Dengue Fever

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     1  Dengue Fever Epidemiology and the Viruses Dr Wilson Lam Division of Infectious Diseases Department of Medicine QEH 3 June 2003
     2  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
     3  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
     4  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
     5  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
     6  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
     7  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
     8  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%)
     9  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
     10  Transmission of viruses Incubation Period: 3-14 days Viraemia & Fever: 5-7 days Vector Humidity: Rainfall & Temp. Susceptible hosts, (population) Source patients Extrinsic Incubation Period: 1-2 weeks
     12  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)
     13  At Risk Population: 2500 million Dengue cases / Yr.: 50 million (DHF: 500 000) Brazil 2001: 390,000 cases (670 DHF) Dengue fever endemic regions
     14  Dengue in Southeast Asia WHO 2001
     15  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
     16  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)
     17  DF – Hong Kong 2002
     18  DF – Hong Kong 2002
     19  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.
     20  DF – Hong Kong 2003
     21  Epidemiological features Dengue fever (DF) Dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) DHF is not DF with haemorrhagic features
     22  DF – epidemiology Spread Endemic or epidemic Travel along transportation routes First appears in seaport and airport cities
     23  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
     24  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
     25  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
     26  DF – epidemiology Age/sex Mostly adults Adult women and pre-school children in some outbreaks Transmission by daytime-biting
     27  Dengue Hemorrhagic Fever (DHF) 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 4 Necessary Criteria (WHO): First recognized in the Philippines in 1953
     28  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)
     29  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
     30  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
     31  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
     35  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
     36  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
     37  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
     38  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
     39  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
     40  Thank you!
     41  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.
     42  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. Laboratory support for case definition
     44  Virological Diagnosis Dengue-specific tests Virus isolation Serology HAI IgM Immunochromatographic IgM EIA Real Time - PCR
     45  Rapid Strip Test: False Positives BOOK K M EBV IgM +ve Sequential testing or confirmation is required.
     46  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 1:640
     47  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.
     48  Ovitrap in hospital area
     49  Sing Pao 20 Oct 2002 Press Release FEHD December 21, 2002 Ovitrap index in Hong Kong
     50  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
     51  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
     52  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