Flaviviruses excluding dengue

Flaviviruses excluding dengue.

Topics covered:

  • Essentials
  • Introduction
  • Laboratory diagnosis
  • Important mosquito-borne flavivirus infections
  • Other mosquito-borne infections
  • Tick-borne infections of the central nervous system
  • Tick-borne haemorrhagic fever
  • Further reading


Flaviviruses, family Flaviviridae, are small single-stranded, positive sense RNA viruses. They comprise 53 species (40 of which can cause human infection), divided into three major groups based on epidemiology and phylogenetics. They are maintained in nature in complex transmission cycles involving a variety of animals and hematophagous arthropods, which transmit infection to humans. IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) is widely used for diagnosis, with confirmation requiring isolation of the virus, or detection of specific antigen or of viral RNA by nucleic acid amplification from a tissue sample.

Mosquito-borne flaviviruses

Dengue and dengue haemorrhagic fever—see: dengue.

Japanese encephalitis virus—widespread distribution throughout Asia; the most important cause of arboviral encephalitis; maintained in a cycle involving Culex mosquitoes and water birds; about 1/250 infections are symptomatic, with manifestations ranging from a febrile illness with headache, through aseptic meningitis, to encephalitis, and death. Many survivors have residual neurological abnormalities. There is no specific treatment. Vaccination should generally be offered to people spending a month or more in endemic areas, especially if travel includes rural areas.

St Louis encephalitis virus—prevalent throughout the western hemisphere from southern Canada to Argentina; maintained in a cycle involving Culex mosquitoes and water birds; 1/16 to 1/425 infections are symptomatic, with manifestations ranging from fever with headache, to aseptic meningitis, to encephalitis, and death. There is no specific treatment. No vaccine is available.

West Nile virus—found in Africa, the Middle East, western Asia, parts of Europe and the Americas; maintained in a cycle involving Culex mosquitoes and water birds; most infections are asymptomatic, but 30% develop a febrile illness, and 1% neuroinvasive disease including meningitis, encephalitis and acute flaccid paralysis. There is no specific treatment. Several equine vaccines are available, and human vaccines are in clinical trials.

Yellow fever virus—found in tropical America and Africa; forest/jungle transmission cycle involves canopy-dwelling mosquitoes and monkeys, urban cycle involves humans as the vertebrate host and Aedes aegypti as the principal vector; 5% of infections present clinically with a viraemic illness, which may be followed after a transient period of remission by relapse with shock, neurological deterioration, jaundice, haemorrhagic manifestations and renal failure. Treatment is symptomatic. A live, attenuated, single-dose vaccine is highly effective.

Other mosquito-borne flaviruses—these include Kunjin, Murray Valley, and Rocio encephalitides and Zika virus.

Tick-transmitted flaviviruses

Tick-borne encephalitis, louping ill, Powassan encephalitis—geographical distribution determined by that of relevant hard tick vectors; rodents are the principal vertebrate hosts, with occupational and vocational pursuits favouring tick exposure risk factors for human disease; most infections are subclinical, but a nonspecific influenza-like febrile illness may be followed after a few days of apparent recovery by aseptic meningitis or meningoencephalitis that may lead to permanent paralysis in some cases. Treatment is supportive. Effective inactivated vaccines are available.

Tick-borne haemorrhagic fevers—these include Kayasanur Forest disease and Al Khumra and Omsk haemorrhagic fevers.


The genus Flavivirus of the family Flaviviridae comprises 53 virus species, 40 of which can cause human infection (Table 1 below). Flaviviruses are small (37–50 nm), spherical particles whose genome is a molecule of single-stranded, positive-sense RNA approximately 11 000 nucleotides in length. Based on epidemiological and phylogenetic characteristics, the flaviviruses are classified into three groups: (1) those that are mosquito-borne, (2) those that are tick-borne, and (3) those for which no arthropod vector has been demonstrated. All flaviviruses of human importance belong to the first two groups; the last group contains a few viruses found in vertebrates.

Most flaviviruses are maintained in nature in complex transmission cycles between wild or domestic animals and one or more haematophagous arthropod vectors. Humans become infected from infected arthropod vectors that take a blood meal, but for most of the flaviviruses humans do not usually develop high viraemias and are not thought to contribute to the transmission cycle. However, some flaviviruses such as dengue and yellow fever viruses do produce high-level viraemias in humans and can be maintained in urban surroundings through a mosquito–human–mosquito transmission cycle.

The epidemiology and geographical distribution of the flaviviruses depend on several factors including the presence of suitable amplifying hosts, the presence and feeding behaviour of a suitable arthropod vector, and the frequency of exposure of nonimmune reservoir hosts and humans to infected vectors. Globalization of trade and travel, human population growth, urbanization, and neglect of mosquito control programmes have produced conditions conducive to increasing incidence and geographical expansion of the flaviviruses. A recent dramatic example is the introduction and subsequent spread of the West Nile virus in the western hemisphere.

Flavivirus infections are not directly communicable between humans. Flavivirus infection in humans can result in asymptomatic infection or a spectrum of clinical illness ranging from nonspecific febrile illness, fever with rash or arthralgia or both, haemorrhagic fever, hepatitis, encephalitis, and death. The same virus can cause a variety of syndromes, and often the majority of those infected are asymptomatic. Although no specific therapy is available, prompt supportive treatment and proper management may substantially reduce mortality from some flavivirus infections.

Laboratory diagnosis

All flaviviruses have common group epitopes on the envelope protein that result in extensive cross-reactions in serological tests. The specificity of antibody should, therefore, be confirmed by cross-neutralization tests in areas where multiple flaviviruses are endemic/enzootic.

The IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) is widely used for diagnosis of flaviviruses. IgM antibody is usually detectable 5 to 8 days after onset of symptoms. Because detectable IgM antibody persists for one or more months after infection with most flaviviruses, its presence does not confirm current infection; people with detectable IgM antibody are considered recent or presumptive cases. Confirmatory laboratory diagnosis of most flaviviruses requires isolation of the virus, detection of specific viral RNA by nucleic acid amplification (NAA) or specific antigen in a clinical sample, or virus-positive immunohistochemistry in autopsy tissues. A fourfold or greater rise in specific neutralizing antibody is confirmation in some infections.

Important mosquito-borne flavivirus infections 

For dengue and dengue haemorrhagic fever, see: dengue. 

Japanese encephalitis

Aetiology and epidemiology

Japanese encephalitis virus is the type species of the Japanese encephalitis antigenic group of flaviviruses that includes several antigenically related viruses, including St Louis encephalitis, West Nile, Koutango, Usutu, Murray Valley encephalitis, Kunjin (a subtype of West Nile), Alfuy, Cacipacore and Yaounde viruses. Sequence analysis of the structural proteins suggests there are several genotypes of Japanese encephalitis in distinct geographical areas.

Japanese encephalitis has a widespread distribution throughout Asia, and its distribution has expanded in recent years with outbreaks in the Pacific, Australia, Nepal, and western India. It is the most important cause of arboviral encephalitis and about 50 000 cases are reported annually. The highest incidence is in temperate and subtropical countries where epidemics may occur. The virus is maintained in a cycle involving Culex mosquitoes and water birds and is transmitted to humans by Culex mosquitoes, primarily species of the Culex tritaeniorhynchus complex which breed in rice fields. Pigs are the primary amplifying host in the peridomestic environment. Epidemics occur in late summer in temperate regions and throughout the year in some tropical areas of Asia. Children have the highest attack rates because of cumulative herd immunity with age.

Table 1 Taxonomy of flaviviruses
Group Species namea Strain name, synonyms, and tentative species names Abbreviation
Mosquito-borne viruses
Aroa virus group Aroa virus Aroa virus AROAV
Bussuquara virus BSQV
Iguape virus IGUV
Naranjal virus NJLV
Dengue virus group Dengue viruses Dengue virus 1 DENV-1
Dengue virus 2 DENV-2
Dengue virus 3 DENV-3
Dengue virus 4 DENV-4
Kedougou virus Kedougou virus KEDV
Japanese encephalitis virus group Cacipacore virus Cacipacore virus CPCV
Japanese encephalitis virus Japanese encephalitis virus JEV
Koutango virus Koutango virus KOUV
Murray Valley encephalitis virus Alfuy virus ALFV
Murray Valley encephalitis virus MVEV
St Louis encephalitis virus St Louis encephalitis virus SLEV
Usutu virus Usutu virus USUV
West Nile virus Kunjin virus KUNV
West Nile virus WNV
Yaounde virus Yaounde virus YAOV
Kokobera virus group Kokobera virus Kokobera virus KOKV
Stratford virus STRV
Ntaya virus group Bagaza virus Bagaza virus BAGV
Ilheus virus Ilheus virus ILHV
Rocio virus ROCV
Israel Turkey meningoencephalitis virus Israel Turkey meningoencephalitis virus ITV
Ntaya virus Ntaya virus NTAV
Tembusu virus Tembusu virus TMUV
Spondweni virus group Zika virus Spondweni virus SPOV
Zika virus ZIKV
Yellow fever virus group Banzi virus Banzi virus BANV
Bouboui virus Bouboui virus BOUV
Edge Hill virus Edge Hill virus EHV
Jugra virus Jugra virus JUGV
Saboya virus Potiskum virus POTV
Saboya virus SABV
Sepik virus Sepik virus SEPV
Uganda S virus Uganda S virus UGSV
Wesselsbron virus Wesselsbron virus WESSV
Yellow fever virus Yellow fever virus YFV
Group Species namea Strain name, synonyms, and tentative species names Abbreviation
Tick-borne viruses
Mammalian tick-borne virus group Gadgets Gully virus Gadgets Gully virus GGYV
Kyasanur Forest disease virus Kyasanur Forest disease virus KFDV
Al Khumra haemorrhagic fever virus AKHFV
Langat virus Langat virus LGTV
Louping ill virus Louping ill virus LIV
British subtype LIV-Brit
Irish subtype LIV-Ir
Spanish subtype LIV-Span
Turkish subtype LIV-Turk
Omsk haemorrhagic fever virus Omsk haemorrhagic fever virus OHFV
Powassan virus Powassan virus POWV
Royal Farm virus Karshi virus KSIV
Royal Farm virus RFV
Tick-borne encephalitis virus Tick-borne encephalitis virus TBEV
European subtype TBEV-Eu
Far Eastern subtype TBEV-FE
Siberian subtype TBEV-Sib
Seabird tick-borne virus group Kadam virus Kadam virus KADV
Meaban virus Meaban virus MEAV
Saumarez Reef virus Saumarez Reef virus SREV
Tyuleniy virus Tyuleniy virus TYUV
Viruses with no known arthropod vector
Entebbe bat virus group Entebbe bat virus Entebbe bat virus ENTV
Sokoluk virus SOKV
Yokose virus Yokose virus YOKV
Modoc virus group Apoi virus Apoi virus APOIV
Cowbone Ridge virus Cowbone Ridge virus CRV
Jutiapa virus Jutiapa virus JUTV
Modoc virus Modoc virus MODV
Sal Vieja virus Sal Vieja virus SVV
San Perlita virus San Perlita virus SPV
Rio Bravo virus group Bukalasa bat virus Bukalasa bat virus BBV
Carey Island virus Carey Island virus CIV
Dakar bat virus Dakar bat virus DBV
Montana myotis leukoencephalitis virus Montana myotis leukoencephalitis virus MMLV
Phnom Penh bat virus Batu cave virus BCV
Phnom Penh bat virus PPBV
Rio Bravo virus Rio Bravo virus RBV
Viruses tentatively placed in the genus Flavivirus
  Cell fusing agent virus   CFAV
Tamana bat virus   TABV

a Species in bold are discussed in the text.

