Dengue and Dengue

Hemorrhagic Fever
Virus, Vector and
Transmission
 Dengue Virus
Causes dengue fever and dengue
hemorrhagic fever
20 million cases of dengue infection
result in an estimated 24000 deaths
annually
Flavivirus group

Transmitted by mosquitoes

Single-stranded RNA

4 serotypes (DEN-1, 2, 3, 4)
 Dengue Viruses
Each serotype provides specific lifetime
immunity, and short-term cross-
immunity
All serotypes can cause severe and
fatal disease
Genetic variation within serotypes

Some genetic variants within each

serotype appear to be more virulent or
have greater epidemic potential
Transmission of Dengue Virus
by Aedes aegypti

Mosquito feeds / Mosquito refeeds /

acquires virus transmits virus

Extrinsic Intrinsic
incubation incubation
period period
Viremia Viremia
0 5 8 12 16 20 24 28
DAYS
Illness Illness
Human #1 Human #2
Aedes aegypti Mosquito
 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
Epidemiology
 World Distribution of Dengue
1999

Areas infested with Aedes aegypti

Areas with Aedes aegypti and recent epidemic dengue
Cases of DHF in Asia, 19551998
700,000
600,000
500,000
400,000
300,000
200,000
100,000
Cases

0
 Mean Annual Number of DHF Cases
Thailand, Indonesia and Vietnam, by Decade

* Provisional data through 1998

 Factors favoring spread of
Dengue
Extensive vector infestation, with
declining vector control
Unreliable water supply systems

Increasing non-biodegradable
containers and poor solid waste disposal
Increased air travel

Increasing population density in urban

areas
 Trouble Ahead
2.5 billion people at risk world-wide
In the Americas, 50-fold increase in
reported cases of DHF (1989-1993
compared to 1984-1988)*
Widespread abundance of Aedes aegypti in
at-risk areas
DHF accounts for 99% of reported
episodes of viral hemorrhagic fever
worldwide
* Organization of American States,
Human Health in the Americas, 1996
Disease Pathogenesis
Risk Factors Reported for DHF
Virusstrain
Pre-existing anti-dengue antibody

previous infection
maternal antibodies in infants
Host genetics
Age
 Risk Factors for DHF
(continued)
Higher risk in secondary infections
Higher risk in locations with two or
more serotypes circulating
simultaneously at high levels
(hyperendemic transmission)
 Increased Probability of
DHF
Hyperendemicity

Increased circulation Increased probability

of viruses of secondary infection

Increased probability of Increased probability of

occurrence of virulent strains immune enhancement

Increased probability of DHF

Gubler & Trent, 1994
Hypothesis on Pathogenesis
of DHF (Part 1)
Persons who have
experienced a dengue
infection develop serum
antibodies that can
neutralize the dengue virus
of that same (homologous)
serotype
Homologous Antibodies
Form Non-infectious
Complexes
1
1

1
1
Dengue 1 virus
Neutralizing antibody to Dengue 1 virus
Non-neutralizing
1 antibody
Complex formed by neutralizing antibody
and virus
Hypothesis on Pathogenesis
of DHF (Part 2)
Ina subsequent infection,
the pre-existing
heterologous antibodies
form complexes with the
new infecting virus
serotype, but do not
neutralize the new virus
Heterologous Antibodies
Form Infectious
Complexes
2

2 2
2

2
Dengue 2 virus
Non-neutralizing antibody to Dengue 1
2 virus
Complex formed by non-neutralizing
antibody and virus
 Clinical
Manifestations of
Dengue and Dengue
Hemorrhagic Fever
Dengue Clinical Syndromes

Undifferentiatedfever
Classic dengue fever

Dengue hemorrhagic fever

Dengue shock syndrome

 Undifferentiated Fever
May be the most common
manifestation of dengue
Prospective study found that 87% of
students infected were either
asymptomatic or only mildly
symptomatic
Other prospective studies including all
age- groups also demonstrate silent
transmission
DS Burke, et al. A prospective study of dengue infections
in Bangkok. Am J Trop Med Hyg 1988; 38:172-80.
 Clinical Characteristics
of Dengue Fever
Fever

Headache

Muscleand joint pain, often severe

Nausea/vomiting

Rash

Hemorrhagic manifestations
 Hemorrhagic Manifestations
of Dengue
Skin hemorrhages:
petechiae, purpura, ecchymoses
Gingival bleeding

