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DENGUE & DENGUE

HEMORRHAGIC FEVER
Kuliah Blok Kedokteran Tropis

INTRODUCTION
Dengue is a viral infection transmitted by mosquitoes, mainly
the Aedes aegypti species.
The virus is contracted from the bite of a striped Aedes
aegypti mosquito that has previously bitten an infected
person. One mosquito bite can inflict the disease.
There are four strains or serotypes of dengue virus namely
DEN-1, DEN-2, DEN-3 and DEN-4.
The mosquito flourishes during rainy seasons but can breed in
water-filled containers, year-round.
The virus is not contagious and cannot be spread directly from
person to person. There must be a person-to-mosquito-toanother-person pathway.
Dengue haemorrhagic fever severe form of dengue. A
second attack by dengue virus of a different serotype from the
first infection.

Approximately 1% of patients with dengue


infection progress to dengue haemorrhagic
fever.

Dengue fever
Main hosts- non human
primates
Human-to-human
transmission through
Aedes spp.
2.5 billion individuals at
risk
40-80 million infected
each year with thousands
of deaths

Causative agent of Dengue


Dengue is cause by a RNA virus
This virus is a member of the viral family
Flaviviridae.
Dengue virus

Bauman, R., (2006). Microbiology disease by systems. San Francisco , CA: Pearson
Benjamin Cumming Publishers

Dengue Virus
1. Causes dengue and dengue hemorrhagic fever
2. It is an arbovirus
3. Transmitted by mosquitoes
4. Composed of single-stranded RNA
5. Has 4 serotypes (DEN-1, 2, 3, 4)

Dengue Virus
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

WHY IS DENGUE SUCH A BIG


PROBLEM TODAY?
Global population Jet travel
growth
Health services
Rural to urban
poorly organized/
migration
underfunded
Growth of cities
Lack of vector
control
Deterioration of
professionals
cities

Global Spread of Dengue

50-100 million infections/year

Countries with active dengue + Aedes aegypti

WORLD-WIDE DENGUE
DISTRIBUTION

Geography distribution of
Dengue

BBB

Blue dot: Geographic extension of dengue 2000-2007


Blue shaded areas: Risk of dengue transmission
Lines: Lines demarcate the area where the vector for dengue exists

VHF and other


infectious diseases
travel quickly
nowadays

IR per 100,000

No of City/Districts Infected

Number of DHF Cases and Infected Areas


in Indonesia (1968 2003)

Incidence Rate (IR)


No of Infected Areas

Dengue (DHF)
Outbreak in
Indonesia (2004)

Outbreak areas
Potential Outbreak areas

The most common epidemic vector of dengue in the world is


the Aedes aegypti mosquito. It can be identified by the white
bands or scale patterns on its legs and thorax.

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

Aedes aegypti life cycle

2-7 days

>4 days

2 days

1.The virus is inoculated into


humans with the mosquito
saliva.
2.The virus localizes and
replicates in various target
organs, for example, local
lymph nodes and the liver.
3.The virus is then released
from these tissues and
spreads through the blood to
infect white blood cells and
other lymphatic tissues.
4.The virus is then released
from these tissues and
circulates in the blood.

5.The mosquito ingests blood containing the virus.


6.The virus replicates in the mosquito midgut, the ovaries,
nerve tissue and fat body. It then escapes into the body
cavity, and later infects the salivary glands.
7.The virus replicates in the salivary glands and when the
mosquito bites another human, the cycle continues.

The transmission cycle of dengue virus by the mosquito Aedes aegypti begins
with a dengue-infected person. This person will have virus circulating in the blood
a viremia that lasts for about five days. During the viremic period, an uninfected
female Aedes aegypti mosquito bites the person and ingests blood that contains
dengue virus. Although there is some evidence of transovarial transmission of
dengue virus in Aedes aegypti, usually mosquitoes are only infected by biting a
viremic person.
Then, within the mosquito, the virus replicates during an extrinsic incubation
period of eight to twelve days.
The mosquito then bites a susceptible person and transmits the virus to him or
her, as well as to every other susceptible person the mosquito bites for the rest of
its lifetime.
The virus then replicates in the second person and produces symptoms. The
symptoms begin to appear an average of four to seven days after the mosquito
bitethis is the intrinsic incubation period, within humans. While the intrinsic
incubation period averages from four to seven days, it can range from three to 14
days.
The viremia begins slightly before the onset of symptoms. Symptoms caused by
dengue infection may last three to 10 days, with an average of five days, after the
onset of symptomsso the illness persists several days after the viremia has
ended.

