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Viral infections of the CNS 1
Acute infections
Ikuo Tsunoda, MD, PhD
MPID 3 (Micro #289
Pathogenesis of Infectious
Diseases II)
March 15, 2016
[email protected]
neural cells
• Neurotropism: the ability to infect
neural cells (neuronotropism means
infections specifically of neurons)
• Neuroinvasiveness: the ability to
gain access to the nervous system
• Neurovirulence: the ability to cause
disease
Four CNS cell types
• Neuron
– Cell body, dendrites, axons
• Oligodendrocyte
– Myelin forming cell
– In the periphery, Schwann cells
• Astrocyte
– Gliosis (scar), blood-brain
barrier (astro = star)
• Microglia
– Monocyte / macrophage lineage
cell
Glial cells = oligodendrocyte + astrocyte +
microglia
Color Atlas of Neuroscience
http://ebooklibrary.thieme.com/SID0000000000000/ebooklibrary/flexibook/pubid-169111625/show_pdf.html?/pdf/pubid-169111625_1039.pdf
CNS cell types and viruses
• Neuron
– Poliovirus (motor neuron), Rabies (limbic
system), West Nile, Herpes, Theiler’s virus
• Oligodendrocyte
– JC virus, Theiler’s virus
• Astrocyte
– Canine distemper virus
• Microglia
– HIV, Theiler’s virus
Myelination and demyelination
Myelin
Oligodendrocyte
Axon
Neuron
Demyelination
Cell death
Tsunoda, Virology, 228: 388-393, 1997
TABLE 5.1 Major Neurotropic Viruses
Herpesviridae
Herpes simplex virus (HSV) I and II
Cytomegalovirus (CMV)
Varicella-zoster virus (VZV)
Arbovirus (alphavirus)
Western equine encephalitis (WEE) virus
Eastern equine encephalitis (EEE) virus
Principles and Practice of Neuropathology
Venezuelean equine encephalitis (VEE) virus
- 2nd Ed. (2003)
Arbovirus (flavivirus)
Japanese encephalitis virus
http://online.statref.com/Document/Document.aspx?FxId=120&SessionId=122CF6EUTITBOLWU
St. Louis encephalitis (SLE) virus
West Nile fever virus
“Although viruses come in a wide
Tickborne encephalitis complex
variety of sizes and shapes and
Arbovirus (Bunyaviridae)
chemical composition, it is not
California (La Crosse) encephalitis virus
essential for the pathologist to
Picornavirus (enterovirus)
commit to memory all the nuances
Poliovirus
of viral taxonomy. “
Coxsackie virus
Paramyxovirus
Measles virus
Mumps virus
Rhabdoviridae
Rabies virus
Arenavirus
Lymphocytic choriomeningitis virus (LCMV)
• Neurotropism: the ability to infect neural
cells (neuronotropism means infections
specifically of neurons)
• Neuroinvasiveness: the ability to gain access
to the nervous system
• Neurovirulence: the ability to cause disease
Portals of entry for
viruses causing
CNS disease
•Barriers
•Skin
•Mucous membranes
– respiratory,
gastrointestinal,
genitourinary
•IgA, mucous film,
cilia, macrophages,
acidity, enzyme,
thermal inactivation
Pathways of neuroinvasion
• Hematogenous route
– Most viral infections are acquired from
blood
• Neural route
– Virus spread to the CNS along peripheral
nerves
• Olfactory route
– Experimental intranasal virus inoculation
results in olfactory bulb infection
Hematogenouse route
• Viral particles in the blood
– 90% clearance in less than 1 hour by the reticuloendothlial
system (macrophages)
• Viruses 1) grow at some extraneural site, 2) establish viremia, and
3) cross to brain
• 1) Extraneural growth
– Initial replication of virus may give prodromal symptoms:
poliovirus→gastrointestinal; lymphocytic choriomeningitis
virus → respiratory; arbovirus → myalgia (muscle infection) ,
• 2) Maintenance of viremia
– Absorb to red blood cells, infect white blood cells
• 3) Invasion of the CNS
– Blood-brain barrier is impervious to viruses
– Infect the vascular endothelial cells of the CNS
