Dr N. Narayan
Figure 1. Rotavirus (A double-capsid particle (left), and a single, inner, capsid (right))
© Dr Linda
Stannard, University of Cape Town, South AfricaROTAVIRUSES AND OTHER VIRAL AGENTS OF GASTROENTERITIS
Selected References
Medical Microbiology, 3rd Ed.-1998; Mosby (Murray, Rosenthal, Kobayashi, Pfaller)
Manual Of Clinical Microbiology, 6th Ed.-1995; ASM Press (Murray, Baron, Pfaller)
Red Book 2000; 25th ed. American Academy of Pediatrics
Textbook of Pediatric Infectious Diseases, 4th ed. 1998 (R. D. Feigin and J. D. Cherry)
Centers for Disease Control and Prevention. http://www.cdc.gov
Viral Gastroenteritis. New England Journal of Medicine; July 1991
p252-264
Viral Gastroenteritis. J Clin Pathol 1996 Dec.;49:874-880 and 959-963.
ROTAVIRUSES
Classification
Family Reoviridae, which includes genus Rotavirus, Reovirus and Colorado Tick Fever virus.
Rotavirus was first identified by electron microscopy in 1973 from duodenal biopsies of children with diarrhea.
Human and animal rotaviruses are known.
Structure
Rotaviruses are non-enveloped, icosahedral, with double capsid (figure 1). Their electron microscopic appearance shows a 60-80nm wheel with radiating spokes (Latin, rota = wheel) (figure 2).
The rotavirus genome contains double stranded (ds) RNA in 11 segments that can be separated by polyacrylamide gel electrophoresis (PAGE).
Major structural proteins
Outer structural proteins - VP7 and VP4. VP4 is the viral hemagglutinin and forms spikes from the surface.
Inner core structural proteins - VP 1, 2, 3, and 6. VP6 is an important antigenic determinant
Groups
There are six different groups (A to F) based on the antigenicity (each group shares common antigens) and the electrophoretic mobility of their RNA segments. Groups D, E and F have not been found in humans. Only group A rotaviruses cause human disease in the United States, primarily in the young (under two years of age - infantile gastroenteritis). However, group A rotaviruses can also cause milder diarrhea older children and adults. Group B has been found to cause human disease in China where there may be annual outbreaks of severe adult and infant diarrhea. More characteristically, group B rotaviruses cause diarrhea in pigs.
Serotypes
There are at least 15 different serotypes of rotaviruses. Six are based on antibodies to VP7 (P type) while nine serotypes, based on VP4 (G type), are known.
Group A viruses are most common, with subgroups that are defined by antigenic differences in VP6 and with 4 different serotypes that affect humans.
WEB RESOURCES
Rotavirus
structure
(Dr LInda Stannard)
Gastroenteritis
Fact Sheet
CDC
Rotavirus Diarrhea in the Child Care Setting
CDC
Rotavirus
CDC pdf file
Figure 2. Transmission electron micrograph of intact rotavirus particles,
double-shelled. Distinctive rim of radiating
capsomeres. CDC/Dr. Erskine Palmer
Pathogenesis
Affected host cells are mature enterocytes lining the middle and upper end of the intestinal villi. In laboratory animals, hepatocytes are also infected. The infectious particle is thought to be an "intermediate sub-viral particle" (ISVP).
Viral attachment protein is probably exposed after protease digestion in the GI tract removes some or all of the outer capsid (VP4). Virus replicates in the host cell cytoplasm. Virions enter the host cell by endocytosis and viral mRNA is transcribed using the viral RNA polymerase that is already present in the virion to form structural protein units of the capsid. The mRNA segments are assembled into the immature capsid and then replicated to form the double stranded RNA genome. Large amounts of viral particles are shed in diarrheal stools.
Histopathology of infected intestines shows villous atrophy and blunting, due to death of the mature enterocytes and infiltration of lamina propria with mononuclear cells. Subsequently there is repopulation of the villous tips with immature secretory cells [crypt hyperplasia].
Cell dysfunction and death results in a net secretion of intestinal fluid, hence the watery diarrhea. Activation of the enteric nervous system may also play a role.
Repopulation with immature secretory cells may contribute to the secondary lactose intolerance that is sometimes seen.
Properties
Rotavirus is stable in the environment and is relatively resistant to handwashing agents. Is susceptible to disinfection with 95% ethanol, ‘Lysol’, formalin and in environments with pH<2.
