Infectious Diseases

Noroviruses

OVERVIEW: What every clinician needs to know

Pathogen name and classification

  • Classification (see Figure 1)

    • Family: Caliciviridae

    • Genus: Norovirus

  • Five genogroups:

    • Classification is based on amino acid identity in the major structural protein.

    • Genogroups I, II and IV affect humans.

    • Genogroups are further divided into genotypes.

    • The majority of norovirus cases and outbreaks can be attributed to genogroup II, genotype 4 (GII.4)

Figure 1:

Norovirus classification and proposed strain nomenclature.

What is the best treatment?

  • Symptomatic treatment for infection:

    • Fluid replacement

    • Electrolyte corrections

  • The best treatment is prevention with proper hand hygiene:

    • Wash hands with running water and plain or antiseptic soap for 20 seconds.

    • Soap and water reduce the number of viruses which adhere to hands.

    • Alcohol-based and other hand sanitizers should be used as an adjunct to proper hand washing.

    • Evidence is mixed on the effectiveness of hand sanitizers due to the inability to grow human norovirus in vitro. Studies do show that alcohol-based hand sanitizer can reduce the amount of viral ribonucleic acid in rodent norovirus. This does not definitively demonstrate effectiveness against human norovirus.

  • Chlorine bleach or heat (see section on management and treatment) should be used to disinfect contaminated surfaces.

  • Food industry:

    • Ill food workers should be restricted from contact with ready-to-eat foods and food contact surfaces.

    • All food workers should adhere to the “no bare-hand contact” recommendation.

  • Prevention of transmission and outbreaks:

    • Chemical disinfectants

      • Cleaners should target high traffic areas with a high risk of contamination.

      • The efficacy of chlorine bleach is well-documented.

      • The US Center for Diseases Control and Prevention (CDC) recommends chlorine bleach products registered with the US Environmental Protection Agency.

      • The recommended bleach concentration is 1,000 to 5,000ppm or five to 25 tablespoons of household bleach per gallon of water.

    • Heat disinfection

    • This is useful for surfaces that cannot tolerate bleach.

    • The CDC recommends pasteurization to 60°C.

  • Exclusion and isolation of infected individuals:

    • This is especially helpful in semi-closed settings with large populations (e.g. cruise ships, acute care hospitals, college dorms, and long-term care facilities).

    • It is based on infection control principles.

    • The aim primarily is to decrease contact with infected individuals during the most contagious phase (the first 24–48 hours).

    • For example, infected patrons of a cruise ship stay within their cabin and infected food-handlers are asked to not work during the infectious period. Per the US Food and Drug Administration code, even asymptomatic workers who test positive can be asked to abstain from working.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology

  • Diarrhea is a common illness worldwide and accounts for approximately 1.8 million deaths in children aged less than 5 years worldwide.

  • Noroviruses have been documented as the leading cause of epidemic acute gastroenteritis in all age groups.

    • They cause more than 90% of all nonbacterial gastroenteritis illnesses.

    • Approximately 21 million illnesses are caused by norovirus each year in the United States.

  • Norovirus infections occur in a wide variety of settings. Outbreaks tend to occur in semi-closed environments that facilitate person-to-person contact.

    • Cruise ships

    • Day-care centers

    • College dormitories

    • Restaurants

    • Catered parties

    • Hospitals

    • Nursing homes

    • Sporting events

  • Norovirus infections are reported year round, but they tend to peak during the colder months.

    • Recently, outbreaks in children aged less than 5 years have occurred during the spring and summer.

    • The number of reported new cases of norovirus infection has increased in the last 20 years.

    • This is due to improved diagnostic testing.

Infection control issues

  • The best treatment is prevention.

    • Prevent infection and transmission with proper hand hygiene.

    • Wash hands with running water and plain or antiseptic soap for 20 seconds.

    • Soap and water reduce the number of viruses which adhere to hands.

    • Alcohol-based and other hand sanitizers should be used as an adjunct to proper hand washing with soap and water when hands have come into contact with contaminated surfaces.

    • Chlorine bleach or heat (see section on management and treatment) should be used to disinfect contaminated surfaces.

  • Vaccine development is in its early phase.

  • No specific antiviral treatment is available.

What host factors protect against this infection?

  • Protective immunity against norovirus is not well understood:

    • In human studies, infected volunteers were susceptible to reinfection with the same strain and heterogeneous strains.

