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VIRAL AGENTS CAUSING GASTROENTERITIS

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Title: VIRAL AGENTS CAUSING GASTROENTERITIS


1
VIRAL AGENTS CAUSINGGASTROENTERITIS
Helmut Albrecht, MDID Division Chief, USC
DOM(based on lecture by Nandini Narayan, MD)
2
Viruses found in the gut (1)
  • A. Associated with gastroenteritis
  • Rotaviruses
  • Adenoviruses 40/41
  • Caliciviruses
  • Norwalk like viruses or SRSV (Small Round
    Structured Viruses)
  • Astroviruses
  • SRV (Small Round Viruses)
  • Coronaviruses
  • Toroviruses

3
Viruses found in the gut (2)
  • B. Found in the gut, not normally associated with
    gastroenteritis
  • Polio
  • Coxsackie A
  • Coxsackie B
  • Echo
  • Enteroviruses 68-71
  • Hepatitis A
  • Hepatitis E
  • Adenoviruses 1-39
  • Reoviruses
  • C. Found in the gut as opportunistic infection
  • CMV
  • HSV
  • VZV
  • HIV

4
VIRAL AGENTS CAUSINGGASTROENTERITIS
  • Pathogens discussed in todays lecture
  • Rotavirus
  • Enteric adenoviruses
  • Caliciviruses
  • Astroviruses
  • Toroviruses

5
ROTAVIRUS
  • Family Reoviridae
  • Genus Rotavirus
  • Other genera Orthreovirus, Coltivirus, orbivirus
    (sheep)

6
ROTAVIRUS- discovery
  • First isolated in 1973 in Australia by Ruth
    Bishop at the Royal Children's Hospital in
    Melbourne.
  • EM identification from duodenal biopsies from
    children with diarrhea.
  • "Virus particles in epithelial cells of duodenal
    mucosa from children with acute non-bacterial
    gastroenteritis," Lancet, 11281-3, 1973.
  • Described in stool samples from children by
    Albert Z. Kapikian, in the US
  • Human and animal strains are recognized

7
Rotavirus
8
ROTAVIRUS STRUCTURE
9
STRUCTURAL FEATURES OF ROTAVIRUS
  • 60-80nm in size
  • Non-enveloped virus
  • EM appearance of a wheel with radiating spokes
  • Icosahedral symmetry
  • Double capsid
  • Double stranded (ds) RNA in 11 segments

10
STRUCTURAL FEATURES OF ROTAVIRUS (contd.)
  • Double capsid (outer and inner capsid)
  • Core with genome
  • Capsid is cleaved by trypsin to form ISVP
  • intermediate/infective sub-viral particle

11
Rotavirus structure
12
ROTAVIRUS- ultrastructure
13
ROTAVIRUSEM STRUCTURE
14
VIRAL STRUCTURAL PROTEINS (VP)
  • Outer structural proteins - VP7 and VP4 VP7
    - Glycoprotein
  • VP4 - protease-cleaved, P protein, viral
    hemagglutinin forms spikes from the surface
  • Inner core structural proteins VP 1, 2, 3, 6
  • VP6 is an important antigenic determinant

15
CLASSIFICATION- Groups
  • 7 Groups (A through G) and 2 subgroups (Iand II)
    based on VP6 differences
  • Group A is the most common
  • Group B (outbreaks in China)
  • Group C (worldwide)

16
CLASSIFICATION - Serotypes
  • Serotypes based on viral capsid proteins inducing
    neutralizing Ab
  • 14 G serotypes based on G protein (VP 7)
    differences
  • 5 predominant strains in U.S. (G1-G4, G9) account
    for 90 of isolates
  • Strain G1 accounts for 73 of infections
  • 20 P serotypes based on P protein (VP4) with
    P4/P8 predominance
  • Common PG combinations are P8G1, P8G2, P4G2, P8G4

17
CLASSIFICATION (contd.)
  • Electropherotypes are based on the mobility of
  • RNA segments by PAGE
  • Useful in epidemiologic studies

18
ROTAVIRUS- PROPERTIES
  • Virus is stable in the environment (months)
  • Relatively resistant to handwashing agents
  • Susceptible to disinfection with 95 ethanol,
    Lysol, formalin

19
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

20
REPLICATION
  • mRNA transcription with viral RNA polymerase
  • Capsid proteins formed, assembled into immature
    capsid
  • RNA replicated to form double stranded RNA genome

