Dengue FeverDengue Fever

Dengue FeverDengue Fever

Dengue virusDengue virus Most prevalent vector-Most prevalent vector-

borne viral illness in the borne viral illness in the worldworld

Main mosquito vector is Main mosquito vector is Aedes aegypti,Aedes aegypti,

Year round Year round transmissiontransmission

Dengue FeverDengue Fever

WHO says some 2.5 billion people, two says some 2.5 billion people, two fifths of the world's population, are now at fifths of the world's population, are now at risk from dengue and estimates that there risk from dengue and estimates that there may be 50 million cases of dengue may be 50 million cases of dengue infection worldwide every year.infection worldwide every year.

epidemic in more than 100 countriesepidemic in more than 100 countries

Dengue feverDengue fever

genus genus Flavivirus, , family family Flaviviridae also known as also known as breakbone feverbreakbone fever..

((bonecrusher diseasebonecrusher disease) -Dandy Fever) -Dandy Fever Aedes aegypti - rarely the - rarely the

Aedes albopictus mosquito,,

DistributionDistribution

Endemic in more than Endemic in more than 100 tropical and 100 tropical and subtropical countries subtropical countries

Pandemic began in Pandemic began in Southeast Asia after WW Southeast Asia after WW II with subsequent global II with subsequent global spread spread

Several epidemics since Several epidemics since 1980s1980s

Distribution is comparable Distribution is comparable to malariato malaria

Manifestations of dengue virus infection:

ASYMPTOMATIC

SYMPTOMATIC

UndifferentiatedFever

Dengue Fever

DengueHaemorrhagicFever

Without haemorrhagic

With unusualhaemorrhagic

No shock

DSS

Virology Virology

Flavivirus familyFlavivirus family Small enveloped Small enveloped

viruses containing viruses containing single stranded single stranded positive RNA positive RNA

Four distinct viral Four distinct viral serotypes (Den-1, serotypes (Den-1, Den-2, Den-3, Den-4)Den-2, Den-3, Den-4)

DengueVirusesDengueViruses

Four closely related single-stranded RNA Dengue Four closely related single-stranded RNA Dengue

viruses (DEN-1, DEN-2, DEN-3 and DEN-4)viruses (DEN-1, DEN-2, DEN-3 and DEN-4)

Each serotype provides specific lifetime immunity, and Each serotype provides specific lifetime immunity, and

short-term cross-immunity (A person can be infected short-term cross-immunity (A person can be infected

as many as four times, once with each serotype)as many as four times, once with each serotype)

All serotypes can cause severe and fatal diseaseAll serotypes can cause severe and fatal disease

PathophysiologyPathophysiology

Transmitted by the Transmitted by the bite of Aedes bite of Aedes mosquito (Aedes mosquito (Aedes aegypti) aegypti)

Incubation 3-14 days Incubation 3-14 days Acute illness and Acute illness and

viremia 3-7 daysviremia 3-7 days Recovery or Recovery or

progression to progression to leakage phaseleakage phase

Dengue MosquitoDengue Mosquito

Aedes aegyptiAedes aegypti is the most important dengue mosquito is the most important dengue mosquito It breeds in collections of water close to dwellingsIt breeds in collections of water close to dwellings Common breeding sites are;Common breeding sites are;

-- Domestic water storage containers - tanks, Domestic water storage containers - tanks, jars, drums, flower vases with waterjars, drums, flower vases with water

-- Roof gutters /sun shadesRoof gutters /sun shades

-- Used tyres, discarded tins, cans, pots, yogurt Used tyres, discarded tins, cans, pots, yogurt cups, polythene bags, tree axils & cups, polythene bags, tree axils &

- - Many more places where rain watercollectsMany more places where rain watercollects

                                                                  

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.