Figure 3. Estimated global distribution of the 800,000 annual deaths caused by
rotavirus diarrhea. CDC
Figure 4. Average time of peak rotavirus activity in the contiguous 48 states,
United States, July 1991 to June 1997 CDC
Figure 5. Month of peak rotavirus activity — United States, July 1996–June
1997
Figure 6. Average time of peak rotavirus activity in the contiguous 48 states, United States, July 1991 to June 1992. This contour plot was derived using the median value for time of peak activity for each laboratory. CDC
Higher resolution movie of above image avi file
Peak
month for reports of rotavirus infections across the US, 1991-97
avi file
Weekly reports of
rotavirus in the US.
Seasonal variation. CDC
Epidemiology
Distribution - Worldwide, causing 600,000-850,000 deaths per year (figure 3).
Seroprevalence studies show that antibody is present in most infants by age 3 years.
In the U.S., there are 20 - 40 deaths per year with 50,000 hospitalizations per year
Dehydration=1-2.5%
Seasonality
In the U.S.A., rotavirus infections occur in the winter months (November through May). The disease spreads across North America from the warmer climates, starting from Mexico and SW USA and gradually progressing N/NE to reach East Coast and Canada in spring (figures 4 - 6). As might be expected, rotavirus infections are seen year round in the tropics.
Incubation period - thought to be <4 days
Contagious Period - Before onset of diarrhea to a few days after end of diarrhea
Age - Rotaviruses infect children at a young age. Older infants and young children (4 months - 2 years) tend to be more symptomatic with diarrhea. Young infants may be protected due to trans-placental transfer of antibody.
Asymptomatic infections are common, especially in adults. Many cases and outbreaks are nosocomial
Group A infections are most common.
Group B has been associated with outbreaks in adults in China
Group C is responsible for sporadic cases of diarrhea in infants around the world.
Spread is mainly person to person via fecal - oral route and through fomites. Spread by food and water is also possible. Spread via respiratory route is speculated.
High numbers of viral particles are shed in diarrheal stools (1010/gm). Infective dose is only 10-100 pfu.
Clinical Features
Fever- can be high grade (>102° F in 30% of patients)
Vomiting, nausea precedes diarrhea.
Diarrhea is usually watery (no blood or leukocytes), lasting 3-9 days, but longer in malnourished and immune deficient individuals. Necrotizing enterocolitis and hemorrhagic gastroenteritis is seen in neonates
Dehydration is the main contributor to mortality.
Secondary malabsorption of lactose and fat, and chronic diarrhea are possible
Diagnosis
Rapid diagnosis - antigen detection in stool by ELISA (uses a monoclonal antibody) and LA. Several kits are commercially available. These detect only Group A rotavirus.
Electron microscopy - also detects non-Group A viruses
Group A rotaviruses can be cultured in monkey kidney cells.
Epidemiologic studies use patterns of viral RNA migration by gel electrophoresis (electropherotyping). Different genetic strains may circulate in a given community.
Treatment
Supportive - rehydration (oral / intravenous)
Antiviral agents not known to be effective
Prevention of spread
Handwashing with good technique
Disinfection of surfaces, toilets, toys
Adequate chlorination of water
Vaccine
Live tetravalent rhesus-human reassortant vaccine (Rotashield) was first licensed for use in infants in August 1998. Contained human G types 1, 2, 4, and simian G type 3.
Post-licensure surveillance indicated a possible relationship between the occurrence of intussusception 3-20 days after the vaccine especially the first dose (15 cases/1.5 million doses were reported).
Use of the vaccine was suspended and it was eventually removed from the market in October 1999, when studies confirmed the link between vaccination and intussusception.
Other vaccine candidates are still being tested.
WEB RESOURCES
SMALL ROUND RNA VIRAL AGENTS CAUSING GASTROENTERITIS
This group of RNA viruses morphologically is subdivided in to 2 sub-groups:
Structured - Small round structured viruses (SRSV), Calicivirus, Astrovirus
Other small viruses that are relatively structureless or featureless - W (Wollan) and Ditchling.
Figure 7. Norwalk virus from stool sample from an individual with gastroenteritis.F.P. Williams, U.S. Environmental Protection Agency
Figure 8. Typical morphology of Norwalk-like viruses seen by transmission electron microscopy. The individual virions have a diameter of only 27nm.
Wadsworth Center
of the New York State Department of Health.
