Facts about yellow fever
1. Name and nature of infecting organism
Yellow fever (YF) is an African mosquito-borne infection of primates. It is caused by a virus of the Flavivirus genus of the Flaviviridae family. In its natural habitat, it is transmitted between monkeys by forest-dwelling primatophilic Aedes mosquitoes. The virus and its vector (Ae. aegypti) were introduced to the Americas, where it is also enzootic in forest habitat, with the slave trade.
Sylvatic infection of humans occurs when they enter the forest to hunt, gather food, harvest timber and so on. Forest-infected persons can initiate human-to-human transmission if suitable peridomestic vectors are present in towns and villages. In the urban environment, Ae. (Stegomyia) aegypti (Linn.), a forest species that has adopted the human domestic environment, is a highly effective vector for yellow fever virus (YFV). This mosquito is also the principal urban vector of dengue and chikungunya viruses.
Yellow fever is distributed in west, central and east Africa and in South America, from Panama to the northern part of Argentina. It has never been detected in Asia. Catastrophic epidemics, with tens of thousands of deaths, have been recorded in rural Africa.
The vector Aedes aegypti was once endemic in Europe, and responsible for large epidemics of YF and dengue. The reason for its disappearance after World War II has never been explained. It is still present in the United States and has been recorded in 21 states. It is conceivable that the vector could become re-established and widespread in Europe, as has happened in recent years with another putative vector, Ae. albopictus.
2. Clinical features
Onset of symptoms is sudden, usually 3–5 days after infection. The disease can cause a wide spectrum of symptoms, from mild to fatal. In clinical cases there is a sudden onset of fever with severe headache, arthralgias and muscle pains. Jaundice may appear on the third day and indicates a poor prognosis. Transaminase elevations are also prognostic. In severe cases there may be spontaneous haemorrhage (‘coffee ground’ vomit), renal failure, delirium, coma and death. Mortality of these clinical cases can be as high as 80%, on a par with Ebola, Marburg and other haemorrhagic viral infections. Convalescence is long, often with serious sequelae.
3. Transmission
3.1 Reservoir
The virus circulates between monkeys in the forest and between humans in village and urban areas. The principal sylvatic vectors breed in tree-holes and similar small collections of water. Infection in African monkeys is asymptomatic or mild; epizootics are signalled when humans acquire the disease. By contrast, the virus is lethal to western hemisphere primates; epizootics are evident ‘when the jungle goes silent’ because of the high mortality of howler monkeys.
3.2 Transmission mode
Bites by infected mosquitoes are the only mode of transmission.
Mosquitoes acquire the virus when they feed on a viraemic host, after which (in a susceptible species) the virus infects many tissues, including the salivary glands. While it can take a matter of weeks (and many blood meals) to become infective, the mosquitoes are infected for life.
New infections in humans can occur when saliva that contains the virus is injected into a non-immune host during subsequent blood meals. The ‘extrinsic incubation period’, the time required for the mosquito to become infective, is about ten days, depending on the temperature. There is also evidence of vertical transmission (transmission directly from the adult female mosquitoes via eggs to adults of the next generation).
Viraemia reaches high titres on the day before onset of symptoms, and is generally high enough to infect mosquitoes for the next four days. Immunity is probably lifelong.
3.3 Risk groups
All unvaccinated persons are at risk in areas of active transmission. In recent years, a number of unvaccinated tourists from Europe and North America have died of the disease after visiting enzootic areas.
Aedes aegypti is ubiquitous and common throughout the tropics, so there is a real and present danger of a major epidemic in many tropical cities.
4. Prevention measures
A safe, effective and inexpensive yellow fever attenuated vaccine, known as YF 17D, has been used for more than half a century. The vaccine is highly effective but routine vaccination is implemented by very few countries.
A YF vaccination certificate is the only vaccination certificate that should be required in international travel. The certificate of vaccination against yellow fever is valid for the life of the person vaccinated, beginning 10 days after the date of vaccination. An individual risk benefit analysis particularly in patients with auto-immune diseases, immune-deficiencies or other related underlying conditions, and also among the elderly should be conducted prior to vaccination taking into account the destination and duration of travel, and the likelihood of exposure to mosquitoes.
At the beginning of the 20th century, urban YF was eliminated from many countries by energetic campaigns to eliminate Ae. aegypti breeding sites. After World War II, targeted application of DDT to infested containers and their surroundings was an outstanding success. According to the Pan American Health Organization, the species was eradicated from 22 countries of the Americas. No substitute for DDT is currently available. Many health authorities resort to insecticidal aerosols delivered from hand-held machines, road vehicles or aircraft. The technique is expensive and ineffective. Moreover, even if a high kill rate were attainable, the impact on adult populations would probably be too short to make an effective impact on transmission. The World Health Organization has recommended ‘community based source reduction’ for several years, but there is no evidence that this has been successful anywhere in the world.
Prevention is also based on protection against mosquito bites. Aedes mosquitoes have diurnal biting activities in both indoor and outdoor environments. Therefore, personal protection measures should be applied all day, especially during the hours of the highest mosquito activity (mid-morning, late afternoon to twilight). Personal protective measures against mosquito bites include the use of mosquito bed nets (preferably insecticide-treated nets), sleeping or resting in screened or air-conditioned rooms, the wearing of clothes that cover most of the body, and the use of mosquito repellent in accordance with the instructions indicated on the product label.
5. Diagnosis
The virus can be detected in blood specimens by RT-PCR, antigen-capture and/or viral isolation. A serological diagnosis can be made by detection of specific IgM antibodies one week after infection. Exposure to YF virus confers lifelong immunity.
6. Management and treatment
Supportive therapy is the only option, although the use of antivirals is an active field of research. Strict avoidance of aspirin and other anticoagulants is important.
7. Key areas of uncertainty
In spite of the wealth of information on the ecology, epidemiology and pathology of the disease, a high probability of large urban outbreaks in unvaccinated populations remains in areas where the Aedes aegypti vector is present.
Adverse (viscerotropic or neurotropic) events following immunisation after YF vaccination have been reported mostly in older age groups and in immunocompromised individuals. These cases would need to be investigated further to gather and verify evidence of the association between vaccine and clinical disease in order to support decision-making regarding YF vaccination.
8. References
Crosby M. The American plague: the untold story of yellow fever, the epidemic that shaped our history. Berkley, California: Berkley Publishing Group; 2007.
Monath TP. Yellow fever: Victor, Victoria? Conqueror, conquest? Epidemics and research in the last forty years and prospects for the future. Am J Trop Med Hyg 1991;45(1):1-43.
Monath TP. Treatment of yellow fever. Antiviral Res 2008;78(1):116-24.
Reiter P. Climate change and mosquito-borne disease. Environ Health Perspect 2001;109 Suppl 1:141-61.
Reiter P, Nathan M. Guidelines for assessing the efficacy of insecticidal space sprays for control of the dengue vector, Aedes aegypti. Geneva: World Health Organization; 2001.