Rotaviruses presented by Dr.Lamia Ghazi Jamjoom

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Viruses Associated with Gastroenteritis
Ghazi Jamjoom
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VIRAL AGENTS CAUSINGGASTROENTERITIS
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VIRAL AGENTS CAUSINGGASTROENTERITIS
Major Viruses

• Rotavirus
• Enteric adenoviruses
• Noroviruses
• a. Norwalk-like
  viruses
• b. Calicivirus
• c. Astrovirus

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Noroviruses

• Norwalk-like Caliciviruses Astroviruses
  other
• viruses
  viruses

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Viruses associated with gastroenteritis (cont)

• Other viruses (minor)
• Coronaviruses
• Parvoviruses
• Pestiviruses
• Toroviruses

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ROTAVIRUS

• Family Reoviridae
• Genus Rotavirus

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ROTAVIRUS

• First isolated in 1973 from children with
  diarrhea
• EM identification from duodenal biopsies
• Human and animal strains

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Rotavirus
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Rotavirus- EM Structure
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ROTAVIRUS

• 60-80nm in size
• Non-enveloped virus
• Double capsid
• EM appearance of a wheel with radiating spokes
• Icosahedral symmetry
• double stranded (ds) RNA in 11 segments
• (double double)

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STRUCTURE

• Double capsid (outer and inner capsid)
• Core with genome
• Capsid is cleaved by trypsin to form
• ISVP- infective sub-viral particle

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ROTAVIRUS- 3D STRUCTURE
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ROTAVIRUS- ultrastructure
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Rotavirus- details of EM structure
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Viral Structural Proteins (VP)

• Outer structural proteins - VP7 and VP4
• VP7glycoprotein
• VP4protease-cleaved, P protein, viral
  hemagglutinin, and forms spikes from the
  surface
• Inner core structural proteins VP 1, 2, 3, 6
• VP6 is an important antigenic determinant

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• Genome is composed of 11 segments of
  double-stranded RNA,
• six
  structural
• coding for
  proteins
• five
  nonstructural

• Seven serological groups have been identified
  (A-G), three of
• which (groups A, B, and C) infect humans .

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STRUCTURE
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Gene coding assignment
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Classification

• Groups, subgoups, serotypes based on viral capsid
  proteins
• 7 Groups (A through G)
• Group A is the most common and has 2 subgroups
• 10 human serotypes based on G protein (VP 7)
• 8 P protein serotypes

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Classification (contd.)

• Electropherotypes
• mobility of RNA segments by PAGE
• Used in epidemiologic studies

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Rotavirus - Properties

• Virus is stable in the environment
• Relatively resistant to handwashing agents
• Susceptible to disinfection with 95 ethanol,
  Lysol, formalin

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Pathogenesis

• Targeted host cells- mature enterocytes lining
  the tips of intestinal villi
• Intermediate/infective sub-viral particle (ISVP)
  produced through proteolysis
• Enter host cell by endocytosis
• Virus replicates in the host cell cytoplasm

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Replication

• mRNA transcription with viral RNA polymerase
• Capsid proteins formed
• mRNA segments formed, assembled into immature
  capsid
• mRNA replicated to form double stranded RNA genome

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Histopathology

• Mature enterocytes lining the tips of intestinal
  villi are affected
• Villous atrophy and blunting
• Death of the mature enterocytes

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Histopathology

• Infiltration of lamina propria with mononuclear
  cells
• Repopulation of the villous tips with immature
  secretory cells crypt hyperplasia

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Histopathology
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Epidemiology - Worldwide

• Millions are affected
• 600,000-850,000 deaths/year
• A major cause of diarrhea-associated
  hospitalizations
• Seroprevalence studies show that antibody is
  present in most by age 3y.

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Rotavirus-Worldwide distribution(source-
centers for disease control and prevention)
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Estimated Global Distribution of The 800,000
Annual Deaths Caused By Rotavirus Diarrhea
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Epidemiology U.S.

• No. of children under 5y. affected 2.7 million
• Physician visits per year 500,000
• Hospitalizations per year 50,000
• Deaths per year 20 - 40
• cases w/ dehydration 1-2.5

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Epidemiology

• Age- 4mo - 2 yearsProtection of younger infants
  through transplacental antibody transfer
• Asymptomatic infections are common, especially in
  adults
• Nosocomial infections
• Outbreaks

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Epidemiology (contd.)

