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
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