Adapted with permission from Fauquet C, Fauquet CM, Mayo MA (eds) (2005). Virus taxonomy: classification and nomenclature of viruses; eighth report of the International Committee on the Taxonomy of Viruses, pp. 986–8. Academic Press, New York.

Clinical characteristics (see also )

Only about 1 in 250 infections results in symptomatic infection, which ranges from a febrile illness with headache, through aseptic meningitis, to encephalitis, and death. After an incubation period of 6 to 16 days, illness usually begins with a prodrome lasting several days followed by abrupt high fever, change in mental status, nausea and vomiting, and headache. Early onset seizures occur in at least one-half of hospitalized children and one-quarter of adults. They are usually generalized tonic–clonic, but may also be partial motor or with more subtle clinical manifestations, such as twitching of a digit or eyebrow, or nystagmus. Patients with subtle seizures are usually in status epilepticus. Extrapyramidal features include dull, expressionless facies, generalized hypertonia, and cogwheel rigidity. Focal motor deficits, including cranial nerve palsies and acute flaccid paralysis resulting from anterior horn cell destruction may also occur. This poliomyelitis-like illness may be the only neurological manifestation of the illness or may proceed or accompany encephalitis. Respiratory dysregulation, coma, abnormal plantar reflexes, and prolonged convulsions are associated with a poor prognosis.

Laboratory examination often reveals a moderate peripheral leukocytosis and mild anaemia. Hyponatraemia, reflecting inappropriate antidiuretic hormone secretion, is common. Cerebrospinal fluid pressure is usually normal, pleocytosis ranges from a few to several hundred cells/mm3, and cerebrospinal fluid protein is moderately elevated in about one-half the cases.

Five to 40% of cases are fatal; young children are more likely to die, and if they survive are more likely to have residual neurological defects. Overall, up to 70% of survivors have residual neurological abnormalities including parkinsonism, paralysis, behavioural changes, and psychological deficits. Evidence suggests that infection fails to clear in some patients, with clinical relapse several months after resolution of the acute illness. The clinical effects of congenital infection are unknown. Spontaneous abortions of women infected in the first and second trimesters have been reported.


The differential diagnosis includes other viral encephalitides including arboviruses, herpes, and enteroviral infections, cerebral malaria, and bacterial infections. Epidemiological features such as place of residence or travel, season, and occurrence of other cases in the community provide clues to the diagnosis. Patients with encephalitis are rarely viraemic, although they may be so during the early acute stage of illness. Specific IgM can be detected in cerebrospinal fluid, serum, or both in nearly all patients by the seventh day after onset. Confirmation can be obtained by demonstrating fourfold or greater changes in specific IgM or neutralizing antibody titre.

Prevention and control

A formalin-inactivated mouse brain vaccine has been used widely in Japan, Korea, Taiwan, Thailand, and other countries in Asia for childhood immunization and is licensed in the United Kingdom, the United States of America, and other developed countries to protect travellers. Hypersensitivity reactions to this vaccine, including generalized urticaria, angio-oedema, and even anaphylaxis, have occurred within minutes to as long as 2 weeks following vaccination at a rate of 1 to 104 per 10 000. An inactivated tissue culture-based vaccine has been used in China and inactivated tissue culture-based vaccine is replacing the mouse brain vaccine in many countries, including for adults in the United States of America. A tissue culture-based live attenuated vaccine (SA 14-14-2) used extensively in China appears to have a remarkably good safety profile and currently is being introduced elsewhere in Asia. The risk to travellers in endemic areas during the transmission season can reach 1 in 5000 per month of exposure. The risk for most short-term travellers may be less than 1 in a million. In general, vaccine should be offered to people spending a month or more in endemic areas during the transmission season, especially if travel includes rural areas. However, there is perennial transmission in both urban and rural areas in Vietnam. Water and crop management and animal husbandry have been used to decrease human exposure to mosquito bites in the peridomestic environment.


No specific therapy is available, but supportive treatment can reduce morbidity and mortality. Interferon-α2a failed to improve clinical outcome in a double-blind placebo-controlled trial. Dexamethasone did not prevent death caused by oedema-induced increases in intracranial pressure in patients with severe encephalitis.

St Louis encephalitis

Aetiology and epidemiology

St Louis encephalitis virus is prevalent throughout the western hemisphere from southern Canada to Argentina. The natural transmission cycle involves wild birds and Culex mosquitoes. Although clinical illness has been sporadically reported throughout much of the western hemisphere, the highest incidence occurs in North America during epidemics. Fewer than 100 human cases are generally reported annually; epidemics with hundreds to thousands of cases have occurred in North America every 10 to 20 years.

