What does the term Flavivirus refer to?

What is Flavivirus?

Flavivirus is a genus of single-stranded RNA viruses that includes over 70 distinct viral species, primarily transmitted by arthropod vectors (mosquitoes and ticks), causing diseases ranging from encephalitis to hemorrhagic fever in humans. 1, 2

Viral Classification and Structure

• Flaviviruses are small, enveloped RNA viruses approximately 45 nm in diameter with a positive-sense, single-stranded RNA genome 3, 4, 5
• The viral genome has a molecular weight of approximately 4 × 10⁶, contains an m7G 'cap' at the 5' end but lacks a poly(A) tract at the 3' end 5
• Structural proteins include envelope glycoprotein (E), core protein (C), and membrane protein (M), with the gene sequence organized as 5'-C-M-E 5

Major Human Pathogens

The most clinically significant flaviviruses affecting humans include:

• Dengue virus (4 serotypes: DENV-1, DENV-2, DENV-3, DENV-4) causing approximately 400 million infections annually worldwide 2, 3
• Yellow fever virus causing hemorrhagic fever with mortality rates of 20-50% in severe cases 1, 6
• Japanese encephalitis virus (5 genotypes) causing 35,000-50,000 cases annually with 20-30% mortality 1, 2
• West Nile virus (2 main strains) causing neuroinvasive disease including acute flaccid paralysis 1, 2, 7
• Zika virus known for causing congenital microcephaly and neurological complications during pregnancy 2, 4
• St. Louis encephalitis virus and tick-borne encephalitis virus 1, 2

Transmission Patterns

• Flaviviruses are primarily arthropod-borne (arboviruses), transmitted through bites of infected mosquitoes or ticks 1, 8
• Mosquito vectors include Aedes species (particularly Ae. aegypti) and Culex species (especially Cx. tritaeniorhynchus) 1
• Humans typically serve as dead-end hosts with insufficient viremia to infect mosquitoes, except during the acute phase when viremia peaks 1, 6
• Rare transmission routes include intrauterine infection, blood transfusion, and organ transplantation 1

Geographic Distribution and Epidemiology

• Historically originated in Africa, primarily affecting tropical and subtropical regions due to mosquito ecological niches 3
• Climate change and vector migration have expanded geographical distribution, with West Nile virus now endemic in North America and Aedes albopictus spreading throughout Europe 2, 3
• Over 3 billion individuals live in areas where flaviviruses are endemic 4

Clinical Spectrum

Flaviviruses cause diverse clinical presentations:

• Neurotropic infections: Encephalitis, meningitis, and acute flaccid paralysis (West Nile, Japanese encephalitis, Zika) 1, 7, 4
• Hemorrhagic fever: Hepatic dysfunction, coagulopathy, and vascular shock syndrome (yellow fever, dengue) 6, 4
• Congenital abnormalities: Microcephaly and fetal death (Zika virus is the first teratogenic arbovirus in humans) 2, 4

Critical Diagnostic Considerations

• All flaviviruses demonstrate significant serological cross-reactivity due to shared antigenic structures, creating substantial diagnostic challenges 1, 2
• IgM antibody testing produces false-positive results due to cross-reactivity between dengue, Zika, West Nile, St. Louis encephalitis, Japanese encephalitis, and yellow fever viruses 2
• Molecular testing (NAAT) during acute infection (particularly within the first 10 days of symptoms) provides more specific results and should be prioritized when clinically feasible 2, 4
• Viral isolation by cell culture is rarely performed due to complexity and biosafety concerns 4

Common Pitfalls

• Do not rely solely on serologic testing in patients with potential exposure to multiple flaviviruses, as cross-reactivity will confound interpretation 2
• Recognize that asymptomatic or mild infections are common, with only 15% of yellow fever infections and <1% of Japanese encephalitis infections progressing to severe disease 1, 6
• Be aware that the incubation period ranges from 3-6 days, and viremia peaks shortly before fever onset, lasting 3-5 days 1, 6