Dr. Sachin Verma MD, FICM, FCCS, ICFCFellowship in Intensive Care MedicineInfection Control Fellows Course Consultant Internal Medicine and Critical CareWeb:- http://www.medicinedoctorinchandigarh.com Mob:- +91-7508677495

References;Harrisons principle of internal medicine -16th edParks textbook of preventive and social medicine -17th edwww.cdc.org

DENGUE

Virus vector and transmission Dengue VirusCauses dengue and dengue hemorrhagic feverIs an arbovirusTransmitted by mosquitoesComposed of single-stranded RNAHas 4 serotypes (DEN-1, 2, 3, 4)

Dengue VirusesEach serotype provides specific lifetime immunity, and short-term cross-immunityAll serotypes can cause severe and fatal diseaseGenetic variation within serotypesSome genetic variants within each serotype appear to be more virulent or have greater epidemic potential

Aedes aegyptiDengue transmitted by infected female mosquitoPrimarily a daytime feederLives around human habitationLays eggs and produces larvae preferentially in artificial containers.Diseases- yellow fever, filaria dengue, chikungunya fever, rift valley fever.

Aedes aegypti: Distribution throughout the world

Model of baseline transmission potential (1961-1990 climate)

Model of future transmission potential (2080s climate)

Population increase onlyPopulation at risk (billions)% of total population2050s3.2342080s3.535Population increase plus climate change (HADCM2)2050s4.1442080s5.252

Replication and Transmissionof Dengue Virus 1. Virus transmitted to human in mosquito saliva2. Virus replicates in target organs3. Virus infects white blood cells and lymphatic tissues4. Virus released and circulates in blood

Replication and Transmissionof Dengue Virus 5. Second mosquito ingests virus with blood6. Virus replicates in mosquito midgut and other organs, infects salivary glands7. Virus replicates in salivary glands

Transmission of Dengue Virusby Aedes aegyptiViremiaViremiaDAYS0581216202428Human #1Human #2Mosquito feeds /acquires virusMosquito refeeds /transmits virusIntrinsicincubationperiod

Clinical Manifestations of Dengue and Dengue Hemorrhagic FeverUndifferentiated feverClassic dengue feverDengue hemorrhagic feverDengue shock syndrome

Undifferentiated FeverMay be the most common manifestation of dengueProspective study found that 87% of patients infected were either asymptomatic or only mildly symptomaticOther prospective studies including all age- groups also demonstrate silent transmission.

Clinical Characteristicsof Dengue FeverFeverHeadacheMuscle and joint painNausea/vomitingRashHemorrhagic manifestations

Hemorrhagic Manifestationsof DengueSkin hemorrhages: petechiae, purpura, ecchymosesGingival bleedingNasal bleedingGastro-intestinal bleeding: hematemesis, melena, hematocheziaHematuriaIncreased menstrual flow

Signs and Symptoms ofEncephalitis/EncephalopathyAssociated with Acute Dengue InfectionDecreased level of consciousness: lethargy, confusion, comaSeizuresNuchal rigidityParesis

Clinical Case Definition forDengue Hemorrhagic FeverFever, or recent history of acute feverHemorrhagic manifestationsLow platelet count (100,000/mm3 or less)Objective evidence of leaky capillaries:elevated hematocrit (20% or more over baseline)low albuminpleural or other effusions4 Necessary Criteria:

Four Grades of DHFGrade 1Fever and nonspecific constitutional symptomsPositive tourniquet test is only hemorrhagic manifestationGrade 2Grade 1 manifestations + spontaneous bleedingGrade 3Signs of circulatory failure (rapid/weak pulse, narrow pulse pressure, hypotension, cold/clammy skin)Grade 4Profound shock (undetectable pulse and BP)

Danger Signs inDengue Hemorrhagic FeverAbdominal pain - intense and sustainedPersistent vomitingAbrupt change from fever to hypothermia, with sweating and prostrationRestlessness or somnolence

Clinical Case Definition for Dengue Shock Syndrome4 criteria for DHFEvidence of circulatory failure manifested indirectly by all of the following:Rapid and weak pulseNarrow pulse pressure ( 20 mm Hg) OR hypotension for ageCold, clammy skin and altered mental statusFrank shock is direct evidence of circulatory failure

Risk Factors Reported for DHFVirus strain :DHF risk is greatest for DEN-2, followed by DEN-3, DEN-4 and DEN-1Pre-existing anti-dengue antibodyprevious infectionmaternal antibodies in infantsHost genetics-females more affected, malnutrition protective.Age(

Unusual Presentationsof Severe Dengue FeverEncephalopathyHepatic damageCardiomyopathySevere gastrointestinal hemorrhage

Increased Probability of DHFHyperendemicityIncreased circulationof virusesIncreased probabilityof secondary infectionIncreased probability ofoccurrence of virulent strainsIncreased probability ofimmune enhancementIncreased probability of DHF

Neutralizing antibody to Dengue 1 virus Dengue 1 virus Pathogenesis of DHF STEP 1- Homologous Antibodies Form Non-infectious Complexes Non-neutralizing antibodyComplex formed by neutralizing antibody and virus

