Dengue Fever

Epidemiology and the Viruses

Dr Wilson Lam
Division of Infectious Diseases
Department of Medicine QEH
3 June 2003
 Dengue fever
Dengue history
The viruses and the vector
Transmission of viruses
Epidemiology
 Global
 Southeast Asia
 Hong Kong

Epidemiological features
 DF
 DHF/DSS

Reimmergence of dengue fever

 Historical background
Dengue like illness date back to more
than 200 years ago
1779-1780 in Asia, Africa and North
America
Viral etiology established by the 1940s
Global pandemic in Southeast Asia
after World War II
 Dengue viruses
SS-RNA arbovirus (Flavivirus)
4 serotypes (DEN-1, 2, 3, 4)
 Based on envelop glycoprotein
 DEN-1 and 3 are more closely related
 DEN-4 less closely related to others
 Virulent variants (genotypes) within serotype

Infection with any serotype confers specific

lifelong immunity
Transient cross-protection to other serotypes
Any serotype can cause severe / fatal disease
 Mosquito vectors
All known vectors belong to genus Aedes
Vector competence and vectorial capacity of
different species vary
 Different species
 Different geographic populations of the same
species
No correlation between clinical features of
subsequent disease
 Mosquito vectors
Subgenus Stegomyia contains the most
important vectors of dengue viruses
 Ae. aegypti, Ae. albopictus and Ae. polynesiensis
Ae. aegypti
 African origin
 Not found in Hong Kong

 Most important vectors worldwide

 Linked with human activities such as uncontrolled

urbanization, deterioration of urban environment
and decreasing standard of sanitation
 Ae. Albopictus (1)
Asian species
 South-East Asia, China, Japan, Indonesia, islands in the
Indian Ocean, Hawaii
 Spreading to the United States, South America, Africa, the
Pacific and south of europe
Originally a forest mosquito feeding on a variety of
animals and breeding in tree holes
Become adapted to human environment
Natural containers such as tree holes, plant axils, cut
bamboo stumps and opened coconuts
Outdoor artificial containers such as water storage
barrels and trash receptacles
 Ae. Albopictus (2)

Can persist as far north as Beijing or

Chicago (average isotherm of 0ºC)
Optimal growth at 25 °C to 30°C
Eggs can resist desiccation for several
months
10 days for egg-larva-purpa-adult cycle
Ae. albopictus females known to
survive for up to 122 days (daily
mortalities 8-15%)
Ae. Albopictus (3)

Density much influenced by rainfall

Feed outdoors during daytime
Peak at 8-9 a.m. & 5-6 p.m.
Multiple bites per feed
Active maximum dispersal range of
females about 400 to 600m
Passive dispersal less important
 Transmission of viruses
Extrinsic
Vector Incubation Period:
Humidity: 1-2 weeks
Rainfall & Temp.

Incubation
Period:
3-14 days

Susceptible hosts,
(population)
Viraemia & Fever: 5-7 days
Source patients
 Transmission of viruses
Extrinsic incubation period
 10 to 14 days
 Depends on
 Ambient temperature
 Humidity

 Viraemic level in the human host

 Virus strains

Intrinsic incubation period

 4 to 7 days (Range 3-14 days)
 Viraemia may exist for 6 to 18 hours before onset
of symptoms
 Symptomatic viraemic period is 4 to 5 days (up to
12 days)
Dengue fever endemic regions

At Risk Population: 2500 million

Dengue cases / Yr.: 50 million (DHF: 500 000)
Brazil 2001: 390,000 cases (670 DHF)
 Dengue in Southeast Asia

WHO 2001
 Stratification of DF/DHF in
South-East Asia Region
Category A (Indonesia,  Category B (Bangladesh,
Myanmar, Thailand) India, Maldives, Sri Lanka)
Major public health problem  DHF is an emergent disease
Leading cause of hospitalization  Cyclical epidemics are
and death among children becoming more frequent
Cyclical epidemics in urban
 Multiple virus serotypes
centres with 3-5 year periodicity
circulating
Spreading to rural areas

Multiple virus serotypes circulating

 Expanding geographically
within countries
Aedes aegypti is the principal

epidemic vector
 Aedes aegypti is the
Role of Aedes albopictus is
principal epidemic vector
uncertain  Role of Aedes albopictus is
uncertain
 DF – Macau
1,502 cases in 2001 mostly indigenous
 First 14 cases reported in late August 2001
 Last case in December

