Arthropod Borne Viral

Infections
Emphasis on the flaviviridae
May 2009
Dr Thamaini
 Summary
• The arboviruses and arboviral infections
– Introduction
– General
– Specific diseases - Japanese encephalitis,
Yellow fever, WEEV, EEEV, Chikungunya, West
Nile virus, St Louis encephalitis virus, Dengue
fever, Rift valley fever, etc
• Control of arthropod borne illness – vaccines, pest
control.
 Introduction
• While arthropods are not the only vectors of
microbial diseases, they comprise the most
significant and important group of vector
organisms.
• Arthropod vectors include the insects (the most
important of the arthropod vectors); the ticks and
mites.
 Introduction
Arthropod-borne viruses (arboviruses) are viruses that can be
transmitted to man by arthropod vectors.
The WHO definition:
“Viruses maintained in nature principally, or to an important
extent, through biological transmission between susceptible
vertebrate hosts by haematophagus arthropods or through
transovarian and possibly venereal transmission in
arthropods: the viruses multiply and produce viremia in the
vertebrates, multiply in the tissues of arthropods, and are
passed on to new vertebrates by the bites of arthropods after a
period of extrinsic incubation.”
 Classification
Arboviruses are now officially classified in six families
1. Togaviridae Genus alphavirus e.g. EEE, WEE, and VEE)
2. Bunyaviridae e.g. Rift Valley Fever. This represents the
largest group of arboviuses.
3. Flaviviridae genus flavivirus e.g. Yellow Fever, dengue,
Japanese Encephalitis
4. Reoviridae genera Coltivirus e.g Colorado tick fever virus
and Orbivirus e.g. Blue tongue virus
5. Orthomyxoviridae e.g Thogotovirus
6. Rhabdoviridae genus Vesiculovirus e.g. vesicular stomatitis
virus and lyssavirus
 Flaviviruses
• The Flavivirus genus comprises more than 60 principally arthropod-
transmitted or zoonotic viruses, of which some 30 are known to
cause human disease.
• The agents are classified in the family Flaviviridae (comprises
flavivirus as well as Pestivirus and Hepacivirus.
• The public health burdens of flaviviral infections such as dengue,
yellow fever (YF), Japanese encephalitis (JE), and tick-borne
encephalitis (TBE) have been of sufficient magnitude to stimulate
the development of vaccines to control the diseases.
• Flaviviral infections are important considerations in the differential
diagnosis of central nervous system (CNS) infection, hemorrhagic
fever, and acute febrile illnesses with arthropathy or rash,
especially in returned travelers.
 VIROLOGY
• Flaviviruses are spherical, positive sense RNA viruses 40 to 60
nm in diameter
• They consist of a lipid envelope covered densely with surface
projections comprising 180 copies of the M (membrane) and
180 copies of the E (envelope) glycoproteins.
• These E protein glycoproteins are organized as dimers, paired
horizontally head to tail, on the virion surface.
• The viruses are unstable in the environment and are sensitive
to heat, ultraviolet radiation, disinfectants (including alcohol
and iodine), and acid pH.
 VIROLOGY
• The nucleocapsid joins the capsid (C) protein to a
single strand of positive-sense RNA of 11
kilobases, which includes a 10-kilobase open
reading frame for a single polyprotein precursor,
flanked by noncoding regions at either end.
• The order of protein gene products from the 5′
end is C, premembrane (preM, a precursor of the
mature M protein), E, and a series of seven
nonstructural proteins needed in the viral
replicative process: NS1, NS2A, NS2B, NS3, NS4A,
NS4B, NS5.
 VIROLOGY
• The E protein exhibits important biologic properties, including
viral-cellular attachment, endosomal membrane fusion, and the
display of sites mediating hemagglutination and viral
neutralization.
• PreM protein chaperones the E protein in the cell secretory
pathway, preventing its misfolding, before it is cleaved to its M
form in the mature virion.
• NS1 is expressed on the surface of infected cells and is also
excreted as a complement-fixing antigen. Although antibodies to
NS1 do not neutralize the virus, they contribute to protective
immunity, probably by complement and cellmediated responses
against infected cells.
 VIROLOGY
• Aside from their replicative functions, NS1, NS2A, NS3, and NS5
display epitopes mediating viral serotype and flavirviral cross-
reactive human leukocyte antigen (HLA)–restricted lymphocytic
responses.
• Viral attachment to unidentified cellular receptors is followed by
endocytic uptake of virus-containing vesicles. Acidic-induced
changes of the viral envelope lead to fusion activity, uncoating
of the nucleocapsid, and viral RNA release into the cytoplasm.
• Glycosaminoglycans and proteoglycans have been implicated as
receptors in some studies, but coreceptors may also be
involved, and viral binding evidently varies with cell type.
 VIROLOGY
• The viral polyprotein is processed by repeated
passage through the rough endoplasmic
reticulum, providing the replicative complex for
further viral RNA and protein synthesis and the
assembly of nascent virions that mature through
the Golgi and trans-Golgi network.
• Immature virions collect in the highly proliferated
endoplasmic reticulum and secretory vesicles
before release,
 VIROLOGY
• Flaviviruses are adapted to grow in a wide variety
of insect, tick, and vertebrate cells and at
temperatures spanning the normal temperatures
of their arthropod, reptilian, mammalian, and
avian hosts.
• A wide range of vertebrates, including mammals,
birds, and reptiles, are naturally infected as
amplifying hosts in the transmission cycle of
alternating arthropod and vertebrate infection.
These infections are usually asymptomatic, but
individual viruses may be pathogenic for
domesticated or wild animals.
 VIROLOGY
• Most flaviviruses can be classified by cross-
neutralization assays into eight antigenic groups
including
– JE complex, consisting of JE, StLE, West Nile, and
Murray Valley encephalitis viruses;
– Dengue complex of dengue 1 through 4 viruses
– Tick-borne virus complex, including CEE, RSSE,
louping ill, Powassan, Kyasanur Forest disease, and
Omsk hemorrhagic fever viruses;
– YF virus;
– And other complex of non–vector-borne rodent-
and bat-associated viruses.
Epidemiology - TRANSMISSION
CYCLE
• The mosquito or tick becomes infected when
feeding on the blood of the viremic animal.
• The virus then replicates in the mosquito or tick
tissues, ultimately infecting the salivary glands.
• The mosquito or tick transmits the virus to a new
host when it injects infective salivary fluid while
taking a blood meal.
• The natural animal hosts of these viruses usually
remain unaffected and viral circulation generally
remains undetected until one of the following
occurs:
 Epidemiology - TRANSMISSION
CYCLE
– Humans encroach on the natural enzootic focus
– Environmental or other conditions that favor
substantial amplification in the primary vector-host
cycle cause a sufficient number of vectors to
become infected so that the human risk is
substantially increased
– The virus escapes the primary cycle via a secondary
vector or vertebrate host, thereby bringing infected,
human-biting vectors in close proximity to human
habitation
• Although infected humans may become ill, they
usually do not develop sufficient viremia to infect
feeding vectors. As a result, humans do not usually
contribute to the transmission cycle.
Man-Arthropod-Man Cycle
Animal-Arthropod-Man Cycle
 Arthropod Vectors

Mosquitoes
Japanese encephalitis, dengue, yellow fever, St. Louis
encephalitis, EEE, WEE, VEE etc.
Ticks
Crimean-Congo haemorrhagic fever, various tick-borne
encephalitides etc.
Sandflies
Sicilian sandfly fever, Rift valley fever.