Disease FactorsDisease Factors

Dengue-2 serotype most virulentDengue-2 serotype most virulent Increased severity with secondary infectionsIncreased severity with secondary infections Increased risk in children <15 years and elderly. Increased risk in children <15 years and elderly. Greatest risk of DHF in infants.Greatest risk of DHF in infants. More severe in femalesMore severe in females Increased mortality with comorbid conditions Increased mortality with comorbid conditions Less common in malnourished childrenLess common in malnourished children

Replication and TransmissionReplication and Transmissionof Dengue Virus (Part 1)of Dengue Virus (Part 1)

1. Virus transmitted to human in mosquito saliva

2. Virus replicateers in target organs localLymph nodes,liver

3. Virus infects white blood cells and lymphatic tissues

4. Virus released and circulates in blood

3

4

1

2

Replication and TransmissionReplication and Transmissionof Dengue Virus (Part 2)of Dengue Virus (Part 2)

5. Second mosquito ingests virus with blood

6. Virus replicates in mosquito midgut and other organs, infects salivary glands

7. Virus replicates in salivary glands

6

7

5

Dengue Clinical SyndromesDengue Clinical Syndromes

Undifferentiated feverUndifferentiated feverClassic dengue feverClassic dengue feverDengue hemorrhagic Dengue hemorrhagic

feverfeverDengue shock syndromeDengue shock syndrome

Undifferentiated FeverUndifferentiated Fever

May be the most common manifestation of May be the most common manifestation of denguedengue

Prospective study found that 87% of Prospective study found that 87% of students infected were either asymptomatic students infected were either asymptomatic or only mildly symptomaticor only mildly symptomatic

Other prospective studies including all age- Other prospective studies including all age- groups also demonstrate silent transmissiongroups also demonstrate silent transmission

Clinical CharacteristicsClinical Characteristicsof Dengue Feverof Dengue Fever

FeverFever HeadacheHeadache Muscle and joint painMuscle and joint pain Nausea/vomitingNausea/vomiting RashRash Hemorrhagic manifestationsHemorrhagic manifestations Retro orbital painRetro orbital pain

Hemorrhagic ManifestationsHemorrhagic Manifestationsof Dengueof Dengue

Skin hemorrhages: Skin hemorrhages: petechiae, purpura, ecchymosespetechiae, purpura, ecchymoses

Gingival bleedingGingival bleeding Nasal bleedingNasal bleeding Gastro-intestinal bleeding: Gastro-intestinal bleeding:

hematemesis, melena, hematemesis, melena, HematuriaHematuria Increased menstrual flowIncreased menstrual flow

Clinical Case Definition forClinical Case Definition forDengue Hemorrhagic FeverDengue Hemorrhagic Fever

Fever, or recent history of acute feverFever, or recent history of acute fever Hemorrhagic manifestationsHemorrhagic manifestations Low platelet count (100,000/mmLow platelet count (100,000/mm33 or less) or less) Objective evidence of “leaky capillaries:”Objective evidence of “leaky capillaries:”

elevated hematocrit (20% or more over elevated hematocrit (20% or more over baseline)baseline)

low albuminlow albumin pleural or other effusionspleural or other effusions

4 Necessary Criteria:4 Necessary Criteria:

Clinical Case Definition for Clinical Case Definition for Dengue Shock SyndromeDengue Shock Syndrome

4 4 criteria for DHFcriteria for DHF Evidence of circulatory failure manifested Evidence of circulatory failure manifested

indirectly by all of the following:indirectly by all of the following: Rapid and weak pulseRapid and weak pulse Narrow pulse pressure (Narrow pulse pressure ( 20 mm Hg) OR 20 mm Hg) OR

hypotension for agehypotension for age Cold, clammy skin and altered mental statusCold, clammy skin and altered mental status

Frank shock is direct evidence of circulatory Frank shock is direct evidence of circulatory failurefailure

Four Grades of DHFFour Grades of DHF

Grade 1Grade 1 Fever and nonspecific constitutional symptomsFever and nonspecific constitutional symptoms Positive tourniquet test is only hemorrhagic Positive tourniquet test is only hemorrhagic

manifestationmanifestation Grade 2Grade 2

Grade 1 manifestations + spontaneous bleedingGrade 1 manifestations + spontaneous bleeding Grade 3Grade 3