• Seasonality
• Winter months (Nov. through May in US)
• Gradual spread W to E
• Year-round in the tropics
• Incubation period - thought to be lt4 days

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Epidemiology U.S.(Source- centers for disease
control and prevention)
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Spread in the U.S.(Source- centers for disease
control and prevention)
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Epidemiology (transmission)

• Mainly person to person via fecal-oral route
• Fomites
• Food and water-borne spread is possible
• Spread via respiratory route is speculated

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Epidemiology (spread)

• Contagious from before onset of diarrhea to a few
  days after end of diarrhea
• Large amounts of viral particles are shed in
  diarrheal stools
• Infective dose is only 10-100 pfu

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EPIDEMIOLOGYDifferences in Groups

• 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

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Clinical Features

• Incubation period - thought to be lt4 days
• Fever- can be high grade (gt102?F in 30)
• Vomiting, nausea precede diarrhea
• Diarrhea
• - usually watery (no blood or leukocytes)
• - lasts 3-9 days
• - longer in malnourished and immune deficient
  indiv.
• - NEC and hemorrhagic GE seen in neonates

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Mechanism of diarrhea

• Watery diarrhea due to net secretion of
  intestinal fluid
• Activation of the enteric nervous system
  -possible role of enterotoxin

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Clinical Features (contd.)

• Dehydration is the main contributor to mortality.
  
• Secondary malabsorption of lactose and fat, and
  chronic diarrhea are possible

42

• Recovery is usually complete.
• However, severe diarrhea without fluid and
  electrolyte
• replacement may result in dehydration and
  death .

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Immunological Aspects

• Immunoglobulin (Ig) A , in the lumen of the gut
  immunity
• to infection .

• Actively or passively acquired antibodies
  (including antibodies in
• colostrum and mothers milk) lessen
  the severity of disease
• but does not consistently prevent reinfection .

• Absence of antibody small amounts of
  virus infection
• and diarrhea .

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Diagnosis

• Antigen detection in stool by ELISA, Latex
  Agglutination (for Group A rotavirus)
• EM- non-Group A viruses also
• Culture- Group A rotaviruses can be cultured in
  monkey kidney cells
• Serology for epidemiologic studies

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Treatment and Prevention

• Treatment-
• Supportive - oral, IV rehydration
• Prevention-
• Handwashing and disinfection of surfaces

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Vaccine

• Live tetravalent rhesus-human reassortant vaccine
  (Rotashield)
• Licensed for use in August 1998
• Removed from the market in October 1999 due to
  risk of intussusception
• Cases were seen 3-20 days after vaccination
• Approx. 15 cases/1.5 million doses
• New vaccine from bovine rotavirus under trial

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GASTROENTERITIS DUE TO ENTERIC ADENOVIRUS
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GASTROENTERITIS DUE TO ADENOVIRUS

• Types 40, 41
• Belong to serogroup F
• Some cases due to types 31, 3, 7

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Diarrhea due to Enteric Adenovirus

• Age lt4 years
• Year round
• Spread via fecal-oral route

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Clinical features of Enteric Adenovirus
gastroenteritis

• Incubation period 3 -10 days
• Diarrhea lasts for 10 -14 days
• Can also cause intussusception, mesenteric
  adenitis, appendicitis

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Diagnosis- Enteric adenoviruses

• Isolation requires special media-Graham 293
• ELISA for rapid detection is available

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HUMAN CALICIVIRUSES
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HUMAN CALICIVIRUSES(HuCV)

• Belong to Family Caliciviridae
• Non-enveloped RNA viruses
• with ss RNA
• 27-35 nm in size
• Contain a single capsid protein

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HUMAN CALICIVIRUSES

• Genomic analysis divides it into 4 groups
• Human caliciviruses belong to 2 genera

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CLASSIFICATION OF HuCV

• NLV (Norovirus)
• Norwalk virus
• Hawaii virus
• Snow Mountain virus
• Montgomery county virus
• Taunton (England)

• SLV (Sapovirus)
• Sapporo virus
• Manchester virus
• Houston/86
• London/92

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Morphology of HuCV- typical

• Typical morphology
• 32 cup-like depressions
• EM appearance of Star of David
• E.g.- Sapporo-like viruses

