Dengue

DengueDengueWhat it is all What it is all

about?about?

Dr. Naghman BashirDr. Naghman BashirFCPS; MRCP (UK)FCPS; MRCP (UK)

Ki Dengue popeKi Dengue popeKea Dengay pepayKea Dengay pepay

Creepy fever due to evil Creepy fever due to evil spiritsspirits

First reported in 1879First reported in 1879

Virus, Vector Virus, Vector and and

TransmissionTransmission

Dengue VirusDengue Virus Causes dengue and dengue Causes dengue and dengue

hemorrhagic feverhemorrhagic fever Is an arbovirusIs an arbovirus Transmitted by mosquitoesTransmitted by mosquitoes Composed of single-stranded RNAComposed of single-stranded RNA Has 4 serotypes (DEN-1, 2, 3, 4)Has 4 serotypes (DEN-1, 2, 3, 4)

Dengue VirusesDengue Viruses Each serotype provides specific Each serotype provides specific

lifetime immunity, and short-term lifetime immunity, and short-term cross-immunitycross-immunity

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

Genetic variation within serotypesGenetic variation within serotypes Some genetic variants within each Some genetic variants within each

serotype appear to be more virulent or serotype appear to be more virulent or have greater epidemic potentialhave greater epidemic potential

Trouble AheadTrouble Ahead 2.5 billion people at risk world-wide2.5 billion people at risk world-wide In the Americas, 50-fold increase in In the Americas, 50-fold increase in

reported cases of DHF (1989-1993 reported cases of DHF (1989-1993 compared to 1984-1988)*compared to 1984-1988)*

Widespread abundance of Widespread abundance of Aedes Aedes aegyptiaegypti in at-risk areas in at-risk areas

* Organization of American States, Human Health in the Americas, 1996

Aedes aegyptiAedes aegypti Dengue transmitted by infected Dengue transmitted by infected

female mosquitofemale mosquito Primarily a daytime feederPrimarily a daytime feeder Lives around human habitationLives around human habitation Lays eggs and produces larvae Lays eggs and produces larvae

preferentially in artificial containerspreferentially in artificial containers

Aedes aegyptiAedes aegypti Mosquito Mosquito

Transmission of Dengue Transmission of Dengue VirusVirus

by by Aedes aegyptiAedes aegypti

Viremia Viremia

Extrinsic incubation

period

DAYS0 5 8 12 16 20 24 28

Human #1 Human #2Illness

Mosquito feeds /acquires virus

Mosquito refeeds /transmits virus

Intrinsicincubation

period

Illness

Replication and Replication and TransmissionTransmission

of Dengue Virus (Part 1)of Dengue Virus (Part 1)1. Virus transmitted to human in mosquito saliva

2. Virus replicates in target organs

3. Virus infects white blood cells and lymphatic tissues

4. Virus released and circulates in blood

3

4

1

2

Replication and Replication and TransmissionTransmission

of 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

Clinical Clinical Manifestations of Manifestations of

Dengue and Dengue and Dengue Dengue

Hemorrhagic Hemorrhagic FeverFever

Dengue Clinical Dengue Clinical SyndromesSyndromes

75%75%

Clinical CharacteristicsClinical Characteristicsof Dengue Feverof Dengue Fever

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

Signs and Symptoms ofSigns and Symptoms ofEncephalitis/EncephalopathEncephalitis/Encephalopath

yyAssociated with Acute Associated with Acute

Dengue InfectionDengue Infection Decreased level of Decreased level of consciousness: lethargy, consciousness: lethargy, confusion, comaconfusion, coma

SeizuresSeizures Nuchal rigidityNuchal rigidity ParesisParesis

Hemorrhagic Hemorrhagic ManifestationsManifestations

of Dengueof Dengue Skin hemorrhages: petechiae, purpura, Skin hemorrhages: petechiae, purpura,

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

hematemesis, melena, hematemesis, melena, hematocheziahematochezia

HematuriaHematuria Increased menstrual flowIncreased menstrual flow

Temperature, Virus Temperature, Virus Positivity and Anti-Positivity and Anti-

Dengue IgM , by Fever Dengue IgM , by Fever DayDay

Dengue IgMMean Max. Temperature Virus

Adapted from Figure 1 in Vaughn et al., J Infect Dis, 1997; 176:322-30.

