Transcript Enteroviruses

Enteroviruses
An Overview
Enteroviruses
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Enteroviruses are a genus of the picornavirus family which replicate
mainly in the gut.
Single stranded naked RNA virus with icosahedral symmetry
Unlike rhinoviruses, they are stable in acid pH
Capsid has 60 copies each of 4 proteins, VP1, VP2, VP3 and VP4
arranged with icosahedral symmetry around a positive sense genome.
At least 71 serotypes are known: divided into 5 groups
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Polioviruses
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Coxsackie A viruses
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Coxsackie B viruses
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Echoviruses
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Enteroviruses (more recently, new enteroviruses subtype have been
allocated sequential numbers (68-71))
Enterovirus Particles
Courtesy of Linda M. Stannard, University of Cape Town, S.A.h
History
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Poliovirus - first identified in 1909 by inoculation of specimens into
monkeys. The virus was first grown in cell culture in 1949 which became
the basis for vaccines.
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Coxsackieviruses - In 1948, a new group of agents were identified by
inoculation into newborn mice from two children with paralytic disease.
These agents were named coxsackieviruses after the town in New York
State. Coxsackieviruses A and B were identified on the basis of the
histopathological changes they produced in Newborn mice and their
capacity to grow in cell cultures.
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Echoviruses - were later identified which produced cytopathic changes in
cell culture and was nonpathogenic for newborn mice and subhuman
primates.
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More recently, new enterovirus types have been allocated sequential
numbers (68 - 71).
Properties of Enteroviruses
Group
Virus types
Poliovirus
Coxsackie
group A
3 types
(1 - 3)
CPE in cell cultures
Monkey
Human cell
kidney
culture
+
23 types
- or E
(A1-22, A24)
Pathology in
newborn mice
Major disease associations
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Paralytic poliomyelitis, aseptic
meningitis, febrile illness.
- or E
+
Aseptic meningitis, herpangina,
febrile illness, conjunctivitis
(A24), hand, foot and mouth disease.
Coxsackie
group B
6 types
(B1-6)
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+
+
Aseptic meningitis, severe neonatal
disease, myopericarditis, Bornholm
disease, encephalitis, febrile
illness.
Echovirus
31 types
(1-9, 11-27
29-33)
+
E
-
Aseptic meningitis, rash, febrile
illness, conjunctivitis, severe
generalized neonatal disease.
+
+
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Polio-like illness, aseptic
meningitis, hand, foot and mouth
(E71), epidemic conjunctivitis (E70)
hepatitis A (E72)
Enterovirus
5 types
(68-72)
Poliovirus
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3 serotypes of poliovirus (1, 2, and3) but no common antigen.
Have identical physical properties but only share 36-52% nucleotide
homology.
Humans are the only susceptible hosts.
Polioviruses are distributed globally. Before the availability of
immunization, almost 100% of the population in developing countries
before the age of 5.
The availability of immunization and the poliovirus eradication
campaign has eradicated poliovirus in most regions of the world except
in the Indian Subcontinent and Africa.
Poliovirus is on course of being eradicated worldwide by the end of
2000 or 2001.
Pathogenesis
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The incubation period is usually 7 - 14 days.
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Following ingestion, the virus multiplies in the oropharyngeal and
intestinal mucosa.
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The lymphatic system, in particular the tonsils and the Peyer's
patches of the ileum are invaded and the virus enters the blood
resulting in a transient viraemia.
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In a minority of cases,the virus may involve the CNS following
dissemination.
Clinical Manifestations
There are 3 possible outcomes of infection:
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Subclinical infection (90 - 95%) - inapparent subclinical infection account
for the vast majority of poliovirus infections.
Abortive infection (4 - 8%) - a minor influenza-like illness occurs,
recovery occurs within a few days and the diagnosis can only be made by
the laboratory. The minor illness may be accompanied by aseptic
meningitis
Major illness (1 - 2%) - the major illness may present 2 - 3 days following
the minor illness or without any preceding minor illness. Signs of aseptic
meningitis are common. Involvement of the anterior horn cells lead to
flaccid paralysis. Involvement of the medulla may lead to respiratory
paralysis and death.
Laboratory Diagnosis
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Virus Isolation
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Mainstay of diagnosis of poliovirus infection
poliovirus can be readily isolated from throat swabs, faeces, and
rectal swabs. It is rarely isolated from the CSF
Can be readily grown and identified in cell culture
Requires molecular techniques to differentiate between the wild
type and the vaccine type.
Serology
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Very rarely used for diagnosis since cell culture is efficient.
Occasionally used for immune status screening for
immunocompromised individuals.
Prevention (1)
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No specific antiviral therapy is available. However the disease may be
prevented through vaccination. There are two vaccines available.
Intramuscular Poliovirus Vaccine (IPV)
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consists of formalin inactivated virus of all 3 poliovirus serotypes.
Produces serum antibodies only: does not induce local immunity and thus will
not prevent local infection of the gut.
However, it will prevent paralytic poliomyelitis since viraemia is essential for
the pathogenesis of the disease.
Oral Poliovirus Vaccine (OPV)
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Consists of live attenuated virus of all 3 serotypes.
Produces local immunity through the induction of an IgA response as well as
systemic immunity.
Rarely causes paralytic poliomyelitis, around 1 in 3 million doses.
Prevention (2)
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Most countries use OPV because of its ability to induce local immunity and
also it is much cheaper to produce than IPV.
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The normal response rate to OPV is close to 100%.
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OPV is used for the WHO poliovirus eradication campaign.
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Because of the slight risk of paralytic poliomyelitis, some Scandinavian
countries have reverted to using IPV. Because of the lack of local immunity,
small community outbreaks of poliovirus infections have been reported.
