar Caliciviruses

The following table compares 2 very similar viruses within the Caliciviridae family:

Table: Comparison of Norovirus and Sapporo virus
OrganismChikungunya virusEastern equine encephalitis virus
Genus Norovirus Sapovirus
Characteristics
  • Nonenveloped
  • ssRNA virus
  • Icosahedral
  • Size: 27‒32 nm
  • Nonenveloped
  • ssRNA virus
  • Icosahedral
  • Size: 30‒38 nm
Transmission Fecal-oral route
Clinical Gastroenteritis
Diagnosis PCR
Management
  • Supportive
  • Rehydration
Prevention Handwashing

Differential Diagnosis

  • Rotavirus: a nonenveloped, double-stranded RNA virus. Transmission occurs through the fecal-oral route. Rotavirus is a common cause of severe gastroenteritis in children. Severe cases can result in dehydration and death. Diagnostic testing is not usually required, but the virus can be detected in stool samples using ELISA or PCR. Oral rehydration therapy is the mainstay of treatment. A live attenuated vaccine is available.
  • Campylobacter jejuni: curved gram-negative bacilli. Common symptoms of infection are fever, headache, severe abdominal pain, myalgias, and diarrhea. The diarrhea is sometimes bloody. Rarely, patients may exhibit arthritis, endocarditis, or meningitis. The diagnosis can be made using a stool culture. Treatment includes rehydration therapy and antibiotics (e.g., macrolides or fluoroquinolones).
  • Shigellosis: an acute bacterial infection of the GI tract. Shigellosis is caused by the gram-negative Shigella species. Patients develop symptoms of fever, tenesmus, and bloody diarrhea. The infection is diagnosed clinically and confirmed using a stool culture. Management can include rehydration therapy and antibiotics (in severe cases or for high-risk patients).
  • Non-typhoidal Salmonella: an infection caused by the gram-negative bacilli, S. enteritidis or S. typhimurium. Vomiting, abdominal cramping, fever, and inflammatory diarrhea may be present. Stool cultures can provide the diagnosis. Management is supportive, and antibiotics are only used for systemic manifestations or to control severe diarrhea.
  • Giardiasis: an infection caused by Giardia lamblia, a flagellated protozoan that can infect the intestinal tract. The hallmark symptom of giardiasis is foul-smelling steatorrhea. Patients who develop chronic infections may experience weight loss, failure to thrive, and vitamin deficiencies as a result of malabsorption. The diagnosis is made through the detection of Giardia organisms, antigens, or DNA in the stool. Management includes supportive treatment and antimicrobial therapy with metronidazole, tinidazole, or nitazoxanide.

References:

  1. Acute infectious nonbacterial gastroenteritis: Etiology and pathogenesis. (1972). Ann Intern Med. 76(6), 993-1008.
  2. Sell, J., Dolan, B. (2018). Common gastrointestinal infections. Prim Care. 45(3), 519-532.
  3. Donaldson, E.F., Lindesmith, L.C., Lobue, A.D., Baric, R.S. (2008). Norovirus pathogenesis: Mechanisms of persistence and immune evasion in human populations. Immunol Rev. 225, 190-211.
  4. Schreiber, D.S., Blacklow, N.R., Trier, J.S. (1973). The mucosal lesion of the proximal small intestine in acute infectious nonbacterial gastroenteritis. N Engl J Med. 288(25), 1318-1323.
  5. Sadkowska-Todys, M., Zieliński, A., Czarkowski, M.P. (2018). Infectious diseases in Poland in 2016. Przegl Epidemiol. 272(2), 129-141.
  6. Atmar, R.L., Ramani, S., Estes, M.K. (2018). Human noroviruses: Recent advances in a 50-year history. Curr Opin Infect Dis. 31(5), 422-432.
  7. CDC. (2014). Norovirus: U.S. Trends and Outbreaks. http://www.cdc.gov/norovirus/trends-outbreaks.html.
  8. Randazzo, W., D’Souza, D.H., Sanchez, G. (2018). Norovirus: The burden of the unknown. Adv Food Nutr Res. 86, 13-53.
  9. Bányai, K., Estes, M.K., Martella, V., Parashar, U.D. (2018). Viral gastroenteritis. Lancet. 14, 392(10142), 175-186.
  10. McIntosh, E.D.G. (2018). Healthcare-associated infections: Potential for prevention through vaccination. Ther Adv Vaccines Immunother. 6(1), 19-27.
  11. De Grazia, S., et al. (2018). Performance evaluation of a newly developed molecular assay for the accurate diagnosis of gastroenteritis associated with norovirus of genogroup II. Arch Virol. 163(12), 3377-3381.
  12. O’Ryan, M.G. (2020). Norovirus. UpToDate. Retrieved May 25, 2021, from https://www.uptodate.com/contents/norovirus
  13. Capece, G., Gignac, E. (2020). Norovirus. [online] StatPearls. Retrieved May 25, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK513265/
  14. Khan, Z.Z., Wills, T.S., Jawarski, M.A., Huycke, M.M. (2018). Norovirus. Medscape. Retrieved May 25, 2021, from https://emedicine.medscape.com/article/224225-overview

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