21
HISTOPATHOLOGY
  • Mature enterocytes lining the tips of intestinal
    villi are affected
  • Villous atrophy and blunting
  • Death of the mature enterocytes

22
HISTOPATHOLOGY
  • Infiltration of lamina propria with mononuclear
    cells
  • Repopulation of the villous tips with immature
    secretory cells crypt hyperplasia

23
HISTOPATHOLOGY
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EPIDEMIOLOGY
  • A major cause of diarrhea-associated
    hospitalizations and deaths
  • Sero-prevalence studies show that antibody is
    present in most by age 3y

26
ROTAVIRAL DISEASE BURDENWorldwide
27
WORLDWIDE DISTRIBUTION OF ROTAVIRUS(Source-
Centers for Disease Control and Prevention)
28
DISEASE BURDENUSA
  • 20-40 deaths/year
  • Cases with dehydration 1-2.5
  • 50,000-70,000 hospitalizations/year
  • Physician visits 500,000/year
  • 2.7- 3.5 million affected each year
  • Economic impact

29
ROTAVIRAL DISEASE BURDEN- U.S.A.Source- MMWR
August 11, 2006 / 55(RR12)1-13
30
EPIDEMIOLOGY
  • Age- children 4mo - 2 years are most
    affectedProtection of younger infants through
    through transplacental antibody transfer
  • Asymptomatic infections are common, especially in
    adults
  • Nosocomial infections
  • Outbreaks
  • Severe Disease young, immunocompromised

31
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

32
EPIDEMIOLOGY(Source- Centers for Disease Control
and Prevention)
33
SEASONAL SPREAD - U.S.(Source- CDC)
34
TRANSMISSION
  • Mainly person to person via fecal-oral route
  • Food and water-borne spread is possible
  • Fomites
  • Spread via respiratory route is speculated

35
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 10-100 pfu

36
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

37
Rotavirus Immunity
  • Antibody against VP7 and VP4 partially protective
  • First infection usually does not lead to
    permanent immunity
  • Reinfection can occur at any age
  • Subsequent infections generally less severe

38
CLINICAL CASE
  • A 22 month old female is admitted to the
    pediatric ward for cough and fever up to 103F.
  • Chest X ray shows left lower lobe pneumonia.
  • She is being treated with intravenous Ceftriaxone
    and her fever is gradually improving.
  • On hospital day 5, she develops diarrhea with 4
    watery stools and a fever of 102F.
  • Stool studies showed no traces of blood and no
    fecal leukocytes.
  • Further studies are pending.

39
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
    individuals.
  • NEC and hemorrhagic GE seen in neonates

40
MECHANISM OF DIARRHEA
  • Watery diarrhea due to net secretion of
    intestinal fluid and loss of absorptive surface
  • Activation of the enteric nervous system
  • Role of NSP4 peptide regions as an enterotoxin

41
CLINICAL FEATURES (contd.)
  • Dehydration is the main contributor to mortality
  • Secondary malabsorption of lactose and fat, and
    chronic diarrhea are possible

42
Clinical appearance of dehydrationPhoto Credit
Dr. D. Mahalanabis, World Health Organization
43
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44
DIAGNOSIS
  • Antigen detection in stool
  • ELISA, LA (Group A rotavirus),
    immunochromatographic assay
  • EM- non-Group A viruses also
  • Culture- Group A rotaviruses can be cultured in
    monkey kidney cells
  • Serology for epidemiologic studies

45
TREATMENT AND PREVENTION
  • Treatment
  • Supportive- oral, IV rehydration
  • Prevention
  • Hand hygiene and disinfection of surfaces
  • Vaccine

46
Rotavirus Vaccine (Rota)
  • Created by genetic reassortment
  • Causes nonhuman rotavirus strains to express
    human rotavirus
  • antigens on their surface
  • Nonhuman rotaviruses have low pathogenicity for
    humans
  • Replicate but do not cause disease

47
ROTAVIRAL VACCINE Historical lessonsPhoto
source- PATH vaccine resource library
  • 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,
    especially the first dose
  • Approx. 15 cases/1.5 million doses given
  • Attributable risk 110,000 (1st dose)

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49
RotaTeq (Merck)
  • Live oral vaccine licensed 2006 in US
  • Contains 5 reassortants (WC3 bovine strain with
    viral surface proteins of human serotypes G1-4
    and P1A)
  • Contains no preservatives or thimerosal
  • 3-dose schedule age 2,4,6 month
  • Minimum age of first doses is 6 weeks
  • First dose should be administered between 6 and
    12 weeks of age (until age 13 weeks)
  • Do not initiate series after 12 weeks of age