Clinical characteristics

The ratio of infection to clinical illness is high, ranging from 425:1 in children to 16:1 in elderly persons. Illness ranges from fever with headache, to aseptic meningitis, to encephalitis, and death. Advanced age is the principal risk factor for both symptomatic disease and severity of encephalitis. After an incubation period of 4 to 21 days, the typical presentation of encephalitis is fever, headache, chills, nausea, and dysuria. Within 1 to 4 days, central nervous system signs appear and may include meningism, tremor, abnormal reflexes, ataxia, cranial nerve palsies, convulsions (especially in children), stupor, and coma. Recovery is usually complete, except that 10 to 25% of very young infants have residual mental deficits, personality changes, muscle weakness, and paralysis. Underlying diseases such as hypertension, diabetes, and alcoholism affect the outcome. The case fatality rate is about 7% overall, but is only 1% of those under 5 years of age as the disease is generally milder in children. Short-lived sequelae of nervousness, memory impairment, and headache occur uncommonly in older children and adults.

The peripheral leucocyte count, serum transaminases, and creatine phosphokinase may be elevated. Hyponatraemia due to the syndrome of inappropriate antidiuretic hormone secretion may be noted in up to one-third of patients. The cerebrospinal fluid contains fewer than 500 cells/mm3, principally leucocytes.


The differential diagnosis includes other viral encephalitides such as West Nile virus and other arboviruses, herpes, and enterovirus, as well as other bacterial and fungal infections of the central nervous system. Epidemiological features (residence, season of the year, and occurrence of other cases in the community) provide diagnostic clues. Because of serological cross-reactivity with other flaviviruses, positive serum samples should be subjected to cross-neutralization tests. From fatal cases, virus may be isolated from brain tissue or demonstrated by immunohistochemistry. Virus has not been isolated from the blood during the acute phase of illness.

Prevention and control

No vaccine is available. Prevention is aimed at personal protection from mosquito bites and mosquito abatement.


Treatment is supportive; no specific therapy is available.

West Nile encephalitis

(see also: Viral infections of the central nervous system)

Aetiology and epidemiology

West Nile virus is maintained in a cycle involving Culex mosquitoes and wild birds and is enzootic in Africa, the Middle East, western Asia, parts of Europe, and the Americas). From the 1950s to the 1970s, sporadic epidemics, rarely associated with severe neurological disease and death, occurred in Israel, France, and Africa. No epidemic activity was then reported until the mid-1990s when epidemics associated with severe neurological disease and death in humans and/or equines and birds were recorded in Algeria, Morocco, Tunisia, Italy, Romania, Israel, southern Russia, and France. The virus was first detected in the New World during an outbreak in New York City in 1999; subsequently, the virus has become enzootic throughout most of the United States of America and southern Canada and has been detected as far south as Argentina. While large outbreaks have occurred annually in the United States of America, human or equine cases have been uncommonly reported in the tropical regions of the Caribbean and Latin America despite serological evidence of widespread enzootic transmission.

In temperate regions, outbreaks typically occur in late summer and early autumn, times when sufficient viral amplification in the bird–mosquito cycle has occurred to produce high mosquito infection rates. Although mosquito transmission accounts for nearly all human infections, infection resulting from receipt of contaminated blood transfusions and transplanted organs, transplacental transmission, needlestick exposure, aerosol exposure in the laboratory, mucous membrane splashes of infected fluids, and possibly ingestion of breast milk from an infected mother have been documented.

Phylogenetic studies indicate five and possibly as many as seven viral lineages: lineage one includes most strains isolated in recent outbreaks in Europe, the Middle East, and North America; lineage two includes many of the strains enzootic in Africa. Kunjin virus (see below) is a variant of West Nile virus and fits within lineage one. The strain introduced into North America was genetically identical to a strain circulating in the Middle East.

Clinical characteristics

Most infections are asymptomatic. Approximately 30% of those infected develop a systemic febrile illness, while less than 1% develop neuroinvasive disease including meningitis, encephalitis, and acute flaccid paralysis. Advanced age is the most important risk factor for developing both encephalitis and death. Certain immunosuppressed persons, such as organ transplant patients, are at extremely high risk of developing neuroinvasive disease after infection. The incubation period is usually 2 to 15 days, but may be longer in the immunosuppressed.

West Nile fever presents as a dengue-like illness with fever, headache, backache, myalgia, muscle weakness, anorexia, nausea, and vomiting that lasts 3 to 6 days. Roseola or a maculopapular rash on the trunk and extremities occurs in about one-half the patients with West Nile fever and generally arises during convalescence. The rash is present in about 20% of neuroinvasive disease patients. Fatigue lasting longer than a month after acute infection is common.

Among patients developing meningitis or encephalitis, fever is present in at least 90%, with weakness, nausea, vomiting, and headache in approximately one-half of patients. Other neurological manifestations include tremor, myoclonus, and parkinsonian features such as rigidity, postural instability, and bradykinesia. West Nile virus infection can cause an acute flaccid paralysis syndrome, even without concurrent meningitis or encephalitis; the paralysis usually results from involvement of the anterior horn cell process. Cranial nerve abnormalities may produce facial paralysis, which has a favourable prognosis. Dysarthria and dysphagia accompanied by acute flaccid paralysis indicate a high risk of impending respiratory failure. West Nile virus infection infrequently causes other forms of weakness, including brachial plexopathy, radiculopathy, and a predominantly demyelinating peripheral neuropathy similar to Guillain–Barré syndrome. Other neurological complications include seizures, cerebellar ataxia, and optic neuritis.

Numerous other manifestations of West Nile virus infection have been reported. Chorioretinitis and vitritis appear commonly, but are usually of minor clinical significance. Other reported ocular findings include iridocyclitis, occlusive vasculitis, and uveitis. Rhabdomyolysis, myocarditis, hepatitis, pancreatitis, central diabetes insipidus, and haemorrhagic manifestations have been documented.