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HUMAN CALICIVIRUSES - SLV
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Morphology of HuCV- atypical

• Atypical morphology
• Smooth surface
• Small Round Structured viruses
• E.g.- Norwalk-like viruses

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SRSV- NORWALK VIRUS
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CLINICAL FEATURES

• Adults and Children
• Usual incubation Period is lt24 hours
• (ranges from 12hrs. to 4 days)
• Short duration of illness lt3 days
• Nausea, vomiting, fever, headache
• Abdominal cramping
• Watery diarrhea

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Epidemiology-Noroviruses

• Worldwide distribution
• gt23 million cases/year in the U.S.
• Major cause of foodborne outbreaks of GE
• Most people have had infections by age 4 years
  (by seroprevalence studies)

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Spread of Norwalk virus

1. Person-to-person Fecal-oral spread
   (stool/vomitus)
2. Fecal contamination of food or water
3. Spread through fomites?

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Epidemiology-Noroviruses

• Asymptomatic infections- seroconversion but
  asymptomatic shedding of virus
• Low infective dose
• Viral excretion during convalesence
• (up to 2 weeks)
• Ability to survive in water chlorination at
• routine levels

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Epidemiology of Outbreaks

• Cruise ships, schools, nursing homes, etc.
• Can involve infants and school-age children
• Source usually is contaminated food and water
  (seafood-oyster and shellfish etc.)

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Diagnosis- Human Caliciviruses

• Specimen- stool , vomitus, environmental swabs,
  not yet on foods
• Immune EM
• RT-PCR in state public health labs.
• Serology for epidemiologic purposes

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HUMAN ASTROVIRUS
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ASTROVIRUS

• Described in relation to an outbreak of
  gastroenteritis in 1975
• Detected by EM
• Immunologically distinct from Human Caliciviruses
• Belong to family Astroviridae
• 8 human serotypes are known

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ASTROVIRUS- structure

• Small ss RNA virus
• Non-enveloped
• 27-32nm in size
• Round with an unbroken, smooth surface
• EM appearance of a 5 or 6 pointed star within
  smooth edge
• Contain 3 structural proteins

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ASTROVIRUS- EM STRUCTURE
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ASTROVIRUS - Epidemiology

• Worldwide
• Mainly in children lt7 years of age.
• Transmission person-to-person via
• fecal-oral route
• Outbreaks due to fecal contamination of
• sea-food or water

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ASTROVIRUS - Clinical Features

• Infants and children are most often affected
• Short incubation period 1-4 days
• Nausea, vomiting, abdominal cramping and watery
  diarrhea
• Constitutional symptoms-fever, malaise, headache

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ASTROVIRUS - Diagnosis

• EM (virus shed in stool in great numbers)
• EIA
• RT-PCR

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Rotaviruses
Ghazi Jamjoom
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• Twenty-five years ago, little was known about
  the causes of diarrhea, which kills an estimated
  3 million infants and children
• worldwide every year.
• Scientists knew that bacteria and parasites were
  implicated in only approximately 10 to 20 of
  all cases of diarrhea..

77

• In 1973,, researchers in Australia discovered a
  virus in infants with severe diarrhea and named
  it rotavirus for its wheel-like shape.
• One year later, NIAID researchers were the first
  to identify rotavirus in the United States.

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Rotavirus Biology

• Rotaviruses belong to the family Reoviridae ,
• genus Rotavirus.

• They have a characteristic wheel-like
• appearance when viewed by electron
• microscopy.

• Nonenveloped, double-shelled

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• Group A rotaviruses
• Endemic worldwide (represents gt 95 of
• currently identified strains in humans )
• The leading cause of severe diarrhea among
• infants and children .
• Accounts for about half of the cases
• requiring hospitalization.

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• Group B rotavirus,
• Also called adult diarrhea rotavirus or
• ADRV
• Has caused major epidemics of severe
• diarrhea affecting thousands of persons
• of all ages in China.