– Carried in infected leukocytes, Trojan horse
Blood-brain barrier (BBB)
• Endothelial cells of the BBB lack fenestration, have a
very low pinocytotic activity and are connected by
tight junctions
• Specific transport systems mediate the transport of
nutrients into the CNS or of toxic metabolites out of
the CNS
• Endothelial cell barrier, endothelial basal membrane,
glia limitans (astorycte endfoot)
α4β1 integrins
=VLA-4
How viruses travel from blood to tissues
• In several well-defined parts of the brain, the capillary epithelium
is fenestrated (with “windows” between cells’ loosely joined
together), and basement membrane is sparse; the choroid plexus
(produces the cerebrospinal fluid)
• Infect directly, or be transported across the endothelium
• Cross the endothelium within infected leukocytes (Trojan horse:
HIV, measles)
How viruses gain access to the CNS
Steps in the
hematogenous
spread of virus into
the CNS
Johnson p52
• Invasion of the CNS
from blood requires
sequence of events
• This explains why
CNS infections are
rare, even though
infections that have
the potential to
cause CNS disease
are common
Neural
pathway for
CNS infection
• Virus is taken up at
sensory or motor
endings and
moved within
axons
• Axonal transport of
virus
– Herpes virus
latency and
exacerbations
Which direction, anterograde or retrograde?
•Spread from the
primary neuron to the
second-order neuron in
the direction of the
nerve impulse is said
to be anterograde
spread
•Anterograde spread
•Virus invades at
dendrites or cell
bodies and spread
to axon terminals
Tracing neuronal
connections in the
nervous system
with viruses
• Some alphaherpes
viruses and
rhabdoviruses
have promise as
self-amplifying
tracers of
synaptically
connected
neurons
Olfactory route
• Olfactory neurons are the only neural cells whose
processes synapse within the CNS and whose distal
axons are in direct contact with the environment
• Experimentally, many viruses can invade the CNS
directory from the olfactory mucosa
Pathways of neuroinvasion
• Hematogenous route
– Poliovirus, mumps, measles, filovirus, HIV,
arbovirus
• Neural route
– Rabies, herpes simplex, varicella-zoster
• Olfactory route
– Experimental herpes simplex, aerosol
infections (rabies in bat-infested caves)
• Neurotropism: the ability to infect neural
cells (neuronotropism means infections
specifically of neurons)
• Neuroinvasiveness: the ability to gain access
to the nervous system
• Neurovirulence: the ability to cause disease
Neurovirulence
• Ability to cause CNS disease
• Experimentally, defined by effects following
intracerebral inoculation
• In humans, difficult to assess
– Neuroinvasiveness and neurotropism are difficult
to sort out
– Poliovirus neurovirulence, using transgenic mice
containing the human poliovirus receptor
• Mumps is highly neuroinvasive, but its neurotropism
appears limited to ependymal cells, which may
account for low neurovirulence
• Human T-cell lymphotoropic virus I (HTLV-I) infects
inflammatory cells, not infect neural cells, but it is
neurovirulent (HAM, HTLV-I-associated myelopathy)
Neuroinvasiveness, tropism and virulence
• Neurotropism: the ability to infect neural
cells (neuronotropism means infections
specifically of neurons)
• Neuroinvasiveness: the ability to gain access
to the nervous system
• Neurovirulence: the ability to cause disease
Which of the following statements is true?
A.A neurotropic virus can enter the central nervous system after
infection of a peripheral site.
B.A neuroinvasive virus can infect neural cells.
C.Herpes simplex virus has high neuroinvasiveness of the central
nervous system, and high neurovirulence.
