ENTEROVIRAL INFECTIONS

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ENTEROVIRAL INFECTIONS

• Dr.B.Boyle

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ENTEROVIRAL INFECTIONSContents of Lecture

• ENTEROVIRUSES
• Also Discuss , Viruses that cause Gastroenteritis
• ROTAVIRUS
• SMALL ROUND STRUCTURED VIRUSES e.g Norwalk virus
  or Novovirus etc.

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ROTAVIRUS
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ROTAVIRUS

• Description
• Epidemiology
• Pathogenesis
• Clinical Features
• Diagnosis
• Treatment
• The Future

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ROTAVIRUS

• First described in 1973 by electron microscopy
  from duodenal biopsy specimens
• Causes 40-60 of cases of diarrhoea in cooler
  months in infants and children lt 2 years

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Morphology-Rotaviruses

• Reoviridae Family
• Non-enveloped icosahedral structure, 70nm
• EM Wheel shape
• Capsid Outer(VP7 and 4) and Inner(VP6) proteins
• Core encloses 11 segments of DS RNA
• Genome encoded Structural proteins VP1-7 and NSP
  1-5, NSP4 has enterotoxinlike activity

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Epidemiology of Rotavirus

• Incubation period 2-4 days
• Those affected 4-24 month old infants, infection
  before and reinfection after this usually
  asymptomatic (Breastfeeding results in milder
  disease)
• Spread within families and institutions
• Human to human, faecal-oral route
• Found on fomites in childcare

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Epidemiology of Rotavirus

• Main cause of severe diarrhoea in children lt 5
  years
• 130 million episodes per year in the world
• Between 600,000-870,000 deaths, mostly in the
  developing world
• Rate of hospitalisation in developed world 2.5
• Seasonal pattern
• Most persons infected by 3 years of age
• Group A predominates

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Classfication-Rotavirus

• Groups,Subgroups and serotypes depending on the
  antigenic properties of the capsid proteins
• Group-VP6, seven exist A-G, 2 subgroups 1-2
• Groups A,B,C cause human infection

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Rotavirus-Pathogensis
Infects
Mature Enterocytes(on tips of Small Intestine
villi)
Villous Atrophy
Compensatory Repopulation by immature Secretor
cells and secondary hyperplasia
Cell death because of villous ischaemia
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Mechanism of diarrhoea?
Enteric nervous system stimulates? Induction Of
intestinal Water And electrolyte secretion
Villous epithelium in relation To secretory
capacity of Crypt cells
Loss of permeability to Macromolecules e.g
Lactose, Due to loss of disaccharideases
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Rotavirus Damage to Small Intestine
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Immune Response to Rotavirus

• Localised Immune response protects against severe
  subsequent infections
• NSP4 protein results in cell mediated immunity

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Outcome of Infection with Viruses

• Lysis of cells e.g Influenza or polio
• Persistent infection e.g. cell remains alive and
  continues to release virus particles e.g.
  Hepatitis B , CHRONIC CARRIER STATE
• Latent Infection , no replication Varicella
  Zoster or retrovirues , if triggered leads to
  lysis
• Transformation of host cells e.g. warts or
  papovaviruses, HTLV 1 and 2

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Clinical Presentation-Rotavirus

• Abrupt onset of vomiting followed within hours by
  watery, brown copious diarrhoea, often lasts 3-8
  days
• If Severe ? Dehydration and death or
  hospitalisation

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DIAGNOSIS

• Clinically
• Latex agglutination
• Kit testing for Group A
• Rv antigen in stool
• Enzyme Immunoassay
• Group A
• Rv antigen in stool
• Less common EM and molecular methods

Pos and neg
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TREATMENT

• REHYRATE, oral and if severe parenteral
• Some studies in immunocompromised persons showing
  the use of Human Immunoglobulin results in a
  reduction in the duration of symptoms and
  decreases viral sheeding
• ISOLATION of patient in hospital with contact
  prescautions

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MANAGEMENT

• In Home Washing of surfaces with soap and water
  which may be contaminated with Rotavirus
• 70 ethanol solution will kill the virus on
  environmental surfaces

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FAMILY PICORNAVIRIDAE
Cardiovirus Aphthousvirus etc
RHINOVIRUS Type 1-100
ENTEROVIRUSES Over 72
POLIO virus type 1,2,3 COXSACKIE A virus type
1-22,24 COXSACKIE B virus type 1-6 E.C.H.O virus
type 1-7,11-27,29-34 Numbered ENTEROVIRUSES type
68-71,73
Since 1967-all new ones are numbered
E.C.H.O enteric cytopathic human orphan
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Characteristics

• VIRON naked , small (25-30 nm) icosahedral
  capsid enclosing postive sense single stranded
  RNA
• Enteroviruses are resistant to p H 3-9, Heat,
  Mild sewage treatment and detergents, conditions
  in GIT FACILATES faecal oral spread

