Arboviral disease and dengue

Dr. Tarek Mahbub Khan
MBBS, M.Phil
Assistant Professor
Department of Virology
1Dr. Tarek/SSMC/2016

TLO
• Epidemiology
• Types of dengue fever
• Pathogenesis and pathology of dengue
• Clinical features
• Phases of dengue hemorrhagic fever• Phases of dengue hemorrhagic fever
• Treatment and prevention of dengue
• Latest advancement of dengue vaccine development

ARBOVIRUS
• Arbovirus are arthropod-borne viruses
• Human arboviruses all are believed to be zoonotic
• Vectors acquire a lifelong infection
• Natural cycle can be maintained by transovarian
transmission in arthropods
• Humans are the accidental host
2/1/2017 3Dr. Tarek/kuin/2015

CLASSIFICATION OF MAJOR
ARBOVIRUSES
Family Genus Virus of medical importance
Togaviridae Alphavirus Chikungunya, EEE, WEE, VEE, Sinbis
viruses
Flaviviridae Flavivirus Dengue, JEV, YFV, WNV,Flaviviridae Flavivirus Dengue, JEV, YFV, WNV,
St. Louis encephalitis virus
Bunyaviridae Bunyavirus Bunyamwera, La Crosse, California
encephalitis virus
Reoviridae Coltivirus Colorado tick fever virus
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TRANSMISSIONCYCLE
Dr. Tarek/SSMC/2016 5
TRANSMISSIONCYCLE

CHARACTERISTICS OF LIFE CYCLE
• Virus has the ability to replicate in the vertebrate host as well as
blood sucking vector
• EXTRINSIC INCUBATION PERIOD: Time required for the virus to• EXTRINSIC INCUBATION PERIOD: Time required for the virus to
form sufficient progeny in the vector. Usually 7-14 days
• INTRINSIC INCUBATION PERIOD: Time interval between vector
bite and appearance of symptom in human
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• VERTICAL TRANSMISSION(TRANSOVARIAN):
– From infected mother vector to her offspring.
• HORIZONTAL TRANSMISSION:
– From infected vector to human
CHARACTERISTICS OF LIFE CYCLE
– From infected vector to human
• Human is the dead end host
(except: YF and Dengue)
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PATHOGENESIS AND PATHOLOGY
OF ARBOVIRUS INFECTION
Initial viral
replication in
Myeloid cell,
lymphoid cell or
in vascular
Primary
viremia
Reach different tissues and
replicates in monocyte,
macrophage, endothelial
cells, lungs, liver, muscles
and brainin vascular
endothelium
and brain
Virus crosses Blood
brain barrier through
olfactory neurons or
cerebral vascular cells
Neuronal degeneration
(Encephalitis)
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EPIDEMIOLOGY OF ARBOVIRAL
DISEASES
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GENOMIC STRUCTURE OF AN
ARBOVIRUS

DISEASE SYNDROMES PRODUCE
BY ARBOVIRUS
• Three clinical syndromes
1. Undifferentiated fever with or without
maculopapular rash
2. Encephalitis2. Encephalitis
• Incubation period is 4-21 days
• Sudden onset of severe headache, chill and fever,
nausea and vomiting, generalized pain
• Within 24-48 hours drowsiness, confusion, tremors
convulsion and coma develops
3. Haemorrhagic fever
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LABORATORY DIAGNOSIS
A. RECOVERY OF VIRUS AND DIRECT DETECTION
– Preferable samples are blood, CSF and tissue
specimens
– Cell culture
– Detection of viral RNA and proteins by PCR
– Viral antigen detection by immunofluorescence
assay or ELISA
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B. SEROLOGY
– Preferable samples are serum and CSF
– Antibodies appears few days after onset of illness
– Neutralizing antibody and hemagglutination-
– Neutralizing antibody and hemagglutination-
inhibiting antibodies are detected
– Most sensitive method of detection is ELISA
– Either virus specific IgM or four fold rise of specific
antibody titer is diagnostic
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CAUSATIVE AGENT
– Dengue virus
• A single stranded RNA virus of flavivirus family
• Enveloped
• Spherical in shape• Spherical in shape
– Four serotypes-DENV 1 to DENV 4
– Infection with particular serotype is lifelong