 Animal Reservoirs

In many cases, the actual reservoir is not known. The

following animals are implicated as reservoirs
Birds Japanese encephalitis, St Louis encephalitis,
EEE, WEE
Pigs Japanese encephalitis
Monkeys Yellow Fever
Rodents VEE, Russian Spring-Summer encephalitis
 Diseases Syndromes
Caused
• Encephalitis - e.g. EEE, WEE, St Louis encephalitis,
Japanese encephalitis.
• Fever and rash - this is usually a non-specific illness
resembling a number of other viral illnesses such as
influenza, rubella, and enterovirus infections. The patients
may go on to develop encephalitis or haemorrhagic fever.
• Haemorrhagic fever - e.g. yellow fever, dengue, Crimean-
Congo haemorrhagic fever.
 Yellow fever
• VIROLOGY
• Yellow fever is the prototype member of the
family Flaviviridae. It is a single serotype and is
antigenically conserved, so that the vaccine
protects against all strains of the virus.
• At the nucleotide sequence level, it is possible to
distinguish seven major genotypes representing
West Africa, Central-East Africa, and South
America.
 Yellow fever -
Epidemiology
• EPIDEMIOLOGY — Yellow fever remains an endemic
and epidemic disease problem mainly in regions of
Africa and South America.
• Epidemic (“urban”) YF is transmitted by A. aegypti
mosquitoes; the mosquitoes are infected after feeding
on viremic humans and then spread the infection in
subsequent feeding attempts. The threat of epidemic
transmission arises when a person with a forest-
acquired infection travels to an A. aegypti–infested
location while viremic.
• During the dry season, the virus survives in infected
mosquito eggs that are resistant to desiccation.
 Yellow fever -
PATHOGENESIS
• Approximately 1000 to 100,000 virus particles are
inoculated intradermally by the infected female
mosquito during blood feeding.
• Virus replication is initiated at the site of
inoculation, probably in dendritic cells in the
epidermis, and spreads through lymphatic
channels to regional lymph nodes.
• Lymphoid cells, particularly monocyte-
macrophages, and large histiocytes appear to be
the preferred cell types for primary replication.
 Yellow fever -
PATHOGENESIS
• Virus reaches other organs via the lymph, and then the
bloodstream, seeding other tissues.
• Visceral organs including the spleen and liver produce large
amounts of virus, which is released into the blood; during
the viremic phase (days three to six), blood-feeding
mosquitoes may become infected.
• Yellow fever is characterized by hepatic dysfunction, renal
failure, coagulopathy, and shock . In fatal cases,
approximately 80 percent of hepatocytes undergo
coagulative necrosis. The midzone of the liver lobule is
principally affected, with sparing of cells bordering the
central vein and portal tracts.
 Yellow fever -
PATHOGENESIS
• Injury to hepatocytes is characterized by
eosinophilic degeneration with condensed nuclear
chromatin (Councilman bodies) ensuing liver cell
death is due to apoptosis. Hepatocytes in the
midzone of the liver lobule express Fas ligand and
lymphocytes infiltrating the liver mediate
apoptosis. Inflammatory cells, present in low
numbers, are mainly CD4+ cells, followed by
smaller numbers of NK and CD8+ cells. There is
no disruption of the reticular architecture of the
liver; in nonfatal cases, healing is complete
without postnecrotic fibrosis.
 Yellow fever -
PATHOGENESIS
• Renal damage is characterized by eosinophilic
degeneration and fatty change of renal tubular
epithelium without inflammation, which is
believed to be a result of both direct viral injury
and nonspecific changes due to hypotension and
the hepatorenal syndrome
• Focal injury to the myocardium, characterized by
cell degeneration and fatty change, is the result
of viral replication.
 Yellow fever -
PATHOGENESIS
• The hemorrhagic diathesis in yellow fever is due to
decreased synthesis of vitamin K-dependent
coagulation factors by the liver, disseminated
intravascular coagulation, and platelet dysfunction.
• The late phase of the disease is characterized by
circulatory shock. The underlying mechanism may
be cytokine dysregulation, as in the sepsis
syndrome.
• Patients dying of yellow fever show cerebral edema
at autopsy, probably the result of microvascular
dysfunction.
 Yellow fever - CLINICAL
FEATURES
• Can cause subclinical infection or an abortive,
nonspecific febrile illness without jaundice
• Life-threatening disease with fever, jaundice,
renal failure and hemorrhage may happen and is
more common in the elderly
• The onset of illness appears abruptly three to six
days after the bite of an infected mosquito. The
classical illness is characterized by three stages:
– Period of infection
– Period of remission
– Period of intoxication
 Yellow fever - CLINICAL
FEATURES
• Period of infection
• Viremia is the hallmark of the period of infection which lasts
for three to four days.
• Symptoms and signs are relatively nonspecific. The patient is
febrile and complains of generalized malaise, headache,
photophobia, generalised pain, anorexia, nausea, vomiting,
restlessness, irritability, and dizziness.
• On physical examination the patient appears acutely ill, with
flushed skin, congestion of the conjunctivae, gums and face;
epigastric tenderness, and tenderness and enlargement of the
liver may be present. The tongue is characteristically red at
the tip and sides, with a white coating in the center.
 Yellow fever - CLINICAL
FEATURES
• Period of remission — A period of remission lasting up to 48 hours
may follow the period of infection; this distinct period is characterized
by the abatement of fever and symptoms. Patients with abortive
infections recover at this stage. However, approximately 15 percent
of those infected with yellow fever virus enter the third stage of the
disease.
• Period of intoxication — The period of intoxication begins on the
third to sixth day after the onset of infection, with return of fever,
prostration, nausea, vomiting, epigastric pain, jaundice, oliguria, and
a hemorrhagic diathesis. The viremia terminates at this stage, and
antibodies appear in the blood. This phase is characterized by
variable dysfunction of multiple organs, including the liver, kidneys,
and cardiovascular system.
 Yellow fever
• Outcome of infection — The outcome is determined
during the second week after onset, at which point the
patient either dies or rapidly recovers. Approximately
20 to 30 percent of patients who enter the period of
intoxication succumb to the disease.
• Complications of yellow fever include bacterial
superinfections, such as pneumonia, parotitis, and
sepsis associated with recovery from renal tubular
necrosis. Late deaths during convalescence occur
rarely and have been attributed to myocarditis,
arrhythmia, or heart failure.
 Yellow fever - Diagnosis
• Differentials
• Dengue hemorrhagic fever
• Leptospirosis (Weil's disease)
• Louse-borne relapsing fever (Borrelia recurrentis)
• Viral hepatitis
• Rift Valley fever
• Q fever
• Typhoid
• Severe malaria.
• Mild yellow fever, characterized by fever,
headache, malaise and myalgias, resembles many
other viral infections like influenza.
 Yellow fever - Diagnosis
• Laboratory diagnosis
• Diagnosis is made by the detection of virus, viral
genome (by PCR) or by serology.
• 1. Virus isolation
• 30 percent of infections may be diagnosed by viral
isolation in the pre-icteric stage
• The virus may also be recovered from post-mortem
liver tissue
• Virus isolation is accomplished by intracerebral
inoculation of suckling mice, intrathoracic inoculation
of mosquitoes, or inoculation of mosquito or
mammalian cell cultures.
 Yellow fever - Diagnosis
• 2. Rapid diagnostic tests 
• Include PCR to detect viral genome in the blood or
tissueas well as monoclonal immunoassays for circulating
antigen.
• Not widely available.