D.Rabies virus has low neuroinvasiveness but high neurovirulence.
E.Mumps virus has high neuroinvasiveness but low neurovirulence.
Answer (E)
Classification by the areas of the CNS
•
•
•
•
Encephalitis: Encephalon + itis = inflammation of brain
Encephalopathy: Any disorder of the brain
Myelitis: Myel+ itis = inflammation of spinal cord
Meningitis: Meninges + itis = inflammation of the meninges
• Lack of cerebral & spinal cord parenchymal involvement
• “Aseptic” implies non-bacterial etiology of syndrome
• Arboviruses often cause combinations called;
• Meningoencephalitis (meninges & brain)
• Encephalomyelitis (brain & spinal cord)
• Poliomyelitis; inflammation in the gray matter of
the spinal cord. [polio- [G. polios] gray matter + G.
myelos, marrow, + -itis, inflammation]
Viral infections of the CNS
• Meningitis
– Inflammation restricted to the meninges
– Echoviruses, Coxsackeiviruses, other enteroviruses, HSV-2,
Mumps, HIV, Lymphocytic choriomeningitis virus (LCMV)
• Polioencephalitis / poliomyelits
– Disease restricted to the gray matter
– Poliovirus, Coxackieviruses, Echoviruses, Enteroviruses,
Rabies, Arboviruses (West Nile, Japanese encephalitis)
• Leukoencephalitis / leukoencephalopathy
– Disease restricted to the white matter
– Papovavirus (JC virus: PML), HIV
• Panencephalitis / panmyelitis
– Disease of both gray and white matter
– HSV-1, HSV-2, CMV, VZV, HIV, Measles (SSPE), Arboviruses
Which of the following statements is true?
A.Four major cell types in the central nervous system (CNS) are
neurons, Schwann cells, astrocytes, and microglia.
B.Astrocytes are monocyte/macrophage lineage cells.
C.The blood-brain barrier is composed of the endothelial cell barrier,
endothelial basal membrane, and microglia foot processes.
D.Olfactory neurons are the only neural cells whose processes
synapse within the CNS and whose distal axons are in direct contact
with the environment
E.Leukoencephalitis / leukoencephalopathy is a disease restricted to
the gray matter.
Answer (D)
Viral Meningitis vs. Encephalitis
Viral Meningitis
(Enteroviruses, HIV, HSV
type 2, Arboviruses)
• Headache
• Stiff neck
• Photophobia
• Little alteration in
consciousness
• No focal signs
Viral Encephalitis
(HSV, Arboviruses,
•
•
•
•
Rabies, Nipah virus)
Altered consciousness
Focal neurological
signs
Seizures
Meningeal signs
Dr. John E. Greenlee, MD,
University of Utah
https://www.youtube.com/w
atch?v=bj2CNkjvY4o
Aseptic meningitis
• “Aseptic meningitis” meningitis is not due to
bacterial cause
• Non-polio enteroviruses are responsible for > 80% of
cases
• Herpes simplex virus type 2, HIV, lymphocytic
choriomeningitis virus, arbovirses, measles
• Mumps, >50% have a CSF lymphocytosis, but only 110% develop clinical features of meningitis
(CSF, cerebrospinal fluid)
• 26,000 – 42,000 hospitalizations / year in the US
• Benign self-limited illness
• Headache, fever, nausea, vomiting, nuchal rigidity
(detected with flexion)
Theiler’s virusinduced meningitis
Coxsackievirus meningitis. Scanty perivascular and
meningeal infiltration of lymphocytes in a patient with
aseptic meningitis. The patient died from myocarditis
Poliomyelits and polioencephalitis
• Most often caused by the genus
Enterovirus
• Poliovirus, coxackievirus, echovirus,
enterovirus
• Until the development of poliovirus vaccine,
poliovirus was responsible for most cases
• Intestinal infection, viremia, hematogenous
spread (experimentally, retrograde axonal
transport from muscle to the CNS)
• Headache, vomiting, neck stiffness, flaccid
paralysis (lower limbs > upper limbs)
• Motor neurons of the spinal cord
• Neuronophagia; microglia aggregation
around infected dying neurons
L. Collier and J. Oxford, 2011
Fig. 16.5. Children crippled by poliomyelitis. Hopefully,
this will soon become a disease of the past.
