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-to-another-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 DengueCausative agent of Dengue
Dengue is cause by a RNA virusDengue is cause by a RNA virus• This virus is a member of the viral family This virus is a member of the viral family
Flaviviridae. Flaviviridae.
Dengue virusDengue virus
Bauman, R., (2006). Microbiology disease by systems. San Francisco , CA: Pearson Benjamin Cumming Publishers
Dengue Virus1. 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 growth
Rural to urban migration
Growth of citiesDeterioration of
cities
Jet travelHealth services
poorly organized/ underfunded
Lack of vector control professionals
Global Spread of Dengue
Countries with active dengue + Aedes aegypti
50-100 million infections/year
WORLD-WIDE DENGUE DISTRIBUTION
Geography distribution of Geography distribution of DengueDengue
BBB
Blue dot: Geographic extension of dengue 2000-2007Blue shaded areas: Risk of dengue transmissionLines: Lines demarcate the area where the vector for dengue exists
• VHF and other infectious diseases travel quickly nowadays
Number of DHF Cases and Infected Areas in Indonesia (1968 –2003)
IR p
er 1
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00
No
of C
ity/D
istr
icts
Inf
ecte
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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 Aedes aegypti life cyclelife 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 bite—this 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 symptoms—so the illness persists several days after the viremia has ended.
Population
Infection
Clinical Cases
DHF/DSS
AsymptomaticInfection
DF(non-DHF)
survive Death
5%
24%
6%
0.8%
76%
94%
99.2%
Fig. 1 Rates in dengue model
by Shepard et al. Vaccine. 2004, 22:1275-1280.
Halstead SB et al. Am J Trop Med Hyg 1969, 18:997-1021.
Age-specific DHF/DSS hospitalization in children and infant.
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 Fever4 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 2–5 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 SEVERE
DF DHF+ Thrombocytopenia +++ ThrombocytopeniaHidden 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 moremore over baseline or
Low albumin, pleural effusion
Four Grades of DHFGrade 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 signs—severe 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 pointmidway between systolic and diastolicpressure for 5 minutes
Positive test: 20 or more petechiaeper 1 inch² (6.25 cm²)
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) ORhypotension 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 failure1. Rapid and weak pulse
2. Narrow pulse pressue (less than 20mm)
3. Hypotension for the age
4. Cold clammy skin
5. 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
PEI = A / B x 100
Pleural Effusion
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 complex1. Anicteric leptospirosis
2. Rickettsial fevers
3. Influenza, Measles, Rubella
• DHF / DSS1. Other hemorrhagic fevers
2. DIC due to septicemia
3. Complicated Malaria
4. 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 INFECTIONSClinical 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 2-5% of secondary infections
DHF IN CHILDREN: PROSPECTIVE COHORT STUDIES
References DHF/2o
Den Inf. DHF/10002o Den Inf.
Russell et al, AJTMH17:600,1968
3/83 36.1
Sangawibha et al, AJE120:653, 1984
4/112 35.7
Burke et al, AJTMH38:172, 1988
7/59 118.6
Graham et al,AJTMH 61:412, 1999
7/120 58.3
DHF IN CHILDREN: PROSPECTIVE POPULATION-
BASED STUDIESReferences DHF/
2o Den Inf DHF/10002o Den Inf
Halstead AcadPress 107,1980
2528/125,728
20.1
Russell et al AJTMH18:600,1968
33/2700 12.2
Sangkawibha et alAJE 120:653,1984
18/920 19.6
AJE
DHF IN CHILDREN: PROSPECTIVE POPULATION-
BASED STUDIESReferences DHF/2o
Den Inf DHF/10002o Den Inf
Guzman et alAJTMH 42:179,1990
1213/ 59,875
20.3
Thein et al AJTMH56:566,1997
138/4181 33.0
Guzman et al AJE152:793, 2000
202/4810 42.0
Established second infection sequences leading to DHF
• 2 – 1 Thailand; Indonesia• 3 – 1 Thailand• 1 – 2 Cuba, 1981; Cuba 1997; Thailand• 3 – 2 Thailand• 4 – 2 Thailand• 1 – 3 Cuba, 2001; Thailand; Indonesia• 2 – 3 Thailand, DF in Cuba• 1 – 4 Thailand• 2 – 4 Indonesia • 3 – 4 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 mm³].
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-
41.5°C) 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
STRATEGIES 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.
There is currently no vaccine available for the dengue fever.
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 Do the 10-Minute Mozzie Wipe-out everyday.everyday.
Remove water from flowerpot plates on alternate days.
Do the 10-Minute Mozzie Wipe-out Do the 10-Minute Mozzie Wipe-out everyday.everyday.
Change water in vases on alternate days.
Do the 10-Minute Mozzie Wipe-out Do the 10-Minute Mozzie Wipe-out everyday.everyday.
Turn over all pails and water storage containers.
Do the 10-Minute Mozzie Wipe-out Do the 10-Minute Mozzie Wipe-out everyday.everyday.
Cover bamboo pole holders when not in use.
Do the 10-Minute Mozzie Wipe-out Do the 10-Minute Mozzie Wipe-out everyday.everyday.
Clear blockages and put Bti insecticide in roof gutters monthly.
Unwanted itemsUnwanted items
Do not litter. Rubbish such as cups and bottles can collect
rain water and breed mosquitoes.
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