• 3. Pathology
• Examination of the liver reveals the typical
pathoanatomic features of yellow fever, including
midzonal necrosis, as noted above. However, liver biopsy
during the illness should never be performed, since fatal
hemorrhage may ensue.
• Postmortem diagnosis may be made by PCR or
immunocytochemical staining for yellow fever antigen in
the liver, heart, spleen or kidney.
 Yellow fever - Diagnosis
• 4. Serology 
• Serologic diagnosis is best accomplished using an
enzyme linked immunosorbent assay (ELISA) for
IgM.
• The presence of IgM antibodies in a single sample
provides a presumptive diagnosis; confirmation is
made by a rise in titer between paired acute and
convalescent samples or a fall between early and
late convalescent samples.
• Cross-reactions with other flaviviruses complicate
the diagnosis of yellow fever by all serologic
methods
 Yellow fever - management
• Symptomatic.
• Supportive measures include maintenance of nutrition
and prevention of hypoglycemia; treatment of
hypotension; administration of oxygen; correction of
metabolic acidosis; treatment of bleeding; dialysis if
indicated by renal failure; and treatment of secondary
infections.
• Treatment with hyperimmune globulin is useful for
postexposure prophylaxis but its benefit after the onset
of clinical illness is unclear.
• Ribavirin is active against yellow fever virus in vitro but
only at very high concentrations that may not be
achievable clinically.
 Yellow Fever - Vaccination
• Highly effective live, attenuated vaccine .(17D)
• Produces high levels of protection, with seroconversion rates
of >95 percent.
• Recommended for travelers to yellow fever endemic areas of
Africa and South America and for residents.
• Serious adverse reactions are rare and include :
• Yellow fever vaccine-associated neurotropic disease (YEL-
AND) — finding of irus, viral genome (by PCR) or IgM
antibody in cerebrospinal fluid.
• Yellow fever vaccine-associated viscerotropic disease (YEL-
AVD) — a disease syndrome resembling wild-type yellow
fever shortly after yellow fever 17D vaccination. Only occurs
in the setting of primary vaccination of nonimmune persons.
 Yellow Fever - Prevention
• Prevention of epidemic A. aegypti–borne YF mainly involves
the reduction of peridomestic breeding sites. Covering the
containers or reservoirs eliminates a principal source of
breeding.
• Surveillance of viral activity by monitoring of viral infection
rates in sylvatic mosquitoes has been proposed as an early
warning system for West and Central Africa, where
outbreaks frequently emerge in a regionwide distribution.
• The discovery of intensified viral activity, even in a small
number of sentinel sites, may be a sufficiently sensitive
predictor of viral activity in a broader area to trigger timely
and effective mass immunization.
 Dengue and Dengue
Hemorrhagic Fever
• EPIDEMIOLOGY
• Four serotypes of dengue virus are transmitted in
the tropics, in an area corresponding to the
distribution of A. aegypti, the principal mosquito
vector
• The virus is mainly maintained in an anthroponotic
cycle
• After the female mosquito feeds on a viremic
person, viral replication in the mosquito over 1 to 2
weeks (extrinsic incubation period) occurs before it
can transmit the virus on subsequent feeding
attempts.
 Dengue and Dengue
Hemorrhagic Fever
• A. aegypti is adapted to breed around human
dwellings, where the insects oviposit in
uncovered water storage containers as well as
miscellaneous containers holding water. Adult
mosquitoes shelter indoors and bite during 1- to
2-hour intervals in the morning and late
afternoon. .
• When the virus is introduced into susceptible
populations, usually by viremic travelers,
epidemic attack rates may reach 50% to 70%.
 Dengue and Dengue
Hemorrhagic Fever
• Because cross-protective immunity among the
serotypes is limited, epidemic transmission recurs with
the introduction of novel virus types. Secondary
infections predispose to DHF hence the concurrent
transmission of multiple viral serotypes establishes the
necessary conditions for endemic DHF.
• Infection can also be transmitted by accidental
needlestick. Transfusion assicated cases may also
occur in endemic regions but because immunity in
recipients is also high, and differentiating a
transfusion-transmitted case from a natural infection
would be difficult.
Approximate potential distribution of Aedes aegypti. (From World Health Organization.
Technical Guide for Diagnosis, Treatment, Surveillance, Prevention, and Control of
Dengue Haemorrhagic Fever, 2nd ed. Geneva: World Health Organization; 1997.)
Distribution of Dengue
 Dengue virus infection
• Dengue viruses are members of the family Flaviviridae
genus Flavivirus.
• They are small enveloped viruses containing a single-
strand RNA genome of positive polarity.
• Replication
• Viral replication involves the following steps:
– Attachment to the cell surface
– Entry into the cytoplasm
– Translation of viral proteins
– Replication of the viral RNA genome
– Formation of virions (encapsidation)
– Release from the cell
 Dengue virus infection
• OVERVIEW OF THE COURSE OF INFECTION — The course of dengue
virus infection is characterized by early events, dissemination, and the
immune response and subsequent viral clearance .
• Early events — Dengue virus is introduced into the skin by the bite of an
infected mosquito, most commonly Aedes aegypti.
• Dissemination — In humans infected with "natural" dengue viruses,
viremia begins approximately 3 to 6 days after inoculation. Viremia is
detectable in humans 6 to 18 hours before the onset of symptoms, and
ends as the fever resolves
• Immune responses and viral clearance — Both innate and adaptive
immune responses induced by dengue virus infection are likely to play a
role in the clearance of infection.
Hypothetical schema of events in acute dengue virus infection. The kinetics and general location of viral
replication are diagrammed in relation to the presence of detectable viremia, general symptoms (fever,
myalgias, headache, rash), and the period of risk for plasma leakage, shock, severe thrombocytopenia, and
bleeding in dengue hemorrhagic fever (DHF). Nonspecific immune responses include the production of
interferons (IFN) and natural killer (NK) cell activity. The kinetics of dengue virus-specific T lymphocyte
activation and the production of dengue virus-specific antibodies occur later and are of lesser magnitude in
primary infections (first exposure to dengue viruses) than in secondary infections (later infection with a
second dengue virus serotype).
 Dengue virus infection
• The antibody response to dengue virus infection
is primarily directed at serotype-specific
determinants, but there is a substantial level of
serotype-crossreactive antibodies.
• The T lymphocyte response to dengue virus
infection also includes both serotype-specific and
serotype-crossreactive responses .
 Dengue virus infection
• Primary versus secondary infection 
• Infection with one of the four serotypes of dengue
virus (primary infection) provides life-long
immunity to infection with a virus of the same
(homologous) serotype .
• However, immunity to the other (heterologous)
dengue serotypes is transient, and individuals can
subsequently be infected with another dengue
serotype (secondary infection).
 Dengue virus infection
• FACTORS INFLUENCING DISEASE SEVERITY 
• Most dengue infection produce mild, nonspecific
symptoms or classic dengue fever.
• Dengue hemorrhagic fever (DHF) and dengue shock
syndrome (DSS), occur in less than 1 percent of
dengue virus infections. Risk factors for these include:
• Viral factors
• Several prospective studies have suggested that the
risk is highest with dengue 2 viruses.
• There are strong suggestion that DHF only occurs
during infection with viruses that fall into specific
genotypes within each dengue serotype
 Dengue virus infection
• Prior dengue exposure 
• Epidemiologic studies have shown that the risk of
severe disease (DHF/DSS) is significantly higher
during a secondary dengue virus infection than
during a primary infection.