Neuronophagia (neuronophagy) in poliomyelitis, a dense
cluster of inflammatory cells marks the site of degeneration of
an infected neuron
White Matter
Gray Matter
anterior horn
Normal spinal cord
Old poliomyeiltis.
Preserved (a) and
affected (b) anterior
horns of spinal cord.
Note the absence of
anterior horn cells
A group of healthcare workers from the United States staffing a clinic in
Madagascar were working with children admitted with acute flaccid
paralysis. The illness began with fever nausea, vomiting, and severe
headache followed by neck stiffness, muscle pain and weakens and
constipation. None of the workers became ill because they had been
vaccinated against this disease. Which viral vaccine protected these
workers?
A. Hepatitis A virus
B.Measles virus
C.Rubella virus
D.Yellow fever virus
E.Poliovirus
Experimental poliomyelitis by Theiler’s
virus infection
Virus infection in neurons in the
gray matter of the spinal cord
Neuronophagia (n) in Theiler’s
virus infection
Tsunoda I and Fujinami RS. (1999). Theiler’s murine encephalomyelitis virus . In: Persistent Viral Infections.
Postpolio syndrome (PPS)
• Development of new muscle weakness 25 to
30 years after paralytic poliomyelitis
• Poliovirus belongs to the family Picornaviridae
• Risk factor: severity of the acute poliomyelitis
• Unknown cause: excessive stress on
remaining motor neurons eventually results in
the dropout of the motor neurons?
• Myopathic and neuropathic features: group
atrophy
Dalakas, 1995
Pathophysiology in
post-polio muscular
atrophy (PPMA).
Post-Polio Syndrome: Pathophysiology
and Clinical Management
Anne Carrington Gawne and Lauro S.
Halstead
Critical Reviews in Physical and
Rehabilitation Medicine, 7(2):147-188
(1995)
Herpesviruses
• Herpes encephalitis caused by HSV-1 and 2
• HSV-1; fever, headache, seizure, coma at any age,
20% patients die despite acyclovir therapy
• HSV-2; neonates born by vaginal delivery to women
with HSV infection, poor feeding lethargy, seizure,
long-term neurologic sequelae
• Hemorrhagic necrosis affecting the temporal lobe
• Infection in neurons, glia, and endothelium
• PCR amplification of viral DNA in the cerebrospinal
fluid (CSF)
Hemorrhagic necrosis in the temporal lobes. Viral antigen in most
neurons. Hemorrhage and inflammation
Case: Herpes simplex virus type 1
• In January, a 74-year-old woman is brought to
the hospital emergency department by her
husband, who states that she had complained of
a fever and headache during the past week.
During the last 2 days, she has been confused
and cannot perform her daily chores. Shortly
after arrival she suffers a seizure. Her physical
examination indicates neck stiffness and her
head MRI shows necrosis in the right temporal
lobe.
