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Yellow fever

Yellow fever
Author
Thomas P Monath, MD, FACP, FASTMH
Section Editor
Martin S Hirsch, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2012. | This topic last updated: Oct 4, 2012.
INTRODUCTION Yellow fever is a mosquito-borne viral hemorrhagic fever with a high case
fatality rate. Clinical manifestations include hepatic dysfunction, renal failure, coagulopathy, and
shock. Travelers to tropical regions of South America and sub-Saharan Africa where the disease
is endemic are at risk for acquisition of infection and require immunization.
Issues related to virology, pathogenesis, epidemiology, clinical manifestations, diagnosis,
treatment, and prevention of yellow fever will be reviewed here.
VIROLOGY, PATHOGENESIS AND HISTOPATHOLOGY Yellow fever is the prototype
member of the family Flaviviridae, a group of small (40 to 60 nm), enveloped, positive-sense,
single-stranded RNA viruses that replicate in the cytoplasm of infected cells. Yellow fever virus
is a single serotype and is antigenically conserved, so 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 (two genotypes), Central-East Africa and Angola (three genotypes),
and South America (two genotypes) [1,2]. Humans are highly susceptible to infection and
disease. Most non-human primate species are susceptible to infection, and some species of nonhuman primates develop clinical manifestations.
An infected female mosquito inoculates approximately 1000 to 100,000 virus particles
intradermally during blood feeding. Virus replication begins 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. The virus reaches other organs via the lymph and
then the bloodstream, seeding other tissues. Large amounts of virus are produced in the liver and
spleen and released into the blood. During the viremic phase (days three to six), infection may be
transmitted to blood-feeding mosquitoes.
Yellow fever is characterized by hepatic dysfunction, renal failure, coagulopathy, and shock [36]. The midzone of the liver lobule is principally affected, with sparing of cells bordering the
central vein and portal tracts [7]. Viral antigen localizes to the midzone, indicating that it is the

site of direct viral injury. Very high virus loads have been found in the liver and spleen of fatal
cases [8].
Injury to hepatocytes is characterized by eosinophilic degeneration with condensed nuclear
chromatin (Councilman bodies), rather than by the ballooning and rarefaction necrosis seen in
viral hepatitis. 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,
mainly CD4+ cells, are present in low numbers; smaller numbers of NK and CD8+ cells are
present [9,10]. There is no disruption of the reticular architecture of the liver. In nonfatal cases,
healing is complete without postnecrotic fibrosis. In fatal cases, approximately 80 percent of
hepatocytes undergo coagulative necrosis.
Renal damage is characterized by eosinophilic degeneration and fatty change of renal tubular
epithelium without inflammation. These findings are believed to be a result of both direct viral
injury and nonspecific changes due to hypotension and the hepatorenal syndrome [5].
Focal injury to the myocardium, characterized by cell degeneration and fatty change, is the result
of viral replication.
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.