Flaviviruses Flashcards
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Flavivirus
2 lineages causing meningiencephalitis
Enveloped (+)ss RNA
Baltimore: IV
Vector - ixodes ticks
Clinical syndrome: encephalitis
Diagnostics: IgM at CDC, PCR
Dengue structure, classification, pathogenesis, receptor
Family: Flaviviridae
Genus: Flavivirus
Enveloped (+)ssRNA
E&M envelope proteins - SEE IMAGE IN ALBUM
4 serotypes: DENV1-4
Baltimore: IV
Vectors: Aedes
- Entry into cells mediated by major viral envelope - E protein to receptor CLEC5A/DC-SIGN. Target cells - macrophages & dendritic cells
- Dissemination- viraemia median 7 days.
- Immune response: induces interferon alpha.
Zika
Family: Flaviviridae
Genus: Flavivirus
(+)ss RNA
Baltimore: IV
There are two distinct lineages of ZIKV; African and Asian.
Vector: Aedes, but can also be transmitted through sexual intercourse and vertically.
Incubation: 2-14 days
Clinical: 80% asymptomatic but symptoms, which are similar to other arboviruses such as dengue virus and chikungunya virus, include maculopapular rash, fever, arthralgia, conjunctivitis, retro-orbital pain and fatigue.
Zika virus has been linked to a number of central and peripheral nervous system disorders including Guillain-Barré syndrome (GBS), transverse myelitis (TM) and meningoencephalitis.
The most common signs and symptoms of Congenital Zika Syndrome include microcephaly; brain anomalies including intracranial calcifications, CNS hypoplasia and ventriculomegaly; ocular anomalies; congenital contractures; and neurological sequelae including motor and cognitive disabilities, seizures and sensorineural hearing loss.
Zika-associated birth defects is highest when infected in the first trimester (8%), followed by the second (6%) and third trimester (3.8%).
ZIKV persists for longer in semen than the female genital tract and is more likely transmitted from men to women than from women to men. UKHSA guidance advises women should avoid becoming pregnant while travelling to a country or area with risk for Zika virus transmission.
On returning to the UK, they should avoid becoming pregnant for a further 2 months if only the woman travelled, and for 3 months if both partners or just the male partner travelled. ZIKV testing is not currently available for asymptomatic individuals in the UK, including for pregnant women or couples trying to conceive.
Diagnostics: IgM, IgG, RT-PCR at RIPL
NO antivirals or vaccine.
WNV/Kunjin
Family: Flaviviridae
Genus: Flavivirus.
Serologically, WNV is a member of the Japanese encephalitis serocomplex, which includes Japanese encephalitis virus and St Louis encephalitis virus.
(+)ssRNA
Baltimore: IV
WNV is maintained in a bird-mosquito-bird transmission cycle. The Culex mosquito species drive transmission of the virus in nature and subsequent spread to humans. Some species of Aedes, Ochlerotatus, and Mansonia mosquitoes have also been implicated as a competent vector in certain parts of the world.
WNV has a fairly worldwide distribution and cases have been reported from all continents except Antarctica. As of June 2023, Ten EU/EEA countries have reported locally acquired human cases of WNV infection including Italy, Greece, Romania, Germany, Hungary, Croatia, Austria, France, Spain, and Slovakia.
WNV shows relatively high levels of sequence diversity and show that they form at least 2 main lineages. Lineage 1 is composed of WNV strains from different geographic regions, and it is subdivided into at least 3 clades. Clade A contains strains from Europe, Africa, the Middle East, and America; clade B represents the Australian (KUNJIN) strains; and clade C contains Indian WNV isolates.
Lineage 2 contains the B 956 prototype strain and other strains isolated so far exclusively in sub-Saharan Africa and Madagascar.
An estimated 70-80% of human WNV infections are subclinical or asymptomatic. Most symptomatic persons experience an acute systemic febrile illness that often includes headache, weakness, myalgia, or arthralgia; gastrointestinal symptoms and a transient maculopapular rash also are commonly reported. Less than 1% of infected persons develop neuroinvasive disease, which typically manifests as meningitis, encephalitis, or as acute flaccid paralysis.
WNV acute flaccid paralysis is usually clinically and pathologically identical to poliovirus-associated poliomyelitis, with damage of anterior horn cells, and may progress to respiratory paralysis requiring mechanical ventilation. WNV-associated Guillain-Barré syndrome and radiculopathy have also been reported.
RIPL offers WNV IgM/IgG on serum and a WNV specific PCR on plasma, CSF, or urine. Seroconversion for IgM typically occurs 3-8 days post onset of symptoms usually persists for 30–90 days. In patients with neuro-invasive disease, IgM can be detected in CSF usually 1-8 days after onset of neurological symptoms.
WNV-specific IgG is typically detectable from 8 days post onset of symptoms onwards and may persist for multiple years. A 4-fold increase in IgG titers can suggest acute infection. The virus is detectable by PCR in plasma from 2-18 days post-infection and up to 5 days post-onset of symptoms.
No specific treatment - supportive.
No vaccines.
TBEV
Family: Flaviviridae
Genus: Flavivirus
(+)ssRNA Enveloped
Baltimore: IV
5 subtypes:
A. European subtype, transmitted by Ixodes ricinus ticks, endemic in rural and forested areas of central, eastern and northern Europe;
B. Far eastern subtype, transmitted mainly by I. persulcatus, endemic in far-eastern Russia and in forested regions of China and Japan; and
C. Siberian subtype, transmitted by I. persulcatus, endemic in Urals region, Siberia and far-eastern Russia, and also in some areas in north-eastern Europe.