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Characteristics

• Rhinovirus labile to acidic p H
• Genome of Enteroviruses is m RNA
• Naked genome is sufficient for infection
• Replication in cytoplasm
• Cytolytic viruses

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Clinical Manifestations of EV Infections(Mostly
Children)

• Neurological e.g Poliomyelitis, Aseptic
  meningitis and encephalitis
• Neonate neonatal sepsis EV 11
• Non-specific febrile illness
• Hepatitis gi etc
• Haemorrhagic conjunctivitis, COX A24
• and EV 71

• Respiratory Symptoms e.g colds, herangina
• Skin Exanthem with meningitis
• Myocarditis
• Those associated with Coxsackie viruses
• Spread Faecal oral route , respiratory route and
  peripartum mother to infant or fomite
  transmission
• IP 3-6 DAYS

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COXSACKIE VIRUSES

• 29 immunogenic types
• Divided into A and B on the basis of different
  pathogenic potential for mice
• Result in a number of different clinical
  presentations

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COXSACKIE VIRUSES

• Herangina
• Summer minor illness
• Aseptic meningitis
• Neonatal Disease
• Colds

• Hand , Foot and mouth illness
• Myocarditis
• ? Diabetes mellitus
• Epidemic myalgia (Bornholm Disease)

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HAND/FOOT/MOUTH
Coxsackie A16
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H/F/M
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ECHO Viruses

• General properties similar to other enteroviruses
• 30 antigenic types
• Results in - 1. Aseptic meningitis
• 2. Rash
• 3.Conjunctivits
• 4. Upper Respiratory
  Tract Infection

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ENTEROVIRUS 71
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Management

• Supportive
• Capsid function inhibitors Pleconaril, broad
  spectrum, potent to Rhino and enteroviruses, good
  oral bioavailibility
• This compound binds to the floor of a VP1 and VP3
  canyon floor , prevents binding to receptor on
  cells
• Used in cases of meningoencephalitis shown to be
  effective
• As humoral immunity is the bodys defence for
  enteroviruses, those who have deficiencies
  (congenital or acquired)are given Intravenous
  Immunoglobulin

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POLIO VIRUS
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Polioviruses

• are RNA , ENTEROVIRUSES
• 3 Serotypes 1, 2 ,3
• Major cause of paralytic poliomyelitis and now
  seeing post polio syndrome
• Global Eradication Programme of WHO

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EPIDEMIOLOGY

• Human host
• Spread Faecal oral or Respiratory routes
• More common in infants and young children, but
  risk of paralytic disease increases with age
• No indigeous wild type polio in U.S since 1979,
  imported in 1993, last wild type case in Ireland
  1984
• Vaccine Associated Paralytic Polio(VAPP) WHEN
  ORAL POLIO VACCINE (OPV) was in use( Reversion to
  wild type) now inactivated polio vaccine
  used(IPV) used in Ireland since 2001

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EPIDEMIOLOGY

• Risk of VAPP is one case per 2.5 million doses,
  greatest risk with first dose
• If using OPV strict hygiene after nappy changing
  or toileting should be observed for 6 weeks

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PRESENT VACCINE SCHEDULE
At birth- 1 month BCG Usually in maternity hospitals
At 2 months Diphtheria Whooping Cough Tetanus Hib Inactivated Polio Meningococcal C 5-in-1(G.P)
At 4 months Diphtheria Whooping Cough Tetanus Hib Inactivated Polio Meningococcal C 5-in-1(G.P)
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PRESENT SCHEDULE
At 6 months Diphtheria Whooping Cough Tetanus Hib Inactivated Polio Meningococcal C 5-in-1(G.P)
At 12- 15 months Measles Mumps Rubella, Hib1 MMR Hib1
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PRESENT SCHEDULE
4-5 YEARS Diphtheria Whooping Cough Tetanus Inactivated Polio Measles Mumps Rubella 4-in-1 MMR
11-12 YEARS Measles Mumps Rubella MMR Omit if 2 previous doses have been given
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PRESENT SCHEDULE
11-14 years Tetanus Diphtheria (low dose) Td
10-14 years if not protected(immune) Under 23 years(Colleges etc) BCG2 (AN INTERVAL OF 4 WEEKS AFTER MMR) Meningococcal C

• From Family Doctor
• 1 A single dose of Hib vaccine if child presents
  after 13 months and has no previous Hib vaccine
• 2 Only those known to be tuberculin negative and
  have no previous BCG
• These immunizations are generally administered
  in schools by Health Boards

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Clinical Presentations of Poliovirus Infection

• Approx. 95 of infections are ASYMPTOMATIC
• Minor illness in 4-8 of lowgrade fever, sore
  throat
• Aseptic Meninigits in 1-5
• Asymmetrical acute flaccid paralysis with
  areflexia of limbs involved in 0.1-2 of
  infections (Respiratory Muscles may be involved)
• Residual Paralytic Diease in 2/3 of these
• Some develop Post-Polio syndrome 30-40 years post
  infection with return of muscle pain and weakness