0

20

40

60

80

100

Perc

ent V

irus

Pos

itive

7

39.5

39.0

38.5

38.0

37.5

37.0

Tem

pera

ture

(deg

rees

Cel

sius

)

Fever Day1 2 3 4 5 6 8 9 10 11

Den

gue

IgM

(EIA

uni

ts)300

150

0

75

225

PetechiaePetechiae

Tourniquet TestTourniquet Test Inflate blood pressure cuff to a Inflate blood pressure cuff to a

point midway between systolic point midway between systolic and diastolic pressure for 5 and diastolic pressure for 5 minutesminutes

Positive test: 20 or more Positive test: 20 or more petechiae per 1 inchpetechiae per 1 inch2 2 (6.25 cm(6.25 cm22))

Pan American Health Organization: Dengue and Dengue Hemorrhagic Fever: Guidelines for Prevention and Control. PAHO: Washington, D.C., 1994: 12.

Positive Tourniquet TestPositive Tourniquet Test

Clinical Case Definition Clinical Case Definition forfor

Dengue Hemorrhagic Dengue Hemorrhagic FeverFever

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 Clinical Case Definition for Dengue Shock for Dengue Shock

SyndromeSyndrome 4 criteria for DHF4 criteria 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) 20 mm Hg)

OR OR hypotension for agehypotension for age Cold, clammy skin and altered mental Cold, clammy skin and altered mental

statusstatus Frank shock is direct evidence of Frank shock is direct evidence of

circulatory failurecirculatory failure

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 Dengue Hemorrhagic

FeverFever 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 somnolenceMartínez Torres E. Salud Pública Mex 37 (supl):29-44, 1995.

Warning Signs for Warning Signs for Dengue ShockDengue Shock

When Patients Develop DSS:• 3 to 6 days after onset of symptoms

Initial Warning Signals:• Disappearance of fever• Drop in platelets• Increase in hematocrit

Alarm Signals:• Severe abdominal pain• Prolonged vomiting• Abrupt change from fever to hypothermia• Change in level of consciousness (irritability or somnolence)

Four Criteria for DHF:• Fever• Hemorrhagic manifestations• Excessive capillary permeability• 100,000/mm3 platelets

Clinical Evaluation in Clinical Evaluation in Dengue FeverDengue Fever

Blood pressureBlood pressure Evidence of bleeding in skin or other Evidence of bleeding in skin or other

sitessites Hydration statusHydration status Evidence of increased vascular Evidence of increased vascular

permeability-- pleural effusions, permeability-- pleural effusions, ascitesascites

Tourniquet testTourniquet test

Disease Disease PathogenesisPathogenesis

Risk Factors Reported Risk Factors Reported for DHFfor DHF

Virus strainVirus strain Pre-existing anti-dengue antibodyPre-existing anti-dengue antibody

previous infectionprevious infection maternal antibodies in infantsmaternal antibodies in infants

Host geneticsHost genetics AgeAge

Risk Factors for DHF Risk Factors for DHF (continued)(continued)

Higher risk in secondary infectionsHigher risk in secondary infections Higher risk in locations with two or Higher risk in locations with two or

more serotypes circulating more serotypes circulating simultaneously at high levels simultaneously at high levels (hyperendemic transmission)(hyperendemic transmission)

Increased Probability of Increased Probability of DHFDHF

Hyperendemicity

Increased circulationof viruses

Increased probabilityof secondary infection

Increased probability ofoccurrence of virulent strains

Increased probability ofimmune enhancement

Increased probability of DHFGubler & Trent, 1994

Neutralizing antibody to Dengue 1 virus

1

1

Dengue 1 virus 1

Homologous Homologous Antibodies Form Non-Antibodies Form Non-infectious Complexesinfectious Complexes

Non-neutralizing antibody

1

1 Complex formed by neutralizing antibody and virus

Hypothesis on Hypothesis on PathogenesisPathogenesis

of DHF (Part 2)of DHF (Part 2) In a subsequent infection, the In a subsequent infection, the

pre-existing pre-existing heterologousheterologous antibodies form complexes antibodies form complexes with the new infecting virus with the new infecting virus serotype, but do not neutralize serotype, but do not neutralize the new virusthe new virus


of DHF (Part 1)of DHF (Part 1) Persons who have Persons who have

experienced a dengue experienced a dengue infection develop serum infection develop serum antibodies that can neutralize antibodies that can neutralize the dengue virus of that same the dengue virus of that same ((homologoushomologous) serotype) serotype