NORWALK VIRUS AND NORWALK-LIKE VIRAL AGENTS
SRSV- Norwalk virus and Norwalk-like agents
Non-enveloped, single stranded RNA viruses. 27-35 nm in size (figure 7 and 8)
Contain a single capsid protein.
Norwalk virus was first detected in stools of patients with gastroenteritis in Norwalk, Ohio in 1972.
27 - 32nm in size with a ragged surface.
Norwalk-like viruses are similar in size and are named after the place where they were first isolated in relation to outbreaks of diarrhea. Different serotypes are-
Hawaii
Snow Mountain (CO)
MC (MD)
Taunton (England)
Otofuke (Japan)
Sapporo (Japan)
WEB RESOURCES
Clinical Features
Adults and children are affected
Relatively short incubation period: <24 hours
Illness is short (<3 days)
Nausea, vomiting, abdominal cramping and watery diarrhea accompanied by headache, fever and malaise
Outbreaks often occur in institutions, cruise ships, etc. through contaminated food or water
Feco-oral spread, perhaps also spread through vomitus
Diagnosis
Immune EM
Serology for epidemiologic purposes
Figure 9. Bovine calcivirus © 1994 Veterinary Sciences Division
- Dr Stewart McNulty at Veterinary Sciences, Queen's University, Belfast.CALICIVIRUS
Described in 1976
Calciviruses are non- enveloped single stranded RNA viruses, 30-45nm in size (figure 9). They appear round in shape with icosahedral symmetry and contain a single capsid protein. The viral surface has 32 cup-shaped depressions (‘calici’= chalice or calyx i.e. cup-like) described as the ‘Star of David’ appearance. Otherwise they are similar to Norwalk group of agents and belong to family caliciviridae
The 5 antigenic types in humans are UK 1 to 4, and Japan/Sapporo
Epidemiology
Worldwide distribution
Outbreaks can involve infants and school-age children
Viral excretion in stool can continue beyond the cessation of symptoms
Transmission-fecal-oral, through contamination of food and person to person (even asymptomatic persons)
Outbreaks related to consumption of contaminated oyster and shellfish have been described. It is thought that the seafood or water or ice becomes contaminated with fecal material from sewage or food handlers.
Most people have had infections by age 4 years (by seroprevalence studies).
Clinical Manifestations
Incubation period - 12hrs. to 4 days
Most infections are asymptomatic
Mild diarrhea, vomiting, anorexia and fever
1/3 have respiratory (flu-like) symptoms (esp. UK3 and UK4strains)
Diagnosis
EM - not widely available, requires higher level of viral excretion for detection
Immune EM, ELISA
Figure 10. Astrovirus © 1994 Veterinary Sciences Division
- Dr Stewart McNulty at Veterinary Sciences, Queen's University, Belfast.
Figure 11. Astrovirus © 1994 Veterinary Sciences Division
- Dr Stewart McNulty at Veterinary Sciences, Queen's University, Belfast.
Figure 12. Human astrovirus US
Environmental Protection Agency
ASTROVIRUS
Described in relation to an outbreak of gastroenteritis in 1975.
Small single stranded RNA, non-enveloped virus, about 27 - 32nm in size. They are round with an unbroken surface (unlike indented surface of calicivirus) (figure 10 - 12)
EM appearance of a 5 or 6 pointed star; contain 3 structural proteins.
Astroviruses are immunologically distinct from Norwalk and Caliciviruses - belong to family Astroviridae
7 human serotypes are known
Clinical Features
Diarrhea, headache, nausea, low-grade fever, vomiting (Iess common)
Epidemiology
Worldwide, mainly in children <7 years of age.
Transmission person-to-person via fecal-oral route
Outbreaks due to fecal contamination of sea-food/water
Diagnosis
EM and Immune EM are especially useful since the virus is often shed in large amounts in stool. Immunfluoresence detects all serotypes.
WEB RESOURCES
Viral Agents of Gastroenteritis Public Health Importance and
Outbreak Management
CDC
GASTROENTERITIS DUE TO ADENOVIRUSES
Adenovirus serotypes implicated in gastroenteritis are 40, 41, 31, 3, 7. They cause diarrheal disease in infants and children <4 years of age. The virus is spread by the feco-oral route and is not shed in the nasopharynx
Incubation period is 8-10 days
Diarrhea lasts 5-12 days, prolonged diarrhea often seen with type 40 infections
Diagnosis - Latex agglutination, ELISA, EM
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