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Dengue Virus Dengue Virus Adenovirus Adenovirus Non Polio Enteroviruses Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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Page 1: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Dengue VirusDengue Virus AdenovirusAdenovirus Non Polio EnterovirusesNon Polio Enteroviruses

• Coxsackie virusCoxsackie virus

• EchovirusEchovirus

• EnterovirusEnterovirus

Page 2: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

DengueDengueClinical Clinical

Manifestations Manifestations and Epidemiologyand Epidemiology

Page 3: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

I. Virus, Vector and I. Virus, Vector and TransmissionTransmission

Page 4: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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)

Page 5: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Dengue VirusesDengue Viruses Each serotype provides specific lifetime Each serotype provides specific lifetime

immunity, and short-term cross-immunity, and short-term cross-immunityimmunity

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

Page 6: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

Page 7: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Replication and TransmissionReplication and Transmissionof 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

Page 8: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

Page 9: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Aedes aegyptiAedes aegypti Mosquito Mosquito

Page 10: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

Page 11: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

II. EpidemiologyII. Epidemiology

Page 12: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

World Distribution of Dengue - 2005World Distribution of Dengue - 2005

Areas infested with Aedes aegypti Areas with Aedes aegypti and dengue epidemic activity

Page 13: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Mean Annual Number of DHF CasesMean Annual Number of DHF CasesThailand, Indonesia and Vietnam, by DecadeThailand, Indonesia and Vietnam, by Decade

* Provisional data through 1998

020406080

100120140160180200

Rep

ort

ed C

ases

(T

ho

usa

nd

s)

1950s 1960s 1970s 1980s 1990s*

Page 14: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

III. Disease PathogenesisIII. Disease Pathogenesis

Page 15: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Risk Factors Reported for Risk Factors Reported for DHFDHF

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

Page 16: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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)

Page 17: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

Page 18: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Hypothesis on PathogenesisHypothesis on Pathogenesisof DHF (Part 1)of DHF (Part 1)

Persons who have experienced Persons who have experienced a dengue infection develop a dengue infection develop serum antibodies that can serum antibodies that can neutralize the dengue virus of neutralize the dengue virus of that same (that same (homologoushomologous) ) serotypeserotype

Page 19: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Neutralizing antibody to Dengue 1 virus

1

1

Dengue 1 virus 1

Homologous Antibodies Form Homologous Antibodies Form Non-infectious ComplexesNon-infectious Complexes

Non-neutralizing antibody

1

1 Complex formed by neutralizing antibody and virus

Page 20: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Hypothesis on PathogenesisHypothesis on Pathogenesisof 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 with antibodies form complexes with the new infecting virus serotype, the new infecting virus serotype, but do not neutralize the new but do not neutralize the new virusvirus

Page 21: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Non-neutralizing antibody to Dengue 1 virus

Dengue 2 virus

2 2

2

2

2

Heterologous Antibodies Form Heterologous Antibodies Form Infectious ComplexesInfectious Complexes

Complex formed by non-neutralizing antibody and virus

2

Page 22: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Hypothesis on PathogenesisHypothesis on Pathogenesisof 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

Page 23: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

2

2

2

2

22

2

22

2

Heterologous Complexes Enter More 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

Page 24: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Hypothesis on PathogenesisHypothesis on Pathogenesisof DHF (Part 4)of DHF (Part 4)

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

Page 25: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Viral Risk FactorsViral Risk Factorsfor DHF Pathogenesisfor DHF Pathogenesis

Virus strain (genotype)Virus strain (genotype)• Epidemic potential: viremia level, Epidemic potential: viremia level,

infectivityinfectivity Virus serotypeVirus serotype

• 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

Page 26: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

IV. Clinical Manifestations of IV. Clinical Manifestations of Dengue and Dengue Dengue and Dengue Hemorrhagic FeverHemorrhagic Fever

Page 27: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Dengue Clinical Dengue Clinical SyndromesSyndromes

Undifferentiated feverUndifferentiated fever Classic dengue feverClassic dengue fever Dengue hemorrhagic feverDengue hemorrhagic fever Dengue shock syndromeDengue shock syndrome

Page 28: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Undifferentiated FeverUndifferentiated Fever

May be the most common May be the most common manifestation of denguemanifestation of dengue

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

Other prospective studies including all Other prospective studies including all age- groups also demonstrate silent age- groups also demonstrate silent transmissiontransmission

Page 29: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Clinical CharacteristicsClinical Characteristicsof Dengue Feverof Dengue Fever