EPIDEMIOLOGY
• Dengue is endemic in more than 100 countries
• Widely distributed in the tropical region
• 50 million or more cases annually
• 400,000 cases of DHF annually• 400,000 cases of DHF annually
• Risk of developing DHF is 0.2% during first attack
• Mortality rate among DHF is 4.1%

VECTORS
• Aedes aegypti species mosquito
• Aedes albopitus species mosquito

RESERVOIR
• Human is the urban reservoir
• Monkey is the jungle reservoir

• MOST commonly by bites of mosquitoes
• In rare case: Blood and organ transplantation, mother to
offspring
• Some people never shows symptoms hence acts as source
TRANSMISSION
• Some people never shows symptoms hence acts as source
• Occurs mainly in the climate of optimal rainfall but periodic
epidemic can occur when large number of people are infected
in a short period

FACTORS THAT FAOURS
TRANSMISSION
• Rapid population growth
• Rural-urban migration
• Inadequate basic urban infrastructure
• Increase in volume of solid waste• Increase in volume of solid waste
• Geographical expansion of the mosquito
• Increased air travel
• Breakdown of vector control measures

TYPES OF DENGUE FEVER
• Classical dengue fever
• Dengue hemorrhagic fever/ dengue shock
syndrome

PATHOGENESIS
• UNCOMPLICATED DENGUE FEVER
– Virus multiply in the reticuloendothelial cells and
vascular endothelium
– endothelial cell swelling and perivascular edema– endothelial cell swelling and perivascular edema
with mononuclear cell infiltration.

• DENGUE HAEMORRHAGIC FEVER/SHOCK
SYNDROME
– Formation of virus-antibody complexes by non-
neutralizing antibody from primary infection:
PATHOGENESIS
• Complement activation :
– cell recruitment and cytokine release
• Activation of macrophage and monocytes
– Release of cytokines
• Activation of previously sensitized T cells by viral
antigen presented by macrophages

PATHOGENESIS OF DENGUE HEMORRHAGIC
FEVER/DENGUE SHOCK SYNDROME
• previous
infection with
one serotype
• Passive
transfer from
• previous
infection with
one serotype
• Passive
transfer from
• Virus-antibody• Virus-antibody
Infection with new
serotype
• Complement activation
• Release of cytokines,
vasoactive mediators
and procoagulants
• Increase vascular
• Complement activation
• Release of cytokines,
vasoactive mediators
and procoagulants
transfer from
infected
mother
transfer from
infected
mother
Preexisting
Dengue
antibody
• Virus-antibody
complex
• Viral entry by non-
neutralizing ,
heterologous,
immune enhancing
Ab into monocytes
and macrophages
• Virus-antibody
complex
• Viral entry by non-
neutralizing ,
heterologous,
immune enhancing
Ab into monocytes
and macrophages
permeability
• DIC
permeability
• DIC
Haemorrhage
Shock
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• DENGUE HAEMORRHAGIC FEVER/SHOCK
SYNDROME
– Perivascular edema and widespread effusions into
serous cavities such as the pleura
PATHOLOGICAL CHANGES
serous cavities such as the pleura
– Hemorrhages
– spleen and lymph nodes show hyperplasia
– focal necrosis in the liver
– disseminated intravascular coagulation

CLINICAL MANIFESTATION
• Classical dengue
– Incubation period: 4-7 days
– Fever is sudden or with prodromal symptoms of
malaise, chill, headachemalaise, chill, headache
– Fever is saddle back in nature associated with
severe bone, muscle and retro-orbital pain
– Rash develops on 3rd / 4th day last for 1-5 days
– Classical dengue is self limiting