• This increased risk during secondary infections may
reflect the differences in immune responses
between primary and secondary dengue virus
infections described above: antibody-dependent
enhancement of infection; enhanced immune
complex formation; and/or accelerated T
lymphocyte responses.
 Dengue virus infection
• Age — 
• Risk for DHF declines with age, especially after age
11 years.
• Infants especially 6 to 12 months of age are at
higher risk for DHF in endemic areas. These
children acquire dengue virus-specific antibodies
transplacentally, and become susceptible to
primary dengue virus infection when antibody
levels decline below the neutralization threshold.
This observation is taken to support the hypothesis
of antibody-dependent enhancement of infection as
a primary factor in determining the risk for DHF.
 Dengue virus infection
• Nutritional status — Unlike other infectious diseases,
DHF/DSS is less common in malnourished children than in
well-nourished children. This negative association may be
related to suppression of cellular immunity in malnutrition.
• Genetic factors — Epidemiologic studies in Cuba and Haiti
showed that DHF occurred more often in whites than in
blacks
• DHF has been associated with specific HLA genes, receptor
polymorphisms of TNF-alpha, vitamin D, Fc gamma IIa, blood
group type, and DC-SIGN genes in some studies.
 Dengue Fever - Clinical
Presentation
• Classic dengue fever is an acute febrile disease
with headaches, musculoskeletal pain, and rash,
but the severity of illness and clinical
manifestations vary with age.
• Infection is often asymptomatic or nonspecific,
consisting of fever, malaise, pharyngeal injection,
upper respiratory symptoms, and rash—
particularly in children. Dengue virus types 2 and
4 may be more likely to cause inapparent
infections in flavivirus-naive persons.
 Dengue Fever - Clinical
Presentation
• Disease severity may be increased among infants
and the elderly.
• After an incubation period of 4 to 7 days, fever—
often with chills, severe frontal headache, and
retro-orbital pain—develops abruptly with a rapid
progression to prostration, severe
musculoskeletal and lumbar back pain, and
abdominal tenderness.
 Dengue Fever - Clinical
Presentation
• Initially, the skin appears flushed, but within 3 to 4
days and with the lysis of fever, an indistinct
macular and sometimes scarlatiniform rash
develops, sparing the palms and soles.
• As the rash fades or desquamates, localized
clusters of petechiae on the extensor surfaces of
the limbs may remain.
• A second episode of fever and symptoms may
ensue (“saddleback” pattern).
• Recovery may be followed by a prolonged period of
listlessness, easy fatigability, and even depression.
 Dengue Fever - Clinical
Presentation
• Although virtually all cases are uncomplicated,
minor bleeding from mucosal surfaces (usually
epistaxis, bleeding from the gums, hematuria,
and metrorrhagia) is not uncommon, and
gastrointestinal hemorrhage and hemoptysis can
occur.
• It is important to differentiate these phenomena
from the bleeding diathesis that accompanies the
life-threatening syndrome of hypotension and
circulatory failure in DHF-DSS.
 Dengue Fever - Clinical
Presentation
• Hepatitis frequently complicates dengue fever.
Neurologic symptoms associated with dengue
fever have been reported sporadically and
attributed to hemorrhages or cerebral edema, but
recovery of virus from the CSF, intrathecal viral-
specific IgM, and immunohistochemical evidence
of infection in the brain indicate the possibility of
primary dengue encephalitis in some cases.
Myositis with rhabdomyolysis has also been
reported.
 Dengue Fever - Clinical
Presentation
• The central clinical features of DHF-DSS are hemorrhagic
phenomena and hypovolemic shock caused by increased
vascular permeability and plasma leakage.
• Reduced perfusion and early signs of shock are manifested
by central cyanosis, restlessness, diaphoresis, and cool,
clammy skin and extremities.
• In the most extreme cases, an unobtainable blood pressure
establish the shock syndrome.
• The platelet count declines and petechiae appear in
widespread distribution with spontaneous ecchymoses.
Bleeding occurs at mucosal surfaces from the
gastrointestinal tract and at venipuncture sites.
 Dengue Fever - Clinical
Presentation
• The presence of pleural and peritoneal effusions is associated
with severe disease. Adult respiratory distress syndrome
(ARDS) may develop with capillary-alveolar leakage.
• With support through the critical period of illness,
spontaneous resolution of vasculopathy and circulatory
failure usually can be expected within 2 to 3 days, with
complete recovery afterward.
• Fatality rates have reached 50% in underserved populations,
but in experienced centers, fewer than 1% of cases are fatal.
• Encephalopathy (often reflecting CNS hemorrhage),
prolonged shock, and hepatic or renal failure are associated
with a poor prognosis.
Clinical spectrum, pathophysiology, and classification of dengue hemorrhagic
fever. (From World Health Organization. Technical Guide for Diagnosis, Treatment,
Surveillance, Prevention, and Control of Dengue Haemorrhagic Fever, 2nd ed.
Geneva: World Health Organization; 1997.)
 Dengue Fever – Treatment
and Prevention
• Antipyretics may help to relieve the symptoms of
dengue fever. Oral rehydration is indicated to replace
losses from vomiting and high fever.
• Attentive clinical monitoring of patients with
suspected DHF-DSS and anticipatory and supportive
care are lifesaving and have reduced fatality rates by
50- to 100-fold.
• The critical activities are monitoring of circulation and
vascular leakage by serial clinical assessments of
pulse, blood pressure, skin perfusion, urine output,
and hematocrit, to trigger intravenous fluid therapy.
• Intravenous gamma globulin has shown no benefit in
a controlled evaluation.
 Dengue Fever – Treatment
and Prevention
• Dengue prevention currently relies on public
health and community-based A. aegypti control
programs to remove and destroy mosquito-
breeding sites.
• Several approaches to vaccine development are
being pursued. The most advanced approach is a
tetravalent combination of attenuated dengue
strains.
JAPANESE ENCEPHALITIS
VIRUS
• JE is transmitted in Asia from Pakistan at the westernmost
edge to far eastern Russia
• The disease is endemic and periodically epidemic in
Southeast Asia, China, and the Asian subcontinent.
• Sporadic cases are reported in tropical Asia, including the
Indonesian and Philippine archipelagoes.
• Within temperate areas, JE is transmitted sporadically
from July to September, at a relatively low incidence and
with periodic seasonal epidemics.
• In subtropical Asia, viral transmission extends from March
to October in a hyperendemic pattern, without easily
detected seasonal epidemics.
A: Yellow Fever, B: Japanese Encephalitis, C: West
Nile Virus, D:Tick born encephalitis
JAPANESE ENCEPHALITIS
VIRUS
• The virus is transmitted by Culex
tritaeniorhynchus and related ground-pool–
breeding mosquitoes to pigs and aquatic birds,
which are the principal viral-amplifying hosts.
• Infected horses and humans are symptomatic but
incidental hosts. Risk of infection is highest in
rural areas because of the mosquitoes association
with rice paddies but because bit pigs and
paddies are found on city edges, rare urban
outbreaks do occur.
JAPANESE ENCEPHALITIS
VIRUS
• The mosquito vectors chiefly feed outdoors, in the
evenings, and prefer animal to human hosts.
• Cases occur chiefly in children between 2 and 10
years of age, with a slight predominance of boys.
In Japan, Korea, and Taiwan, children are
protected by immunizations, and cases occur
principally in elderly persons, reflecting waning
immunity or other biologic factors associated with
senescence.
 JAPANESE ENCEPHALITIS
VIRUS - Clinical
manifestations
• Only about one in 250 JE virus infections results in
symptomatic illness.