Non-neutralizing antibody to Dengue 1 virus

Dengue 2 virus

2 2

2

2

2

Heterologous Heterologous Antibodies Form Antibodies Form

Infectious Infectious ComplexesComplexes

Complex formed by non-neutralizing antibody and virus

2


of DHF (Part 3)of DHF (Part 3) Antibody-dependent Antibody-dependent

enhancement enhancement is the process in is the process in which certain strains of dengue which certain strains of dengue virus, complexed with non-virus, complexed with non-neutralizing antibodies, can neutralizing antibodies, can enter a greater proportion of enter a greater proportion of cells of the mononuclear cells of the mononuclear lineage, thus increasing virus lineage, thus increasing virus productionproduction

2

2

22

22

2

22

2

Heterologous Complexes Heterologous Complexes Enter More Monocytes, Enter More Monocytes, Where Virus ReplicatesWhere Virus Replicates


Dengue 2 virus 2

Complex formed by non-neutralizing antibody and Dengue 2 virus

2


of DHF (Part 4)of DHF (Part 4) Infected monocytes release Infected monocytes release

vasoactive mediators, resulting in vasoactive mediators, resulting in increased vascular permeability and increased vascular permeability and hemorrhagic manifestations that hemorrhagic manifestations that characterize DHF and DSScharacterize DHF and DSS

2

2

22

22

2

22

2

Heterologous Complexes Heterologous Complexes Enter More Monocytes, Enter More Monocytes, Where Virus ReplicatesWhere Virus Replicates


Dengue 2 virus 2

Complex formed by non-neutralizing antibody and Dengue 2 virus

2

Viral Risk FactorsViral Risk Factorsfor DHF Pathogenesisfor DHF Pathogenesis Virus strain (genotype)Virus strain (genotype)

Epidemic potential: viremia Epidemic potential: viremia level, infectivitylevel, infectivity

Virus serotypeVirus serotype DHF risk is greatest for DEN-2, DHF risk is greatest for DEN-2,

followed by DEN-3, DEN-4 and followed by DEN-3, DEN-4 and DEN-1DEN-1

DiagnosisDiagnosis

Travel HistoryTravel History Important for assessment of Important for assessment of

symptomatic patients in non-endemic symptomatic patients in non-endemic areasareas

Determine whether the patient Determine whether the patient travelled to a dengue-endemic areatravelled to a dengue-endemic area

Determine when the travel occurredDetermine when the travel occurred If the patient developed fever more than If the patient developed fever more than

2 weeks after travel, eliminate dengue 2 weeks after travel, eliminate dengue from the differential diagnosisfrom the differential diagnosis

Differential Diagnosis of Differential Diagnosis of DengueDengue

InfluenzaInfluenza MeaslesMeasles RubellaRubella MalariaMalaria Typhoid feverTyphoid fever LeptospirosisLeptospirosis MeningococcemiaMeningococcemia Rickettsial infectionsRickettsial infections Bacterial sepsisBacterial sepsis Other viral hemorrhagic feversOther viral hemorrhagic fevers

Laboratory TestsLaboratory Testsin Dengue Feverin Dengue Fever

Clinical laboratory testsClinical laboratory tests CBC--WBC, platelets, hematocritCBC--WBC, platelets, hematocrit AlbuminAlbumin Liver function testsLiver function tests Urine--check for microscopic hematuriaUrine--check for microscopic hematuria

Dengue-specific testsDengue-specific tests Virus isolationVirus isolation SerologySerology

Laboratory Methods for Laboratory Methods for Dengue Diagnosis, CDC Dengue Diagnosis, CDC

Dengue BranchDengue Branch Virus isolation to determine Virus isolation to determine

serotype of the infecting virusserotype of the infecting virus IgM ELISA test for serologic IgM ELISA test for serologic

diagnosisdiagnosis

Virus Isolation:Virus Isolation:Cell CultureCell Culture

Virus Isolation:Virus Isolation:Cell CultureCell Culture

Virus Isolation:Virus Isolation:Mosquito InoculationMosquito Inoculation

Virus Isolation:Virus Isolation:Fluorescent Antibody Fluorescent Antibody

TestTest

ELISA Test for ELISA Test for Serologic DiagnosisSerologic Diagnosis

ELISA PlateELISA Plate

TreatmentTreatment

General General RecommendationsRecommendationsfor Medical Carefor Medical Care

Epidemiologic considerationsEpidemiologic considerations Season of yearSeason of year Travel historyTravel history