Nasal bleeding

Gastro-intestinal bleeding:
hematemesis, melena,
hematochezia
Hematuria

Increased menstrual flow

Differential Diagnosis of Dengue
Influenza
Measles

Rubella

Malaria

Typhoid fever

Leptospirosis

Meningococcemia

Rickettsial infections

Bacterial sepsis

Other viral hemorrhagic fevers

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
Tourniquet Test
Positive Tourniquet Test
 Dengue vs DHF
Allpreviously uninfected persons are at
risk of Dengue infection
First infection is Dengue Fever, not DHF
DHF occurs only in individuals who have a
prior history of dengue
Infants 3-12 months due to maternal
antibody
Children 2-12 years due to prior infection
Adults in endemic areas (Indonesia) are
generally not at risk
 Dengue hemorrhagic
fever (DHF)
DHF is characterized by four major clinical
manifestations:
high fever
hemorrhagic phenomena
often with hepatomegaly
in severe cases, signs of circulatory failure.
Severe patients may develop hypovolemic
shock resulting from plasma leakage.
Severe DHF is called dengue shock
syndrome (DSS) and can be fatal.
 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
 Clinical Case Definition for
Dengue Shock Syndrome
4 criteria for DHF plus
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
Frank shock is direct evidence of
circulatory failure
 Four Grades of DHF
Grade 1
Fever and nonspecific constitutional symptoms
Positive tourniquet test is only hemorrhagic
manifestation
Grade 2
Grade 1 manifestations + spontaneous bleeding
Grade 3
Signs of circulatory failure (rapid/weak pulse, narrow
pulse pressure, hypotension, cold/clammy skin)
Grade 4
Profound shock (undetectable pulse and BP)
Dengue Hemorrhagic Fever
DHF
Petechiae
 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
 Dengue
Treatment
Treatment of Dengue Fever
(Part 1)
Fluids

Rest

Antipyretics(avoid aspirin and

non-steroidal anti-inflammatory
drugs)
Monitor blood pressure,
hematocrit, platelet count, level
of consciousness
Treatment of Dengue Fever
(Part 2)
Continue monitoring after
defervescence, particularly for children
If any doubt, provide intravenous fluids,
guided by serial hematocrits, blood
pressure, and urine output
In mild DHF the volume of fluid needed
is similar to the treatment of diarrhea
with mild to moderate isotonic
dehydration (5%-8% deficit)
Note: In DHF the deficit is created by
plasma leakage from intravascular
space. Body weight cannot be used to
estimate deficit
Treatment of Dengue Hemorrhagic
Fever/Dengue Shock Syndrome
(Part 3a)
Close clinical monitoring.
BP q30-60 min
Serial hematocrit q4h
Chart and graph findings
Maintain secure IV access
Oxygen
Treatment of Dengue Hemorrhagic
Fever/Dengue Shock Syndrome
(Part 3b)
Major focus of therapy:
Monitor and Maintain Intravascular Fluid
Volume

IV crystalloid (Normal Saline, Lactated Ringers)

Titrate fluids to maintain blood pressure
Monitor hematocrit to detect hemoconcentration
Pressors not generally useful. Cardiac function is
good; intravascular volume deficit that must be
corrected.
Shock stage generally lasts less than 48 hours and
is followed by diuresis.
Treatment of Dengue Hemorrhagic
Fever/Dengue Shock Syndrome
(Part 3c)
Avoid invasive procedures when
possible
Pleural tap/drainage not indicated unless
respiratory distress necessitates
drainage
No evidence that the use of steroids,
intravenous immune globulin, or
platelet transfusions to shorten the
duration or decrease the severity of
thrombocytopenia is effective
Case Fatality Rate (CFR) of DHF
vs. Case Frequency
80
60
40
CFR

20
1 0
%
1 10 100 1000 10000
Cases
DHF: Clinical care
Clinical care: charting
and hematocrit checks
DHF: Principles of Therapy
Prevention
 Vector Control Methods:
Chemical Control
Larvicides may be used to kill
immature aquatic stages
Ultra-low volume fumigation
ineffective against adult mosquitoes
Mosquitoes may have resistance to
commercial aerosol sprays
 Vector Control Methods:
Biological and Environmental
Control
Biological control
Largely experimental
Option: place fish in containers
to eat larvae
Environmental control
Elimination of larval habitats
Most likely method to be
effective in the long term
 Purpose of Control
Reduce female vector density to a
level below which epidemic vector
transmission will not occur
Based on the assumption that
eliminating or reducing the number of
larval habitats in the domestic
environment will control the vector
The minimum vector density to
prevent epidemic transmission is
unknown
Reasons Why the Eradication Failed
Not all countries were willing to eradicate
Aedes aegypti.
The program lost political importance in the
majority of the countries that achieved
eradication.
Once re-infestation was observed reaction
was too late.
High cost of materials, equipment, salaries
and social benefits.
Aedes aegypti Resistance to organochloride
insecticides.
Rapid and uncontrolled growth of urban
centers.
 Hemispheric Eradication of
Aedes aegypti :
No Longer Realistic
Problem greater than during
previous campaign
Insufficient resources

Resistance to vertical disease

control programs and use of
insecticides
Lack of effective insecticides

Low priority, lack of sustainability

The majority of the obstacles for
dengue control continue to be the
same as they were in the past.
 Tidak berhasilnya program pengkontrolan
terhadap dengue diseb
Kurangya partisipasi masyarakat dalam usaha pencegahan
Terbatasnya sarana air bersih dan sanitasi yang buruk di
daerah yang beresiko
Pemerintah kurang cepat dalam menjalankan program
pencegahan dan kontrol terhadap dengue
Tidak seragamnya kebijaksanaan kesehatan untuk
kelangsungan program
Pola hidup masyarakat yang tidak mendukung pelaksanaan
program
Buruknya koordinasi diantara kalangan pemerintah

After Arias, PAHO