• The incubation period is 5 to 14 days. Mild clinical
illness, such as aseptic meningitis and a simple
febrile illness with headache, usually go
undetected. The illness resolves in five to seven
days if there is no central nervous system
involvement.
 JAPANESE ENCEPHALITIS
VIRUS - Clinical
manifestations
• Patients with encephalitis often present with
vomiting, reduced consciousness, and seizures .
Other more subtle clinical manifestations, such as
twitching of a digit or eyebrow, or nystagmus,
may be seen. Extrapyramidal features include
dull, expressionless facies, generalized
hypertonia, and cogwheel rigidity
• JE virus infection can also present as acute flaccid
paralysis due to anterior horn cell destruction,
primarily in children..
 JAPANESE ENCEPHALITIS
VIRUS - Clinical
manifestations
• Initial leukocytosis is followed by leukopenia. CSF
analysis usually shows a lymphocytic pleocytosis,
except early in the illness when pleocytosis may
be neutrophilic or absent.
• MRI is more sensitive than CT scan. Both
commonly show abnormalities in the thalamus,
basal ganglia, midbrain, pons, and medulla.
Electroencephalography may show generalized
slowing, theta and delta coma, burst suppression,
and epileptiform activity.
JAPANESE ENCEPHALITIS
VIRUS - Diagnosis
• Can be made by demonstration of IgM antibody
by capture immunoassay of CSF, a fourfold rise in
serum antibody titers against JE virus, or isolation
of virus from or demonstration of viral antigen or
genomic sequences in tissue, blood, or CSF..
• Serum IgM antibodies alone should be confirmed
by demonstration of IgG antibody by another
serologic assay (eg, neutralization).
JAPANESE ENCEPHALITIS
VIRUS - Treatment
• Treatment is supportive. Supportive care focuses
on reducing intracranial pressure, optimization of
system blood pressure to maintain adequate
cerebral perfusion pressure, control of seizures,
and prevention of secondary complications
• Randomized, double-blind, placebo-controlled
trials have shown no benefit from interferon alfa-2a
or dexamethasone.
• Outcome — Mortality among hospitalized patients
is approximately 30 percent, and approximately
one-half of survivors have severe neurological
sequelae.
JAPANESE ENCEPHALITIS
VIRUS - Prevention 
• A formalin-inactivated vaccine prepared in mice infected with the
Nakayama strain of JE virus is used internationally. However, the
vaccine's cost has limited its use in many countries where the
virus is endemic.
• An inactivated cell culture-derived Japanese encephalitis vaccine
(Ixiaro®) has been developed as well.
• A live, attenuated vaccine is available in China and is being
introduced elsewhere in Asia.
• Safety — The principal vaccine-associated adverse event of
concern is hypersensitivity.
• Also several cases of acute disseminated encephalomyelitis have
suggested possible causal relationship with thh vaccine
West Nile virus infection
• Member of the Japanese encephalitis virus
antigenic complex
• WN virus causes both sporadic infection and
outbreaks that may be associated with severe
neurologic disease.
 West Nile virus infection
• EPIDEMIOLOGY
• WN virus is one of the most widely distributed of all arboviruses
with an extensive distribution in the Old World, throughout Africa,
the Middle East, parts of Europe and the former Soviet Union,
South Asia, and Australia.
• West Nile virus is transmitted in an enzootic cycle between birds,
by mosquitoes especially of the Culex species. Transovarial
transmission of the virus in mosquitoes probably provides for
viral overwintering.
• The means by which West Nile virus is introduced to new areas
are not completely understood. Migratory birds are thought to be
important for movement of the virus.
Transmission cycle for WNE
West Nile virus infection
• Transmission  
• Mostly transmitted by bites of mosquitoes of the
Culex species.
• Birds are the primary amplifying hosts. Humans and
otehr vertebrates serve as incidental hosts and are
not important for transmission since viremia is both
short-lived and low-grade.
• Other routes of transmission include via transfusion
products, by transplanted organs, transplacental
transmission , percutaneous exposure, conjunctival
exposure , and transmission via breast milk is also
likely.
 West Nile virus infection
• PATHOGENESIS
• The pathogenesis of severe infection with WN virus is not well
understood.
• Dissemination — During feeding, the mosquito injects virus-laden
saliva into the host. The virus then replicates in skin Langerhans
dendritic cells. The denndritic cells migrate to regional lymph nodes
and replicate producing a viremia that seeds various organs and
tissues, such as liver and kidney.
• WN virus enters the CNS by hematogenous spread, passive transport
through endothelium or choroid plexus epithelial cells, transport by
infected immune cells that traffic to the CNS or by direct axonal
retrograde transport from infected peripheral neurons
West Nile virus infection
• Humoral and cellular immunity — As with
other flaviviruses, humoral immunity is critical for
protection from WN virus.
• The presence of neutralizing antibody correlates
with protection from flaviviruses and passive
transfer of IgG antibody can protect against WN
challenge
• T cell responses are also critical for protection
from WN virus
 West Nile virus infection
• CLINICAL MANIFESTATIONS — Most persons infected with the
WN virus are asymptomatic. Symptoms are seen in only about
20 percent of infected patients. The typical incubation period for
infection ranges from 2 to 14 days. Immunity after recovery is
thought to be life-long.
• 1. West Nile fever — The usual presentation is a self-limited
febrile illness, called West Nile fever, which is characterized by
fever, headache, malaise, back pain, myalgias, and anorexia
persisting for three to six days.
• Rash appears in approximately one-half the patients with WN
fever. The rash is typically maculopapular, involves the chest,
back and arms, and generally lasts for less than one week.
West Nile virus infection
• 2. Neuroinvasive disease — WN virus infection
can present as encephalitis, meningitis, or flaccid
paralysis or a mixed pattern of disease.
• Encephalitis or meningoencephalitis are more
common than meningitis in contemporary
outbreaks . Older age, alcohol abuse, and diabetes
are more associated with West Nile encephalitis
• Hemorrhagic manifestations of West Nile Virus
have rarely been documented. Fatal hemorrhagic
fever was reported in a 59-year-old male who
presented with multi-organ failure and palpable
purpura on physical examination.
West Nile virus infection
• Laboratory findings
• Total leukocyte counts in peripheral blood are
mostly normal or elevated. In cases with signs of
CNS involvement, the cerebrospinal fluid (CSF)
usually demonstrates a pleocytosis often with a
predominance of lymphocytes as well as an
elevated protein concentration.
 West Nile virus infection
• Serologic testing — The IgM antibody capture enzyme-linked
immunosorbent assay (MAC-ELISA) is optimal for IgM detection
because it is simple, sensitive, and applicable to serum and CSF
samples.
• Testing for IgG antibodies by ELISA is available and can
determine if West Nile virus infection previously has occurred,
but is without utility in the acute clinical diagnostic setting.
• False positive ELISA testing can occur due to recent immunization
with particular vaccines (yellow fever or Japanese encephalitis) or
due to infections with other related flaviviruses (eg, St. Louis
encephalitis, dengue)
 West Nile virus infection
• The plaque reduction neutralization test (PRNT), the
most specific test for the arthropod-borne flaviviruses,
can help distinguish false positive results of MAC-ELISA
or other assays (eg, indirect immunofluorescence,
hemagglutination inhibition). The PRNT may also help
distinguish serologic cross-reactions among the
flaviviruses.