Recovery from West Nile fever and meningitis is usually complete. Among those with encephalitis, approximately one-half of survivors have residual neurological deficits and initial disease severity may not predict eventual clinical outcome. Case fatality rates among those with encephalitis are approximately 10%. Most patients with acute flaccid paralysis have incomplete recovery of limb strength, often resulting in profound residual deficits. Quadriplegia and respiratory failure are associated with high morbidity and mortality, and recovery is slow and typically incomplete.


Epidemiological features (residence, season of the year, and occurrence of other cases in the community) provide diagnostic clues. The differential diagnosis includes other causes of acute febrile illness; other viral encephalitides including arboviruses, herpes, and enterovirus, as well as other bacterial and fungal infections of the central nervous system; and other causes of acute flaccid paralysis. West Nile virus should strongly be considered when myoclonic jerking, parkinsonian features, or acute flaccid paralysis occur with encephalitis during peak transmission times. In patients with acute flaccid paralysis, neurological examination should differentiate anterior horn cell dysfunction from Guillain–Barré syndrome.

The cerebrospinal fluid usually contains moderately elevated protein and up to 2000 cells/mm3, with neutrophils predominating early in infection followed by lymphocytic predominance. IgM ELISA of serum or cerebrospinal fluid samples is positive in nearly all patients by the eighth day after clinical onset, although some immunocompromised patients may either fail to develop or have delayed onset of demonstrable IgM antibodies. Nucleic acid amplification testing (NAT) of serum or cerebrospinal fluid may aid in the diagnosis of these patients. In patients with West Nile fever, NAT may increase the yield of testing of early acute-phase samples. In areas endemic for other flaviviruses, serological cross-reactivity may complicate diagnosis and positive samples should be tested by cross-neutralization.

Prevention and control

Several equine vaccines are available. Human vaccines are in clinical trials. Mosquito repellents containing N,N-diethyl-3-methylbenzamide (DEET), picaridin, or oil of lemon eucalyptus are recommended. Community prevention is aimed at surveillance and mosquito abatement. Universal blood donor screening using NAT has markedly reduced the risk of transfusion-related transmission in the United States of America and Canada.


Treatment is supportive; no specific therapy is available. It is imperative that appropriate diagnostic testing including lumbar puncture, electromyography, and nerve conduction studies be obtained before initiating therapies for Guillain–Barré syndrome or other inflammatory neuropathies.

Yellow fever

Aetiology and epidemiology

Yellow fever was first described in the 17th century and was one of the great plagues of humans for over 400 years. In 1900, mosquito transmission and the viral aetiology were proved. The virus was isolated in 1927 and a vaccine developed in 1937. The virus is present in tropical America and Africa, but does not occur in Asia. Epidemics still occur, especially in West Africa. Between 1986 and 1991, a series of outbreaks in Nigeria caused an estimated 100 000 cases (although only about 5000 were officially reported), with attack rates in affected areas of 30/1000 and case fatality rates exceeding 20%. In South America, the disease affects up to 300 people annually, principally young men working in forest areas exposed to haemagogus mosquitoes breeding in tree holes (jungle yellow fever). Disease in unvaccinated travellers is rare; however, at least six have died in the United States of America and Europe of infection acquired in South America and Africa in recent years. In 2008, yellow fever was reported from the Democratic Republic of the Congo, Côte d’Ivoire, Central African Republic, Liberia, Peru, Brazil, Argentina, and Paraguay.

Yellow fever virus has two cycles of transmission, jungle (sylvatic) yellow fever and urban yellow fever. The forest or jungle transmission cycle involves canopy-dwelling mosquitoes and monkeys. The urban cycle involves humans as the vertebrate host and Aedes aegypti as the principal vector. In the past 30 years, Ae aegypti has reinvaded Central and South America and a small outbreak of urban yellow fever occurred in Bolivia in 1998. Sporadic urban transmission has occurred in other South American countries in recent years, including Brazil and Paraguay. Epidemics in Africa often occur in moist savannah regions, involving forest (sylvatic) or peridomestic Aedes mosquitoes and humans as viraemic hosts. In dry areas and urban centres, epidemic transmission occurs where water-storage practices breed domestic Ae aegypti. Several hundred thousand people are infected annually and outbreaks are frequent.

Clinical characteristics

Approximately 1 in 20 infections results in clinical disease with jaundice. In its classic form, disease occurs abruptly after an incubation period of 3 to 6 days. The initial phase (‘period of infection’) is characterized by viraemia, fever, chills, headache, photophobia, lumbosacral pain, myalgia, nausea, and prostration. On examination, the patient may have a relative bradycardia and conjunctival injection. Within several days, the patient may recover transiently (‘period of remission’) only to relapse (‘period of intoxication’) with jaundice, albuminuria, oliguria, haemorrhagic manifestations (especially ‘black vomit’ haematemesis), delirium, stupor, metabolic acidosis, and shock. The prognosis in such cases is poor; 20 to 50% die during the second week of illness.

Clinical laboratory tests reveal leukopenia, thrombocytopenia, hepatic dysfunction, and renal failure. The bleeding diathesis is caused by decreased synthesis of clotting factors and may be complicated by disseminated intravascular coagulation. Pathological findings include midzonal hepatic necrosis and eosinophilic degeneration of hepatocytes (Councilman bodies), possibly representing apoptosis, and acute renal tubular necrosis. Focal myocarditis, brain swelling, and petechial haemorrhages contribute to pathogenesis. Recovery is complete, without postnecrotic hepatic cirrhosis.