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

Page 30: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Signs and Symptoms ofSigns and Symptoms ofEncephalitis/EncephalopathyEncephalitis/Encephalopathy

Associated with Acute Dengue InfectionAssociated with Acute Dengue Infection

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

SeizuresSeizures Nuchal rigidityNuchal rigidity ParesisParesis

Page 31: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

Page 32: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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:

Page 33: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Clinical Case Definition for Clinical Case Definition for Dengue Shock SyndromeDengue Shock 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 Frank shock is direct evidence of circulatory failurecirculatory failure

Page 34: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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)

Page 35: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

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

Page 36: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Warning Signs for Dengue Warning Signs for Dengue ShockShock

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 somnolence)

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

Page 37: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Unusual PresentationsUnusual Presentationsof Severe Dengue Feverof Severe Dengue Fever

EncephalopathyEncephalopathy Hepatic damageHepatic damage CardiomyopathyCardiomyopathy Severe gastrointestinal Severe gastrointestinal

hemorrhagehemorrhage

Page 38: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

V. DiagnosisV. Diagnosis

Page 39: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

General RecommendationsGeneral Recommendationsfor Medical Carefor Medical Care

Epidemiologic considerationsEpidemiologic considerations• Season of yearSeason of year

• Travel historyTravel history DiagnosisDiagnosis TreatmentTreatment Follow-upFollow-up

Page 40: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

Page 41: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

Page 42: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Clinical Evaluation in Dengue Clinical Evaluation in Dengue FeverFever

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, ascitespermeability-- pleural effusions, ascites Tourniquet testTourniquet test

Page 43: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

PetechiaePetechiae

Page 44: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Vaughn DW, Green S, Kalayanarooj S, et al. Dengue in the early febrilephase: viremia and antibody responses. J Infect Dis 1997; 176:322-30.

A

B

PEI = A/B x 100

Pleural Effusion IndexPleural Effusion Index

Page 45: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Tourniquet TestTourniquet Test

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

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

Page 46: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Positive Tourniquet TestPositive Tourniquet Test

Page 47: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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 Urine--check for microscopic

hematuriahematuria Dengue-specific testsDengue-specific tests

• Virus isolationVirus isolation• SerologySerology

Page 48: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

Page 49: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Virus Isolation:Virus Isolation:Cell CultureCell Culture

Page 50: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Virus Isolation:Virus Isolation:Cell CultureCell Culture

Page 51: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Virus Isolation:Virus Isolation:Mosquito InoculationMosquito Inoculation

Page 52: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Virus Isolation:Virus Isolation:Fluorescent Antibody TestFluorescent Antibody Test

Page 53: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

ELISA Test for ELISA Test for Serologic DiagnosisSerologic Diagnosis

Page 54: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

ELISA PlateELISA Plate

Page 55: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Collection and Processing Collection and Processing of Samples for Laboratory of 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

Page 56: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Temperature, Virus Positivity and Temperature, Virus Positivity and Anti-Dengue IgM , by Fever DayAnti-Dengue IgM , by Fever Day

Dengue IgMMean Max. Temperature Virus

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

Fever Day

0

20

40

60

80

100

Per

cen

t V

iru

s P

osit

ive

-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

Page 57: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

VI. TreatmentVI. Treatment

Page 58: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

Page 59: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

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

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

Page 60: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Treatment of Dengue Treatment of Dengue FeverFever

(Part 1)(Part 1) 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 platelet count, level of consciousnessconsciousness

Page 61: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Mosquito BarriersMosquito Barriers

Only needed until fever subsides, Only needed until fever subsides, to prevent to prevent Aedes aegyptiAedes aegypti mosquitoes from biting patients mosquitoes from biting patients and acquiring virusand acquiring virus

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

Page 62: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Treatment of Dengue FeverTreatment of Dengue Fever(Part 2)(Part 2)

Continue monitoring after defervescenceContinue monitoring after defervescence If any doubt, provide intravenous fluids, If any doubt, provide intravenous fluids,

guided by serial hematocrits, blood guided by serial hematocrits, blood pressure, and urine outputpressure, and urine output

The volume of fluid needed is similar to 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%-8% moderate isotonic dehydration (5%-8% deficit)deficit)

Page 63: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Treatment of Dengue FeverTreatment of Dengue Fever(Part 3)(Part 3)

Avoid invasive procedures when possibleAvoid invasive procedures when possible Unknown if the use of steroids, intravenous Unknown if the use of steroids, intravenous