    • Individuals with pre-existing antibodies to a certain norovirus strain were protected from reinfection if repeated exposure to the same strain occurred within a short time period.

    • Two studies showed antibody protection can last anywhere from 8 weeks to 6 months.

    • A subgroup of people exposed to norovirus does not become ill.

    • This suggests that natural immunity exists.

    • At the same time, individuals with high levels of antibody to a certain norovirus strain can still become ill.

  • This paradox is explained by the concept of host susceptibility factors.

    • Noroviruses recognize histo-blood group antigens (HSGA):

      • HSGAs reside on digestive tract mucosal cells.

      • HSGAs such as H-type, ABO blood group, and Lewis antigens are proposed receptors in which norovirus binds.

      • Susceptibility to norovirus infection is associated with expression of certain HSGAs.

    • Resistance to norovirus infections has been associated with mutations of the fucosyltransferase 2 gene (FUT2), which leads to no HSGA expression on the intestinal cell surface.

      • Secretors: individuals with normal FUT2 are susceptible to norovirus infection.

      • Nonsecretors: individuals with mutated FUT2 are less susceptible to norovirus infection

      • This concept does not fully explain why some individuals are immune to norovirus infection while others are not (even if they have been infected before).

      • Therefore, additional research on immunity mechanisms should occur.

  • Noroviruses infect people of all ages, but tend to infect those aged less than 5 years or aged more than 65 years.

  • Norovirus infections affect a wide spectrum of groups:

    • Young children

    • The elderly

    • Travelers

    • Soldiers

    • College students

    • Immunocompromised patients

What are the clinical manifestations of infection with this organism?

  • "Hyperemesis hemis”, otherwise known as “winter vomiting disease”, was first described in 1929.

    • It is characterized by sudden-onset, self-limiting vomiting and diarrhea.

    • It is reported year round.

    • The incidence peaks in colder months.

  • Noroviruses are named after the original strain, known as “Norwalk virus,” which caused an acute gastroenteritis outbreak in Norwalk, Ohio in 1968.

  • Major symptoms are nausea, vomiting, nonbloody diarrhea, and abdominal pain.

What common complications are associated with infection with this pathogen?

  • The most common complications are dehydration, electrolyte imbalances, and weight loss.

  • Long-term sequelae can potentially include prolonged acute symptoms and viral shedding.

  • Outbreaks have been associated with necrotizing enterocolitis and postinfectious irritable bowel syndrome.

  • Deaths have been reported in nursing homes secondary to dehydration and electrolyte imbalances.

How should I identify the organism?

  • Since the 1990s, molecular diagnostic assays have led to a greater understanding of how norovirus infection outbreaks occur.

  • The absence of rapid and sensitive assays and the inability to culture human norovirus has deterred further progress in characterizing and controlling norovirus infection outbreaks.

  • Laboratory diagnostic methods including real-time reverse transcription polymerase chain reaction (RT-PCR), enzyme immunoassay (EIA), and electron microscopy are used to detect norovirus ribonucleic acid in water, food, stool, emesis, etc.

  • Real time RT-PCR is the test most clinical laboratories perform to detect norovirus (Figure 2):

    • RT-PCR is more sensitive than EIA.

    • RT-PCR is the benchmark for diagnosis to detect norovirus.

  • EIA is used to identify norovirus:

    • EIA is more specific than RT-PCR.

    • EIA is less sensitive than RT-PCR.

    • EIA is not as sensitive because:

      • It is more genotype-specific

      • Results can vary based on the circulating strain

      • Six specimens are required to achieve more than 90% sensitivity during an outbreak

    • Negative EIA should be confirmed by RT-PCR.

  • Electron microscopy:

    • Norovirus morphology is a small, round-structured virus.

    • Specimen:

      • Stool—whole stool specimens are preferred over rectal swabs.

        • A whole stool has a greater viral load.

    • Specimens from at least five symptomatic individuals are recommended for laboratory confirmation during an outbreak.

    • Specimens are ideally collected during the acute phase (first 24–48 hours) of the infection.

  • The gold standard for genotyping norovirus strains is full capsid sequencing.

    • This is not sufficient to differentiate between GII.4 variants.

  • A confirmed outbreak of acute gastroenteritis secondary to norovirus infection is achieved when stool or emesis specimens from two or more symptomatic people are positive for norovirus via electron microscope, RT-PCR, or EIA.