Varicella-zoster virus (VZV) infection
• VZV is the cause of chickenpox
(varicella), an acute febrile
exanthematous illeness
• Latent infections in neurons of the
cranial and dorsal root ganglia
• Reactivation of virus leads to disorders
of the peripheral nervous system,
shingles (zoster, Greek for ‘girdle’
shingles often produces a girdle or belt
of blisters or lesions around one side
of the waist)
• Rash and postherpetic neuralgia
• Treatment; anti-viral, steroids,
antidepressants, etc
Cytomegalovirus (CMV) encephalitis
• In the US, 80% of the population is seropositive
• CMV encephalitis in adults occurs in AIDS patients
– Confusion, gait disturbances, cranial nerve palsy
• Neonatal infections occur in the pregnant mother
with a primary infection
– Petechiae, hepatosplenomegaly, microcephaly
– Surviving infants have mental retardation, seizures,
spasticity, hearing loss and optic atrophy
• Antiviral agents improve the outcome of infection
• Any cell type within the CNS may be infected; the
virus often identified within ependymal cells
(cytomegalic cells contain viral inclusions)
Cytomegalic
cells
Inclusion bodies known as “owl eye” inclusions
Rabies
•
•
•
•
•
•
•
A fatal infection caused by rabies virus
60,000 death per year (Asia and Africa)
Animal bite (aerosol transmission with
infection in olfactory epithelium)
Replicate in muscle, taken up by axons
at the neuromuscular junction
Reached the CNS via intra-axonal
transport
Polioencephalomyelitis,
neuronophagia
Postexposure prophylaxis prevents
clinical illness
– Wound cleansing, postexposure
vaccination, hyperimmune globulin
motor fibers
Rabies neuropathology
(a) Purkinje cells contain Negri bodies, cytoplasmic
inclusions. (b) Immunohistochemical demonstration of
viral antigen within infected Purkinje cells
http://rabidthebook.com/
Arboviral Encephalitis
What is an “arbovirus”?
Three key properties…
• Transmitted between vertebrate hosts by the bite
of infected arthropods
• i.e., arthropod-borne
• Multiply and produce viremia in vertebrate hosts
• Multiply in the tissues of arthropod vectors
(WHO Definition)
Remember: Arbovirus is an epidemiological classification, not taxonomic!
Arboviral Encephalitides
• Viruses transmitted to humans by bite of infected arthropod
• Typically mosquitoes & ticks
• Major causes of encephalitis worldwide
• Predominantly caused by viruses belonging to three families
• Flaviviridae, Flavivirus (e.g., JE, SLE, TBE & WNV)
• Togaviridae, Alphavirus (e.g., VEEV, WEEV & EEEV)
• Bunyaviridae, Bunyavirus (e.g., La Crosse virus)
Arbovirus Infection of Humans
Commonalities
• Subcutaneous inoculation of virus by arthropod vector
• Mosquito, tick, sandfly etc.
• Human is typically a “dead-end” host (no transmission)
• EXCEPTIONS: DEN & YFV
• MOST infections are asymptomatic or cause mild biphasic
febrile illness, but resolve without complication
• Earliest symptoms are “flu-like”
• Fever, headache, malaise & myalgia
• Severity of disease often age-dependent
• Worse disease & higher mortality in very young &/or elderly patients
Arbovirus Infection of Humans
Early Pathogenesis
• Virus deposited in dermis infects DCs
• Infected DCs migrate to draining lymph node
• Virus replicates in lymph nodes
• Free virus enters efferent lymphatics
• Enters circulatory system (serum viremia)
• Corresponds with febrile illness
Dendritic Cell (DC)
• Virus replicates in host tissues & organs (virus tropism)
• Causes disease…
Arboviral Encephalitides
Pathology
• In the CNS, arboviruses
primarily infect neurons: may
directly kill neurons
• Lymphocytes infiltration
West Nile viral antigen in neurons and their processes