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Poliomyelitis
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Poliomyelitis
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Pathogenesis of Enteroviral Infection
Evades
Virus
Replicates in Nasopharnyx
Binds Enterocytes Receptor coded by Ch 19
Acidic PH
Endocytosed , replication in Peyers patches
Minor Viraemia, Replication in organs
Anterior Motor Neuron horn cells To CNS
Major Viraemia Trophism Virulence
Skeletal Muscle Neuromuscular Endplate
Ascends along Motor Nerves
Spinal, Bulbar, Medullary
Redspecifc for polio
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Communciability

• This is greatest shortly before and after onset
  of clinical illness when virus in the throat and
  it is excreted in high concentrations in faeces
• For OPV RECIPIENTS, VIRUS IN THE THROAT 1-2 WEEKS
  AND FAECES FOR SEVERAL WEEKS USUALLY MAX 6-8
  WEEKS IN NORMAL IMMUNOCOMPOTENT INDIVIDUAL.

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Surveillance

• For Acute flaccid paralysis
• Since September 1998
• Two faecal specimens 24-48 hours apart for viral
  culture as soon as possible after onset of acute
  flaccid paralysis
• Faeces most likely to yield virus

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Diagnosis

• Clinical Presentation
• Laboratory Diagnosis
• Faecal, Throat (2 or more samples), CSF(Culture
  and RT-PCR)

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TREATMENT/PREVENTION

• Supportive
• Prevention is by Vaccination.
• Global Eradiation Programme
• Part of Routine immunisation schedule and
  travellers to endemic areas should be vaccinated

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Global Eradication programme
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SLV-NLV-Novovirus-Calciviruses

• Family Calciviridae
• Single Stranded RNA, ps
• Consists of Single Structural Capsid protein with
  icosahedric symmetry but has 32 cup-shaped
  depressions on the axes of the Icosahedron hence
  the name calyx
• Multiple antigenic types

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Epidemiology

• Genotype 1,11 and 4 are associated with outbreaks
• Often affecting institutions
• Commonest cause of gastroenteritis outbreaks in
  2nd quarter 2005, with 32 outbreaks and 675
  persons ill, 72 of cases
• Present circulating genotype in Ireland since
  2004 is Genotype 11.4 JAM strain
• Review Lopman et al Lancet Feb 2004

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Pathogenesis of Disease

• Not fully understood although some evidence
  suggesting it may be simliar to Rotavirus
• Causes delayed gastric emptying
• Immunity infection induces specific IG G/A/M
  even if there is previous exposure
• 2 weeks post infection there is ? in jejunal Ig A
  , resistance to reinfection lasts 4-6 months,
• NO LONG TERM PROTECTION
• Accounts for gt85 of non-bacterial outbreaks of
  gastroenteritis

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EPIDEMIOLOGY

• Sporadic cases however causes epidemic outbreaks
• Examples on cruise ships, hotels, Institutions
  and hospitals
• Spread Person to person via faecal oral route or
  through contaminated food or water or fomites
• Incubation Period 12-72 hours
• Vomitus /Faeces infectious

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CLINICAL FEATURES

• DIARRHOEA
• VOMITING
• Commonly accompanied by fever, malaise, myalgia
  and abdominal cramps
• Symptoms last 1 day to 70 hours usually
• Virus excreted 5 to 7 days after the onset of
  symptoms in half of people although may last 13
  days

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Diagnosis(sample stool)

• Electron Microscopy
• Labour intense
• Relatively insensitive
• Used in Sporadacic cases
• EIA
• Stool tested, can have a result in a few hours
• Not labour intensive
• Evaluation of kits must be carried out for
  sensitivity/specificity

• Reverse Transcriptase Polymerase chain reaction
  (RT-PCR)
• Used in outbreaks as large numbers can be
  processed efficiently

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Treatment

• Supportive therapy rehydration, electrolyte
  replacement
• Isolation of Hospitalised patient
• Control Measures Standard and Contact
  precautions
• No Vaccine

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Suspect an outbreak in hospital if

• Projectile vomiting in gt50 of cases
• Duration of illness 12-60 hours
• Incubation period 15-48 hours
• Staff and patients ill
• Stools negative for bacterial pathogens and
  C.difficile and other viruses

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Control Measures in Hospital Outbreaks

• Isolation or Cohort
• Contact Precautions- disposable plastic apron/
  gloves, Hand Hygiene
• Close Ward to Admissions
• Non-essential personnel excluded
• Avoid Transfers
• If Staff unwell not return to work until free
  from symptoms 48 hours
• Increase frequency of ward cleaning

• Vomit/Faeces to be cleaned and disinfected
  promptly
• Hypochlorite(0.1) used to disinfect surfaces
• Cohort Staff
• Limit Movement
• Ward not reopened until 72 hours after last new
  case or after last vomiting/diarrhoea
• Terminal cleaning

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The Future

• Plasmidic DNA and Antigen Vaccines
• Interrrupt Transmission
• Supportive Therapy