 All were minor cases without complications

 Origin and cause unknown

 Mostly serotype DEN-2 (2 cases of DEN-1)

Up to end September 2002

 Only 1 imported case (Thailand)
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 Dengue in Hong Kong
From 1994 to 2001, inclusive
 Cases: DF (68), DHF (4)
 All were imported cases
 Peak incidence at September (?return from travel)
2002 (up to 19 October)
 20 indigenous cases
 all DF, aged 20 to 72 yrs., Male: 13

 16 cases related to Ma Wan (6 residents, 10 CSW)

 onset: early July to 25 September

 All except one, were DEN-1

 index case was suspected on 19 Sep. 2002

 HK strains were different phylogenetically from Macau

strains.
 DF – Hong Kong 2003
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 Epidemiological features
Dengue fever (DF)
Dengue haemorrhagic fever (DHF) and
dengue shock syndrome (DSS)
DHF is not DF with haemorrhagic features
 DF – epidemiology
Spread
 Endemic or epidemic
 Travel along transportation routes

 First appears in seaport and airport cities

 DF – epidemiology
Seasonality
 Usually rainy seasons
 Vectors, such as Ae. albopictus, that have outdoor larval
habitats more affected by rainfall
 High humidity
 Longer mosquito survival
 High temperature
 Vector distribution
 Adult longevity

 Shorter extrinsic incubation period

 Smaller females – more blood meals

 Water cooler recirculation troughs during dry

seasons
 DF – epidemiology
Severity
 Vary in rate of transmission, percentage of
population involved and clinical severity
 Age
 Pre-adolescent children less severe
 Nearly all adults overt illness

 Immune status
 Highly immune population less reported disease
 DF – epidemiology
Severity
 Ethnicity
 Strain variation
 Disease severity and haemorrhagic phenomenon vary
from outbreak to outbreak
 Unique serotype or viral strain-specific factors

 Level of circulating viruses

 DF – epidemiology
Age/sex
 Mostly adults
 Adult women and pre-school children in some
outbreaks
 Transmission by daytime-biting
 Dengue Hemorrhagic Fever
(DHF)

4 Necessary Criteria (WHO):

Fever, or recent history of acute fever
Hemorrhagic manifestations (grade I & II)
Low platelet count (≤ 100,000/mm3)
Objective evidence of “leaky capillaries:”
 elevated hematocrit (≥ 20% over baseline)
 low albumin / hypoproteinaemia

 pleural or other effusions

First recognized in the Philippines in 1953

Dengue Shock Syndrome (DSS)

4 criteria for DHF

Evidence of circulatory failure:
 Rapid and weak pulse
 Narrow pulse pressure ( 20 mm Hg) OR
hypotension for age
 Cold, clammy skin/altered mental status
(grade III)
 or profound Shock (grade IV)
 DHF/DSS – epidemiology
Early reports
 1897 Northern Australia
 1928 Greece
 1935 Taiwan
 1950 Thailand
 mid-1980s Southern China and Hainan Island

Asian DHF/DSS epidemics

 Multiple types of dengue viruses simultaneously or
sequentially endemic
 Secondary-type antibody responses observed
 Only during secondary dengue infections
 DHF/DSS epidemiology
Infection parity and enhancing
antibodies
 Secondary-type dengue infections
 Primary in infants born to dengue-immune
mothers
 Antigens shared between first and second
infecting serotypes
 Shift the spectrum towards more severe
disease
 DHF/DSS epidemiology
Pathogenesis of antibody dependent
enhancement
 Serum antibodies developed can neutralize
dengue virus of that same serotype (homologous)
 Pre-existing heterologous antibodies form
complexes but no neutralization
 Infected monocytes release vasoactive mediators
 Increased vascular permeability
 Haemorrhagic manifestations
 DHF/DSS epidemiology
Protective antibodies
 Low levels of cross-reactvie neutralizing
antibody protect against DHF/DSS
 Different viral antigens?
 Epitopes closely similar to serotype-specific
neutralizing epitopes of another virus
 Different host response?
 Human immune system responds differently to
a single specific repertoire
 DHF/DSS epidemiology
Viral strain
 Severity
 Viruses
which causes mild and severe disease
appear genetically identical
 Occurrence or non-occurrence
 Only dengue viruses of Asian origins at
epidemic proportion
 Distribution of heterotypic and non-heterotypic

antigens
 DHF/DSS epidemiology
Age
 Greatest susceptibility to shock is 8 to 10 years
 ? Capillaries of of children more prone to cytokine-
mediated increased permeability
Sex
 Shock cases and deaths more frequently in female
than in male children
 ? Immune responses of females more competent