Signs of circulatory failure (rapid/weak pulse, narrow Signs of circulatory failure (rapid/weak pulse, narrow pulse pressure, hypotension, cold/clammy skin)pulse pressure, hypotension, cold/clammy skin)

Grade 4Grade 4 Profound shock (undetectable pulse and BP)Profound shock (undetectable pulse and BP)

Danger Signs inDanger Signs inDengue Hemorrhagic FeverDengue Hemorrhagic Fever

Abdominal pain - intense and Abdominal pain - intense and sustainedsustained

Persistent vomitingPersistent vomiting Abrupt change from fever to Abrupt change from fever to

hypothermia, with sweating and hypothermia, with sweating and prostrationprostration

Restlessness or somnolenceRestlessness or somnolence

Unusual PresentationsUnusual Presentationsof Severe Dengue Feverof Severe Dengue Fever

EncephalopathyEncephalopathy Hepatic damageHepatic damage CardiomyopathyCardiomyopathy Severe gastrointestinal Severe gastrointestinal

hemorrhagehemorrhage

Signs and Symptoms ofSigns and Symptoms ofEncephalitis/EncephalopathyEncephalitis/Encephalopathy

Associated with Acute Dengue Associated with Acute Dengue InfectionInfection

Decreased level of Decreased level of consciousness: lethargy, consciousness: lethargy, confusion, comaconfusion, coma

SeizuresSeizures Nuchal rigidityNuchal rigidity ParesisParesis

Physical ExamPhysical Exam

Nonspecific findingsNonspecific findings Conjunctival injection, Conjunctival injection,

pharyngeal erythema, pharyngeal erythema, lymphadenopathy, lymphadenopathy, hepatomegaly (20-hepatomegaly (20-50%)50%)

Macular or Macular or maculopapular rash maculopapular rash (50%)(50%)

Laboratory FindingsLaboratory Findings

LeukopeniaLeukopenia Thrombocytopenia (<100,000)Thrombocytopenia (<100,000) Modest liver enzyme elevation (2-5x nml)Modest liver enzyme elevation (2-5x nml) Serology:Serology:• Acute phase serum IgM (+6-90 days) ELISAAcute phase serum IgM (+6-90 days) ELISA• Acute and convalescent IgG (99% sens, 96% Acute and convalescent IgG (99% sens, 96%

spec) spec) • Hemagglutination inhibition assay (HI) is gold Hemagglutination inhibition assay (HI) is gold

standard. Paired acute and convalescent HI standard. Paired acute and convalescent HI assay, positive if >4 fold titer rise assay, positive if >4 fold titer rise

tourniquet testtourniquet test The tourniquet test is performed by inflating a blood The tourniquet test is performed by inflating a blood

pressure cuff to a point mid-way between the systolic pressure cuff to a point mid-way between the systolic andand

diastolic pressures for five minutes. A test is diastolic pressures for five minutes. A test is considered positive when 10 or more petechiae per considered positive when 10 or more petechiae per 2.5 cm2 (1 inch)2.5 cm2 (1 inch)

are observed. In DHF, the test usually gives a are observed. In DHF, the test usually gives a definite positive result (i.e. >20 petechiae). The test definite positive result (i.e. >20 petechiae). The test may bemay be

negative or mildly positive during the phase of negative or mildly positive during the phase of profound shock.profound shock.

DengueDengue is currently classified as an is currently classified as an emerging or re-emerging infectious emerging or re-emerging infectious diseasedisease

1.1. Overcrowded population.Overcrowded population.2.2. Unplanned & uncontrolled Unplanned & uncontrolled

urbanization.urbanization.3.3. Lack of effective mosquito control.Lack of effective mosquito control.4.4. Increased air travel.Increased air travel.5.5. Decay of public health measures.Decay of public health measures.