DENGUE RASH
AND TOURNIQUET TEST
Maculopapular rash Positive: > 10 petechiae in 1 inch2

• Dengue hemorrhagic fever/Dengue shock
syndrome
– Thrombocytopenia
– Haemoconcentration
CLINICAL MANIFESTATION
– Haemoconcentration
– Superficial and deep hemorrhage
– Circulatory failure

PHASES OF DHF
CRITICALFEBRILE CONVALESCENCE
Last: 2-7 days
Fever
Bone pain
Temp. Normal
Plasma leak
Effusions
Shock
Hemorrhage
24-48 hours
Resolution of plasma
leak and recovery
2-4 days

IMMUNE RESPONSE IN DENGUE

• RT-PCR: Detects viral nucleic acid from acute phase serum
roughly during fever (within 5 days)
• Serology:
– MAC ELISA: Virus specific IgM capture ELISA (after 5 days)
– IgG ELISA: Primary and secondary dengue infection
– ICT: Detects both IgM and IgG
• NS1 ELISA: Detects viral antigens after 1 day of onset
• PRNT: Plaque reduction and neutralization test is done to
determine infecting serotype in convalescence period

• CBC: Leucopenia, Thrombocytopenia, HCT(↑)
• USG abdomen: Hepatitis, Ascites

MANAGEMENT
• TREATMENT
– Classical dengue: Symptomatic, Fluid and Nutrition
– Haemorrhagic/DSS:
• Symptomatic
• Adequate IV fluid (Colloidal or Crystalloid)
• Fresh frozen plasma
• Platelet concentrates or whole blood transfusion
• PREVENTION
– Mosquito control
– Epidemic preparedness and response

• Unlike Yellow fever and Japanese encephalitis, there is no
licensed vaccines for Dengue.
• Major hurdles in production of dengue vaccine:
– Lack of animal model reproduce human dengue
– Presence of multiple serotypes
ADVANCES IN DENGUE VACCINE
– Presence of multiple serotypes
– Risk of immune enhancement in new infection when
antibody wanes
• Many of the vaccines are in clinical trials

PROPOSED TYPES OF DENGUE
VACCINES
• Biologically derived live attenuated dengue vaccine:
– Mouse brain-derived dengue virus vaccines
– Tissue culture derived live attenuated dengue vaccine
• Recombinant live virus vaccines attenuated by engineered
mutationsmutations
• Inactivated dengue virus vaccine
• Recombinant subunit protein vaccines
• DNA vaccines
• Virus-vectored DENV vaccines

CHIKUNGUNYA
• Virus belongs to Togaviridae family
• First isolated in 1953 in Tanzania
• Transmitted by mosquito bite• Transmitted by mosquito bite
• Most commonly in Africa and Asia , but recently
cases isolated in Europe
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TRANSMISSION OF
CHIKUNGUNYA
• Mosquito bite:
– Ades aegypti : Bite in day time, breeds in household
containers
– Ades albopictus (Asian tiger mosquito): Human transmission
in Asia, Africa and Europein Asia, Africa and Europe
• Monkeys and other wild animals can be reservoir of
virus
• Pregnant women can transmit the virus during
delivery, no breast milk transmission
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GEOGRAPHIC DISTRIBUTION
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CLINICAL FEATURES OF
CHIKUNGUNYA FEVER
• Incubation periods: 3-7 days
• Fever, headache, muscle pain, headache, joint pain,
rash are common symptoms
• Hemorrhagic manifestation is not common
• Rare incidence of first trimester abortion
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DIAGNOSIS
• Presumptive diagnosis is made on clinical features,
recent travel history, epidemiological trend in the
particular area
• Specimens: Blood, CSFSpecimens: Blood, CSF
• TESTS:
– Screening: IgM or IgG ELISA
– PCR
– Histopathology by Immunohistochemistry
– Virus culture
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MANAGEMENT
• TREATMENT
– Symptomatic
– Acetaminophen, Naproxen (Avoid Aspirin)
• PREVENTION
– No vaccine
– Avoid mosquito bite (use insects repellent, nets)
– Prevent infected person from going outside for first few days
of illness
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GENERAL PROPERTIES
• Single stranded RNA virus
• Genus flavivirus
• Closely related to dengue, yellow fever, Japanese• Closely related to dengue, yellow fever, Japanese
encephalitis