MMWR 200655(RR-12)1-13.
50
Rotavirus Efficacy and Safety Trial (REST)
  • 70,000 enrollees in 11 countries
  • 34,000 enrolled in the US
  • Conducted from 2001 to 2004
  • Double-blind (with sponsor blinding),
    placebo-controlled, randomized
  • Data published in Jan. 2006
  • Vesikari T, Matson DO, Dennehy P, et al. Safety
    and efficacy of a pentavalent human-bovine (WC3)
    reassortant rotavirus vaccine. N Engl J Med
    200635423--33.

51
Efficacy of RotaTeq
  • 98 reduction in severe RV GE within first year
    of vaccination
  • 96 reduction in hospitalization
  • 74 reduction of RV GE (any grade of severity)
    within first year of vaccination
  • 71 reduction of RV GE in first 2 years of
    vaccination

52
Incidence of intussuception-RotaTeq New Eng J
Med 2006 35423-33
53
Rotarix?
  • Live attenuated monovalent vaccine
  • Manufactured by Avant Immunotherapeutics
  • Contains the G1P8 human rotavirus strain
  • Studied in Latin America in large trials
  • 2 dose schedule
  • Safety established- intussusception not
    increased, efficacious
  • Licensed in other countries

54
GASTROENTERITIS DUE TO ENTERIC ADENOVIRUS
55
Adenovirus Gastroenteritis
  • Isolated 1953 by Rowe from adenoidal tissue
  • Linear double-stranded DNA
  • 70-75nm in diameter
  • Genus Mammalian AV (mastadenoviruses)
  • 6 human subgenera (A-F)
  • 51 human serotypes (1-51)
  • Known oncogenic potential of some serotypes
  • Commonly used as vectors in
  • gene therapy and vaccine delivery

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Adenoviral core/capsid proteins
59
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Adenovirus Gastroenteritis
  • Types 40, 41
  • Belong to serogroup F
  • Isolation requires special media-Graham 29
  • ELISA for rapid detection is available

61
Diarrhea due to Enteric Adenovirus
  • Age lt4 years
  • Ubiquitous
  • Year round
  • Spread via fecal-oral route

62
CLINICAL FEATURES- Adenovirus gastroenteritis
  • Incubation period 3 -10 days
  • Diarrhea lasts for 10 -14 days
  • Can also cause intussusception, mesenteric
    adenitis, appendicitis
  • Treatment with cidofovir promising for severe
    disease in immunocompromised

63
HUMAN CALICIVIRUSES
64
HUMAN CALICIVIRUSES(HuCV)
  • Family Caliciviridae
  • Non-enveloped RNA viruses
  • with ss sense RNA
  • 27-35 nm in size
  • Contains single capsid protein

65
Calicivirus
  • Norwalk virus and Norwalk-like
  • Sapporo-like viruses
  • Vesivirus
  • Lagovirus

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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

68
MORPHOLOGY- typical
  • 32 cup-like depressions
  • EM appearance of Star of David
  • 31-35 nm size
  • E.g.- Sapporo-like viruses

69
HUMAN CALICIVIRUSES - SLV
70
Morphology of HuCV- atypical
  • Smaller size- approx. 27 nm
  • Rough, feathery surface but no internal pattern
  • Small Round Structured viruses
  • E.g.- Norwalk-like viruses

71
NOROVIRUS
  • Photo source- http//www.kyobiken.or.jp/norovirus.
    JPG

72
Norwalk virus
  • winter vomiting disease 1968, Norwalk OH
  • Cause 40 of nonbacterial epidemics
  • 45 foodborne, 52 shell fish associated
    outbreaks
  • Explosive epidemics
  • camps, cruise ships, nursing homes
  • Food borne illness
  • raw shellfish

73
EPIDEMIOLOGY - Noroviruses
  • Worldwide distribution
  • gt23 million cases/year in the U.S.
  • Major cause of food-borne outbreaks of GE (gt50)
  • Most people have had infections by age 4 years
    (by sero-prevalence studies)

74
Norwalk virus Clinical Features
  • 24 hour (range 12-96) incubation period
  • Vomiting prominent
  • Headache, myalgia, fever
  • Diarrhea 1-3 days, less severe than rotavirus
  • Affects all ages
  • Treatment symptomatic
  • rehydration, antidiarrheals
  • Complications rare
  • immunocompromised