Exposure and travel history provide important clues to aetiology. The differential diagnosis includes viral hepatitis, leptospirosis, rickettsial infections, dengue haemorrhagic fever, Rift Valley fever, Ebola, and Crimean–Congo haemorrhagic fever. Serological cross-reactions with other flaviviruses may complicate serology. Postmortem histopathological examination of the liver is diagnostic, with or without immunocytochemical staining for viral antigen. Liver biopsy should never be performed on living patients as it may precipitate haemorrhage.

Prevention and control

The live attenuated 17D vaccine, delivered as a single 0.5-ml subcutaneous dose, is highly effective and has minimal side effects. Immunity is probably lifelong, but for travel certification revaccination is recommended every 10 years. People with documented egg allergy should not be immunized or should be skin tested with the vaccine. The vaccine must not be given to children under 6 months of age, in whom there is a risk of postvaccinal encephalitis, and it is best to delay vaccination until 9 months of age. On theoretical grounds, immunosuppressed patients (including those with clinical AIDS) should not be immunized. The immune response in HIV-infected persons is impaired. Evidence suggests that vaccine-associated viscerotropic disease is much more common in patients with a history of thymic tumour and thymectomy is contraindicated.

No evidence of clinical congenital infection has been found. Immunization during pregnancy is contraindicated, but, if inadvertently performed, recipients should be reassured and followed. The immune response in pregnancy was found to be impaired. Fatal infection following vaccination with the 17D strain has been rarely reported, although postvaccination encephalitis and Guillain–Barré syndrome in adults (incidence 0.4 and 1.9 cases per million doses of vaccine, respectively) and viscerotropic disease (incidence 0.1–2.5 per million vaccinees) may be increasing. Both of these conditions are more frequent among older vaccinees. Other control measures include reducing the principal urban mosquito vector Ae aegypti in tropical urban centres.


Treatment is symptomatic. Intensive care requires prompt awareness and treatment of acidosis, shock, and metabolic imbalance. Patients with renal failure may require dialysis.

Other mosquito-borne infections


Genomic sequencing indicates that Kunjin virus is a variant of West Nile virus. It is found over most of tropical Australia and Queensland and has a similar transmission cycle involving birds and Culex mosquitoes. Infection is usually asymptomatic, but occasional cases of encephalitis have been reported. Infections are generally milder than with Murray Valley encephalitis and are not life threatening. Kunjin virus infections that are nonencephalopathic usually present with fever, often with polyarthralgia. Cases occur sporadically with only 43 reported from 1998 to 2005. Treatment is supportive; there is no vaccine.

Murray Valley encephalitis

Murray Valley encephalitis is enzootic in New Guinea, north Western Australia, and the Northern Territory, and possibly in northern Queensland. The virus has a transmission cycle involving birds and Culex mosquitoes and is transmitted to humans by Culex annulirostris mosquitoes from the end of March to early June. Only 1 in 1000 to 2000 infections results in clinical illness; of those that have neurological disease, approximately one-third are fatal and one-quarter have residual neurological deficits. Clinical illness resembles Japanese encephalitis. Children and elderly people are at the highest risk. In 1974, the largest recorded epidemic involved 58 cases and 10 deaths; since then, sporadic cases have been identified. Serological diagnosis is complicated by the presence of the closely related Kunjin virus, which also causes encephalitis. Treatment is supportive; there is no vaccine.

Rocio encephalitis

Rocio virus is a member of the Ntaya virus group and is considered a subtype of Ilheus virus; it is known only in Brazil. Epidemics from 1973 to 1980 caused 1021 cases, principally among young adult male agricultural workers and fisherman. Since then, only sporadic illness has been reported. The virus has been isolated from Psorophora ferox mosquitoes and Aedes scapularis mosquitoes may be involved in Rocio virus transmission. Wild birds are the likely amplifying hosts. Symptoms include fever, headache, anorexia, nausea, vomiting, myalgia, and malaise followed by confusion, reflex disturbance, motor impairment, and cerebellar dysfunction. The mortality rate is approximately 10%, and 20% of patients have neurological sequelae. Virus is not recoverable from blood, but postmortem diagnosis may be made by virus isolation from brain tissue. Treatment is supportive; there is no vaccine.

Zika virus infection

This flavivirus was first identified in 1947 in rhesus monkey serum in Uganda. It has been responsible for small epidemics in Uganda, Nigeria, Malaysia, and Indonesia. It causes a mild dengue-like illness (fever, conjunctival injection, rash, and arthralgia). A total of 120 confirmed and probable cases occurred in Yap, Micronesia, and possibly Guam, from March to May 2007. Mosquitoes (Aedes aegypti, Ae africanus) are known vectors.

Tick-borne infections of the central nervous system 

Tick-borne encephalitis

Aetiology and epidemiology

There are three subtypes of tick-borne encephalitis virus defined phylogenetically, European, Far Eastern, and Siberian, which differ only slightly in viral protein structure. These viruses, along with the louping ill, Powassan, Kyasanur Forest disease, and Omsk haemorrhagic fever viruses, belong to the tick-borne encephalitis antigenic complex. The disease caused by the Far Eastern subtype is also known as Russian spring/summer encephalitis and Russian epidemic encephalitis; the European subtype as also known as FSME (Frühsommer-Meningoenzephalitis), early-summer encephalitis, and Kumlinge’s disease.