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• Group C rotavirus
• Has been associated with rare and sporadic
• cases of diarrhea in children in many
• countries.
• First outbreaks were reported from Japan
• and England

84

• Subgroups classification based upon
  neutralization epitopes of the outer capsid
  proteins, VP4 and VP7

Antigenic specificity of VP7
G serotypes
Antigenic specificity of VP4
P serotypes
Fourteen G serotypes and twenty one P serotypes
have been detected in humans.
Neutralization assays measure reactivity
predominantly to VP7 proteins.
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Distribution of Rotavirus Strains From A Global
Collection of 2,748 Strains.
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Transmission

• Rotavirus infection is very contagious .
• Viral particles pass in the stool of infected
  persons before and after they have symptoms of
  the illness .
• Spread is by the oral-fecal route

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• The virus can survive for long periods on hard
  surfaces (e.g.
• toys and tables) and is not killed by
  standard
• disinfectants... children forget to wash
  their hands often
• enough, especially before eating and after
  using the toilet.
• toilet Get
  infected
• Infected food handlers may contaminate foods
  that require
• handling and no further cooking, such as
  salads, fruits.

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• The infective dose is presumed to be 10-100
  infectious viral particles. Because a
  person with rotavirus diarrhea often excretes
  large numbers of the virus (108-1010
  infectious particles/ml of
• feces), infection doses can be readily
  acquired .

89

• Asymptomatic rotavirus excretion has been well
  documented may play a role in
  perpetuating
• endemic disease .
• N.B some have reported low titers of virus in
  respiratory
• tract secretions and other body fluids..

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Epidemiology
91

• Rotavirus is the single most important cause of
  life-threatening diarrhea in children younger
  than 2 years.
• Affects approximately 130 million infants and
  children worldwide.

• In the United States alone, rotavirus causes
  more than 3 million cases of childhood diarrhea
  each year, leading to an estimated 55,000 to
  100,000 hospitalizations and 20 to 100 deaths.

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When do people get infected ?

• In the United States, rotavirus causes
  outbreaks of diarrhea
• during the winter months.
• In temperate areas, it occurs primarily in the
  winter.
• In the tropics it occurs throughout the year.

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Who catch the infection ?

• Humans of all ages are susceptible to rotavirus
  infection,
• although Children , premature infants, the
  elderly,
• and the immunocompromised are prone to more
  severe symptoms caused by infection with group
  A rotavirus.

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An infants first bout of diarrhea from
rotavirus is the most severe , subsequent
reinfections decrease in severity. These
findings indicated that infants gradually develop
partial immunity to the virus and that a vaccine
might prevent the disease.
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Pathogenesis

• Rotavirus can survive in the acidic environment
  , in a buffered
• stomach , or in a stomach after a meal.

• Virus adsorption to columnar
  epithelial cells
• viral
  replication
• shortening and blunting of the microvilli and
  mononuclear cell infiltration into the lamina
  propria

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• Temporary lactose intolerance may occur.

• NSP4 protein may act in a toxin-like manner
  

Neuronal alteration in water absorption
Calcium ion influx into enterocytes
Release of neuronal activators

• Loss of the ability to absorb water
  net secretion
• of water and loss of ions
  watery diarrhea

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Watery diarrhea dehydration
(most commonly isotonic) and may lead to
metabolic acidosis and death .
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Symptoms and Signs

• The incubation period ranges from 1-3 days .
• Symptoms often start with vomiting followed by
  4-8 days of
• diarrhea.

• Some may have a slight rise in temperature .

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Immunological Aspects

• Immunoglobulin (Ig) A , in the lumen of the gut
  immunity
• to infection .

• Actively or passively acquired antibodies
  (including antibodies in
• colostrum and mothers milk) lessen
  the severity of disease
• but does not consistently prevent reinfection .

• Absence of antibody small amounts of
  virus infection
• and diarrhea .

100

• Infection in infants and small children is
  generally symptomatic .
• In adults infection is usually asymptomatic .
• Asymptomatic rotavirus infections are common in
  neonates
• because of passively acquired maternal
  immunity , breast
• feeding , and possible infection with less
  virulent strains

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Diagnosis

• 
  (EIA)
• 1) Identification of the viral antigen in the
  patient's stool
• 
  latex
  agglutination
• most widely used screening test for
  clinical specimens .
• 2) Electron microscopy (EM)
• 3) polyacrylamide gel electrophoresis (PAGE) is
  used in some laboratories for RNA typing.
• 4) A reverse transcription-polymerase chain
  reaction (RT-PCR) has been developed to detect
  and identify all three groups of human
  rotaviruses.