75
SPREAD
  • Person-to-person fecal-oral spread
    (stool/vomitus)
  • Fecal contamination of food or water
  • Fomites (stool/vomitus)
  • Ingestion of aerosolized particles

76
SPREAD OF NOROVIRUS
  • A study has shown that where fingers come into
    contact with virus-contaminated material,
    Norovirus can be consistently transferred via the
    fingers to melamine surfaces and from there to
    other typical hand-contact surfaces, such as
    taps, door handles and telephone receivers..It
    was found that contaminated fingers could,
    sequentially transfer virus to up to seven clean
    surfaces. Norovirus can survive for up to
    several days in the environment and still cause
    infection.
  • ENVIRON. HEALTH JOURNAL March 2005, pages 22-24

77
SPREAD- Viability of Caliciviruses
  • Survive on surfaces for several days
  • Survive in water chlorinated at routine levels
    (up to 10 ppm)
  • Survive freezing, heating up to 60C
  • Evidently survive in steamed shellfish

78
EPIDEMIOLOGY
  • Asymptomatic infections- seroconversion but
  • asymptomatic shedding of virus
  • Low infective dose (10 pfu)
  • Viral excretion during convalesence ( 2 wk.)
  • Protective immunity short-lived
  • NLV cross protection?
  • Blood group antigens predilection?

79
EPIDEMIOLOGY Outbreaks
  • Cruise ships, schools, nursing homes,
  • Can involve infants and school-age children
  • Source usually is contaminated food and water
    (E.g. seafood-oyster and shellfish, salads, cake
    icing, raw fruit etc.)
  • Rapid secondary spread
  • Photo source- http//www.seattlest.com

80
DIAGNOSIS
  • Specimen- stool, vomitus, food, environmental
    swabs (during outbreak investigations)
  • RT-PCR in state public health labs.
  • Serology for epidemiologic purposes
  • Immune EM is less used

81
Control of spread of CV GE
  • Unclear as to which is the best method of
    disinfection of surfaces
  • CDC recommends environmental disinfection of
    non-porous surfaces with 1000 ppm bleach solution
    (1 part bleach 50 parts water)

82
HUMAN ASTROVIRUS
83
ASTROVIRUS
  • Described in relation to an outbreak of
    gastroenteritis in 1975
  • Detected by EM
  • Immunologically distinct from Hu CV
  • Animal strains are known

84
Classification of Astrovirus
  • Genus Astrovirus
  • Family Astroviridae
  • Human serotypes HuAstV 1-8

85
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
  • Genome has been sequenced

86
ASTROVIRUS- STRUCTUREPhoto source-
http//www.ncbi.nlm.nih.gov/ICTVdb/Images/Cornelia
/astro3.htm
87
ASTROVIRUS - Clinical Features
  • Infants and children are most often affected
  • Elderly and immune compromised persons also
  • Short incubation period 1-4 days
  • Nausea, vomiting, abdominal cramping and watery
    diarrhea
  • Constitutional symptoms-fever, malaise, headache

88
ASTROVIRUS - Epidemiology
  • Endemic worldwide
  • True disease burden is not yet clear
  • Mainly in children lt7 years of age
  • Transmission- person-to-person fecal-oral
  • Outbreaks due to fecal contamination of
  • sea-food or water

89
Outbreaks of AstrovirusSource-
http//www.ozestuaries.org/indicators/shellfish_cl
osures.jsp
90
ASTROVIRUS - Diagnosis
  • EM (virus shed in stool in great numbers)
  • EIA
  • RT-PCR

91
Toroviruses
  • Family Coronaviridae
  • Genus Torovirus
  • Human and animal pathogen
  • Pleomorphic, coated ss () RNA virus
  • Core doughnut-shaped (torus)
  • Watery diarrhea in 2 12 months old
  • Diagnosis EM

92
Cytomegalovirus
  • Herpesvirus
  • Immune competent
  • Mononucleosis-type syndrome
  • Immunocompromised
  • retinitis
  • hepatitis
  • gastrointestinal involvement (colon)

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Cytomegalovirus colitis
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Request Stool for viruses
  • Hospital 1 Enterovirus, adenovirus,
    herpesviruses (CMV, HSV)
  • Hospital 2 CMV
  • Hospital 3 Enterovirus
  • Hospital 4 Stop sending us this!
  • Hospital 5 Please resubmit in viral cx
    medium! gt HSV, CMV
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