DiagnosisDiagnosis TreatmentTreatment Follow-upFollow-up

Outpatient TriageOutpatient Triage No hemorrhagic manifestations and No hemorrhagic manifestations and

patient is well-hydrated: patient is well-hydrated: home home treatmenttreatment

Hemorrhagic manifestations or Hemorrhagic manifestations or hydration borderline: hydration borderline: outpatient outpatient observation center or hospitalizationobservation center or hospitalization

Warning signs (even without Warning signs (even without profound shock) or DSS: profound shock) or DSS: hospitalizehospitalize

Patient Follow-UpPatient Follow-Up Patients treated at homePatients treated at home

Instruction regarding danger signsInstruction regarding danger signs Consider repeat clinical evaluationConsider repeat clinical evaluation

Patients with bleeding manifestationsPatients with bleeding manifestations Serial hematocrits and platelets at least daily Serial hematocrits and platelets at least daily

until temperature normal for 1 to 2 daysuntil temperature normal for 1 to 2 days All patientsAll patients

If blood sample taken in first 5 days after If blood sample taken in first 5 days after onset, need convalescent sample between days onset, need convalescent sample between days 6 - 306 - 30

All hospitalized patients need samples on All hospitalized patients need samples on admission and at discharge or deathadmission and at discharge or death

Treatment of Dengue Treatment of Dengue FeverFever

(Part 1)(Part 1) FluidsFluids RestRest Antipyretics (avoid aspirin and Antipyretics (avoid aspirin and

non-steroidal anti-inflammatory non-steroidal anti-inflammatory drugs)drugs)

Monitor blood pressure, Monitor blood pressure, hematocrit, platelet count, level hematocrit, platelet count, level of consciousnessof consciousness

Mosquito BarriersMosquito Barriers Only needed until fever subsides, to Only needed until fever subsides, to

prevent prevent Aedes aegyptiAedes aegypti mosquitoes mosquitoes from biting patients and acquiring from biting patients and acquiring virusvirus

Keep patient in screened sickroom Keep patient in screened sickroom or under a mosquito netor under a mosquito net


(Part 2)(Part 2) Continue monitoring after Continue monitoring after

defervescencedefervescence If any doubt, provide intravenous If any doubt, provide intravenous

fluids, guided by serial hematocrits, fluids, guided by serial hematocrits, blood pressure, and urine outputblood pressure, and urine output

The volume of fluid needed is similar The volume of fluid needed is similar to the treatment of diarrhea with mild to the treatment of diarrhea with mild to moderate isotonic dehydration (5%-to moderate isotonic dehydration (5%-8% deficit)8% deficit)

Fluid for Moderate Fluid for Moderate DehydrationDehydration

(Intravenous)(Intravenous)weight in lbs ml/lb/day weight in kgs ml/kg/day

< 15 100 < 7 220

16 - 25 75 7 - 11 165

26 - 40 60 12 - 18 132

41 - 88 40 19 - 40 88Adapted from Guidelines for Treatment of Dengue Fever/Dengue Haemorrhagic Fever in Small Hospitals, WHO, 1999.

Rehydrating Patients Rehydrating Patients Over 40 kgOver 40 kg

Volume required for rehydration is Volume required for rehydration is twicetwice the recommended maintenance the recommended maintenance requirementrequirement

Formula for calculating maintenance Formula for calculating maintenance volume: volume: 1500 + 20 x (weight in kg - 20)1500 + 20 x (weight in kg - 20)

For example, maintenance volume for 55 For example, maintenance volume for 55 kg patient is: 1500 + 20 x (55-20) = kg patient is: 1500 + 20 x (55-20) = 2200 ml2200 ml

For this patient, the rehydration volume For this patient, the rehydration volume would be 2 x 2200, or 4400 mlwould be 2 x 2200, or 4400 ml

Pan American Health Organization: Dengue and DengueHemorrhagic Fever: Guidelines for Prevention and Control.PAHO: Washington, D.C., 1994: 67.


