11. Arboviruses & Dengue

8/7/2019 11. Arboviruses & Dengue

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ARBOVIRUSES

(Arthropod-Borne viruses)

y Originally defined as:Viruses transmitted by arthropod (mainly insect) vectors

y 1985 W.H.O criteria:Arboviruses: those maintained in nature through biological transmission between

susceptible vertebrate hosts by haematopahous arthropods. They multiply and produce

viraemia in vertebrate, multiply in the tissues of arthropods and are passed on to new

vertebrates when arthropod takes a subsequent blood meal after a period of extrinsic

incubation.

y International Catalogue of arboviruses- The term arbovirus jas NO taxonomic significance- 535 heterogenous groups of viruses- Under 7 taxonomic families- Many are zoonotic viruses that do not require an arthropod vector!

ARBOVIRUSES (This table is not complete!! I couldnt type it out in time! Sorry!!!!!)

Toga Alphavirus

Ungrouped

Flavi Flavivirus

Bunya Bunya

Phlebo

Nairo

Uukuu

HantavirusOrbovirus

Unassigned

Vesiculovirus

SOME IMPORTANT ARBOVIRUSES

Family: Togaviridae

Genus: Alphavirus

No. of members: 28 (mosquito-borne)

Some important members:-

y Western equine encephalitis (WEE)y Eastern equine encephalitis (EEE)y Venezuelan equine encephalitis (VEE)y Chikugunya


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y Ross riverGenus: Rubivirus, spp. Rubella virus (not ar-bo)

Family: Flaviviridae

Genus: Flavivirus

Amount of members: ~80

Some important members:-

A. Mosquito-borne- St. Louis encephalitis- Japanese B encephalitis- Murray Valley encephalitis- Yellow Fever- Dengue- Ilheus- West Nile

B. Tick-borne- Louping ill- Powassan- Tick-borne encephalitis- Kyasanur-Forest- Omsk Haemorrhagic fever

Genus: Hepacivirus

Family: Bunyaviridae

Genus: Bunyavirus

Amount of members: 212

Some important members:

y La Crossey Snowshoe harey Oropouche

Genus: Phlebovirus

y Rift valley fevery Punta Toroy Sandfly fevery Tascana

Genus: Nairovirus


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y Crimeas-Congo haemorrhagic feverGenus: Hantavirus

y Sin Nombre (not ar-bo)Family: Rhabdoviridae

Genus: Lyssavirus

Species: rabies virus (not ar-bo), 1 serotype

Other spp: Lagosm Mokota, Duvenhage, Kotonkan, Obodhiang

Important diseases caused by Arboviruses:-

y Yellow fevery Dengue / DHFy Japanese encephalitisy Rubella (not ar-bo)y Hepatitis C (not ar-bo), also Hep-Gy Rabies (not ar-bo)

DENGUE & Dengue haemorrhagic gever & Dengue shock syndrome (DF, DHF, DSS)

History

y 1780: Breakbone fever outbreak in Philadelphia, USAy 1800s: sporadic outbreaksy 1934: Floridal 1945 New Orleansy 1897: Australia Clinical description of dengue complicated by haemorrhages, shock and

death in outnreaks

y 1928 Greece, 1931 Formosay 1903: Mosquito-borne transmission of infection by Aedes aegypti demonstrated.y 1944: Sabin

- Isolated virus- Failure of 2 viral strains to cross protect humans

= evidence of serotypes

y 1956: Hammond characterized 2 morey After WWII: Start of a PENDEMIC with intensidied transmission of multiple viral serotypes in

SEAsia -> Outbreaks of DHF DSS

y In last 2 decades similar patterns of intensified transmission and DHF-DSS in:- SE Asia- Americas- Oceania

y Due to:- Urbanization- Population growth


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- mobilityy If virus introduced into susceptible population (usually by viraemic travelers) epidemic attack

rates can reach 50-70%!!!

y Cross protective immunity among serotypes = LIMITED!= Epidemic transmission recurs (Pak Nasa: actually, it doesnt recur. It occurs) when novel

serotype introduced.y Secondart infections predispose to DHF

= Virtually all DHF cases are in children with secondary infections

- Relative risk in secondary infection to develop DHF = 100xy Infants ( Maternal)

y DHF in primarily infected persons rare and anecdotal. ? contributory role of viral strain &host factors like rate, specific HLA type, etc

y DHA slightly predominant in- Girls- Well nourished children

y SEA= Hyperendemic areas, dengue infection rate : 5-10%

= DHF incidence rate: 10-300/100,000

= DHF usually in children < 15 years, but age range is increasing

y World= Population at risk: 3 billion

= 100million dengue cases annually

= 500 thousand DHF cases annually

Cuba

y Early 1970s- A. aegypti neatly eradicated- Control efforts decreased

y Late 70s A. aegypti reestablishedy Before 1977 Only D-2 & D-3 viruses (+), DHF (-)y 1977 D-1 virus introducedy 1981- D-4 virus introfucedy 1981 Novel D-2 strain introduced

- 116,143 hospitalizations = 10,000DSSy 1997 - ? last outbreak after intense mosquito control programme!

Anecdotes:-

1. Transmission via accidental needlestick: 12. From BM donor: 1

From blood donors: ??