Population

5%
Infection

76%
Asymptomatic
Infection

24%

Clinical Cases 6%
94%
DF
(non-DHF)

Fig. 1 Rates in dengue model


by Shepard et al. Vaccine. 2004, 22:1275-1280.

99.2%
survive

DHF/DSS

0.8%
Death

Age-specific DHF/DSS hospitalization in children and infant.

Halstead SB et al. Am J Trop Med Hyg 1969, 18:997-1021.

There are actually four dengue clinical


syndromes:
1. Undifferentiated fever;
2. Classic dengue fever;
3. Dengue hemorrhagic fever, or DHF; and
4. Dengue shock syndrome, or DSS.
Dengue shock syndrome is actually a severe
form of DHF.

Clinical Case Definition for Dengue Fever


Classical Dengue fever or Break bone fever is an acute febrile
viral disease frequently presenting with headaches, bone or joint
pain, muscular pains,rash,and leucopenia

Clinical Case Definition for Dengue Hemorrhagic Fever


4 Necessary Criteria:
1. Fever, or recent history of acute fever
2. Hemorrhagic manifestations
3. Low platelet count (100,000/mm3 or less)
4. Objective evidence of leaky capillaries:
elevated hematocrit (20% or more over baseline)
low albumin
pleural or other effusions

DENGUE
FEVER
Incubation period = 5 days
Fever = 5 days
Leukopenia
Moderate thrombocytopenia

Simmons et al
Phil J Sci 44:1-252, 1931

Clinical Manifestations- DF

IP of 2 7 days - typical patient develops


Sudden onset of fever, chills, headache
Back pain with severe myalgia, arthralgia
Retro-orbital pain break bone fever
Macular rash in axillary area
Adenopathy, palatal vesicles, scleral inj.
Maculo-papular rash on trunk
extremities
Epistaxis and scattered petechiae

Other manifestations- DF

Anorexia. Nausea, vomiting


In apparent illness-to acute incapacitation
Illness is about 25 days, biphasic course
Pain on eye movements
Pain on palpating abdominal muscles
Primarily not a respiratory illness
Rare - aseptic meningitis
Complete recovery is the rule - asthenia

Treatment of DF

Supportive measures - Vector barrier


Avoid Aspirin and if possible NSAIDs
Steroids should not be used
Fluid replacement to avoid hemoconc.
Children below 12 require careful watch
for DHF / DSS
No antiviral agents are of proven value

DISEASE SPECTRUM
MILD
DF

SEVERE
DHF

+ Thrombocytopenia +++ Thrombocytopenia


Hidden Vasc. Perm1?
Overt Vasc. Perm.
1. Wills BA et al J Infect Dis 190:810-818, 2004

DENGUE HEMORRHAGIC
FEVER/DENGUE SHOCK
SYNDROME (DHF/DSS)
Dengue vasculopathy

Dengue Haemorrhagic Fever


(DHF)

Vascular instability
Decreased vascular integrity
Assault on macro vasculature
Decreased platelet function
Increased vascular permeability
Vascular disruption and local bleeds
Hypotension, hemoconcentration- shock

Criteria for DHF


Fever, or recent history of acute fever
Hemorrhagic manifestations
Low platelet count (100,000/mm 3 or
less)
Objective evidence of leaky capillaries:
Elevated hematocrit -20% or more
more over baseline or
Low albumin, pleural effusion

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)

