YFV patofysiologiasta

Large vaccination campaigns and A aegypti control programs have decreased the incidence of yellow fever worldwide. Despite the availability of an effective live-attenuated 17D vaccine, yellow fever has reemerged across Africa and South America. The populations at highest risk for the illness are those in the poorest countries in the world that lack funding or infrastructure to support a widespread vaccination program. A aegypti mosquitoes are now present in the Americas, and there is a concern that large yellow fever outbreaks could occur.

Flaviviruses, including those that cause yellow fever, also have a potential use as a biologic weapon.³ For more information, see the article CBRNE - Viral Hemorrhagic Fevers in eMedicine’s Emergency Medicine volume.

Pathophysiology

Yellow fever virus is a positive-sense, single-stranded, RNA-enveloped flavivirus with a diameter of about 50-60 nm. The virus is transmitted via the saliva of an infected mosquito. Local replication of the virus takes place in the skin and regional lymph nodes. Viremia and dissemination follows.

The virus gains entrance through receptor-mediated endocytosis. RNA synthesis occurs in the cytoplasm and protein synthesis in the endoplasmic reticulum. Virions are released through the cell membrane. Its viral envelope contains a lipid bilayer taken from the infected cell. Virulence factors include the following:

• Capsid protein C facilitates viral binding.
• Membrane protein M is a minor glycoprotein.
• E proteins initiate infection and mediate viral entry.
• Nonstructural protein 1 (NS1) may play a role in RNA replication.
• NS2A protein is involved in RNA replication and packaging.
• NS2B and NS3 form a complex and are involved in polyprotein processing and replication of RNA.
• NS5 has a major role in RNA replication.

The E protein interacts with the cellular receptor, and virions are endocytosed into the dendritic cells. Subsequently, epidermal dendritic cells and lymph channels disseminate virions. After invasion in the host, Kupffer cells (fixed liver macrophages) are infected within 24 hours.

The infection quickly disseminates to kidneys, lymph nodes, spleen, and bone marrow. Renal failure occurs as renal tubules undergo fatty change and eosinophilic degeneration, likely due to direct viral effect, hypotension, and hepatic involvement.

Liver involvement is a late manifestation of the infection. Direct viral effects lead to apoptotic cell death of the midzonal hepatic cells. Vitamin K–depleted clotting factors and disseminated intravascular coagulation lead to coagulopathy and bleeding. Hepatic involvement is associated with higher risk of mortality.

Finally, circulatory shock develops secondary to cytokine storm, with evidence of increased levels of interleukin (IL)–6, IL-1 receptor antagonist, inferno-inducible protein-10, and tumor necrosis factor (TNF)–alpha. Viral antigens are found diffusely in kidneys, myocardium, and hepatocytes. In individuals who survive yellow fever, the recovery is complete, with no residual fibrosis.