(Part 3)(Part 3) Avoid invasive procedures when Avoid invasive procedures when

possiblepossible Unknown if the use of steroids, Unknown if the use of steroids,

intravenous immune globulin, or intravenous immune globulin, or platelet transfusions to shorten the platelet transfusions to shorten the duration or decrease the severity of duration or decrease the severity of thrombocytopenia is effectivethrombocytopenia is effective

Patients in shock may require Patients in shock may require treatment in an intensive care unittreatment in an intensive care unit

Indications for Indications for Hospital DischargeHospital Discharge

Absence of fever for 24 hours (without Absence of fever for 24 hours (without anti-fever therapy) and return of anti-fever therapy) and return of appetiteappetite

Visible improvement in clinical pictureVisible improvement in clinical picture Stable hematocritStable hematocrit 3 days after recovery from shock3 days after recovery from shock Platelets Platelets 50,000/mm 50,000/mm33

No respiratory distress from pleural No respiratory distress from pleural effusions/asciteseffusions/ascites

Pan American Health Organization: Dengue and DengueHemorrhagic Fever: Guidelines for Prevention and Control.PAHO: Washington, D.C., 1994: 69.

Common Misconceptions Common Misconceptions aboutabout

Dengue 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 DHF is a distinct condition, which even well-treated patients may distinct condition, which even well-treated patients may developdevelop

Positive tourniquet test = DHFPositive tourniquet test = DHF Tourniquet test is a nonspecific indicator of capillary Tourniquet test is a nonspecific indicator of capillary

fragilityfragility

More Common More Common Misconceptions about Misconceptions about Dengue Hemorrhagic Dengue Hemorrhagic

FeverFever DHF is a pediatric diseaseDHF is a pediatric disease

All age groups are involved in the All age groups are involved in the AmericasAmericas

DHF is a problem of low income DHF is a problem of low income familiesfamilies All socioeconomic groups are affectedAll socioeconomic groups are affected

Tourists will certainly get DHF with Tourists will certainly get DHF with a second infectiona second infection Tourists are at low risk to acquire DHFTourists are at low risk to acquire DHF

Dengue Vaccine?Dengue Vaccine? No licensed vaccine at presentNo licensed vaccine at present Effective vaccine must be tetravalentEffective vaccine must be tetravalent Field testing of an attenuated Field testing of an attenuated

tetravalent vaccine currently tetravalent vaccine currently underwayunderway

Effective, safe and affordable Effective, safe and affordable vaccine will not be available in the vaccine will not be available in the immediate futureimmediate future

PreventionPrevention

Early Eradication Early Eradication CampaignsCampaignsSucceededSucceeded

Adequate local and external funding Adequate local and external funding for personnel, equipment and for personnel, equipment and insecticidesinsecticides

Emphasis on source reductionEmphasis on source reduction Effective residual insecticideEffective residual insecticide Centralized, vertically-structured Centralized, vertically-structured

programs with military-type programs with military-type organization, strict supervision, high organization, strict supervision, high level of disciplinelevel of discipline

Reinfestation by Reinfestation by Aedes Aedes aegyptiaegypti

1930s 1970 1998

Hemispheric Hemispheric Eradication ofEradication of

Aedes aegyptiAedes aegypti No No Longer RealisticLonger Realistic Problem greater than during Problem greater than during

previous campaignprevious campaign Insufficient resourcesInsufficient resources Resistance to vertical disease Resistance to vertical disease

control programs and use of control programs and use of insecticidesinsecticides

Lack of effective insecticidesLack of effective insecticides Low priority, lack of sustainabilityLow priority, lack of sustainability

Lessons for FutureLessons for FutureDengue Prevention Dengue Prevention

ProgramsPrograms Efforts should focus on sustainable Efforts should focus on sustainable

environmental control rather than eradicationenvironmental control rather than eradication Control programs should be community-based Control programs should be community-based

and -integrated. They cannot rely solely on and -integrated. They cannot rely solely on insecticides nor require large budgetsinsecticides nor require large budgets

Need to promote dengue as a priority among Need to promote dengue as a priority among health officials and the general publichealth officials and the general public

Community ApproachesCommunity Approaches Typically define communities Typically define communities

geographicallygeographically More likely to be sustainableMore likely to be sustainable Advantages: built-in manpower, help Advantages: built-in manpower, help

develop resources and empower develop resources and empower community organizationscommunity organizations

Disadvantages: more difficult to Disadvantages: more difficult to organize, take longer to get off the organize, take longer to get off the groundground

Thank YouThank YouMerciMerciGrazieGrazieGraciasGraciasDankeDanke

Health & Medicine

Dengue