DENGUE VIRAL

Titiek Djannatun
Department of Microbiology Faculty of Medicine
YARSI University
ARBOVIRUS YANG SEBABKAN PENYAKIT DEMAM DAN HEMORRHAGIC

VIRUS PENYAKIT DISTRIBUSI VEKTOR HEW.

RESERVOAR
YELLOW FEVER (ALPHAVIRUS) FEVER, HEPATITIS AFRIKA, AMERIKA Aedes spp Monyet hutan
TENGAH & SELATAN

DENGUE (4 SEROTIPE) FEVER, RASH (HEM INDIA, ASIA TENGGARA, NYAMUK Monyet hutan
(FLAVIVIRUS) SYOK SYNDROME) PASIFIK, AMERIKA
SELATAN, KARIBIA
KYASANUR FOREST (FLAVIVIRUS) HEMORRHAGIC INDIA TICK MONYET, RODENTS
FEVER

ROSS RIVER (BUNYAVIRUS) FEVER, ARTHRALGIA, AUSTRALIA, KEP NYAMUK UNGGAS

ARTHRITIS PASIFIK

RIFT VALLEY FEVER (BUNYAVIRUS) FEVER, KADANG AFRIKA NYAMUK SAPI, ONTA, DOMBA
HEMORRHAGIC

SANDFLY FEVER (BUNYAVIRUS) FEVER ASIA, AMERIKA TICKSANDFL GERBILS

SELATAN, YS
MEDITERANIAN
CONGO CRIMERIAN FEVER, ASIA, AFRIKA TICK RODENTS
HEMORRHAGIC FEVER HEMORRHAGIC
(BUNYAVIRUS)

COLORADO TICK FEVER FEVER, MYALGIA USA (ROCKY TICK RODENTS

(REOVIRUS) MOUNTAINS)

LA CROSSE (BUNYAVIRUS) FEVER USA NYAMUK RODENTS, DLL

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Dengue Fever
What is it?
Mode of transmission
Symptoms and treatment
Prevention
What is Dengue Fever?
Dengue fever, also know as breakbone fever, is an acute
communicable disease caused by virus.
Caused by Dengue viruses (categorizes into types
1,2,3,4)
Symptoms:
fever, headache, skin rash, muscle and joint pain
Severe form: hemorrhagic fever, fluid leakage, bleeding in the GI
tract (could be fatal)
Prevalent in tropical countries (urban disease)
Spread by mosquito (Aedes aegypti but in Hongkong by
Aedes albopictus) as vector
Aedes albopictus as a potential vector (in lab) this
mosquito lifes outside home
History of Dengue
Earliest record as water poison in Chinese
encyclopedia (265 to 420 A.D.)
17th century reports of disease in Panama, West
Indies and Southeast Asia.
Global pandemic following world war II
In Americas:
1950s to 1970s disease was rare due to
mosquito control
Once mosquito control was stopped the disease
re-emerged
Dengue
Dengue is the biggest arbovirus problem in the world today with
over 2 million cases per year. Dengue is found in SE Asia, Africa
and the Caribbean and S America.
Flavivirus, 4 serotypes, transmitted by Aedes mosquitoes which
reside in water-filled containers.
Human infections arise from a human-mosquitoe-human cycle
Classically, dengue presents with a high fever, lymphadenopathy,
myalgia, bone and joint pains, headache, and a maculopapular rash.
Severe cases may present with haemorrhagic fever and shock with a
mortality of 5-10%. (Dengue haemorrhagic fever or Dengue shock
syndrome.)
Increased incidence of Dengue
Uncontrolled urbanization
Poor water, sewer an waste management
Lack of effective mosquito management
Global travel (for work and vacation)
Lack of public health infrastructure in many
countries

(Demographic and Societal changes)

Distribution of Dengue
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Mode of Transmission
A healthy person gets the disease when he is
bitten by an infected mosquito. The virus enters
his blood from the mosquitos saliva.

An infected person could transmit the virus to

mosquitoes if he is bitten by a mosquito anytime
from the onset to the subsidence of the fever (a
period of about 6 to 7 days). The disease is then
spread by mosquitoes.