Hum Pathol 35: 983-990, 2004
Arboviral Encephalitides
Clinical Manifestations
•
•
•
•
Fever, malaise, chills, myalgia, myositis, lymphadenopathy
Rash may occur
Headache
Pharyngitis & GI symptoms may occur
• Nausea, vomiting, diarrhea & abdominal pain
• Altered level of consciousness
•
•
•
•
Disorientation
Behavioral disturbances
Speech disturbances
Focal or neurological signs (hemiparesis or seizures)
• Death follows within 2-10 days
Arboviral Encephalitides
Convalescence & Sequelae
• Disease runs its course in 3-6 days, with rapid recovery
• Prolonged convalescence in 30-50% of cases
• Asthenia, irritability, tremulousness, sleeplessness,
depression, memory loss & headaches may last up to 3 years
• Severe neurological sequelae including epilepsy
• 20% of patients have symptoms persisting for longer
• Gait & speech disturbance, sensorimotor impairment,
psychoneurotic complaints & tremors
• Old age & severity of acute illness predispose to sequelae
Virus
Geographical
Distribution
Age-group
affected
Mortality
Symptoms &
sequelae
WEEV
West, midwest US
Infants & adults
(>50 yrs)
EEEV
East, Gulf-coast,
south US
Children & adults
>30%
Headache, altered
consciousness, seizures
VEEV
South America &
south US
Adults
Rare
Headache, myalgia,
pharyngitis
SLE
Central, west &
south US
Adults (>50 yrs)
20%
Headache, nausea,
vomiting, disorientation
WNV
Africa, Middle
East, Europe & US
Adults
Low
LAC
Central & east US
Children
Moderate in infants,
Headache, altered
low in other ages consciousness, seizures
10-15%
Seizures, myelitis,
optic neuritis
Seizures, paralysis,
focal weakness
Arboviral Encephalitides - USA
La Crosse virus (Bunya):
• Aseptic meningitis & encephalitis
• Primarily in school age children
• Mortality rate low
• 10-15% of survivors have neurological deficits
Equine encephalitis viruses (Alpha):
• Short prodromal illness, then fever, headache, seizures
• May progress to stupor & coma
• MRI shows focal lesions in basal ganglia, thalami & brain stem
• 30-40% mortality rate
• >30% of survivors have severe neurological sequelae
La Crosse encephalitis virus
• In 1960, isolated in La Crosse,
Wisconsin, USA
• US mid-Atlantic and mid-western states
• Disease in children
• Annual incidence, 20-30 per 100 000
La Crosse
Making Sense out of Arbovirus
Encephalitis (Important points)
• The names given these agents do not
even remotely reflect geographic reality
• Eastern equine encephalitis: predominantly
East Coast
• Venezuelan: South and Central America;
southern Florida
• Western equine: Pacific, Mountain, Central ,
Southwest
• Saint Louis: the greater Saint Louis area
encompassing almost all of central U.S.
• California / La Crosse: most of U.S.
Dr. John E. Greenlee, University of Utah
Geographic Distribution of
Arbovirus Encephalitis
Dr. John E.
Greenlee,
University of
Utah
West Nile virus
Amer J Trop Med Hygine 1940, 40: 471-492
1. + 2. - original West Nile district until 1950s
1. - West Nile district 1960s - 1970s
2. - former East Madi district (latter Adjumani
district) since 1970s
Arboviral Encephalitides - USA
West Nile virus (Flavi):
• Well described disease in Africa & Middle East
• Arrived in NY in August 1999
• 62 cases & 7 deaths
• Abrupt onset of fever, headache, neck stiffness & vomiting
• Progression to depressed consciousness, disorientation &
weakness
• Reappeared & expanded in following years
• Established enzootic transmission cycle in birds & mosquitoes
• Migratory birds contribute to dispersal
• No treatment, no vaccine
Which of the individuals listed below is the most
likely to develop a serious disease from West
Nile virus?