The geographical distribution of disease is determined by that of their hard tick vectors: Ixodes persulcatus for the Far Eastern subtype causing human disease principally from the Baltic countries to north-eastern China and northern Japan, and Ixodes ricinus for the European subtype which occurs from the Urals in Russia to the Alsace region of France, Scandinavia to the north, and parts of the Mediterranean areas along the Adriatic coast to the south. Several other tick species play a role as minor vectors. Switzerland reports more than 100 cases each year, while 3000 clinical cases are reported in Europe. The incidence is increasing in all countries except Austria where an aggressive vaccination policy has proved effective. The Siberian subtype is found in Siberia and the Baltic states. In Russia more than 10 000 cases of tick-borne encephalitis are reported each year.

Infections occur during the period of tick activity from April to November. In Novosibirsk, south-west Siberia, more than 20 000 tick bites are reported annually. Tick-borne encephalitis is largely a rural infection; occupational and vocational pursuits favouring tick exposure are risk factors. Human infection and outbreaks following consumption of raw milk or cheese from asymptomatic goats or, more rarely, sheep or cows have been described. Hundreds to thousands of cases occur annually, with reported attack rates up to 200/100 000 residents in Latvia, the Urals, and western Siberia. Aerosolized virus has caused laboratory infections.

Clinical characteristics

Most human infections are subclinical. The illness produced by each subtype is generally similar but that produced by the Far Eastern subtype carries a worse prognosis. The incubation period is 7 to 14 days (range 2–28 days); incubation periods of 3 to 4 days follow milk-borne exposure. The European subtype typically produces a biphasic illness. The first phase is a nonspecific, influenza-like, febrile illness lasting 2 to 7 days followed by an afebrile and relatively asymptomatic period lasting 2 to 10 days. Flushing, conjunctival haemorrhage, nausea, vomiting, dizziness, and myalgia are common findings.

Approximately one-third of patients then develop higher fevers with aseptic meningitis or meningoencephalitis. The Far Eastern subtype usually progresses without an asymptomatic phase. Signs and symptoms of meningitis, meningoencephalitis, meningoencephalomyelitis, myelitis, or meningoradiculitis include somnolence, coma, asymmetrical paresis of the cranial nerves, tremors of the extremities, nystagmus, severe pain in the extremities, and flaccid paralysis of the neck and upper extremities.

Permanent paralysis develops in 2 to 10% of patients with the European subtype and 10 to 25% with the Far Eastern subtype. Corresponding case fatality rates are 0.5 to 2.0% and 5 to 20% for the European and Far Eastern subtypes, respectively. Severity of illness with the Siberian subtype is intermediate between the European and Far Eastern subtypes, with a case fatality rate of 1 to 3%.

Laboratory findings include neutrophilia, although neutropenia, thrombocytopenia, and elevated liver enzyme levels may occur early. The cerebrospinal fluid white blood cell count is usually below 500 cells/mm3, primarily of mononuclear cells.


The differential diagnosis is similar to Japanese encephalitis; the pattern of flaccid paralysis may be confused with poliomyelitis. A history of bite by small ixodid ticks is elicited in fewer than one-half of patients. Specific diagnosis is made by virus isolation from blood or cerebrospinal fluid during the first week of illness, or by serological tests including IgM enzyme immunoassay and a neutralization test.

Prevention and control

Effective inactivated vaccines are available in Europe in formulations for adults and children. Two doses 4 to 6 weeks apart followed by a booster at 1 year are recommended for those walking and camping in tick-infested coniferous forests of endemic areas, especially during the tick season (May–October). Mass vaccination in Austria produced a dramatic decline in disease incidence. Vaccines appear to produce equal protection against the eastern and western strains. Rapid immunization schedules are available for those with impending travel to endemic areas during the tick season. Tick bites should be prevented by the use of repellents containing DEET and use of permethrin on clothing and camping gear, and attached ticks should be discovered and removed as soon as possible. Unpasteurized goats’ milk products should be avoided.


Treatment is supportive.

Louping ill

This is a disease of veterinary importance causing neurological illness in sheep and to a lesser extent in cows, horses, farmed deer, sheepdogs, and pigs. The virus, isolated in 1931, is a member of the tick-borne encephalitis complex and is transmitted by Ixodes ricinus. Louping ill occurs in the hill country along the western coast of Scotland and northern England, Ireland, and Norway. Natural infections resulting in human disease have been rare, but laboratory infections are not uncommon. Naturally acquired human infections have mainly occurred in persons with occupational exposure to animals. Some of these cases were attributable to contact with sheep blood. Infection from tick bite is rare. The human disease is typically aseptic meningitis or encephalitis; no fatal infections have occurred. Avoidance of tick bites in enzootic areas is recommended. The licensed tick-borne encephalitis vaccine may be protective.

Powassan encephalitis

The virus was first isolated from the brain of a patient who died in Powassan, Ontario in 1958. Since then, more than 30 human cases have been recognized in eastern Canada and the eastern United States of America, primarily in children, with a case fatality rate of 10% and a high incidence of residual neurological dysfunction. Serological surveys indicate an antibody prevalence of 1 to 4%. The distribution of the virus in North America is considerably wider than indicated by human cases, and the diagnosis should be suspected in any case of summer–autumn encephalitis. The virus is transmitted between Ixodes Cookei (ricinus complex) ticks and rodents. Cases have also occurred in Russia where the primary vector is IX. persulcatus. The clinical features are those of viral encephalitis, with localizing neurological signs and convulsions. There is no specific treatment or vaccine.