DHF Clinical Criteria

This thermometer illustrates the developments in the illness that are


progressive warning signs that DSS may occur.
The initial evaluation is made by determining how many days have passed
since the onset of symptoms.
Most patients who develop DSS do so 3-6 days after onset of symptoms.
Therefore, if a patient is seven days into the illness, it is likely that the worst
is over.
If the fever goes between three and six days after the symptoms began, this is
a warning signal that the patient must be closely observed, as shock often
occurs at or around the disappearance of fever.
Other early warning signs to be alert for include a drop in platelets, an
increase in hematocrit, or other signs of plasma leakage.
If you document hemoconcentration and thrombocytopenia and other signs
of DHF and the patient meets the criteria for DHF, the prognosis and the
patient's risk category have changed. Though dengue fever does not often
cause fatalities, a greater proportion of DHF cases are fatal.
The next concern would be observation of the danger signssevere
abdominal pain, change in mental status, vomiting and abrupt change from
fever to hypothermia. These often herald the onset of DSS.
The goal of treatment is to prevent shock. The plasma leakage syndrome is
self-limited. If you can support the patient through the plasma leakage phase
and provide sufficient fluids to prevent shock, the illness will resolve itself.

Hemorrhagic Manifestations of Dengue


Skin
hemorrhages:
petechiae, purpura, ecchymoses
Gingival bleeding
Nasal bleeding
Gastrointestinal
bleeding:
Hematemesis, melena, hematochezia
Hematuria
Increased menstrual flow

Clinical tests for DHF

Petechiae after tourniquet test


Overt bleed from previous GI lesions
Platelet count less than 100,000/ul
Low pulse pressure, cyanosis, effusions
Hypotension, Shock

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 inch (6.25 cm)

Tourniquet Test

Hemorrhagic Manifestations
Skin hemorrhages:
petechiae, purpura, ecchymoses
Gingival bleeding
Nasal bleeding
Gastro-intestinal bleeding:
hematemesis, melena, hematochezia
Haematuria
Increased menstrual flow

Petechiae

Danger Signs in Dengue Hemorrhagic


Fever
Abdominal pain - intense and sustained
Persistent vomiting
Abrupt change from fever to hypothermia,
with sweating and prostration
Restlessness or somnolence

*All of these are signs of impending shock and


should alert clinicians that the patient needs close
observation and fluids.

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
Frank shock is direct evidence of circulatory failure

DSS GRADE III

Criteria for DSS

The four criteria of DHF


Evidence of circulatory failure
1.
2.
3.
4.
5.

Rapid and weak pulse


Narrow pulse pressue (less than 20mm)
Hypotension for the age
Cold clammy skin
Altered mental status

Four Grades of DHF/DSS


Grade 1
Fever, Const. Symptoms, +ve tourniquet test
Grade 2
Grade 1 + Spontaneous bleeding
Grade 3
Signs of circulatory failure
Grade 4
Profound shock - B.P. Pulse not recordable

Capillary Damage

Ecchymosis Periorbital
Edema

Large Subcutaneous Bleed

Pleural Effusion

PEI = A / B x 100

DSS GRADE IV

dengue tourniquet test

DHF

DHF / DSS
Intensive Care
Oxygen
Rehydration
Barrier Nursing
Mosquito Screen

DHF- Poor Prognostic Signs

Girl children under 12 with DHF/DSS


Severe hypotension and shock
Multifocal bleeding abdominal pain
CNS encepahlopathy, fits, coma
Watch for preorbital edema, proteinuria
postural or otherwise hypotension
Serotype 2 infection after type 4
Malnutrition is protective

Management of DHF/DSS

Close monitoring of hypotension/shock


Oxygen administration
IV. Infusion of crystalloids/colloids
Platelet transfusion
Clotting factors replacement
Case fatality is 5% in good centers

Fluid Balance

Continue monitoring after defervescence


Serial hematocrits, BP, Urine output
Fluid replacement is twice the requirement
1500 ml + 2 x (weight-20) for 60 kg wt.
Eg. {1500 + 2 x (60-20)} x 2
= {1500 + (2x 40)} x 2 = (1500 + 800) x 2
= 2300 x 2 = 4600 ml = 10 pints

Unusual Presentations of
Dengue

Encephalopathy
Hepatic damage
Cardiomyopathy
Severe GI bleeding

Signs and Symptoms of


Encephalitis/Encephalopathy Associated with
Acute Dengue Infection
Decreased level of consciousness:
lethargy, confusion, coma
Seizures
Nuchal rigidity
Paresis

Differential Diagnosis

FM complex
1. Anicteric leptospirosis
2. Rickettsial fevers
3. Influenza, Measles, Rubella

DHF / DSS
1.
2.
3.
4.