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Poliovirus was targeted for eradication by the WHO by the end of year 2000
(now 2005). To this end, an extensive monitoring network had been set up.
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Poliovirus has been eradicated from most regions of the world except the
Indian subcontinent and sub-Saharan Africa. It is possible that the WHO target
may be achieved.
Current Status of Wild Poliovirus Transmission
Coxsackieviruses
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Coxsackieviruses are distinguished from other enteroviruses by their
pathogenicity for suckling rather than adult mice. They are divided into 2
groups on the basis of the lesions observed in suckling mice.
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Group A viruses produce a diffuse myositis with acute inflammation and
necrosis of fibers of voluntary muscles.
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Group B viruses produce focal areas of degeneration in the brain, necrosis
in the skeletal muscles, and inflammatory changes in the dorsal fat pads,
the pancreas and occasionally the myocardium.
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Each of the 23 group A and 6 group B coxsackieviruses have a type specific
antigen.
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In addition, all from group B and one from group A (A9) share a group Ag.
Cross-reactivities have also been demonstrated between several group A
viruses but no common group antigen has been found.
Echoviruses
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The first echoviruses were accidentally discovered in human faeces,
unassociated with human disease during epidemiological studies of
polioviruses. The viruses were named echoviruses (enteric, cytopathic,
human, orphan viruses).
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These viruses were produced CPE in cell cultures, but did not induce
detectable pathological lesions in suckling mice.
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Altogether, There are 32 echoviruses (types 1-34; echovirus 10 and 28
were found to be other viruses and thus the numbers are unused)
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There is no group echovirus Ag but heterotypic cross-reactions occur
between a few pairs.
New Enteroviruses
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Newly identified picornaviruses that are not polioviruses are no longer
classified separated into the species coxsackie and echovirus because of
the ambiguities presented by overlapping host range variations.
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4 new enteroviruses have been identified (68 - 72). Enterovirus 70 is the
causative agent epidemics of acute haemorrhagic conjunctivitis that
swept through Africa, Asia, India and Europe from 1969 to 1974. The
virus is occasionally neurovirulent.
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Enterovirus 71 appears to be highly pathogenic and has been associated
with epidemics of a variety of acute diseases, including aseptic
meningitis, encephalitis, paralytic poliomyelitis-like disease and handfoot-mouth disease.
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Enterovirus 72 was originally assigned to hepatitis A virus, but it had
now been assigned to a new family called heptoviruses.
Diseases associated with Enteroviruses
Syndrome
Polio
Paralytic disease
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Meningitis-encephalitis +
Carditis
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Neonatal disease
Pleurodynia
Herpangina
Rash disease
Haemorr. conjunctivitis Respiratory infections
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Undifferentiated fever
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Diabetes/pancreatitis
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Cox A
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Cox B
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Echo
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Disease Associations (1)
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Paralytic Disease - most commonly associated with polioviruses but other
enteroviruses may also be responsible, notably enterovirus 71
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Meningitis - caused by all groups of enteroviruses, most commonly seen in
children under 5 years of age.
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Encephalitis - focal or generalized encephalitis may accompany meningitis.
Most patients recover completely with no neurological deficit.
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Undifferentiated febrile illness - may be seen with all groups of enteroviruses.
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Hand foot mouth disease - usually caused by group A coxsackieviruses
although group B coxsackieviruses and other enteroviruses have been caused
outbreaks.
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Herpangina - caused by group A coxsackieviruses.
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Epidemic Pleurodynia (Bornholm disease) - normally caused by group B
coxsackieviruses.
Disease Associations (2)
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Myocarditis - group B coxsackieviruses are the major cause of myocarditis,
although it may be caused by other enteroviruses. It may present in neonates as
part of neonatal infection and is often fatal. In adults, the disease is rarely fatal.
Respiratory Infections - several enteroviruses are associated with the common
cold.
Rubelliform rashes - a rash disease resembling rubella may be seen with several
coxsackie A, B, and echoviruses.
Neonatal Infection - some coxsackie B viruses and echoviruses may cause
infection in newborn infants. The virus is usually transmitted perinatally during
the birth process and symptoms vary from a mild febrile illness to a severe
fulminating multisystem disease and death.
Conjunctivitis - associated with several types of enteroviruses, notably
Coxsackie A24 and Enterovirus 70 (haemorrhagic conjunctivitis)
Pancreatitis/Diabetes - associated with Coxsackie B virus infection. The extent
of the role of the virus in diabetes is unknown.
Laboratory Diagnosis
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Virus Isolation
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Mainstay of diagnosis of enterovirus infection
Coxsackie B and Echoviruses can be readily grown in cell culture from
throat swabs, faeces, and rectal swabs. They can also be isolated from the
CSF
Coxsackie A viruses cannot be easily isolated in cell culture. They can be
isolated readily in suckling mice but this is not offered by most diagnostic
laboratories because of practical considerations. Molecular techniques
may provide a better alternative.
Serology
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Very rarely used for diagnosis since cell culture is efficient.
Neutralization tests or EIAs are used but are very cumbersome and thus
not offered by most diagnostic laboratories
Cytopathic Effect
(Virology Laboratory, New-Yale Haven Hospital)
Management and Prevention
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There is no specific antiviral therapy available against enteroviruses
other than polio.
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Some authorities use IVIG in the treatment of neonatal infections or
severe infections in immunocompromised individuals. However, the
efficacy is uncertain.
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HNIG have been to prevent outbreaks of neonatal infection with good
results.
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There is no vaccine available mainly because of the multiplicity of
serotypes. There is little interest in developing a vaccine except against
enterovirus 71 and coxsackie B viruses.