Dengue fever is not spread by contact

with infected persons.
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Transmission

Infected
mosquito

Healthy person Infected

Incubation Period: 3 to 14 days
person
Most commonly 4 to 7 days
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Types

Classical Dengue
dengue haemorrhagic
fever
Dengue

Dengue haemorrhagic fever and shock syndrome appear most

often in patients previously infected by a different serotype of
dengue, thus suggesting an immunopathological mechanism.
Diagnosis is made by serology.
No specific antiviral therapy is available.
Prevention of dengue in endemic areas depends on mosquito
eradication. The population should remove all containers from
their premises which may serve as vessels for egg deposition.
A live attenuated vaccine is being tried in Thailand with
encouraging results.
Vectors

Aedes aegyti Aedes albopictus

The life cycle of a vector mosquito is divided

into the 4 stages: egg, larva, pupa and adult
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Symptoms of Classical Dengue (1)

Fever: continuous for 3 to 5 days

Severe headache

Painful limbs, joint pain, muscle

pain, back pain, pain behind
eyeballs
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Symptoms of Classical Dengue

(2)

Rash appears on the 3rd to 4th day after onset.

Nausea, vomiting.
Slight gum bleeding and nasal bleeding.
Extreme fatigue and depression may follow
recovery.
In very rare cases, the condition may worsen

into dengue haemorrhagic fever, leading to

haemorrhage, shock or even death.
Dengue Virus
Member of Flaviviridea
Same family as West Nile virus, Japanese encephalitis virus, tick-borne
encephalitis virus
Uses mosquito (Aedes aegypti) as a vector for infecting humans
Genus Flavivirus
4 strains DENV1, 2, 3, 4
Rod shape, 45-60nm in diameter
Haemagglutinable
Thermolabile
Sensitive to inactivated by diethyl ether-2, Na-dioxicolate, acid
pH, detergent
Stable at 700C
Replication in sitoplasma and passage in RES
Anatomy of the Dengue Virus
Enveloped virus
Has a lipid bilayer coat
Genetic material is
ssRNA virus (+ive
sense)
RNA is covered by
nucleocapsid

Nature Structural Biology 10, 907 - 912 (2003)

Dengue Virus: RNA and Proteins

11kb positive sense RNA

Structural proteins
C
prM
E
Non-structural proteins
NS1
NS2A/B
NS3
NS4A/B
Complete Dengue virus structure (PDB ID 1k4r)
NS5 Kuhn et al., 2002
180 copies of E protein
PATHOGENESIS FLAVIVIRUS
PATHOGENESIS FLAVIVIRUS
MANIFESTASI KLINIS
DEMAM DENGUE
Masa inkubasi 1-2 minggu, menggigil, demam sampai 400C
sakit kepala, sendi dan otot
Demam menurun setelah 7 hari makulapapula exanthema betis

DEMAM BERDARAH DENGUE

Perdarahan pada kulit dan organ
Ptechie, hidung berdarah (juga pada lubang lain), Feses berdarah,
Hematuria

DENGUE SYOK SYNDROME

Perdarahan pada organ
Masa darah pada otak CNS
10-40% MENINGGAL
 Typical infectious cycle

1. Attachment
2. Penetration
3. Uncoating
4. Transcription and/or
translation
5. Replication
6. Assembly
7. Release
RNA virus
replication
Replication Strategy of ss(+)RNA Viruses
Steps in Replication
1. Translation of virion RNA as mRNA (early products = RNA-
Dependent RNA Pol)

2. Synthesis of (-)sense RNA on (+)sense template by RDRP (=

formation of replicative complex, RC)

3. Synthesis of (+)sense RNA, mRNA and (-)sense RNA

4. Translation of (+)sense and mRNA, synthesis of structural

protein

5. Assembly of structural protein and (+)sense RNA and

maturation of virions
MORPHOGENESIS FLAVIVIRUS
Patogenesis Dengue

Virus menginfeksi monosit akibatnya CD4+ dan CD8+

(Limfosit T) Teraktivasi

CD8+ (limfosit T) serang monosit dan berinteraksi

dengan CD4+ Cytokine teraktivasi (IL-1, IL-2, TNF-)
Permeabilitas kapiler meningkat sebabkan
hemorrhagic dan syok syndrome (lebih hebat lagi pada
infeksi yang kedua)
Patogenesis Dengue
Secondary heterologous dengue infection
hypothesis/ The sequential infection hypothesis
Terjadi pada individu yang terinfeksi kedua kali
dengan serotype yang berbeda
Pada anak-anak dapat terjadi karena mendapat
Ab dengue dari ibu secara pasif (Ab maternal)
Kondisi pasien mendadak buruk DSS, Syok,
hemokosentrasi
Patogenesis Dengue
Ab tidak nenetralisasi virus (amnestik Ab) terbentuk Ag-Ab
kompleks yang meningkat:
Mempercepat masuknya virus pada sel monosit membantu
penyebaran virus lebih cepat
Komplemen teraktivasi dilepaskan zat-zat anafilatoksik (C3a, C5a)
permeabilitas dinding kapiler meningkat perembesan plasma
Kompleks Ag-Ab menempel pada trombosit trombosit dimusnahkan
oleh SRE terutama dalam hati dan limpa Penurunan jumlah dan
fungsi trombosit (trombositopenia)
Trombosit melepaskan faktor yang mengaktivasi sistem koagulasi
DIC meluas dan kerusakan hati
Kerusakan endotel pembuluh darah, merangsang aktivasi faktor-faktor
pembekuan renjatan hipovolemik, perdarahan dan asidosis
MANIFESTASI KLINIS
SYOK Hipersensitivitas
Hemokosentrasi

