This family contains 68 members. Yellow fever virus is the prototype virus. Uncomplicated dengue fever and the severe dengue haemorrhagic fever/dengue shock syndrome (DHF/ DSS) are the most important flavivirus diseases transmitted pan-tropically to humans by peridomestic urban breeding mosquitoes. The hepatitis C viruses are also classified as flaviviruses but are covered on page 706. Significant tickborne viruses are tick-borne encephalitis and Kyasanur forest disease. Important mosquito-borne viruses are Japanese,St Louis and Murray Valley encephalitis viruses and West Nile virus (in addition to yellow fever and dengue viruses).
YELLOW FEVER
Yellow fever, caused by a flavivirus, is normally a zoonosis of monkeys that inhabit tropical rainforests in West and Central Africa and South and Central America, among whom it may cause devastating epidemics. It is transmitted by mosquitoes living in tree-tops . Aedes africanus in Africa and the Haemagogus species in America are the vectors. The infection is brought down to humans either by infected mosquitoes when trees are felled, or by monkeys raiding human plantations. In the latter case Aedes simpsoni, which breeds in the axils of banana plants, may transmit the disease to humans. In towns yellow fever may be transmitted between humans by Aedes aegypti which breeds efficiently in small collections of water. The distribution of this mosquito is far wider than that of yellow fever and poses a continual risk of spread.
Humans are infectious during the viraemic phase, which starts 3-6 days after the bite of the infected mosquito and lasts for 4–5 days. Mosquitoes become infectious 8-12 days after biting a patient and remain so for the rest of their 6-8week lifespan. They may pass on the virus transovarially.
The incubation period is 3–6 days.
Pathology
In the liver, acute mid-zonal necrosis leads to deposits of hyalin called Councilman bodies, and intranuclear eosinophilic inclusions called Torres bodies; another characteristic feature is the absence of inflammatory infiltrate. The kidneys show tubular degeneration, which may partly be due to reduced blood flow. Widespread petechial haemorrhages are most marked in the stomach and duodenum. Haemorrhage is due to liver damage and disseminated intravascular coagulation.
Clinical features
Yellow fever is often a mild febrile illness lasting less than a week. However, the classical disease starts suddenly with rigors and high fever. Backache, headache and bone pains are severe. Nausea and vomiting start. The face is flushed and the conjunctivae are infected. Bradycardia and leucopenia are characteristic of this phase of the illness, which lasts 3 days and is followed by a remission lasting a few hours or days.
The third stage is characterised by return of fever, and the onset of jaundice, petechial haemorrhages in the mucosae, ecchymoses, haematemesis and oliguria. Patients commonly die in the third stage, often after a period of coma.
Investigations
Diagnostic procedures are listed in the information box.
Management
Patients should be nursed under a mosquito net (where the
| DIAGNOSIS OF YELLOW FEVER |
|---|
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vector is present) until the viraemic stage has passed. Treatment is supportive, with meticulous attention to fluid and electrolyte balance, urine output and blood pressure. Blood transfusions, plasma expanders and peritoneal dialysis may be necessary.
Prevention
A single vaccination with the 17 D non-pathogenic strain of virus gives full protection for at least 10 years. The vaccine does not produce appreciable sideeffects, unless there is allergy to egg protein. Vaccination is not recommended in children under 9 months of age because of a slight risk of encephalitis, nor in people who are immunosuppressed, whether it be the result of immunosuppressive therapy or of underlying disease. Vaccination should be avoided in pregnant women as there is a theoretical risk of fetal infection. The UK Health Departments advise that if a pregnant woman must travel to a high-risk area she should be immunised, since the risk from yellow fever outweighs that of immunisation.
Only travellers possessing valid certificates of vaccination against yellow fever are allowed to proceed from an endemic area to receptive areas, by which is meant countries free from the disease but in which the potential exists.
In this way the disease has been kept out of Asia. Mosquito control of airports should be maintained. The urban disease can be eradicated by the abolition of the breeding places of Aedes aegypti by the use of residual insecticides in houses and by mass vaccination in endemic areas. Vaccination is the only means of preventing humans from being infected from forest reservoirs.
DENGUE
This disease is the most common flavivirus infection of humans and is a risk in many tropical and subtropical countries , especially in coastal areas during the hot season when mosquitoes are numerous. The principal vector is Aedes aegypti. It is endemic in Southeast Asia but there are increasingly frequent large epidemics in the Caribbean and Americas; it should be considered in the differential diagnosis of fever in the returning traveller in the UK. There are four serotypes of dengue virus, all of which produce a similar clinical syndrome; homotypic immunity is life-long but heterotypic immunity between serotypes lasts only a few months. The incubation period from being bitten by an infected mosquito is usually 2-7 days.
Clinical features
The disease varies in severity. The clinical features are listed in the information box. Subclinical infections are common.
| CLINICAL FEATURES OF DENGUE FEVER |
|---|
| Prodrome |
| 2 days' malaise and headache |
| Acute onset |
| Fever, backache, arthralgias, headache, generalised pains ('breakbone fever'), pain on eye movement, lacrimation, anorexia, nausea, vomiting, relative bradycardia, prostration, depression, lymphadenopathy, scleral injection |
| Fever |
| Continuous or 'saddle-back', with break on fourth or fifth day; usually lasts 7-8 days |
| Rash |
| Transient macular in first 1-2 days. Maculo-papular, scarlet morbilliform from days 3-5 on trunk, spreading centrifugally sparing palms and soles. May desquamate on resolution |
| Convalescence |
| Slow |
Dengue haemorrhagic fever or dengue shock syndrome
This occurs mainly in children in South-east Asia, but is sometimes seen in adults in epidemics elsewhere. In mild forms there is thrombocytopenia and haemoconcentration. In the most severe form, after 3-4 days of fever, hypotension and circulatory failure develop with features of a capillary leak syndrome. Minor (petechiae, ecchymoses, epistaxis) or major (gastrointestinal bleeding) haemorrhagic signs may occur. The pathogenesis is unclear but preexisting immunity to a dengue virus serotype heterotypic to the one causing the current infection predisposes to the syndrome. In vitro such heterotypic antibody causes enhanced virus entry and replication in monocytes; it is believed that enhancing antibody from previous dengue infection with a different serotype, or from acquired maternal antibody in infants, facilitates development of a very heavy viral load. Disseminated intravascular coagulation, complement activation and release of vasoactive mediators may contribute to the pathogenesis of the syndrome, possibly triggered by immunopathological mechanisms. Cytokine release is thought to be the cause of vascular damage at the site of post-capillary endothelial junctions. Even with treatment the case fatality may be up to 10%.
Investigations
Diagnosis of dengue is usually easy in an endemic area when a patient has the characteristic symptoms and signs. However, mild cases may resemble other viral disease. Leucopenia is usual, and thrombocytopenia common. The virus can be recovered from the blood and there are tests for viral antigen. Antibody titres rise but serological tests may detect cross-reacting antibodies from other flaviviruses, including yellow fever vaccine.
Management and prevention
There is no specific treatment. The severe pains can be relieved by paracetamol, but occasionally opiates are required. Aspirin should be avoided. Volume replacement, blood transfusions and management of capillary leak are indicated in shock syndrome. Corticosteroids have not been shown to help. No existing antivirals are effective.
Patients are nursed under a mosquito net. Breeding places of Aedes mosquitoes should be abolished and the adults destroyed by insecticides. There is as yet no vaccine but a tetravalent live attenuated version is at an advanced stage of development.