TreatmentTreatment

No specific therapyNo specific therapy Supportive measures:Supportive measures: adequate hydration adequate hydration acetaminophen (if no liver dysfunction)acetaminophen (if no liver dysfunction) avoid NSAIDs avoid NSAIDs DHF or DHF w/ shock:DHF or DHF w/ shock: IV fluid resuscitation and hospitalizationIV fluid resuscitation and hospitalization blood or platelet transfusion as neededblood or platelet transfusion as needed

TreatmentTreatment Treatment with corticosteroids shown not to Treatment with corticosteroids shown not to

reduce mortality with severe dengue shock reduce mortality with severe dengue shock • 2 studies of 63 and 92 pediatric DHF shock pts 2 studies of 63 and 92 pediatric DHF shock pts

treated w/ hydrocortisone 50mg/kg x1 or treated w/ hydrocortisone 50mg/kg x1 or methylprednisolone 30mg/kg x1 dose vs methylprednisolone 30mg/kg x1 dose vs placebo.placebo.

• Study of 95 pediatric DHF shock pts treated with Study of 95 pediatric DHF shock pts treated with carbazochrome sodium sulfate (AC-17) vs B carbazochrome sodium sulfate (AC-17) vs B vitamins for 3 daysvitamins for 3 days

Ribavirin very weak in vitro and in vivo activity Ribavirin very weak in vitro and in vivo activity against flavivirusesagainst flaviviruses

Traditional and emerging Traditional and emerging treatmentstreatments

Emerging evidence suggests that Emerging evidence suggests that mycophenolic acid and ribavirin inhibit mycophenolic acid and ribavirin inhibit dengue replication. dengue replication.

Brazilian traditional medicine,-cat's claw Brazilian traditional medicine,-cat's claw herbherb

Malaysia,-natural medicine. Mas Amirtha Malaysia,-natural medicine. Mas Amirtha and Semaluand Semalu

Philippines -tawa-tawa herbs and sweet Philippines -tawa-tawa herbs and sweet potato tops juicepotato tops juice

VaccinationVaccination

No current dengue vaccineNo current dengue vaccine Estimated availability in 5-10 yearsEstimated availability in 5-10 years Vaccine development is problematic as the Vaccine development is problematic as the

vaccine must provide immunity to all 4 serotypesvaccine must provide immunity to all 4 serotypes Lack of dengue animal modelLack of dengue animal model Live attenuated tetravalent vaccines under Live attenuated tetravalent vaccines under

phase 2 trials phase 2 trials New approaches include infectious clone DNA New approaches include infectious clone DNA

and naked DNA vaccinesand naked DNA vaccines

Mortality/MorbidityMortality/Morbidity

Treated DHF/DSS is associated with a 3% Treated DHF/DSS is associated with a 3% mortality rate.mortality rate.

Untreated DHF/DSS is associated with a Untreated DHF/DSS is associated with a 50% mortality rate.50% mortality rate.

Differential DiagnosesDifferential Diagnoses

HepatitisHepatitis Tick-Borne Diseases, Rocky Mountain Tick-Borne Diseases, Rocky Mountain

Spotted FeverSpotted Fever MalariaMalaria Yellow FeverYellow Fever MeningitisMeningitis Pediatrics, Bacteremia and SepsisPediatrics, Bacteremia and Sepsis Pediatrics, Meningitis and EncephalitisPediatrics, Meningitis and Encephalitis

PreventionPrevention

Biological: Biological: Target larval stage of Aedes in large water Target larval stage of Aedes in large water

storage containers storage containers Larvivorous fish (Gambusia), endotoxin Larvivorous fish (Gambusia), endotoxin

producing bacteria (Bacillus), copepod producing bacteria (Bacillus), copepod crustaceans (mesocyclops) crustaceans (mesocyclops)

Chemical: Chemical: Insecticide treatment of water containersInsecticide treatment of water containers Space spraying (thermal fogs)Space spraying (thermal fogs)

Public HealthPublic Health

Major and escalating global public health Major and escalating global public health problemproblem

Global demographic changes: urbanization and Global demographic changes: urbanization and population growth with substandard housing, population growth with substandard housing, water, and waster management systemswater, and waster management systems

Deteriorating public health infrastructure with Deteriorating public health infrastructure with limited resources resulting in “crisis limited resources resulting in “crisis management” not preventionmanagement” not prevention

Increased travel Increased travel Lack of effective mosquito control Lack of effective mosquito control

Mosquito control: Mosquito control: Options availableOptions available

“Mosquitoes take about 7 days to

complete life cycle.