Beberapa hari setelah infeksi kedua dibentuk

kompleks virus dan Ab Ab tidak menambah
netralisasi virus Komplemen teraktivasi
memacu infeksi virus ke sel-sel mononuklear
meningkat + pelepasan sitokin, mediator vasoaktif+
pro koagulan Pembekuan intra vaskuler
Tersebar DIC SYNDROME DEMAM
BERDARAH
Diagnosis

Serology - usually used to make a diagnosis of arbovirus

infections.
Culture - a number of cell lines may be used, including
mosquito cell lines. However, it is rarely carried out since
many of the pathogens are group 3 or 4 pathogens.
Direct detection tests - e.g detection of antigen and nucleic
acids are available but again there are safety issues.
Isolation and Serology
Isolation:
Intra cerebral inoculation at baby mouse
Mammalia cell culture (LLC-MK2)
Intra thoracal inoculation at mosquito
Hemagglutinin inhibition test

Serology
CFT
Netralisasi test
Mc ELISA
IgG ELISA
Dengue rapid test
PCR
Prevention

Surveillance - of disease and vector populations

Control of vector - pesticides, elimination of breeding
grounds
Personal protection - screening of houses, bed nets, insect
repellants
Vaccination - available for a number of arboviral infections
e.g. Yellow fever, Japanese encephalitis, Russian tick-
borne encephalitis
Dengue: Prevention & Treatment
Mosquito control
Community based most effective
Vaccine
Live attenuated virus (currently acts like an antiviral)
Effective vaccine in development
Antivirals
Potential target RNA dependent RNA polymerase
PENCEGAHAN DAN PENGOBATAN DENGUE
Tidak ada obat/vaksin untuk pencegahan dengue
Pencegahan Jangan sampai terinfeksi
Istirahat dan minum banyak
Pada derajat IV Cairan tubuh harus dimonitor
Obat mengatasi gejala (symptomatic)
Fever Acetaminophen
Aspirin dan ibuprofen Hindari ANTIKOAGULAN
Live Attenuated Vaccine CLINICAL TRIAL
Sedang dikembangkan vaksin secara bioteknologi dan genetic
engineering
Pencegahan HINDARI GIGITAN Aedes aegypti (PAGI,
MENJELANG MALAM)
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Protect Yourself against Dengue

Fever

As yet, there is no effective vaccine against

dengue fever. Therefore, the best prevention is
to avoid being bitten by mosquitoes by paying
attention to the following:

Avoid staying in dark, outdoor places such as

brushwood, pavilions or the shade of a tree
during the hours when Aedes albopictus and
Aedes aegypti are active.
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Control the Spread of Dengue

Fever

Prevent the patient from being

bitten by mosquitoes.
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Prevention of
Mosquito Bites
Avoid going out in the hours
when Aedes albopictus feed
or wear light-coloured,
long-sleeved clothing and
trousers.
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Prevention of
Mosquito Bites

Your place of
accommodation should
have air-conditioners or
mosquito nets. Otherwise,
hang mosquito screens
around your bed, use
insecticides or coil
incenses to repel
mosquitoes.
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Elimination of Mosquitoes

Cover water containers

tightly so that
mosquitoes cant get in
to lay eggs.
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Elimination of Mosquitoes
Dispose of domestic
wastes properly to
prevent the
accumulation of
stagnant water.

Dispose of empty bottles,

cans and lunchboxes
properly, such as into a
covered bin.
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Elimination of Mosquitoes
Change water for vases

and aquatic plants at

least once a week,
leaving no water under

the pots or in the

bottom saucers.

Scrub the container

surfaces thoroughly to
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Elimination of Mosquitoes

Remove or puncture any

dumped tyres to prevent
the accumulation of
stagnant water.
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Elimination of Mosquitoes

Ditches should be free from blockage.

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Elimination of Mosquitoes

Fill up uneven ground surfaces to prevent the

accumulation of stagnant water.
 48

If you suspect that you have

dengue fever, the most
important thing to do is to
see a doctor.
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Prevention of Dengue Fever - A Whole School Approach

Lets remove stagnant water

and eliminate mosquitoes