D. Baikalian subtype, transmitted by Ixodes persulcatus, and found in East Siberia
E. Himalayan subtype, for which Marmota himalayana is the primary host, and found in the Qinghai-Tibet Plateau in China
Raw milk is also a mode of acquisition
Reservoir: rodents
Incubation: 4-28 days
Clinical: 2/3rd infections asymptomatic. Remaining BIPHASIC with initial viraemia, long asymptomatic phase, and then Meningoencephalitis.
Mortality: 0.5-2% in European and Siberian.
Far eastern: 35%
Diagnostics: RIPL. TBE antibodies appear 0–6 days after onset and are usually detected when neurological symptoms are present. Specific IgM antibodies can persist for up to 10 months in vaccinees or individuals who acquired the infection naturally; IgG antibody cross-reaction is possibly observed with other flaviviruses. Detection by PCR methods could be valuable for an early differential diagnosis of TBE.
Treatment: NO antivirals.
Prevention: inactivated vaccine in endemic countries.
UK: Tico-vac. virus grown in chick fibroblasts and then inactivated by formaldehyde. Strain: Neudörfl virus strain.
Dosing: 0.5 ml x 3 doses 0,1, 12 months after second dose.
HAIRS assessment for UK done in 2023: Low risk, routine vaccination no recommended.
JEV
Family: Flaviviridae
Genus: Flavivirus
(+)ss RNA enveloped
Baltimore: IV
5 genotypes - all
Similar clinical syndrome
Vector: Culex
Incubation: 5-15 days
Clinical: Most asymptomatic. 1 in 250 develop encephalitis.
Diagnostics: IgM in serum and CSF at the time of symptoms. RT-PCR in early disease.
Therapeutics: No specific antiviral.
Vaccine: inactivated vaccine produced in vero cells. IXIARO.
Dosing: 0.5ml at 0, 28 days
Booster at 1 year if ongoing risk.
Rapid: 0,7 days
Yellow fever
Family: Flaviviridae
Genus: Flavivirus
(+)ssRNA Enveloped
Baltimore: IV
Vector: Aedes
Reservoir: Monkeys
Incubation: 3-5 days
Clinical: 15% develop clinical symptoms. LJaundice and transaminitis. Haemorrhage.
Mortality: 80% in clinical cases.
Diagnostics: IgM - 7 days after infection. RT-PCR offered at RIPL.
Treatment: NO antiviral.
Vaccine: STAMARIL- live attenuated using the 17D strain grown in embryo aged chick eggs.
Dosing: 0.5ml single dose.
Booster > 10 years If ongoing risk/immunosuppressed.
Can be given with other live vaccines except MMR - 28 day gap advised due to lower efficacy of MMR when co-administered.
Administer 10 days prior to travel.
ADRS:
1. Post vaccine encephalitis in infants < 6 months. YEL-AND. 0.8/10,000 doses
2. YEL-AVD - associated visceral disease. Especially in immunodeficiency. 0.3/100,000 doses
Usutu
Family: Flaviviridae
Genus: Flavivirus
(+)ss RNA Enveloped
Baltimore: IV
3 African lineages and multiple strains.
Vector: Culex
Reservoir: Black birds, owls, cuckoos
Incubation: 3-12 days.
Clinical: asymptomatic in majority. meningoencephalitis.
Diagnostics: Roche WNV RT-PCR cross reactive. Serology also cross reactive.
RIPL has a developmental USUV PCR.
Therapeutics: ?Ribavirin in animal models.
No vaccines.
HAIRS- found in UK birds. No human cases. Low to
Moderate risk.
Dengue secondary infection
ADE - antibody dependent enhancement mediated by IgG - not fully understood but thought to have increased viral entry & replication followed by RNAemia.
Antibody fucosylation.
Factors influencing severity in DENV
- Viral factors - Serotype 2 highest risk. Associated with certain genotypes within each serotype (virulent genotypes)
- Previous dengue
- Young age
- Nutritional status
- Ethnicity & genetics
Dengue incubation
3-14 days
Capillary leak in DHF
NS1 binds to endothelial cells and activated toll like receptor 4 (TLR4 - also binds F protein of RSV!) inducing endothelial permeability.
Coupled with increased levels of pro-inflammatory markers & cytokines leads to capillary leak.
Leukopenia & thrombocytopenia in DENV
Leukopenia - direct effect of virus on BM
Thrombocytopenia- adsorption of curious or virus-antibody immune complexes to platelet surface with activation of complement leading to platelet destruction.
Also molecular mimicry between DENV viral proteins and coagulation factors.
Non mosquito transmission of DENV
- Nosocomial - blood products
- Vertical - when mum ill 10 days prior to delivery but NO impact on pregnancy
- Breast feeding
- Sexual
Current DENV syndrome classification
- Dengue without warning signs
- Dengue with warning signs:
*Abdo pain/tenderness
*Persistent vomiting
*Thirds spacing of fluid
*Mucosal bleeding
*Lethargy
*Hepatomegaly
*Increased PCV/reduced platelets - Severe dengue:
*shock
*Third spacing with Resp distress
*Severe bleeding (defined by clinician)
*AST/ALT>1000
*Impaired consciousness
*Organ failure