• Clinicians should also bear in mind that IgM antibody
to WN virus may persist for six months or longer. Since
most infected persons are asymptomatic, residents in
endemic areas may have detectable IgM antibody from
previous WN virus infection that is unrelated to their
current clinical illness
 West Nile virus infection
• Viral isolation or nucleic acid testing 
• It is possible to isolate WN virus or to detect viral antigen
or nucleic acid in CSF, tissue, or other body fluids.
• Viral isolation and detection of viral antigen have lower
sensitivity than nucleic acid detection and are not
recommended for routine clinical diagnosis.
• Nucleic acid amplification testing may have utility in
certain clinical settings as an adjunct to IgM ELISA.
• Nucleic acid amplification is used for blood donor
screening.
 St. Louis encephalitis
• St. Louis encephalitis virus is a member of the
family Flaviviridae together with West Nile virus,
Japanese encephalitis virus, Murray Valley
encephalitis virus, yellow fever virus, and dengue
virus.
• SLE virus is antigenically closely related to West
Nile virus, which causes a similar disease.
 St. Louis encephalitis -
Epidemiology
• The disease occurs in endemic and epidemic form
in North and South America.
• Outbreak-associated cases of StLE have been
reported from virtually all U.S. states, as well as
Southern Canada, Northern Mexico and various
south american and central american republics.
• In the United States, the virus is transmitted to
birds in three distinct cycles overlapping those of
West Nile virus: by C. pipiens and Culex
quinquefasciatus in the midwestern and eastern
states, by Culex nigripalpus in Florida, and by Culex
tarsalis in the Great Plains and farther west.
 St. Louis encephalitis -
Epidemiology
• Humans are infected incidentally from the enzootic cycle.
• Characteristics of the vectors and their respective transmission cycles
define epidemiologic features in each location.
• Unlike other epidemic viral encephalitides in the United States, such
as West Nile and eastern and western equine encephalitis, SLE rarely
causes disease in horses.
• SLE occurs during the summer months when mosquito vectors are
active and peaks during August and September. Transmission may
occur as late as December in warmer climates, such as Florida and
southern California. Prior infection with dengue virus does not cross-
protect against SLE.
Human cases of West Nile fever and encephalitis by
state and year of first recognition, United States,
1999–2003.
 St. Louis encephalitis -
PATHOGENESIS
• After inoculation of the virus into the human host
via mosquito saliva, viral replication is initiated in
local tissues and regional lymph nodes.
• Subsequent spread occurs initially to extraneural
tissues via the lymphatics and blood.
• SLE virus replicates in a wide array of cell types,
including connective tissue, skeletal muscle, exo-
and endocrine glands, and reticuloendothelial
tissues.
• Viremia is terminated approximately one week after
infection by neutralizing antibodies and cytotoxic T
cells.
 St. Louis encephalitis -
PATHOGENESIS
• The mechanism by which SLE virus reaches the
brain remains uncertain, but may include direct
invasion at sites of compromised
microvasculature or at the choroid plexus, where
the endothelium is "fenestrated".
• After the virus reaches the brain, infection
spreads rapidly. Retrograde axonal transport from
peripheral nerves to the spinal cord may explain
the occurrence of myelitis in cases of SLE.
 St. Louis encephalitis -
Pathogenesis
• Neuronal damage is probably mediated in part by
caspase-3-dependent apoptosis, as shown for
West Nile, JE and other flaviviruses .
• The increased susceptibility of elderly persons to
SLE virus (see below) may be due to mechanical
factors (eg, hypertension, atherosclerosis) that
compromise the integrity of the blood-brain
barrier or to reduced immune responsiveness.
 St. Louis encephalitis -
Pathogenesis
• Over-activity of angiotensin I-converting enzyme
(ACE-1) in advanced age may exacerbate a
pathological host response to infection. Increased
production of ACE-1 results in increased
angiotensin II, a powerful pro-inflammatory
cytokine.
• Most infections with SLE are subclinical. The
hereditary and acquired factors responsible for
overt and severe infection in a small subset of
patients remain unknown.
 St. Louis encephalitis -
Pathogenesis
• Recovery from infection is mediated by
neutralizing antibodies and CD8+ T cells. In cases
with CNS infections, CD8+ T cells are recruited to
and clear virus from brain tissue. Infection with
SLE virus results in a long-lasting neutralizing
antibody response that is responsible for
protection against reinfection.
• There is no data indicating that chronic infections
occurs in humans.
 St. Louis encephalitis -
CLINICAL FEATURES
• Human infection with SLE virus only rarely results in
clinical illness.
• The most important risk factor for the development of
symptomatic encephalitis is age, with elderly persons at
highest risk.
• Among symptomatic patients, the incubation period for
SLE has been estimated to be 4 to 21 days.
• The spectrum of clinical illness includes nonspecific
fever with headache, aseptic meningitis, and fatal
meningoencephalitis. The severity of encephalitis and
its lethality are greatest in the elderly.
 St. Louis encephalitis -
Laboratory findings
• Non specific - WBC count is normal or may be mildly
elevated, particularly in children. Alanine aminotransferase
and creatine phosphokinase levels are modestly elevated.
Proteinuria, microscopic hematuria, pyuria, and mild
azotemia are also found in some patients.
• The lumbar puncture opening pressure is mildly elevated.
CSF protein concentrations are mildly elevated while the
glucose concentrations are normal or mildly depressed.
• The proportion of mononuclear cells increases from 40 to
50 percent in CSF obtained during the initial illness to more
than 80 percent by day seven.
 St. Louis encephalitis –
Laboratory Findings
• Specific:
• The diagnosis of SLE is generally made by
serology, particularly the IgM ELISA. The presence
of IgM antibodies in a single serum provides a
presumptive diagnosis, and a significant rise or
fall between appropriately timed acute-
convalescent or early-late convalescent sera is
diagnostic.
• However, antigenic cross-reactions with other
flaviviruses, particularly West Nile virus, can be a
problem.
 St. Louis encephalitis –
Laboratory Findings
• The finding of IgM antibody in CSF indicates brain
infection and local antibody production.
• Polymerase chain reaction (PCR) analysis of CSF to
exclude HSV or enteroviral infection may also be useful.
• Virus isolation from the blood or CSF has generally been
unsuccessful. However, the virus may be recovered
from brain tissue, including the basal ganglia, cervical
cord and cerebellum, following inoculation of
mammalian or mosquito cell culture or baby mice.
• Viral antigen can also be detected by
immunofluorescence in brain tissue sections.
 St. Louis encephalitis
• TREATMENT 
• No specific antiviral therapy is of proven efficacy.
• Supportive treatment is the mainstay of therapy.
• PREVENTION
• There is no available vaccine against SLE virus.
• Some states and counties at historical risk of SLE
undertake routine surveillance of virus activity using
sentinel chickens (tested at intervals for serologic
conversion) or mosquito collections for virus testing.
• Mosquito control is also indicated to interrupt
transmission once human cases appear.
 TICK-BORNE
ENCEPHALITIS VIRUS
• Tick-borne encephalitis (TBE) is caused by three
closely related viruses (family Flaviviridae, genus
Flavivirus):
– The Far Eastern subtype (formerly Russian
spring-summer encephalitis)
– The Siberian subtype (formerly western-
Siberian)
– The Western European subtype (formerly
Central European encephalitis)
 TICK-BORNE
ENCEPHALITIS VIRUS
• The Far Eastern subtype is transmitted in eastern
Russia, Korea, China, and parts of Japan; the
European subtype and related viral strains are
found in Scandinavia, Europe, and eastern states
of the former Soviet Union; and the Siberian
subtype is found in western Siberia.