Other hemorrhagic fevers


DIC due to septicemia
Complicated Malaria
Meningococcemia

Laboratory Diagnosis

Complete Blood Counts


Hematocrit
Platelet Count
Serum GOT, GPT
Serum Albumin
Proteinuria, hematuria
Immunological Tests
Chest Skiagram

Laboratory Diagnosis

Leucopenia. Thrombocytopenia
Increased SGOT, SGPT
Rising Ab titre in paired sera
Antigen detection ELISA
IgM-capture ELISA within few hours
Reverse transcription PCR confirmatory
IgG ELISA significant of past infection

LABORATORY CRITERIA

ISOLATION OF DENQUE VIRUS


INCREASED IgM OR IgM ANTIBODIES TITRES
DENQUE ANTIGEN DETECTION BY
IMMUNOHISTOCHEMISTRY,IMMUNOFLUROSCENCE,ELISA
PCR
LEUCOPENIA,THROMPOCYTOPENIA

Immuno Detection Tests

ELISA Plate

IgM-capture ELISA

Common Misconceptions- DHF


Dengue + bleeding = DHF
DHF is fatal only due to hemorrhage
No Majority of deaths are due to shock
Poorly managed DF turns into DHF
Positive tourniquet = DHF
it is not specific for DHF,
it indicates capillary fragility of any origin

More Common Misconceptions


DHF is only a pediatric illness
No, All ages may be involved
DHF is a problem of poor families
No, in fact they may not have
immune complexes to required level
Tourists will get DHF
No, in fact they are at low risk

Immunization

Each serotype produces life long immunity


There is not efficacious vaccine available
Vaccine needs to be tetravalent
Live attenuated vaccines possible
Several candidate vaccines are on trials
It may be harmful to vaccinate in view
of the pathogenesis of DHF/DSS

WHY TWO SYNDROMES,


BENIGN and SEVERE?
Observed in two immunological
settings.
1. Primary infections in infants.
2. Secondary infections in children
and adults.

PRIMARY INFECTIONS
Clinical Features
!

In children
DEN 1 & 3 mild illness
DEN 2 & 4 no illness

In adults
DEN 1 & 3 Disease/Infection ~1; g.i. hemorrhages
may accompany peptic ulcer disease.
DEN 2 & 4 - mild - moderate

Two-infections
The epidemiological data
DHF documented in children (> 1 yr)
who circulate infection-acquired
dengue antibody. Four prospective
cohort and 6 prospective
population-based studies.
In most studies, DHF comprises 25% of secondary infections

DHF IN CHILDREN: PROSPECTIVE


COHORT STUDIES
References

DHF/2 DHF/1000
o
Den Inf. 2 Den Inf.
Russell et al, AJTMH
3/83
36.1
17:600,1968
Sangawibha et al, AJE 4/112
35.7
120:653, 1984
Burke et al, AJTMH
7/59
118.6
38:172, 1988
Graham et al,
7/120
58.3
AJTMH 61:412, 1999

DHF IN CHILDREN:
PROSPECTIVE POPULATIONBASED STUDIES
References

DHF/ DHF/1000
2o Den Inf 2o Den Inf
Halstead Acad
2528/
20.1
Press 107,1980
125,728
Russell et al AJTMH 33/2700
12.2
18:600,1968
Sangkawibha et al
18/920
19.6
AJE 120:653,1984
AJE

DHF IN CHILDREN:
PROSPECTIVE POPULATIONBASED STUDIES
References

DHF/2 DHF/1000
o
Den Inf 2 Den Inf
Guzman et al
1213/
20.3
AJTMH 42:179,1990 59,875
Thein et al AJTMH 138/4181
33.0
56:566,1997
Guzman et al AJE
202/4810
42.0
152:793, 2000

Established second infection


sequences leading to DHF

21
31
12
32
42
13
23
14
24
34

Thailand; Indonesia
Thailand
Cuba, 1981; Cuba 1997; Thailand
Thailand
Thailand
Cuba, 2001; Thailand; Indonesia
Thailand, DF in Cuba
Thailand
Indonesia
Thailand