  • Clinical diagnosis of a norovirus outbreak can be made based on Kaplan criteria as follows:

    • Stool culture negative for bacteria

    • Vomiting in greater than or equal to 50% of cases

    • Mean or median incubation period of 24 to 48 hours

    • Mean or median illness duration of 12 to 60 hours

    • Criteria are specific

    • Criteria lack sensitivity

      • 30% of norovirus infections do not meet these criteria.

Figure 2:

Genomic regions targeted by RT-PCR assays for Norovirus detection.

How does this organism cause disease?

  • Noroviruses are hosted by humans.

    • Transmission is generally fecal to oral.

    • Transmission via infectious emesis through aerosolization and mechanical transmission (hand-to-mouth contact from contaminated surfaces) in semi-closed environments can also occur.

    • Often, the primary case is exposure to contaminated food or water which is then propagated by person-to-person contact.

  • Norovirus is extremely contagious:

    • It has a low infectious dose.

      • It can be as low as 18 viral particles.

    • It has an increased risk of secondary spread.

    • Viral shedding can precede symptoms in 30% of exposed individuals.

  • Up to 30% cases of norovirus infection are asymptomatic.

  • Norovirus can live in a wide variety of environments:

    • For example, door knobs; recreational and drinking water; food items such as fruits, vegetables, and oysters which have been contaminated by sewage.

    • Norovirus can withstand temperatures ranging from freezing to 60°C.

  • There is the opportunity for repeated infections in the same individuals. This is because the strains easily mutate and there is a lack of long-term immunity.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Becker, KM, Moe, CL, Southwick, KL, MacCormack, JN. "Transmission of Norwalk virus during football game". N Engl J Med. vol. 343. 2000. pp. 1223-7.

(Interesting, if somewhat disgusting, description of the spread of norovirus during a game from infected players of one football team to the opposing team).

"Updated Norovirus outbreak management and disease prevention guidelines". MMWR Recomm Rep. vol. 60. 2011. pp. 1-18.

(Advice from the CDC about prevention of norovirus infections and recommendations for how to deal with an outbreak and prevent further transmission of infection)

"Norovirus". http://www.cdc.gov/norovirus/about/index.html..

(Most recent CDC guidance on norovirus infections)

Glass, RI, Parashar, UD, Estes, MK. "Norovirus gastroenteritis". N Engl J Med. vol. 361. 2009. pp. 1776-85.

(Nice overview of norovirus infections)

Harris, JP, Lopman, BA, O'Brien, SJ. "Infection control measures for Norovirus: a systematic review of outbreaks in semi-enclosed settings". J Hosp Infect. vol. 74. 2010. pp. 1-9.

(Review of how to prevent transmission of norovirus in settings such as nursing homes, where this infection can spread quickly and cause much morbidity)

Khan, RR, Lawson, AD, Minnich, LL. "Gastrointestinal norovirus infection associated with exacerbation of inflammatory bowel disease". J Pediatr Gastroenterol Nutr. vol. 48. 2009. pp. 328-33.

(Another complication of infection with norovirus in a select population)

Liu, P, Yuen, Y, Hsiao, HM, Jaykus, LA, Moe, C. "Effectiveness of liquid soap and hand sanitizer against Norwalk virus on contaminated hands". Appl Environ Microbiol. vol. 76. 2010. pp. 394-9.

(comparison of use of soap and water and hand sanitizers for cleansing hands to prevent spread of norovirus showing both have effects in decreasing organism burden)

"Recommendations on bare hand contact with ready-to-eat foods". http://www.fsis.usda.gov/Frame/frameredirect.asp?main=http://www.fsis.usda.gov/ophs/nacmcf/1999/report_barehand.htm..

Turcios-Ruiz, RM, Axelrod, P, St John, K, Bullitt, E, Donahue, J, Robinson, N, Friss, HE. "Outbreak of necrotizing enterocolitis caused by Norovirus in a neonatal intensive care unit". J Pediatr. vol. 153. 2008. pp. 339-44.

(Description of severe complication of norovirus infection in neonates)

Zheng, DP, Ando, T, Frankhauser, RL, Beard, RS, Glass, RI, Monroe, SS. "Norovirus Classification and Proposed Strain Nomenclature". Virology. vol. 346. 2006. pp. 12-23.

(Classification system proposed for noroviruses)
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