Dr. Sachin Verma MD, FICM, FCCS, ICFCDr. Sachin Verma MD, FICM, FCCS, ICFC

Fellowship in Intensive Care MedicineFellowship in Intensive Care Medicine

Infection Control Fellows Course Infection Control Fellows Course

Consultant Internal Medicine and Critical CareConsultant Internal Medicine and Critical Care

Web:- Web:- http://www.medicinedoctorinchandigarh.com

Mob:- +91-7508677495Mob:- +91-7508677495

References;References;1.1. HarrisonHarrison´s´s principle of internal medicine -16 principle of internal medicine -16 thth ed ed

2.2. ParkPark´s textbook of preventive and social medicine -17´s textbook of preventive and social medicine -17 thth ed ed

3.3. www.cdc.orgwww.cdc.org

DENGUEDENGUE

Virus vector and transmission Virus vector and transmission Dengue VirusDengue Virus

Causes dengue and dengue hemorrhagic feverCauses dengue and dengue hemorrhagic 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 lifetime Each serotype provides specific lifetime immunity, and short-term cross-immunityimmunity, and short-term cross-immunity

All serotypes can cause severe and fatal All serotypes can cause severe and fatal diseasedisease

Genetic variation within serotypesGenetic variation within serotypes

Some genetic variants within each serotype Some genetic variants within each serotype appear to be more virulent or have greater appear to be more virulent or have greater epidemic potentialepidemic potential

Aedes aegyptiAedes aegyptiDengue transmitted by Dengue transmitted by infected female mosquitoinfected female mosquito

Primarily a daytime feederPrimarily a daytime feeder

Lives around human Lives around human habitationhabitation

Lays eggs and produces Lays eggs and produces larvae preferentially in larvae preferentially in artificial containers.artificial containers.

Diseases- yellow fever, filaria Diseases- yellow fever, filaria dengue, chikungunya fever, dengue, chikungunya fever, rift valley fever. rift valley fever.

Aedes aegypti: Distribution

throughout the world

Model of baseline transmission Model of baseline transmission potential (1961-1990 climate)potential (1961-1990 climate)

Model of future transmission Model of future transmission potential (2080s climate)potential (2080s climate)

Population increase onlyPopulation increase only

Population at Population at risk (billions)risk (billions)

% of total % of total populationpopulation

2050s2050s 3.23.2 3434

2080s2080s 3.53.5 3535

Population increase plus Population increase plus climate change (HADCM2)climate change (HADCM2)

2050s2050s 4.14.1 4444

2080s2080s 5.25.2 5252

Replication and TransmissionReplication and Transmissionof Dengue Virus of Dengue Virus

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 TransmissionReplication and Transmissionof Dengue Virus of Dengue Virus

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

Transmission of Dengue VirusTransmission of Dengue Virusby by Aedes aegyptiAedes aegypti

Viremia Viremia

Extrinsic incubation

period

DAYS0 5 8 12 16 20 24 28

Human #1 Human #2

Illness

Mosquito feeds /acquires virus

Mosquito refeeds /transmits virus

Intrinsicincubation

period

Illness

Clinical Manifestations of Dengue and Clinical Manifestations of Dengue and Dengue Hemorrhagic FeverDengue Hemorrhagic Fever

Undifferentiated feverUndifferentiated fever

Classic dengue feverClassic dengue fever

Dengue hemorrhagic feverDengue hemorrhagic fever

Dengue 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 patients Prospective study found that 87% of patients infected were either asymptomatic or only mildly infected were either asymptomatic or only mildly symptomaticsymptomatic

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

Hemorrhagic ManifestationsHemorrhagic Manifestationsof 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, hematocheziahematemesis, melena, hematochezia

HematuriaHematuria

Increased menstrual flowIncreased menstrual flow

Signs and Symptoms ofSigns and Symptoms ofEncephalitis/EncephalopathyEncephalitis/Encephalopathy

Associated with Acute Dengue Associated with Acute Dengue InfectionInfection

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

SeizuresSeizures

Nuchal rigidityNuchal rigidity

ParesisParesis

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:

Four Grades of DHFFour Grades of DHFGrade 1Grade 1– Fever and nonspecific constitutional symptomsFever and nonspecific constitutional symptoms

