arthropod borne infections

Arthropod Borne Viral Infections

Emphasis on the flaviviridaeMay 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 families1. 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 Encephalitis4. Reoviridae genera Coltivirus e.g Colorado tick fever virus and Orbivirus e.g. Blue tongue virus5. Orthomyxoviridae e.g Thogotovirus6. 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

MosquitoesJapanese encephalitis, dengue, yellow fever, St. Louis encephalitis, EEE, WEE, VEE etc.

TicksCrimean-Congo haemorrhagic fever, various tick-borne encephalitides etc.

SandfliesSicilian 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 encephalitisMonkeys Yellow FeverRodents 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.


• 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%.


• 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.)

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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.


• 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.


• 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.


• 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.


• 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.


• 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.


• 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.


• 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..


• 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.


• 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.


• 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 .


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


• 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.


• 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.


• 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] .

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• 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.


• 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).


• 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


• 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.



• 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.

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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:


• 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.


• 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.


• 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.