Several important features of dengue disease


Dengue virus infection causes diverse disease spectrum from
mild DF to severe DHF/DSS.
Dengue disease can occur in infant, children, and adult.
Severe DHF/DSS is more prevalent in secondary infection with
different serotype of dengue virus.
Antibody-dependent enhancement is hypothesized to explain
the severe DHF/DSS in secondary infection.
Thrombocytopenia and plasma leakage are two major
characteristics of DHF/DSS.
The pathogenesis of DHF/DSS is not clearly demonstrated. The
progression from DF to DHF/DSS is not predictable.
Supportive care is the only way to treat the DHF/DSS patients.
Dengue vaccine is not commercially available yet.

DIAGNOSIS
Classic symptoms : high fever, a petechial rash
with thrombocytopenia & relative leukopenia
(decrease in the number of circulating WBC in the
blood).
WHO definition of DHF :
Fever
Haemorrhagic tendency [positive tourniquet test
(> than 20 petechiae per square inch),
spontaneous bruising, bleeding from mucosa,
gingiva, injection sites, vomiting blood or bloody
diarrhea].
Thrombocytopaenia [<100,000 platelets per mm].
Evidence of plasma leakage [rise in hematocrit
level > than 20%].
Serology (identification of antibodies in the blood
serum) & polymerase chain reaction (PCR) to
confirm the diagnosis of dengue if clinically
indicated.

SYMPTOMS
Sudden high fever (39-41.5C)
for 2 to 7 days
Headache
Pain behind the eyes
Muscle pain, joint pain, bone
pain (break-bone fever)
After 1 to 2 days of fever, the
patient develops initial rash
with discoloured spots, often
described as Isles of white in
a sea of red
Second rash may develop to
palms and soles, and skin
may peel off (desquamate) &
body temperature drops

TREATMENTS
No specific antiviral treatment, only supportive
treatment is given to such patients.
If the patient is dehydrating, adequate fluids are
to be taken.
Intravenous fluid is administered if the patient is
unable to maintain oral intake.
For severe body ache, painkillers may be needed.
For severe headache and for joint and muscle
pain, acetaminophen/paracetamol and codeine
may be given.
If there is significant bleeding, blood or platelet
transfusion will be carried out.
Note : Aspirin should be avoided as this drug
may worsen the bleeding tendency (because
of its anticoagulant effects & the increased
risk of developing Reye syndrome).

PREVENTIONS
There is currently no vaccine
STRATEGIES
available
for
the
dengue
fever.
Individual roles. People are urged to
empty stagnant water from old tires,
trash cans & flower pots.
Mosquito control. Place larvicide e.g.
Abate or any other suitable insecticides
into any exposed water container. Use
mosquito repellant sprays that contain
NNDB or DEET.
Enforcement. Local authorities from
Ministry of Health conduct on-site check &
destroy larvae at residential premises &
construction sites. Fines may be imposed
on the owner of properties.

PREVENTIONS
Fogging with insecticide. Fogging
would be carried out by local
authorities in housing area where 2 or
more cases of dengue fever are
reported within one week.
Information. In Nov 2007, the
Ministry of Health carried out a major
campaign against Aedes. During the
campaign free packages of Abate
were distributed. Leaflets & brochures
to inform the public on ways to
prevent & curb Aedes breeding are
distributed.
Awareness campaign. Schools &
local communities are encouraged to
carry out communal cleaning
activities. Public awareness
campaigns through strategically
placed posters & television
advertisements are also done.

Do the 10-Minute Mozzie Wipe-out everyday.

Remove water from flowerpot plates on


alternate days.

Do the 10-Minute Mozzie Wipe-out everyday.

Change water in vases on alternate days.

Do the 10-Minute Mozzie Wipe-out everyday.

Turn over all pails and water


storage containers.

Do the 10-Minute Mozzie Wipe-out everyday.

Cover bamboo pole holders


when not in use.

Do the 10-Minute Mozzie Wipe-out everyday.

Clear blockages and put Bti insecticide in roof


gutters monthly.

Unwanted items

Do not litter. Rubbish such as cups


and bottles can collect rain water
and breed mosquitoes.

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