Yellow fever virus is the prototype member of the Flaviviridae family. It causes yellow fever, an acute, febrile, mosquito borne illness that occurs in the tropics and subtropics of Africa and South America. Severe cases are characterized by liver and renal dysfunction and hemorrhage, with a high mortality rate.
Based on sequence analysis, at least seven genotypes of yellow fever virus have been identified, five in Africa and two in South America. There is a single serotype.
Yellow fever virus multiplies in many different types of animals and in mosquitoes and grows in embryonated eggs, chick embryo cell cultures, and cell lines, including those of monkey, human, hamster, and mosquito origin.
Pathogenesis and Pathology
The virus is introduced by a mosquito through the skin, where it multiplies. It spreads to the local lymph nodes, liver, spleen, kidney, bone marrow, and myocardium, where it may persist for days. It is present in the blood early during infection.
The lesions of yellow fever are caused by the localization and propagation of the virus in a particular organ. Infections may result in necrotic lesions in the liver and kidney. Degenerative changes also occur in the spleen, lymph nodes, and heart. Serious disease is characterized by hemorrhage and circulatory collapse. Virus injury to the myocardium may contribute to shock.
Clinical Findings
The incubation period is 3–6 days. At the abrupt onset, the patient has fever, chills, headache, dizziness, myalgia, and backache followed by nausea, vomiting, and bradycardia. During this initial period, which lasts several days, the patient is viremic and a source of infection for mosquitoes. Most patients recover at this point, but in about 15% of cases, the disease progresses to a more severe form, with fever, jaundice, renal failure, and hemorrhagic manifestations. The vomitus may be black with altered blood. When the disease progresses to the severe stage (hepatorenal failure), the mortality rate is high (20% or higher), especially among young children and elderly adults. Death occurs on day 7–10 of illness. Encephalitis is rare.
On the other hand, the infection may be so mild as to go unrecognized. Regardless of severity, there are no sequelae; patients either die or recover completely.
Laboratory Diagnosis
A. Virus Detection or Isolation
Virus antigen or nucleic acid can be identified in tissue specimens using immunohistochemistry, ELISA antigen capture, or PCR tests. The virus may be recovered from the blood the first 4 days after onset or from postmortem tissue by intracerebral inoculation of mice or by use of cell lines.
B. Serology
IgM antibodies appear during the first week of illness. The detection of IgM antibody by ELISA capture in a single sample provides a presumptive diagnosis, with confirmation by a fourfold or greater rise in titer of neutralizing antibody between acute phase and convalescent phase serum samples. Older serologic methods, such as HI, have largely been replaced by ELISA. Specific hemagglutination-inhibiting antibodies appear first followed rapidly by antibodies to other flaviviruses.
Immunity
Neutralizing antibodies develop about 1 week into the illness and are responsible for viral clearance. Neutralizing anti bodies endure for life and provide complete protection from disease. Demonstration of neutralizing antibodies is the only useful test for immunity to yellow fever.
Epidemiology
Two major epidemiologic cycles of transmission of yellow fever are recognized: (1) urban yellow fever and (2) sylvatic, or jungle yellow fever (Figure 1). Urban yellow fever involves person-to-person transmission by domestic Aedes mosquitoes. In the Western Hemisphere and West Africa, this species is primarily Aedes aegypti, which breeds in the accumulations of water that accompany human settlement. In areas where A. aegypti has been eliminated or suppressed, urban yellow fever has disappeared.
Fig1. Transmission cycles of yellow fever and dengue viruses. These viruses have enzootic maintenance cycles involving Aedes vectors and nonhuman primates. Dengue viruses are transmitted principally between humans and A. aegypti that breed in domestic water containers. In the case of yellow fever, sylvatic (jungle) transmission is widespread throughout the geographic distribution of the virus. In tropical America, human yellow fever cases derive from contact with forest mosquito vectors, and there have been no cases of urban (A. aegypti borne) yellow fever for more than 50 years. In Africa, sylvatic vectors are responsible for monkey–monkey and interhuman virus transmission, and there is frequent involvement of A. aegypti in urban and dry savanna regions. (Adapted from Monath TP, Heinz FX: Flaviviruses. In Fields BN, Knipe DM, Howley PM [editors-in-chief]. Fields Virology, 3rd ed. Lippincott-Raven, 1996.)
Jungle yellow fever is primarily a disease of monkeys. In South America and Africa, it is transmitted from monkey to monkey by arboreal mosquitoes (ie, Haemagogus and Aedes) that inhabit the moist forest canopy. The infection in animals may be severe or inapparent. The virus multiplies in mosquitoes, which remain infectious for life. Persons involved in forest-clearing activities come in contact with these mosquitoes in the forest and become infected.
Yellow fever has not invaded Asia even though the vector, A. aegypti, is widely distributed there.
Yellow fever continues to infect and kill thousands of per sons worldwide because they have failed to be immunized. It is estimated that annually, severe yellow fever strikes 200,000 persons, of whom about 30,000 (15%) die. The majority of outbreaks (~90%) occur in Africa. Epidemics usually occur in a typical emergence zone for yellow fever: humid and semihumid savanna adjoining a rain forest where the sylvatic cycle is maintained in a large monkey population. During epidemics in Africa, the infection:case ratio ranges from 20:1 to 2:1. All age groups are susceptible.
Yellow fever in the Americas presents epidemiologic features typical of its sylvatic cycle: Most cases are in boys and men ages 15–45 years and engaged in agricultural or forestry activities.
Treatment, Prevention, and Control
There is no antiviral drug therapy.
Vigorous mosquito abatement programs have virtu ally eliminated urban yellow fever throughout much of South America; however, vector control is impractical in many parts of Africa. The last reported outbreak of yellow fever in the United States occurred in 1905. However, with the speed of modern air travel, the threat of a yellow fever outbreak exists wherever A. aegypti is present. Most countries insist upon proper mosquito control on airplanes and vaccination of all persons at least 10 days before arrival in or from an endemic zone.
The 17D strain of yellow fever virus is an excellent attenuated live-virus vaccine. During the serial passage of a pan tropic strain of yellow fever virus through tissue cultures, the relatively avirulent 17D strain was recovered. This strain lost its capacity to induce viscerotropic or neurotropic disease and has been used as a vaccine for more than 70 years.
The virulent Asibi strain of yellow fever virus has been sequenced and its sequence compared with that of the 17D vaccine strain, which was derived from it. These two strains are separated by more than 240 passages. The two RNA genomes (10,862 nucleotides long) differ at 68 nucleotide positions, resulting in a total of 32 amino acid differences.
Vaccine is prepared in eggs and dispensed as a dried powder. It is a live virus and must be kept cold. A single dose produces a good antibody response in more than 95% of vaccinated persons that persists for at least 30 years. After vaccination, the virus multiplies and may be isolated from the blood before antibodies develop.
Vaccination is contraindicated for infants younger than 9 months of age, during pregnancy, and in persons with egg allergies or altered immune systems (eg, human immunodeficiency virus infection with low CD4 T cell counts, malignancy, organ transplantation).
The 17D vaccine is safe. More than 400 million doses of yellow fever vaccine have been administered, and severe adverse reactions are extremely rare. There have been about two dozen cases worldwide of vaccine-associated neurotropic disease (postvaccinal encephalitis), most of which occurred in infants. In 2000, a serious syndrome called yellow fever vaccine-associated viscerotropic dis ease was described. Fewer than 20 cases of multiple organ system failure in vaccine recipients have been reported worldwide.
Vaccination is the most effective preventive measure against yellow fever, a potentially severe infection with a high death rate for which there is no specific treatment.
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