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• Serotypes can be identified using monoclonal
  antibodies
• against VP7 and VP4.
• Neutralization is detected on tissue cultures as
  a CPE
• Antigenic specificity of VP7 G
  serotypes
• Antigenic specificity of VP4 P
  serotypes

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Treatment

• Treatment is nonspecific and consists of
• 1) Oral rehydration therapy to
  prevent dehydration.
• 2) About one in 40 children with
  rotavirus gastroenteritis will
• require hospitalization for
  intravenous fluids .
• For persons with healthy immune systems,
  rotavirus gastroenteritis is
• a self-limited illness, lasting for only a few
  days.

105
prevention

• Even in the cleanest environments with the best
  hygiene, most children
• still become infected with rotavirus before
  age 4 or 5.

• Total prevention of the spread of rotavirus is
  virtually impossible.

• In hospitals health officials control rotavirus
  outbreaks by isolating
• infected patients and by ordering strict
  hand-washing procedures.

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Rotavirus Vaccine
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Rotavirus vaccine

• Scientists knew that although many strains of
  rotavirus exist, only four
• cause the majority of diarrhea cases in young
  children in the United
• States.

• Aiming for prevention NIAID researchers
  developed a vaccine
• (RRV-TV) designed to protect against the
  four strains of rotavirus .

108

• During the 1970s, NIAID scientists
  analyzed the genetic material of
• rotavirus, Identified two important
  proteins , VP4 and VP7 produced
• by the genes , and determined the
  function of these proteins.

• Proteins on the surface of the virus were found
  to be critical for triggering
• an immune response in the body against
  rotavirus.
• NIAID researchers focused on these proteins to
  develop a vaccine.

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• Tetravalent Oral Live-Attenuated Vaccine
• The oral vaccine contains four different, live
  attenuated viral strains,
• serotypes ( 1,2,3,4) .
• One strain (serotype 3) is an unmodified rhesus
  monkey rotavirus
• (RRV) which does not cause disease in humans
  
• The other three are made by reassortment
  (genetic recombination)
• of that monkey RRV with three human
  rotaviruses of serotypes
• 1,2,4.

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• Each reassortant vaccine strain contains 10
  monkey RRV genes and
• the VP7 gene for one serotype of the human
  rotavirus envelope
• proteins
• VP-7 (serotype 1) , VP-7 (serotype 2) ,
  VP-7 (serotype 4)
• The combined vaccine provided comprehensive
  protection
• against the four serotypes (1,2,3,4)

111

• Studies showed that high doses of the RRV-TV
  vaccine, designed to
• protect against four strains of rotavirus,
  were very effective in
• preventing severe, dehydrating rotavirus
  disease.
• Breast-feeding did not interfere with the
  effectiveness of
• the rotavirus vaccine ensuring
  good nutrition in infants

112

• In August 1998, the first live attenuated
  rotavirus vaccine (Rotashieldregistered Wyeth
  Lederle Vaccines and Pediatrics) was approved
  for use in infants by the Food and Drug
  Administration. The Advisory Committee on
  Immunization Practices has recommended that this
  vaccine be given as a three-dose schedule to
  infants aged 2, 4, and 6 months.

113

• However, on July 15, 1999, the US Centers for
  Disease Control and
• Prevention (CDC) recommended that doctors stop
  giving the
• rotavirus vaccine to infants.
• On October 22, 1999, the Advisory Committee on
  Immunization
• Practices voted to stop recommending the
  vaccine
• Why?

114

• Centers for Disease Control and Prevention
  (CDC) advisory committee
• received an overwhelming amount of data
  all indicating a strong
• association between ( rotavirus vaccine )
  and bowel obstruction among
• some infants during the first one to two
  weeks following vaccination.

• Apparently, many infants who received the
  rotavirus vaccine developed
• Intussception of the bowel within one to three
  weeks after receiving
• a dose or two of the vaccine.

115
Medline Search

• Oct. 15, a total of 102 confirmed and
  presumptive cases of intussusception following
  receipt of ltlt rotavirus vaccinegtgt were reported
  to the Vaccine Adverse Events Reporting System
  (VAERS). 57 had onset within seven days of
  receipt of the vaccine and 29 underwent surgery
  seven required bowel resection. One fatal case
  was reported in a 5-month-old, according to John
  Livengood, MD, director of the Epidemiology and
  Surveillance Division, National Immunization
  Program, CDC.