– Positive tourniquet test is only hemorrhagic manifestationPositive tourniquet test is only hemorrhagic manifestation

Grade 2Grade 2– Grade 1 manifestations + spontaneous bleedingGrade 1 manifestations + spontaneous bleeding

Grade 3Grade 3– Signs of circulatory failure (rapid/weak pulse, narrow pulse Signs of circulatory failure (rapid/weak pulse, narrow pulse

pressure, hypotension, cold/clammy skin)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 sustainedAbdominal pain - intense and sustained

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

Clinical Case Definition for Dengue Clinical Case Definition for Dengue Shock SyndromeShock Syndrome

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 statusCold, clammy skin and altered mental status

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

Risk Factors Reported for DHFRisk Factors Reported for DHF

Virus strain :Virus strain :DHF risk is greatest for DEN-2, followed DHF risk is greatest for DEN-2, followed by DEN-3, DEN-4 and DEN-1by DEN-3, DEN-4 and DEN-1

Pre-existing anti-dengue antibodyPre-existing anti-dengue antibody– previous infectionprevious infection– maternal antibodies in infantsmaternal antibodies in infants

Host genetics-females more affected, Host genetics-females more affected, malnutrition protective.malnutrition protective.

Age(<12)Age(<12)

Unusual PresentationsUnusual Presentationsof Severe Dengue Feverof Severe Dengue Fever

EncephalopathyEncephalopathy

Hepatic damageHepatic damage

CardiomyopathyCardiomyopathy

Severe gastrointestinal hemorrhageSevere gastrointestinal hemorrhage

Increased Probability of DHFIncreased Probability of DHFHyperendemicity

Increased circulationof viruses

Increased probabilityof secondary infection

Increased probability ofoccurrence of virulent strains

Increased probability ofimmune enhancement

Increased probability of DHF

Neutralizing antibody to Dengue 1 virus

1

1

Dengue 1 virus 1

Pathogenesis of DHFPathogenesis of DHFSTEP 1- Homologous Antibodies Form Non-STEP 1- Homologous Antibodies Form Non-

infectious Complexes infectious Complexes

Non-neutralizing antibody

1

1 Complex formed by neutralizing antibody and virus

Non-neutralizing antibody to Dengue 1 virus

Dengue 2 virus

2 2

2

2

2

STEP2- Heterologous Antibodies of first STEP2- Heterologous Antibodies of first serotype infection form Infectious Complexes serotype infection form Infectious Complexes

with second serotypewith second serotype

Complex formed by non-neutralizing antibody and virus

2

2

2

2

2

22

2

22

2

STEP3 - Heterologous Complexes Enter More STEP3 - Heterologous Complexes Enter More Monocytes, Where Virus ReplicatesMonocytes, Where Virus Replicates

Non-neutralizing antibody

Dengue 2 virus 2

Complex formed by non-neutralizing antibody and Dengue 2 virus

2

STEP4 –DHF pathogenesisSTEP4 –DHF pathogenesis

Infected monocytes release vasoactive Infected monocytes release vasoactive mediators, resulting in increased vascular mediators, resulting in increased vascular permeability and hemorrhagic manifestations permeability and hemorrhagic manifestations that characterize DHF and DSSthat characterize DHF and DSS

Clinical Evaluation in Dengue FeverClinical Evaluation in Dengue Fever

Blood pressureBlood pressure

Evidence of bleeding in skin or other sitesEvidence of bleeding in skin or other sites

Hydration statusHydration status

Evidence of increased vascular Evidence of increased vascular permeability-- pleural effusions, ascitespermeability-- pleural effusions, ascites

Tourniquet testTourniquet test

PetechiaePetechiae

Tourniquet TestTourniquet Test

Inflate blood pressure Inflate blood pressure cuff to a point midway cuff to a point midway between systolic and between systolic and diastolic pressure for 5 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))

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 Dengue Diagnosis-Laboratory Methods for Dengue Diagnosis-

Virus isolation to determine serotype of Virus isolation to determine serotype of the infecting virusthe infecting virus

IgM ELISA test for serologic diagnosisIgM ELISA test for serologic diagnosis

Virus isolation: cell culture, mosquito inoculation& Virus isolation: cell culture, mosquito inoculation& fluroscent antibody test fluroscent antibody test