Non-neutralizing antibody to Dengue 1 virus Dengue 2 virus STEP2- Heterologous Antibodies of first serotype infection form Infectious Complexes with second serotypeComplex formed by non-neutralizing antibody and virus

STEP3 - Heterologous Complexes Enter More Monocytes, Where Virus ReplicatesNon-neutralizing antibodyDengue 2 virus Complex formed by non-neutralizing antibody and Dengue 2 virus

STEP4 DHF pathogenesisInfected monocytes release vasoactive mediators, resulting in increased vascular permeability and hemorrhagic manifestations that characterize DHF and DSS

Clinical Evaluation in Dengue FeverBlood pressureEvidence of bleeding in skin or other sitesHydration statusEvidence of increased vascular permeability-- pleural effusions, ascitesTourniquet test

Petechiae

Tourniquet TestInflate blood pressure cuff to a point midway between systolic and diastolic pressure for 5 minutesPositive test: 20 or more petechiae per 1 inch2 (6.25 cm2)

Laboratory Testsin Dengue FeverClinical laboratory testsCBC--WBC, platelets, hematocritAlbuminLiver function testsUrine--check for microscopic hematuriaDengue-specific testsVirus isolationSerology

Laboratory Methods for Dengue Diagnosis-Virus isolation to determine serotype of the infecting virusIgM ELISA test for serologic diagnosis

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

ELISA Plate

Collection and Processing of Samples for Laboratory DiagnosisType ofSpecimenTime ofCollectionType ofAnalysisAcute-phaseblood(0-5 days after onset)When patient presents;collect second sampleduring convalescenceVirus isolationand/or serologyConvalescent-phaseblood(6 days after onset)Between days 6 and 21after onsetSerology

Temperature, Virus Positivity and Anti-Dengue IgM , by Fever DayDengue IgMMean Max. TemperatureVirusFever DayPercent Virus Positive-4-3-2-1012345639.539.038.538.037.537.0Temperature (degrees Celsius)Dengue IgM (EIA units)

Management of dengue fever Outpatient TriageNo hemorrhagic manifestations and patient is well-hydrated: home treatmentHemorrhagic manifestations or hydration borderline: outpatient observation center or hospitalizationWarning signs (even without profound shock) or DSS: hospitalize

Warning Signs for Dengue ShockWhen Patients Develop DSS: 3 to 6 days after onset of symptomsInitial Warning Signals: Disappearance of fever Drop in platelets Increase in hematocritAlarm 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

Treatment of Dengue Fever

FluidsRestAntipyretics (avoid aspirin and non-steroidal anti-inflammatory drugs)Monitor blood pressure, hematocrit, platelet count, level of consciousness

Treatment of Dengue Fever

Continue monitoring after defervescenceIf any doubt, provide intravenous fluids, guided by serial hematocrits, blood pressure, and urine outputThe volume of fluid needed is similar to the treatment of diarrhea with mild to moderate isotonic dehydration (5%-8% deficit)

Rehydrating Patients Over 40 kgVolume required for rehydration is twice the recommended maintenance requirementFormula for calculating maintenance volume: 1500 + 20 x (weight in kg - 20)For example, maintenance volume for 55 kg patient is: 1500 + 20 x (55-20) = 2200 mlFor this patient, the rehydration volume would be 2 x 2200, or 4400 ml.

Treatment of Dengue Fever

Avoid invasive procedures when possibleUnknown if the use of steroids, intravenous immune globulin, or platelet transfusions to shorten the duration or decrease the severity of thrombocytopenia is effectivePatients in shock may require treatment in an intensive care unit

Indications for Hospital DischargeAbsence of fever for 24 hours (without anti-fever therapy) and return of appetiteVisible improvement in clinical pictureStable hematocrit3 days after recovery from shockPlatelets 50,000/mm3No respiratory distress from pleural effusions/ascites

Common Misconceptions aboutDengue Hemorrhagic FeverDengue + bleeding = DHFNeed 4 WHO criteria, capillary permeabilityDHF kills only by hemorrhagePatient dies as a result of shockPoor management turns dengue into DHFPoorly managed dengue can be more severe, but DHF is a distinct condition, which even well-treated patients may developPositive tourniquet test = DHFTourniquet test is a nonspecific indicator of capillary fragility

DHF is a pediatric diseaseAll age groups are involved in the AmericasDHF is a problem of low income familiesAll socioeconomic groups are affectedTourists will certainly get DHF with a second infectionTourists are at low risk to acquire DHF

Vector Control Methods:Chemical ControlLarvicides (organophosphorus compounds fenthion ,abate) may be used to kill immature aquatic stagesUltra-low volume fumigation ineffective against adult mosquitoesMosquitoes may have resistance to commercial aerosol sprays

Vector Control Methods:Biological and Environmental ControlBiological controlLargely experimentalOption: place fish in containers to eat larvaeEnvironmental controlElimination of larval habitatsMost likely method to be effective in the long term

Purpose of ControlReduce female vector density to a level below which epidemic vector transmission will not occurBased on the assumption that eliminating or reducing the number of larval habitats in the domestic environment will control the vectorThe minimum vector density to prevent epidemic transmission is unknown

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