116

• The risk of intussusception was increased
  19-fold in the first 3 to 7
• days after vaccination and almost fourfold
  (3.6) in the 8 to 14 days
• after vaccination (Plt0.0002).

117

• These data indicate that the risk of
  intussusception is increased by 80 after
  rotavirus vaccination in an ever vs. never
  comparison. For dose one, the risk of
  intussusception increased 25-fold in the first
  three to seven days following vaccination and
  7.1-fold in eight to 14 days after vaccination.
  For dose two, the risk of intussusception
  increase 13.4-fold in three to seven days after
  rotavirus vaccination.

118

•  
• Children who have already received the vaccine
  and have not had
• problems do not appear to be at risk now.
• In the meantime, research on better vaccines for
  rotavirus
• continues.

119
Vaccine adverse reactions
120

• Percentage of children with adverse reactions
  during 5 days of surveillance following each of
  three doses of tetravalent rhesus-rotavirus
  vaccine (RRV-TV) or placebo.
• percentage with fever (as measured by axillary
  temperatures).On day 4, 2.2 of RRV-TV
  recipients vs. 0.2 of placebo recipients became
  febrile (p 0.02).
• b) percentage with diarrhea.
• c) percentage with vomiting. Adapted from (43).

121
following receipt of doses 1, 2, or 3 of RRV-TV.
The number of children who have received RRV-TV
is unknown, however, the observed rate of
intussusception among vaccine recipients during
the first 3 weeks after immunization appears to
be greater than expected, with the highest rate
during the first week following vaccination.
These initial data suggest that intussusception
occurs at a younger age in vaccine recipients
than in unvaccinated children.

122
Prevention In 1998, the U.S. Food and Drug
Administration approved a live virus vaccine
(Rotashield) for use in children. However, the
Advisory Committee on Immunization Practices
(ACIP) recommended that Rotashield no longer be
recommended for infants in the United States
because of data that indicated a strong
association betweenRotashield and
intussusception (bowel obstruction) among some
infants during the first 1-2 weeks following
vaccination.  More information about rotavirus
vaccine is available from the National
Immunization Program
Sanitary measures adequate for bacteria and
parasites seem to be ineffective in endemic
control of rotavirus, as similar incidence of
rotavirus infection is observed in countries with
both high and low health standards
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Rotavirus Infection at KAAUH ?
125
A 1293 fecal samples were collected from
patients of different age groups with
gastroenteritis over a period of 6 years 8
months (November 1995 July 2002) in Jeddah.
126
708 males (54.76)
1293 585 females
( 45.24) All were tested using enzyme linked
immunosorbent assay (ELISA).
127
Number of infected patients 136
73 males (53.68)
63 females (46.32)
5.65 males
of infected patients 10.52
4.87 females
128
of infected males 10.31 of infected
females 10.77
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Statistics
130
N127 (total number of patients
between 0 years - 40 years) Mean 2.69
years Std.Error .4590
131
Descriptive Statistics
N127(total number of patients between 0 years-40
years) Mean 2.69 years Std.Error .4590
132
Distribution of Age of Patients
5.7
(years)
133
Numbers of Infected Males to Females in Different
Age Groups
0-28
28d-1y
1-3
3-6
6-18
gt18
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Distribution of Age of Patients Excluding The
Out-Liers
(years)
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Infected Saudies non Saudies
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Infections Among Males Females (saudies non
saudies)
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Infections in( Males Females ) in Different
Seasons
139
Infections of males to females in different
seasons
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Infections in Males in Different Seasons
Infections in Females in Different Seasons
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Duration of Illness
(days)
143
Numbers of patients from different Age Groups (
Males to Females )
144
Number of Patients in Different Seasons (Males
Females )
145
Number of Patients in Different Seasons (Males
Females )
146
Number of Infected Males Females in Each
Nationality
147
Infections Among Different Nationalities in Each
Season
148
Distribution of Different Durations of Illness
(days)
149
Means of Infections Among Different Age Groups
150
conclusion

• Rotavirus was found to be most prevalent among
  
• infants and young children .
• There is no significant difference in incidence
  
• depending on the sex.
• Most of the cases were presented to the hospital
  in the
• winter.
• The mean duration of illness is 3.3 days, with
  the
• majority having symptoms of gastroenteritis
  for 3-5 days.

151
Saudi non
152
Saudi non T-test