The first three Stages: eggs,larva

and pupa are aquatic.

Therefore, the best way to

prevent mosquito breeding isto remove

stagnant clear water”

Common Misconceptions aboutCommon Misconceptions aboutDengue Hemorrhagic FeverDengue Hemorrhagic Fever

Dengue + bleeding = DHFDengue + bleeding = DHF

Need 4 WHO criteria & capillary permeabilityNeed 4 WHO criteria & capillary permeability

DHF kills only by hemorrhageDHF kills only by hemorrhage

Patient dies as a result of shockPatient dies as a result of shock

Poor management turns dengue into DHFPoor management turns dengue into DHF

Poorly managed dengue can be more severe, Poorly managed dengue can be more severe, butbut DHF is a distinct DHF is a distinct

condition, which even well-treated patients may developcondition, which even well-treated patients may develop

DHF is a pediatric diseaseDHF is a pediatric disease

All age groups are involvedAll age groups are involved

DHF is a problem of low income familiesDHF is a problem of low income families

All socioeconomic groups are affectedAll socioeconomic groups are affected

Important Instructions for Important Instructions for Treatment of DHFTreatment of DHF

Ø Cases of DHF should be observed every hour.Ø Cases of DHF should be observed every hour.

Ø Serial platelet and haematocrit determinations, drop Ø Serial platelet and haematocrit determinations, drop inin

plaelets and rise in haematocrits are essential for earlyplaelets and rise in haematocrits are essential for early

diagnosis of DHF.diagnosis of DHF.

Ø Timely intravenous therapy – isotonic crystalloid Ø Timely intravenous therapy – isotonic crystalloid solution –solution –

can prevent shock and/or lessen its severity.can prevent shock and/or lessen its severity.

Ø If the patient’s condition becomes worse despite Ø If the patient’s condition becomes worse despite givinggiving

20ml/kg/hr for one hour, replace crystalloid solution 20ml/kg/hr for one hour, replace crystalloid solution withwith

colloid solution such as Dextran or plasma. As soon ascolloid solution such as Dextran or plasma. As soon as

improvement occurs replace with crystalloid.improvement occurs replace with crystalloid.

Important Instructions for Important Instructions for Treatment of DHFTreatment of DHF

Ø In case of shock, give oxygen.Ø In case of shock, give oxygen.

Ø For correction of acidosis (sign: deep Ø For correction of acidosis (sign: deep breathing), use sodium bicarbonate.breathing), use sodium bicarbonate.

What not to doWhat not to do

Ø Do not give Aspirin or Brufen for treatment of fever.Ø Do not give Aspirin or Brufen for treatment of fever. Ø Avoid giving intravenous therapy before there is evidence ofØ Avoid giving intravenous therapy before there is evidence of haemorrhage and bleeding.haemorrhage and bleeding. Ø Avoid giving blood transfusion unless indicated, reduction inØ Avoid giving blood transfusion unless indicated, reduction in haematocrit or severe bleeding.haematocrit or severe bleeding. Ø Avoid giving steroids. They do not show any benefit.Ø Avoid giving steroids. They do not show any benefit. Ø Do not use antibioticsØ Do not use antibiotics Ø Do not change the speed of fluid rapidly, i.e. avoid rapidlyØ Do not change the speed of fluid rapidly, i.e. avoid rapidly increasing or rapidly slowing the speed of fluids.increasing or rapidly slowing the speed of fluids. Ø Insertion of nasogastric tube to determine concealedØ Insertion of nasogastric tube to determine concealed bleeding or to stop bleeding (by cold lavage) is bleeding or to stop bleeding (by cold lavage) is notnot recommended since it is hazardous.recommended since it is hazardous.

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