ELISA PlateELISA Plate

Collection and Processing of Collection and Processing of Samples for Laboratory Samples for Laboratory

DiagnosisDiagnosisType of

SpecimenTime of

CollectionType ofAnalysis

Acute-phaseblood

(0-5 days after onset)

When patient presents;collect second sampleduring convalescence

Virus isolationand/or serology

Convalescent-phaseblood

(6 days after onset)

Between days 6 and 21after onset

Serology

Temperature, Virus Positivity Temperature, Virus Positivity and Anti-Dengue IgM , by and Anti-Dengue IgM , by

Fever DayFever Day

Dengue IgMMean Max. Temperature Virus

Fever Day

0

20

40

60

80

100P

erce

nt

Vir

us

Pos

itiv

e

-4 -3 -2 -1 0 1 2 3 4 5 6

39.5

39.0

38.5

38.0

37.5

37.0

Tem

per

atu

re (

deg

rees

Cel

siu

s)

Den

gue

IgM

(E

IA u

nit

s)300

150

0

75

225

Management of dengue fever Management of dengue fever Outpatient TriageOutpatient Triage

No hemorrhagic manifestations and patient is No hemorrhagic manifestations and patient is well-hydrated: well-hydrated: home treatmenthome treatment

Hemorrhagic manifestations or hydration Hemorrhagic manifestations or hydration borderline: borderline: outpatient observation center or outpatient observation center or hospitalizationhospitalization

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

Warning Signs for Dengue ShockWarning Signs for Dengue Shock

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

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

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

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)

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

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

Treatment of Dengue FeverTreatment of Dengue Fever

FluidsFluids

RestRest

Antipyretics (avoid aspirin and non-Antipyretics (avoid aspirin and non-steroidal anti-inflammatory drugs)steroidal anti-inflammatory drugs)

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

Treatment of Dengue FeverTreatment of Dengue Fever

Continue monitoring after defervescenceContinue monitoring after defervescence

If any doubt, provide intravenous fluids, guided If any doubt, provide intravenous fluids, guided by serial hematocrits, blood pressure, and urine by serial hematocrits, blood pressure, and urine outputoutput

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

Rehydrating Patients Over 40 kgRehydrating Patients Over 40 kg

Volume required for rehydration is Volume required for rehydration is twicetwice the the recommended maintenance requirementrecommended maintenance requirement

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

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

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

Treatment of Dengue FeverTreatment of Dengue Fever

Avoid invasive procedures when possibleAvoid invasive procedures when possible

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

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

Indications for Hospital Indications for Hospital DischargeDischarge

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

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

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 DHF is a

distinct condition, which even well-treated patients may developdistinct condition, which even well-treated patients may develop

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

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 familiesDHF is a problem of low income families All socioeconomic groups are affectedAll socioeconomic groups are affected

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

Vector Control Methods:Vector Control Methods:Chemical ControlChemical Control

Larvicides (organophosphorus compounds – Larvicides (organophosphorus compounds – fenthion ,abate) may be used to kill immature fenthion ,abate) may be used to kill immature aquatic stagesaquatic stages

Ultra-low volume fumigation ineffective against Ultra-low volume fumigation ineffective against adult mosquitoesadult mosquitoes

Mosquitoes may have resistance to commercial Mosquitoes may have resistance to commercial aerosol spraysaerosol sprays

Vector Control Methods:Vector Control Methods:Biological and Environmental Biological and Environmental

ControlControlBiological controlBiological control– Largely experimentalLargely experimental– Option: place fish in containers to eat Option: place fish in containers to eat

larvaelarvae

Environmental controlEnvironmental control– Elimination of larval habitatsElimination of larval habitats– Most likely method to be effective in the Most likely method to be effective in the

long termlong term

Purpose of ControlPurpose of Control

Reduce female vector density to a level Reduce female vector density to a level below which epidemic vector transmission below which epidemic vector transmission will not occurwill not occur

Based on the assumption that eliminating or Based on the assumption that eliminating or reducing the number of larval habitats in the reducing the number of larval habitats in the domestic environment will control the vectordomestic environment will control the vector

The minimum vector density to prevent The minimum vector density to prevent epidemic transmission is unknownepidemic transmission is unknown