What is the pathophysiology of yellow fever?

Pathophysiology of Yellow Fever

Yellow fever virus causes disease through direct viral cytopathic effects on hepatocytes, renal cells, and myocardium, combined with immune-mediated tissue damage and consumptive coagulopathy that occurs independently of hepatocellular destruction.

Viral Characteristics and Initial Infection

• Yellow fever virus (YFV) is an RNA virus belonging to the genus Flavivirus, antigenically related to West Nile virus, St. Louis encephalitis virus, and Japanese encephalitis virus 1.
• Following mosquito inoculation, the virus enters the bloodstream and replicates in target tissues, producing high levels of viremia that peak shortly before fever onset and persist for 3-5 days 1.
• The incubation period ranges from 3-6 days before clinical manifestations appear 1.

Organ System Pathology

Hepatic Involvement

• Hepatocytes are a major target of YFV infection, with direct viral cytopathic effects causing hepatocellular necrosis 2.
• Massive hepatocyte infection and destruction leads to jaundice, a hallmark of severe disease 1.
• Liver failure results in impaired synthesis of clotting factors, contributing to but not fully explaining the coagulopathy 2.
• The characteristic mid-zonal necrosis with sparing of periportal hepatocytes distinguishes yellow fever from other viral hepatitides 3.

Coagulopathy Mechanism

• Severe yellow fever produces a consumptive coagulopathy that occurs independently of hepatocellular tropism and massive hepatic injury 2.
• Elevated plasma D-dimer levels in Brazilian patients with severe disease indicate active fibrin degradation and consumption of clotting factors 2.
• Research comparing YFV infection in rhesus macaques versus humanized mice (hFRG) demonstrated that only primates developed consumptive coagulopathy despite both species showing substantial hepatocyte infection and liver damage 2.
• This finding indicates that infection of cell types other than hepatocytes—likely endothelial cells and immune cells—contributes critically to the hemorrhagic manifestations 2.

Renal Pathology

• Renal failure develops in severe cases through direct viral infection of renal tubular cells and immune-mediated damage 1.
• Hepatorenal dysfunction carries a case-fatality ratio of 20-50% 1, 4.

Hemorrhagic Manifestations

• Thrombocytopenia develops through both consumptive processes and direct viral effects on megakaryocytes 1.
• Abnormal clotting and coagulation result from the dual mechanisms of decreased hepatic synthesis and consumptive coagulopathy 1, 2.
• Hemorrhagic symptoms represent a defining feature of severe disease, distinguishing yellow fever as a viral hemorrhagic fever 3, 5.

Clinical Spectrum and Disease Progression

• The majority of YFV infections remain asymptomatic or produce only mild, undifferentiated febrile illness 1, 3.
• Symptomatic disease manifests abruptly with fever, prostration, headache, photophobia, lumbosacral pain, extremity pain (particularly knee joints), epigastric pain, anorexia, and vomiting 1.
• Approximately 15% of symptomatic patients progress to severe disease with jaundice, hemorrhagic manifestations, and multisystem organ failure 1.
• The fatality rate of severe yellow fever with hepatorenal dysfunction is approximately 20% overall, reaching 20-50% in those with severe disease 1.

Immune Response and Pathogenesis

• The pathogenesis involves both direct viral cytopathic effects and immune-mediated tissue damage 2.
• High viremia levels enable bloodborne transmission theoretically through transfusions or needlestick injuries, though mosquito transmission remains the primary route 1.
• The selective pressure exerted by urban vectors like Aedes aegypti increases transmission of viral strains capable of producing higher viremia in humans, potentially explaining the greater severity of urban versus sylvatic yellow fever 5.

Geographic Variation in Virulence

• Two geographical viral genotypes exist corresponding to West Africa and Central/East Africa 5.
• West African strains appear more virulent in urban epidemics, with major epidemics predominantly occurring in West Africa despite wild viral cycles existing throughout sub-Saharan Africa 5.
• The virulence of yellow fever virus in its wild sylvatic cycle affecting humans is notably lower than in urban epidemic cycles 5.