 ? Capillary bed of females more prone to

increased capillary permeability
 DHF/DSS epidemiology
Nutritional status
 Moderate to severe protein-calorie
malnutrition reduces risk to DHF/DSS in
dengue infected children
 Malnutrition suppresses cellular immune
responses
Preceding host conditions
 Peptic ulcer and menstrual periods risk
factors for severe bleeding
 Reemergence of DF/DHF
Unprecedented human population growth
Unplanned and uncontrolled urbanization
Inadequate waste management and water
supply
Increased distribution and densities of vector
mosquitoes
Lack of effective mosquito control
Increased movement and spread of dengue
viruses
Thank you!
 Dengue Fever: Case Definition

For Epidemiological Purposes:

Suspected case:
 An acute febrile illness characterized by intense
headache, retro-orbital pain, myalgia, arthralgia,
rash, leucopenia or haemorrhagic manifestations.
Probable case: A clinically compatible case with
supportive serology.
Confirmed case: A clinically compatible case with
laboratory confirmation.
Laboratory support for case
definition
Supportive serologic findings:
• An antibody titer of ≥ 1280 or
• a positive IgM antibody test
on a single serum sample to Dengue
antigen.

Criteria for laboratory confirmation: (≥ one)

• Isolation of Dengue virus from patient samples;
• A ≥ 4x change in antibody titers to Dengue
antigens in paired serum samples;
• Detection of Dengue virus genomic sequences
patient samples by PCR.
 Serological Profile
Primary Infection: IgM>IgG
Temperature (degrees Celsius)

100 Secondary Infection: IgG>IgM 300

Dengue IgM (EIA units)

39.5
Percent Virus Positive

80
39.0 225
60
38.5
150
38.0 40 viraemia
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
Vaughn et al., J Infect Dis, 1997; 176:322-30.
 Virological Diagnosis
Dengue-specific tests
 Virusisolation
 Serology
 HAI

 IgM
Immunochromatographic
 IgM EIA

 Real Time - PCR

 Rapid Strip Test: False
Positives
Samples tested 744
False +ve 26
Specificity 96.5%

* information from GVU, DH on 19 October 2002

Sequential testing or confirmation is

required.
BOOK K M
EBV IgM +ve
 Rapid Strip Test: False
Positives
• Fever for 2 weeks • myalgia, hearing
• Live in Sai Kung
impairment
area • Fundi: haemorrhage
• Cleaning work • ALT: 561,
• headache, skin rash, • Chest: basal crepitations
• prolonged PT/APTT
• Weil-Felix: OX-K 1:640
 Ovitrap index

Ovitrap
 black container, with rough surface, water
 placed 1m above the ground, 100m apart
 50 traps in an area of 0.5 km2
 incubate for 1 week at 25°C

Index
 the % of trap showing Aedes albopictus
larva
 reflects the extent (but not the density) of
infestation.
Ovitrap in hospital area
Ovitrap index in %
Ovitrap index in Hong Kong
35
30 2
001
25 2
002
20
15
10
5

September

November

December
October
August
0
J uly

Sing Pao 20 Oct 2002

Press Release FEHD December 21, 2002
Control of Dengue Fever

 Statutory Notification since 1994

 Laboratory surveillance
 Active case finding
 Self-reporting (DH hotline: 2961 8966)
 Global surveillance
 Case investigation
 Information dissemination
Control of Dengue Fever

Case investigation
 confirm diagnosis
 travel history
 local movement
 potential mosquito breeding sites
 S/S among travel & local collaterals
 medical surveillance of collaterals
Blood Transfusion transmitted DF
Donor: M/17 lives in Ma Wan.
• Date of donation: 17/07/2002 well and
asymptomatic
• attended YCH AED on 24 July, DX: Viral rash
• ? DF during case finding exercise in Ma Wan in
October
• blood tested positive for Dengue
• his serum sample in BTS archive was PCR +ve

Recipient: F/72, QMH anaemia

• received RBC on 24/8/2002 (D7 post-donation)
• fever on 27/8/2002 (D3 post-transfusion)
• No travel history
• fever resolved after 4 days
• blood taken on 7/10/2002 was IgM +ve and IgG HAI
titre of 1:2560