•A 4-month-old hospitalized with a serious respiratory infection
•A 3-year-old with croup
•A 65-year-old camper returning from a 2-week wilderness experience in
Minnesota
•A 21-year-old college student returning from a vacation in Costa Rica
•A 24 year-old tour guide in the four corners of the southwestern United
States
Arboviral Encephalitides
Treatments
• Efficacy of antiviral drugs limited & not well evaluated
• Interferon α
• Ribavirin
Combination
• Treatments mostly supportive
• Treat non-specific symptoms (esp. in semi- & comatose
patients)
• Antipyretic (Ibuprofen) – reduces fever
• Phenytoin, Diazepam– inhibits seizures associated with
encephalitis
• Dexamethasone, Methlyprednisolone – decreases
inflammation, reduces capillary permeability, suppresses
inflammatory cell migration
Arboviral Encephalitides
Vaccines
• Licensed efficacious inactivated vaccine available for JE
• No licensed vaccine for SLE, WNV, LAC, EEE, WEE or VEE
• Live-attenuated JE vaccine (not used outside China)
• Unlicensed live-attenuated vaccine for VEE
• Febrile illness in 20% of vaccinees, failure to immunize in 20%
• Unlicensed inactivated vaccines for EEE & WEE
• Poor immunogenicity
• Research ongoing to develop safer, more efficacious
vaccines
• Many approaches being tested (e.g., subunit, recombinant & DNA)
Questions
• Name four major cell types in the CNS and
explain them in 1-2 sentences each (2
points)
• Explain three routes of neuroinvasion, using
keywords: blood-brain barrier, axonal
transport, and experimental intranasal
infection (4 points)
• Explain “neurotropism,”
“neuroinvasiveness,” and “neurovirulence”
in CNS virus infections (4 points)
http://lib.sh.lsuhsc.edu/ebooks/ebooksSubjectaz.php?page=a
Five Families Contain Arboviruses
• Togaviridae (Toga = cloak, i.e., lipid envelope)
• Genus Alphavirus (NOT Rubivirus)
• Flaviviridae (Flavus = yellow, YFV causes jaundice)
• Genus Flavivirus (NOT Hepacivirus)
• Bunyaviridae
• Genera Bunya-, Phlebo- & Nairovirus (NOT
Hantavirus)
• Rhabdoviridae
• Reoviridae
2001;951:13-24
Arbovirus Infection of Humans
Febrile Illness with Arthralgia:
Flavi:
West Nile virus (WNV), dengue virus (DEN)
Hemorrhagic Fevers:
Flavi:
Yellow fever virus (YFV), DEN
Bunya: Crimean-Congo hemorrhagic fever virus (CCHF), Rift
Valley fever virus (RVF)
Encephalitides:
Flavi:
Saint Louis (SLE), Japanese (JE) & tick-borne (TBE)
encephalitis viruses, & WNV
Alpha:
Venezuelan (VEE), eastern (EEE) & western (WEE)
equine encephalitis viruses
Bunya: La Crosse virus (LAC)
West Nile Virus
Old World
• Family Flaviviridae, genus Flavivirus
• Avian reservoir hosts; vectored by mosquitoes
• Virus “hyperendemic” in Africa & Middle East
• High seroprevalence precludes epidemic outbreaks
• Declining endemic transmission increasing risk of epidemics
• Most symptomatic infections go unrecognized
• Clinically undifferentiated febrile disease in children
• Epidemic attack rates in low immunity areas up to
60%
• Most cases mild & mortality rates very low
• CNS infection is rare in Old World WNV infections
West Nile Virus
New World - USA
• Arrived in NY in August 1999
• Reappeared & expanded in following years
• Established enzootic transmission cycle in birds &
mosquitoes
• Migratory birds contribute to dispersal determined by
surveillance in birds
• Abrupt onset of febrile illness
• Fever, headache, neck stiffness & vomiting
• Rash in ~50% of cases
• Progression to neurologic signs
• Depressed consciousness, disorientation & weakness
• Differs from Old World WNV infections
• Case fatality rate ~20-30%
Arbovirus Infection of Humans
Attack Rates
• Ratio of inapparent (asymptomatic) to apparent
(symptomatic) arboviral infection is very high
• For every person presenting with symptoms, 10’s to 1000’s of
people were infected (seropositive), but did not have symptoms
• i.e., low attack rate
• Due to relative inability of the arboviruses to establish
symptomatic infection in the host
• Related to virus dose (NOT genetics)
• Human genetics/immune responses