• Louping ill virus is found in the British Isles, and
Powassan virus in North America and northern
Asia.
 TICK-BORNE
ENCEPHALITIS VIRUS
• Closely related tick-borne flaviviruses include
Turkish and Spanish sheep encephalitis viruses,
which are found in southern Europe, and two
viruses that cause hemorrhagic fever—Kyasanur
Forest disease virus in India and Omsk
hemorrhagic fever virus in Siberia.
 TICK-BORNE
ENCEPHALITIS VIRUS
• Vector — Ixodes persulcatus, which occurs from eastern
Europe to China and northern Japan, is the primary vector of
the far eastern and Siberian subtypes, whereas Ixodes ricinus,
which occurs from Scandinavia in the north to Greece and the
former Yugoslavia in the south, is the primary vector of the
western European subtype.
• The viruses are transmitted horizontally between ticks and
vertebrates and through the winter by vertical transmission in
the ticks and latent infections in hibernating animals. The virus
passes transovarially and transtadially, from egg to larva,
nymph, and adult, so all stages of the tick and both male and
female ticks transmit infections to animals and humans.
 TICK-BORNE
ENCEPHALITIS VIRUS
• In addition, it appears that virus may be
transmitted between ticks, as they feed on the
skin of the same host, via infected host
reticuloendothelial and inflammatory cells,
without the need for host viremia.
• Larval and nymphal ticks feed principally on birds
and small mammals, and adult ticks on larger
mammals such as roe deer, deer, domestic goats,
sheep, cows, dogs, cats, and humans.
 TICK-BORNE
ENCEPHALITIS VIRUS
• Human infections are incidental to the
transmission cycle. Animal movements can
spread ticks and the virus to new foci.
• TBE virus is stable at acid pH, and consumption of
unpasteurized milk or milk products from infected
goats, sheep, or cows previously accounted for
10% to 20% of cases in some parts of central
Europe.
 TICK-BORNE
ENCEPHALITIS VIRUS
• Slaughter or butchering of infected animals or
meat is a principal mode of transmission for
louping ill virus to humans and also has been
reported in TBE and in outbreaks of Alkhurma virus.
• Infection has also been acquired from infected ticks
carried to households on fomites.
• In addition to TBE virus, I. ricinus also transmits
several borrelia responsible for Lyme disease (as
well as Anaplasma phagocytophilum, Babesia
microti, and several species of rickettsia), and dual
infections of ticks and humans are observed.
 TICK-BORNE
ENCEPHALITIS VIRUS
• Clinical manifestations
• The incubation period of TBE generally lasts
between 7 and 14 days. The different viral
subtypes have different clinical syndromes and
varying severity.
 TICK-BORNE
ENCEPHALITIS VIRUS
• The far eastern subtype may be associated with
the following syndromes :
• A febrile form, with fever lasting several days.
• A meningeal form, which has a similar onset as
the febrile form, but is associated with symptoms
such as severe headaches, photophobia, eye
pain, and gastrointestinal complaints. May aslo
cause meningoencephalitis.
• A poliomyelitic form, with prodromal symptoms
that evolves into paralysis of the neck, shoulder,
or upper limbs with little recovery.
 TICK-BORNE
ENCEPHALITIS VIRUS
• A polyradiculoneuritic form, which is a biphasic
illness that begins with fever, headache, and
gastrointestinal complaints. This is followed by an
afebrile period of seven to 14 days, and then a
second phase with fever and meningeal or focal
neurologic symptoms, with complete recovery.
This biphasic form is mostly seen with the
western European subtype.
 TICK-BORNE
ENCEPHALITIS VIRUS
• A chronic form in patients with the Siberian
subtype. There are two types of the chronic form.
In one type, long-term sequelae of any of the
acute forms may progress over months to years.
In the other type, neurologic symptoms occur
years after the tick bite without associated acute
disease symptoms).
 TICK-BORNE
ENCEPHALITIS VIRUS
• Diagnosis — The diagnosis of TBE can be made
by demonstration of IgM antibody by capture
immunoassay of CSF, a fourfold rise in serum
antibody titers against TBE virus, or isolation of
virus from or demonstration of viral antigen or
genomic sequences in tissue, blood, or CSF .
• Serum IgM antibodies alone should be confirmed
by demonstration of IgG antibody by another
serologic assay (eg, neutralization).
 TICK-BORNE
ENCEPHALITIS VIRUS
• Treatment and prevention — Treatment is
mainly supportive.
• Effective vaccines are available in Europe and
from many travel clinics in Canada.
• Travelers with extensive outdoor exposures from
camping or related activities in endemic regions
during the spring and summer months should
consider being vaccinated.
• Other prevention strategies include avoiding tick
bites and pasteurization of milk.
 POWASSAN VIRUS
• Powassan virus is a rare cause of encephalitis in
eastern Canada and the northeastern United
States.
• Asymptomatic infection is common. Infection
mostly occurs from June to September.
• Few patients recall a tick bite, since Ixodid ticks
are small and can be easily overlooked.
• Symptomatic patients typically present with
fever, weakness, somnolence, gastrointestinal
complaints, headache, and confusion, and
seizures can occur.
 POWASSAN VIRUS
• The diagnosis of Powassan virus infection can be
made by demonstration of IgM antibody by capture
immunoassay of CSF, a fourfold rise in serum
antibody titers against the virus, or isolation of virus
from or demonstration of viral antigen or genomic
sequences in tissue, blood, or CSF.
• There is no specific treatment or vaccine.
• Prevention of tick bites by using repellents, avoiding
or clearing brushy areas, wearing light colored
clothing may be effective.
• Removing ticks soon after outdoor exposure is
advisable.
 COLORADO TICK FEVER
VIRUS
• The Colorado tick fever virus (genus Coltivirus,
family Reoviridae) is transmitted to humans in
the western United States and Canada mainly by
the wood tick, Dermacentor andersoni.
• The distribution of human disease corresponds to
the wood tick's distribution in mountainous areas
at 4000- to 10,000-foot elevations.
• Transmission occurs from March to September,
but peaks from April to June.
• Transmission via blood transfusion has been
described.
 COLORADO TICK FEVER
VIRUS
• The mean incubation period is three to four days, and 90 percent
of patients report tick bites or tick exposure.
• Fever, chills, myalgias, and prostration are common presenting
symptoms
• Headache often occurs during the acute febrile phase.
• Approximately 15 percent of patients experience a petechial or
maculopapular rash and leukopenia is a common finding.
• Although the acute symptoms last about one week, fever may
recur several days later, and fatigue is often prolonged.
• Five to 10 percent of children develop meningitis or encephalitis.
 COLORADO TICK FEVER
VIRUS
• Serologic tests are often not positive for 10 to 14 days
after symptom onset.
• In comparison, reverse transcriptase polymerase chain
reaction (PCR) may be diagnostic from the first day of
symptoms
• The virus infects marrow erythrocytic precursors, which
accounts for the ability to recover the virus from
peripheral blood up to six weeks after illness onset.
• Treatment is supportive and the prognosis is generally
favorable.
• Prevention consists of avoidance of tick bites in endemic
areas.
 Other Flaviviridae
• MURRAY VALLEY ENCEPHALITIS — Murray
Valley encephalitis occurs in Australia, New
Guinea, and probably islands in the eastern part
of the Indonesian archipelago. MVE virus is
believed to be maintained in a natural cycle
involving water birds and Culex annulirostris
mosquitoes. Humans are likely dead-end hosts.