DENGUE


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EPIDEMIOLOGY

y 4 serotypes of dengue virus transmitted in tropics (DEN1, DEN2, DEN3, DEN4)- Area between 35N & 35S (Latitude)- Directly proportional to the distribution of A. aegypti

y Principal vector: A. aegyptiy Others:

- A. albopictus- A. polynesiensi (Tahiti)- A. scutellaris hebrideus (N. Guinea)- A. cooki (Niue)

y Definitive host: Humany Reservoir: Humany So, it is NOT a zoonosisy After feeding on viraemic patient, viral replication in mosquito = 1-2 weeks (extrinsic

incubation period)

y Feed: Several times during 1-4 weeks life spany A.aegypti

- Breed around humans- Oviposits in stagnant water- Adults -> shelter indoor bite during 1-2 hours intervals in mornings and late afternoons- In endemic areas, 1 in 20mosquitoes infected- 0.8 2.0 km flying distance

y Transmission in tropical areas maintained throughout the year and during rainy seasony humidity, lifespany temperature, extrinsic incubation period

Pathogenesis

y Usually Dengue Fever self-limited infectiony Bite -> tissues (2-3 days, hematogenous)y Virus circulate for 4-5 days in:

- Infected monocytes & macrophages- B cells- T cells

y Fever viraemiay Fever , viraemia 1 day later

Typify DF - ? cytokine responsey Myalgia cardinal feature of DF

Histophatological Exmination:

- Perivascular mononuclear infiltrate + lipid accumulation- Some cases mitochondrial changes + muscle necrosis- CPK (creatinine phosphokinase)

y Musculoskeletal pain (breakbone fever)People wonder whether there is viral infection of bone marrow. Because:


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- Peripheral cytopenias- Haemophagocytosis (+)

y Rash lymphatic dermal vasculitisy hepatic transaminases in 80%

Fatal cases

-

Kuppfer cell hypertrophy- Focal ballooning and necrosis of hepatocytes- Mild fatty change- Occasional councilmans body

y Shock in DHF-DSS due t sudden extravasation of plasma into extravascular compartmentincluding pleura and abdominal cavity.

y Usually when fever has - TNF- IL-8- IFN-gamma- Complement activation

y Result: loss of fluid, and hypoproteinaemia/albuminaemiay Reversal usually within 48 hours

Dengue Hemorrhagic Fever (DHF)

y Role of heterologous Abs in secondary infection- Enchancing Abs- i.e uptake of virus and replication in Fc-bearing cells

(Ab-mediated immune enhancement)

TNF-alpha, CD8, IL-2

= Cross reactive CD4+ amd CD8+ cells

= IFN-gamma and IL-2

y DHF -> Propensity after DEN-2 & DEN-3 infections (Pak Nasa: thats for you to remember)VIROLOGY

y Etiology- Family: Arboviridae- Genus: Flaviviridae- Species: Dengue virus- Serotypes: 4 (1,2,3,4)

y Virion- Spheric/cubic- 40-60 nm- Consist of

i. Lipid enveolopeii. Covered densely with surface projections (Membrane glycoproteins and

envelope glycoproteins)

- E gp (envelope glycoproteins) organized as dimmers paired horizontally head to tail onvirion surface


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y Viruses unstable, sensitive to:-- Heat- UV- Disinfectants (alcohol, iodine, etc)- Acid/low pH-

Ether & deoxycholatey (+) ssRNA of11kby E gp exhibits important biological properties

- Viral-cellular attachment- Endosomal membrane fusion- Site for hemagglutination and neutralization

Clinical Features of Dengue Fever

Acute febrile disease with:

y Headachey Musculoskeletal painy Rash (Hess test)

80% asymptomatic in infants/children

If ill:

y Fevery Malaisey Irritabilityy Pharyngeal injection (URTI)y Rash

Adult:

y > Sever & > acutey Chills, severe frontal headachey Retro-orbital painy Severe musculoskeletal painy Severe lumbal back painy Skin flushedy General signs and symptoms

Then fever

Second episode of fever and symptoms recur -> SADDLEBACK PATTERN

Followed by:

y Listlessnessy Fatigability


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y DepressionDHF-DSS

y Hemorrhagic phenomenay Hypovolaemic shock

o (Usually after fever has )y Effusion

i. Pleura (80%)ii. Ascites (>95%)iii. Gallbladder oedema (>95%)iv. Peri/parerenal (77%)v. Heptaic/splenicvi. Pericardial

y -> Myocardial dysfunction, metabolic acidosis, respiratory distress -> deathy Fatality rate

-

Up to50%

- Least reported 1%

y Encephalopathy -> CNS hemorrhagey Liver & Renal failure

Laboratory Diagnosis

y Viral isolation- 1st week after onset- Serotype (Personal health reasons)

y Specimen- Biopsy- Autopsy

y Culture- Suckling mice- Mosquito cell lines (C6/36, AP61- Vero- LLCMK2- PS, etc

y PCRy Serology

- Blood/serum- CSF- Elisa (IgM, IgG)

i. 7-10 days after onset: 95% sensitiveii. IgM & IgG -> 100% (as early as 4-5 days)

y Other tests- IIF- HA


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Treatment

y Symptomaticy Supportive

Prevention

y Mainstay- Public health- Personal (home)

Public Health

y Insecticidal fogging (? Usefulness)y Vaccine under development

11. Arboviruses & Dengue

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