TRANSMISSION
• Primarily through mosquito (Aedes species) bites
• Maternal-fetal:
– Intrauterine
– Perinatal– Perinatal
• Sexual transmission from infected male partner
• Laboratory exposure
• Direct contact (in case of heavy viral load)
• May be possible through:
– Blood transfusion, organ transplant, breast feeding

THE DISEASE
• INCUBATION PERIOD:
• 3-14 days
• Viremia ranges from few days to 1 week
• Virus remains longer in semen than blood• Virus remains longer in semen than blood

• Many infections asymptomatic
• Most common symptoms
– Acute onset of fever
– Maculopapular rash
THE DISEASE
Maculopapular rash
– Joint pain
– Conjunctivitis
• Other symptoms include muscle pain and
headache

COMPARISON BETWEEN ZIKA,
DENGUE AND CHIKUNGUNYA

LABORATORY TESTS
• Real time reverse transcriptase-polymerase chain
reaction (rRT-PCR) for viral RNA in clinical specimens
collected < 7 days (serum) or <14 days (urine) after
illness onsetillness onset
• Serology for IgM and neutralizing antibodies in
serum collected up to 12 weeks after illness onset

• Plaque reduction neutralization test (PRNT) for
presence of virus-specific neutralizing antibodies in
paired serum samples
LABORATORY TESTS
• Immunohistochemical (IHC) staining for viral
antigens or RT-PCR on fixed tissues

SERO-CROSS REACTIVITY
• Zika virus serology (IgM) can be positive due to
antibodies against related flaviviruses (e.g., dengue
and yellow fever viruses)
• Neutralizing antibody testing may discriminateNeutralizing antibody testing may discriminate
between cross-reacting antibodies in primary
flavivirus infections
• Difficult to distinguish infecting virus in people
previously infected with or vaccinated against a
related flavivirus

ZIKA AND THE PREGNANCY
• Zika virus can pass from a pregnant woman to her
fetus during pregnancy or around the time of birth.
• Zika infection in pregnancy is a cause of microcephaly
and other severe brain defects.and other severe brain defects.
• Other problems:
– Eye defects, hearing loss, impaired growth, and fetal loss.

MICROCEPHALY
• Head circumference (HC) at birth is less than the 3rd
percentile for gestational age and sex.
• If HC at birth is not available, HC less than the 3rd• If HC at birth is not available, HC less than the 3rd
percentile for age and sex within the first 6 weeks of
life.

TESTING ALGORITHM FOR ZIKA SUSPECTED
INFECTION IN PREGNANT MOTHER

• There are no vaccine or medicine Zika.
• Treat the symptoms of Zika
• Rest, Drink fluids to prevent dehydration
• Take acetaminophen to reduce fever and pain
MANAGEMENT
• Take acetaminophen to reduce fever and pain
• Do not take aspirin or other non-steroidal anti-
inflammatory drugs (NSAIDS) until dengue can be
ruled out to reduce the risk of bleeding.

REFERENCES
• Jawetz, Melnick, Adelberg. Medical Microbiology. 25th ed.
Lange publication; 2010.
• Kenneth J.R, C. George Ray, editors. Sherris Medical
Microbiology.4th edition. McGraw-Hill, Inc; 2004.
• Alan L. Rothman. Current topics in Microbiology and• Alan L. Rothman. Current topics in Microbiology and
Immunology, vol 336: Springer-Verlag Berlin Heidelberg, 2010.
• http://www.who.int/csr/disease/dengue/impact/en/
• http://www.cdc.gov/Dengue/epidemiology/index.html
• http://kpkesihatan.com/2015/04/

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