• Rarely causes clinical illness which resembles
Japanese encephalitis.
 Togaviruses
• EASTERN EQUINE ENCEPHALITIS VIRUS
• Eastern equine encephalitis (EEE) virus (family
Togaviridae, genus Alphavirus) is widely
distributed throughout North, Central, and South
America and the Caribbean.
• In North America, wild birds and Culiseta
melanura, a mosquito that is found in swamp
areas that support cedar, red maple and loblolly
bay trees, maintain the virus.
 EASTERN EQUINE
ENCEPHALITIS VIRUS
• Laboratory-acquired infections have occurred,
and EEE virus is a potential agent of bioterrorism
through the aerosol route.
• Although infections can occur throughout the
year, peak incidence is in August and September.
In the United States, human infections are usually
sporadic and small outbreaks occur each
summer, mostly along the Atlantic and Gulf
coasts.
• Clinical manifestations
 EASTERN EQUINE
ENCEPHALITIS VIRUS
• The incubation period usually exceeds one week
after the mosquito bite.
• The illness often begins with a prodrome lasting
several days, with fever, headache, nausea and
vomiting being common.
• Approximately two percent of infected adults and
six percent of infected children develop
encephalitis.
 EASTERN EQUINE
ENCEPHALITIS VIRUS
• The diagnosis of EEE can be made by demonstration of IgM antibody
by capture immunoassay of CSF, a fourfold rise in serum antibody
titers against EEE virus, or isolation of virus from or demonstration of
viral antigen or genomic sequences in tissue, blood, or CSF Serum
IgM antibodies alone should be confirmed by demonstration of IgG
antibody by another serologic assay (eg, neutralization or
hemagglutination inhibition).
• EEE virus is the most severe of the arboviral encephalitides, with a
mortality of at least 30 percent
• Death can occur within three to five days of onset and, among
survivors, complete recovery is uncommon.
 EASTERN EQUINE
ENCEPHALITIS VIRUS
• There is no specific therapy for EEE.
• Inactivated vaccines have been successful in
horses and an inactivated vaccine has been used
in laboratory workers or others at high risk of
exposure, but is not commercially available.
• Prevention focuses on avoidance of mosquito
bites and mosquito control in suburban areas.
 WESTERN EQUINE
ENCEPHALITIS VIRUS
• Western equine encephalitis (WEE) virus (family
Togaviridae, genus Alphavirus) is a complex of
closely related viruses found in North and South
America.
• Flooding, which increases breeding of Culex
mosquitoes, may precipitate summer outbreaks.
• WEE is a potential agent of bioterrorism through
the aerosol route.
• Fewer than 1 in 1000 infected adults develop
encephalitis, but the frequency is greater in
children, particularly infants [ 5] .
 WESTERN EQUINE
ENCEPHALITIS VIRUS
• Following an incubation period of about seven
days, headache, vomiting, stiff neck, and
backache are typical; restlessness, irritability, and
seizures are common in children.
• Although rare in adults and older children,
neurologic sequelae are relatively common in
infants. The case fatality rate is 3 to 7 percent.
 WESTERN EQUINE
ENCEPHALITIS VIRUS
• The diagnosis of WEE can be made by
demonstration of IgM antibody by capture
immunoassay of CSF, a fourfold rise in serum
antibody titers against EEE virus, or isolation of
virus from or demonstration of viral antigen or
genomic sequences in tissue, blood, or CSF.
Serum IgM antibodies alone should be confirmed
by demonstration of IgG antibody by another
serologic assay (eg, neutralization or
hemagglutination inhibition).
 WESTERN EQUINE
ENCEPHALITIS VIRUS
• Prevention focuses on mosquito control and
personal measures to avoid mosquito bites.
Inactivated vaccine is available for horses.
Although inactivated vaccine has been used for
laboratory staff and others at high risk of
exposure, it is not commercially available for use
in humans. No specific treatment is available.
LA CROSSE (CALIFORNIA)
ENCEPHALITIS VIRUS
• La Crosse virus (LAC, family Bunyaviridae, genus
Bunyavirus) is the most pathogenic member of the
California encephalitis serogroup, which includes
the California encephalitis, trivittatus, snowshoe
hare, and Jamestown Canyon viruses.
• LAC is transmitted via Aedes triseriatus (eastern
tree hole mosquito), and mammalian hosts include
the eastern chipmunk, tree squirrels, and foxes.
• Human infections occur in the central and eastern
United States, mostly in school-aged children from
July through September
LA CROSSE (CALIFORNIA)
ENCEPHALITIS VIRUS
• Most infections are asymptomatic.
• The diagnosis of LAC can be made by
demonstration of IgM antibody by capture
immunoassay of CSF, a fourfold rise in serum
antibody titers against LAC virus, or isolation of
virus from or demonstration of viral antigen or
genomic sequences in tissue, blood, or CSF
• Viral isolation from the CSF is rare.
LA CROSSE (CALIFORNIA)
ENCEPHALITIS VIRUS
• Serum IgM antibodies alone should be confirmed
by demonstration of IgG antibody by another
serologic assay (eg, neutralization).
• Treatment is supportive, with emphasis on control
of cerebral edema and seizures.
• Ribavirin has been used, but efficacy is unproven.
• Prevention rests on avoidance of mosquito bites.
 VENEZUELAN EQUINE
ENCEPHALITIS VIRUS
• Six subtypes (I-VI) within the Venezuelan equine
encephalitis (VEE) virus (family Togaviridae,
genus Alphavirus) complex have been identified.
• Five antigenic variants exist within subtype I (IAB,
IC, ID, IE, IF).
• These subtypes and variants are classified as
epizootic (can produce outbreaks of illness in
animals) or enzootic (infects animals in a region,
but often produces asymptomatic or sporadic
illness in animals), based upon their apparent
virulence and epidemiology:
 VENEZUELAN EQUINE
ENCEPHALITIS VIRUS
• Epizootic variants of subtype I (IAB and IC) cause
equine epizootics and are associated with more
severe human disease.
• Enzootic strains (ID-F, II [Everglades], III
[Mucambo, Tonate], IV [Pixuna], V [Cabassou], VI
[Rio Negro]) do not cause epizootics in horses,
but may produce sporadic disease in humans.
• Epizootic strains are transmitted by many
mosquitoes, and enzootic strains by Culex
mosquitoes.
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ENCEPHALITIS VIRUS
• After an incubation period of one to six days, there is a brief
febrile illness of sudden onset, characterized by malaise, nausea
or vomiting, headache, and myalgia. Less than 0.5 percent of
adults and less than 4 percent of children develop encephalitis,
characterized by nuchal rigidity, seizures, coma, and paralysis.
Long-term sequelae and fatalities are uncommon.
• The diagnosis of VEE can be made by demonstration of IgM
antibody by capture immunoassay of CSF, a fourfold rise in
serum antibody titers against SLE virus, or isolation of virus from
or demonstration of viral antigen or genomic sequences in
tissue, blood, or CSF.
• Viremia is usually not detectable in serum.
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ENCEPHALITIS VIRUS
• Serum IgM antibodies alone should be confirmed by
demonstration of IgG antibody by another serologic assay
(eg, neutralization or hemagglutination inhibition).
• Effective prevention of both human and equine disease can
be accomplished by immunizing equines, which serve as the
primary amplification hosts for the epizootic VEE viruses and
without which there would be little human disease.
• During epidemics, mosquito vectors can be controlled by
insecticides.
• Live attenuated and inactivated vaccines have been used for
laboratory workers; however, human vaccines are not
commercially available.