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

00,0

00

No

of C

ity/D

istr

icts

Inf

ecte

d

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.

الحمد لله