Dengue Fever

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Dengue Fever

• Epidemiology and the Viruses
• Dr Wilson Lam
• Division of Infectious Diseases
• Department of Medicine QEH
• 3 June 2003

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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

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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

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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

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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

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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

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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

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Ae. Albopictus (2)

• Can persist as far north as Beijing or Chicago
  (average isotherm of 0ºC)
• Optimal growth at 25 C to 30C
• 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)

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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

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Transmission of viruses
Extrinsic Incubation Period 1-2 weeks
Vector Humidity Rainfall Temp.
Incubation Period 3-14 days
Susceptible hosts, (population) Source patients
Viraemia Fever 5-7 days
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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)

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Dengue fever endemic regions
At Risk Population 2500 million Dengue cases /
Yr. 50 million (DHF 500 000) Brazil
2001 390,000 cases (670 DHF)
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Dengue in Southeast Asia
WHO 2001
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Stratification of DF/DHF in South-East Asia Region

• Category B (Bangladesh, India, Maldives, Sri
  Lanka)
• DHF is an emergent disease
• Cyclical epidemics are becoming more frequent
• Multiple virus serotypes circulating
• Expanding geographically within countries
• Aedes aegypti is the principal epidemic vector
• Role of Aedes albopictus is uncertain

• Category A (Indonesia, Myanmar, Thailand)
• Major public health problem
• Leading cause of hospitalization and death among
  children
• Cyclical epidemics in urban centres with 3-5 year
  periodicity
• Spreading to rural areas
• Multiple virus serotypes circulating
• Aedes aegypti is the principal epidemic vector
• Role of Aedes albopictus is uncertain

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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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DF Hong Kong 2002
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DF Hong Kong 2002
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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.

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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

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DF epidemiology

• Spread
• Endemic or epidemic
• Travel along transportation routes
• First appears in seaport and airport cities

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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

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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

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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

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DF epidemiology

• Age/sex
• Mostly adults
• Adult women and pre-school children in some
  outbreaks
• Transmission by daytime-biting

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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
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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)

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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

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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

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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

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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

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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

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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

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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

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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

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Thank you!
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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.

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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.

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Serological Profile
Primary Infection IgMgtIgG Secondary Infection
IgGgtIgM
39.5
39.0
38.5
Temperature (degrees Celsius)
Dengue IgM (EIA units)
Percent Virus Positive
38.0
viraemia
37.5
37.0
-4
-3
-2
-1
0
1
2
3
4
5
6
Fever Day
Dengue IgM
Mean Max. Temperature
Virus
Vaughn et al., J Infect Dis, 1997 176322-30.
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Virological Diagnosis

• Dengue-specific tests
• Virus isolation
• Serology
• HAI
• IgM Immunochromatographic
• IgM EIA
• Real Time - PCR

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Rapid Strip Test False Positives
Sequential testing or confirmation is required.
BOOK K M EBV IgM ve
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Rapid Strip Test False Positives

• Fever for 2 weeks
• Live in Sai Kung area
• Cleaning work
• headache, skin rash,

• myalgia, hearing impairment
• Fundi haemorrhage
• ALT 561,
• Chest basal crepitations
• prolonged PT/APTT
• Weil-Felix OX-K 1640

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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 25C
• Index
• the of trap showing Aedes albopictus larva
• reflects the extent (but not the density) of
  infestation.

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Ovitrap in hospital area
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Ovitrap index in Hong Kong
Sing Pao 20 Oct 2002 Press Release FEHD December
21, 2002
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Control of Dengue Fever

• Statutory Notification since 1994
• Laboratory surveillance
• Active case finding
• Self-reporting (DH hotline [phone])
• Global surveillance
• Case investigation
• Information dissemination

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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

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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 12560