Flaviviruses are a family of over 68 viruses that are small, spherical and enveloped, containing single-stranded RNA. Major flaviviruses that cause disease in humans include yellow fever virus, dengue viruses, West Nile virus and Japanese encephalitis virus. Dengue virus has four serotypes and is transmitted by Aedes aegypti mosquitoes. Dengue causes a spectrum of illness from mild fever to severe dengue hemorrhagic fever and dengue shock syndrome. Diagnosis involves virus isolation, serology and PCR. Treatment focuses on fluid replacement and management of bleeding and shock.

1. Flaviviruses
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2. Flaviviridae
• >68 viruses
• small
• spherical
• enveloped
• SS RNA
• cross-related
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3. Flaviviruses
• Yellow Fever virus
• Dengue viruses
• St. Louis encephalitis virus
• Japanese encephalitis virus
• West Nile virus
• Murray Valley encephalitis virus, tick-borne
encephalitis viruses and others
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4. Yellow Fever
• vector: Aedes aegypti
• Latin America, Caribbean, Africa
• inapparent to severe infection (jaundice, hemorrhage,
albuminuria)
• hepatic necrosis, Councilman and Torres bodies
• Dx: cell culture, serology, PCR, immunohistochemistry
• supportive treatment
• live attenuated 17D vaccine
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5. Dengue Fever/Dengue
Hemorrhagic Fever
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6. Dengue Virus
• Causes dengue
and dengue
hemorrhagic fever
• Transmitted by
mosquitoes
• Has 4 serotypes
(DEN-1, 2, 3, 4)
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7. Aedes aegypti
• Dengue transmitted by
infected female
mosquito
• Primarily a daytime
feeder
• Lives around human
habitation
• Lays eggs and produces
larvae preferentially in
artificial containers with
clean stagnant water
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8. Dengue Clinical Presentations
• Undifferentiated fever – may be
the most common presentation*
• Classic dengue fever
• Dengue hemorrhagic fever
• Dengue shock syndrome
*DS Burke, et al. A prospective study of dengue infections
in Bangkok. Am J Trop Med Hyg 1988; 38:172-80.
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9. Spectrum of Dengue
Illness
Undifferentiated Dengue Fever Dengue Hemorrhagic
illness Fever
Classic
Dengue Dengue
Shock
Syndrome
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10. Clinical Characteristics
of Dengue Fever
• Fever
• Headache
• Muscle and joint pain
• Nausea/vomiting
• Rash
• Hemorrhagic manifestations
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11. Hemorrhagic Manifestations
of Dengue
• Skin hemorrhages:
petechiae, purpura,
ecchymoses
• Gum bleeding
• Nose bleeding
• Gastro-intestinal bleeding:
hematemesis, melena,
hematochezia
• Hematuria
• Increased menstrual flow
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12. Tourniquet Test
• Inflate blood pressure
cuff to a point midway
between systolic and
diastolic pressure for 5
minutes
• Positive test: 20 or
more petechiae per 1
inch2 (6.25 cm2)
Pan American Health Organization: Dengue and Dengue
Hemorrhagic Fever: Guidelines for Prevention and
Control. PAHO: Washington, D.C., 1994: 12.