Tick-borne haemorrhagic fever

Kyasanur Forest disease

Aetiology and epidemiology

This virus is a member of the tick-borne encephalitis antigenic complex. The virus has been isolated from humans, monkeys, and ticks since it was first recognized in 1957 during an outbreak of haemorrhagic fever affecting wild monkeys in Karnataka (then Mysore) State, India. Several hundred cases are reported annually, principally among people working in the forest in Karnataka State. In 1983, 1555 cases, including 150 deaths, occurred. The peak seasonal incidence is from January/February to May. The virus is transmitted by Haemaphysalis spinigera ticks in a life cycle that involves small mammals, monkeys, birds, cattle, and large mammals at various stages. Humans are incidental hosts and are primarily infected by nymphs. Al Khurma virus, a subtype of Kyasanur Forest virus, causes haemorrhagic fever in Saudi Arabia (see below).

Clinical characteristics

After an incubation period of 3 to 8 days, fever starts abruptly with chills, headache, myalgia, abdominal pain, nausea, vomiting, and diarrhoea. Physical signs include bradycardia, lymphadenopathy, and haemorrhagic manifestations. Hypotension is frequently noted during the end of the acute stage. Fatal cases develop shock and pulmonary oedema. A biphasic illness is not uncommon, with resolution of the first phase in 5 to 12 days and return of the fever and signs of meningoencephalitis after an interval of 1 to 3 weeks. Localizing neurological signs are infrequent, and residual defects are rare; convalescence is prolonged. Laboratory abnormalities include leukopenia, thrombocytopenia, and elevated serum transaminases during the acute phase. Fatality rates are 2 to 10%.


Diagnosis is by virus isolation from blood collected during the first week after onset or by serological tests. Virus isolation should be conducted under biosafety level 4 conditions. Prevention and control Tick bites should be avoided in endemic areas. A formalin-inactivated vaccine is available in India.


Treatment is supportive; specific therapy is not available.

Al Khumra (‘Alkhurma’) haemorrhagic fever

In 1995, a subtype of Kyasanur Forest disease virus was isolated from patients from Al Khumra, south of Jeddah, Saudi Arabia, with clinical symptoms ranging from febrile illness with headache, malaise, myalgia, nausea, and vomiting to fatal haemorrhagic disease. It has been referred to incorrectly as ‘Alkhurma haemorrhagic fever’. From 2001 to 2003, 20 cases were identified by national surveillance in Saudi Arabia. Human infections are associated with handling meat or drinking unpasteurized camels’ milk. The virus seems to be associated with sheep, goats, and camels, which do not manifest disease themselves, and to be transmitted by ticks. Its natural reservoir is unknown but the camel tick Hyalomma dromedarii is a prime suspect. Fever, headache, malaise, and myalgia are common. About one-half of patients exhibit haemorrhagic manifestations ranging from mild bleeding (epistaxis) to haemorrhagic shock and disseminated intravascular coagulation with thrombocytopenia. Most have elevated serum concentrations of liver transaminases, lactate dehydrogenase, creatine kinase, and bilirubin, and some develop renal failure. About 35% of patients develop encephalitis and the case fatality rate is 25%. Important differential diagnoses include Crimea–Congo haemorrhagic fever and Rift Valley fever which share its epidemiological features. Compared to Rift Valley fever, there is no visual loss, scotomas, or haemolysis in Al Khumra haemorrhagic fever, but haemorrhage is more common and the case fatality rate is higher.

Omsk haemorrhagic fever

This disease was first recognized in 1945 in western Siberia. Cases were frequent between 1945 and 1949, with morbidity rates of 500 to 1400/100 000, but subsequently have been rare, mainly occurring among residents of rural areas working in the fields. Human infections are acquired by dermacentor tick bite or contact with infected muskrats. After an incubation period typically of 3 to 7 days, the disease begins with the abrupt onset of fever, headache, myalgia, facial flushing, conjunctival suffusion, minor haemorrhagic manifestations, and leukopenia. Recovery occurs in the second week, and the case fatality rate is low (0.5–3%). The differential diagnosis includes tularaemia, rickettsial infection, and leptospirosis. Specific diagnosis is made by virus isolation from blood during the acute phase or by serological tests. Only a few laboratories outside Russia with biocontainment level 4 facilities are capable of providing laboratory assistance. Tick-borne encephalitis vaccines may cross-protect against Omsk haemorrhagic fever.

Further reading


Gould EA, et al. (2006). Potential arbovirus emergence and implications for the United Kingdom. Emerg Infect Dis, 12, 549–54. 

Gritsun TS, Lashkevich VA, Gould EA (2003). Tick-borne encephalitis. Antiviral Res, 57, 129–46.

Gubler DF, Kuno G, Markoff L (2007). Flaviviruses. In: Knipe DM, Howley PM (eds) Fields virology, 5th edition. Lippincott Williams & Wilkins, Philadelphia.

Günther G, Haglund M (2005). Tick-borne encephalopathies. Epidemiology, diagnosis, treatment and prevention. CNS Drugs, 19, 1009–32.

Hayes EB, Gubler DJ (2006). West Nile virus: epidemiology and clinical features of an emerging epidemic in the United States. Annu Rev Med, 57, 181–94.

Hayes EB, et al. (2005). Virology, pathology, and clinical manifestations of West Nile virus disease. Emerg Infect Dis, 11, 1174–9.

Mackenzie JS, Gubler DJ, Petersen LR (2004). Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med Suppl, 10, S98–109.

Madani TA (2005). Alkhumra virus infection, a new viral hemorrhagic fever in Saudi Arabia. J Infect, 51, 91–7.

Marfin AA, et al. (2005). Yellow fever and Japanese encephalitis vaccines: indications and complications. Infect Dis Clin North Am, 19, 151–68.

Pattnaik P (2006). Kyasanur forest disease: an epidemiological view in India. Rev Med Microbiol, 16, 151–65. Solomon T (2003). Recent advances in Japanese encephalitis. J Neurovirol, 9, 274–83.