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13. Clinical Case Definition for
Dengue Hemorrhagic Fever
4 Necessary Criteria:
• Fever, or recent history of acute fever
• Hemorrhagic manifestations
• Low platelet count (100,000/mm3 or less)
• Objective evidence of “leaky capillaries:”
– elevated hematocrit (20% or more over baseline)
– low albumin
– pleural or other effusions
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14. Vaughn DW, Green S, Kalayanarooj S, et al. Dengue in the early febrile
CENTERS FOR DISEASE CONTROL
phase: viremia and antibody responses. J Infect Dis 1997; 176:322-30. AND PREVENTION
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15. Dengue Hemorrhagic Fever
T Lack of
appettite
40
C Vomiting
Headache Fall in platelets
39 Abdominal pain Increased
hematocrit
Muscle/joint
pain
38 hemorrhagic
manifestations; Shock
+torniquet test
37
Rash
Flushing
36 rash
Day 1 2 3 4 5 6 7
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16. Friday, June 18, 2010

17. Clinical Case Definition for
Dengue Shock Syndrome
• 4 criteria for DHF
• Evidence of circulatory failure manifested
indirectly by all of the following:
– Rapid and weak pulse
– Narrow pulse pressure (≤ 20 mm Hg) OR
hypotension for age
– Cold, clammy skin and altered mental status
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18. Clinical Evaluation in Dengue
Fever
• Blood pressure
• Evidence of bleeding in skin or other sites
• Hydration status
• Evidence of increased vascular
permeability-- pleural effusions, ascites
• Tourniquet test
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19. Warning Signs for Dengue Shock
Alarm Signals:
• Severe abdominal pain
• Prolonged vomiting
Four Criteria for DHF: • Abrupt change from
• Fever fever to hypothermia
• Hemorrhagic manifestations •Change in level of
• Excessive capillary consciousness
permeability (irritability or somnolence)
• ≤ 100,000/mm3 platelets
Initial Warning Signals:
• Disappearance of fever When Patients Develop
• Drop in platelets DSS:
• Increase in hematocrit • 3 to 6 days after onset of
symptoms
CDC
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20. Differential Diagnosis of
Dengue
• Influenza • Leptospirosis
• Measles • Meningococcemia
• Rubella • Rickettsial infections
• Malaria • Bacterial sepsis
• Other viral
• Typhoid fever
hemorrhagic fevers
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21. Laboratory Tests
in Dengue Fever
• Clinical laboratory tests
– CBC--WBC, platelets, hematocrit
– Albumin
– Liver function tests
– Urine--check for microscopic hematuria
• Dengue-specific tests
– Virus isolation
– Serology
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22. Laboratory Methods for
Dengue Diagnosis
• Virus isolation to determine serotype of
the infecting virus
• IgM ELISA test for serologic diagnosis
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23. Temperature, Virus Positivity
and Anti-Dengue IgM , by
Fever Day
Temperature (degrees Celsius)
100 300
Dengue IgM (EIA units)
39.5
Percent Virus Positive
80
39.0 225
38.5 60
150
38.0 40
37.5 20 75
37.0
0 0
-4 -3 -2 -1 0 1 2 3 4 5 6
Fever Day
Mean Max. Temperature Virus Dengue IgM
Adapted from Figure 1 in Vaughn et al.,
J Infect Dis, 1997; 176:322-30.
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24. Management
• No hemorrhagic manifestations and patient
is well-hydrated: home treatment
• Hemorrhagic manifestations or hydration
borderline: consider hospitalization
• Warning signs (even without profound
shock) or DSS: hospitalize
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25. Management of Dengue Fever
• Fluids
• Antipyretics (avoid
aspirin and non-steroidal
anti-inflammatory drugs)
• Monitor blood pressure,
hematocrit, platelet
count, level of
consciousness, intake &
output
• Blood products only
when needed
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26. Mosquito Barriers
• Only needed until fever subsides, to
prevent Aedes aegypti mosquitoes from
biting patients and acquiring virus
• Keep patient in screened sickroom or
under a mosquito net
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27. Prevention:
• Public education
• Vector control
• vaccine in development
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28. St. Louis encephalitis
Murray Valley encephalitis
West Nile Fever
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29. Japanese encephalitis virus
• single serotype, 5 genotypes based on E
protein
• Asia, including SEA
• cycle: birds - Culex mosquitoes - swine
• humans, horses
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30. Japanese encephalitis
• 99% subclinical
• lethargy, behavioral changes, motor
abnormalities
• Dx: CSF analysis, EEG, IgM ELISA, NT, HI,
CF, PCR
• Rx: supportive
• Prevention: inactivated vaccine (3 yr
protection)
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31. 31
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32. THANK YOU!
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