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

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

Page 64: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

Indications for Hospital DischargeIndications for Hospital Discharge 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

Page 65: N Dengue Virus n Adenovirus n Non Polio Enteroviruses Coxsackie virus Coxsackie virus Echovirus Echovirus Enterovirus Enterovirus

CommonCommon MisconceptionsMisconceptions about 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 Tourniquet test is a nonspecific indicator of capillary

fragilityfragility

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More Common Misconceptions More Common Misconceptions about Dengue Hemorrhagic Feverabout Dengue Hemorrhagic Fever

DHF is a pediatric diseaseDHF is a pediatric disease All age groups are involved in the AmericasAll age groups are involved in the Americas

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

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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 underwaytetravalent vaccine currently underway Effective, safe and affordable vaccine Effective, safe and affordable vaccine

will not be available in the immediate will not be available in the immediate futurefuture

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VII. PreventionVII. Prevention

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Early Eradication CampaignsEarly Eradication CampaignsSucceededSucceeded

Adequate local and external funding for Adequate local and external funding for personnel, equipment and insecticidespersonnel, equipment and insecticides

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

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Reinfestation by Reinfestation by Aedes aegyptiAedes aegypti

1930s 1970 1998

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Lessons for FutureLessons for FutureDengue Prevention ProgramsDengue Prevention Programs

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

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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

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Community ParticipationCommunity Participation

First must educate the public in the First must educate the public in the basics of dengue, such as:basics of dengue, such as:• Where the mosquito lays her eggsWhere the mosquito lays her eggs

• The link between larvae and adult The link between larvae and adult mosquitoesmosquitoes

• General information about dengue General information about dengue transmission, symptoms and transmission, symptoms and treatmenttreatment

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Barriers and Motivation Barriers and Motivation (Part 2)(Part 2)

Structural factorsStructural factors• laws regarding laws regarding Aedes aegyptiAedes aegypti habitats habitats

Environmental factorsEnvironmental factors• lack of potable water, need to store waterlack of potable water, need to store water• inadequate solid waste disposalinadequate solid waste disposal

Attitudinal factorsAttitudinal factors• beliefs: causes, treatment, prevention of febrile illnessesbeliefs: causes, treatment, prevention of febrile illnesses

Community factorsCommunity factors• community history and structurecommunity history and structure• other priority problems in the communityother priority problems in the community

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Cues: Water ShortagesCues: Water Shortagesand Rationingand Rationing

For locations where there are For locations where there are seasonal or other temporary water seasonal or other temporary water shortagesshortages

Provide information on how to Provide information on how to properly store waterproperly store water

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Cues: RainfallCues: Rainfall

Link rainfall to the creation of larval Link rainfall to the creation of larval habitatshabitats

This mental link can remind people This mental link can remind people to look for and eliminate larval to look for and eliminate larval habitats after it rainshabitats after it rains

Eliminates larval habitats Eliminates larval habitats influenced by rainfall, and perhaps influenced by rainfall, and perhaps others as wellothers as well

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Adenovirus Infection

Age incidence: 6mo – 5 y/o

Mode of transmission

1.Direct contact – airborne or droplet

2. Indirect contact with articles and environment

3.Fecal oral route

Incubation period: 2-14 days – respiratory

3-10 days - GIT

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Adenovirus Infection

Clinical Manifestations:

3. GIT

a. gastroenteritis

b. mesenteric lymphodenitis

c. intususception

d. appendicitis

e. hepatitis

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Adenovirus Infection

51 serotypes

Types 3, 4, 7, 21 – respiratory

8, 18, 37 – epidemic heretoconjunctivitis

40, 41, 31 - gastroenteritis

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Adenovirus Infection

Clinical Manifestations:

1.Respiratory

a. Colds/nasopharyngitis, tonsillitis

b. Pharyngo- conjunctival fever

c. bronchitis

d. pneumonia

e. pertussis – like syndrome

2. Ocular

- epidemic conjunctivitis

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Adenovirus Infection

Clinical Manifestations:

3. GIT

a. gastroenteritis

b. mesenteric lymphodenitis

c. intususception

d. appendicitis

e. hepatitis

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Adenovirus Infection

Clinical Manifestations:

4. GUT

a. acute hemorrhagic cystitis

b. nephritis

c. orchitis

5. Heart

a. myocarditis/pericarditis

6. Neurology

a. meningitis/encephalitis

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Adenovirus Infection

Diagnosis

1.Clinical

2.Viral isolation

3.Other:

a. Immunoflourescence

b. ELISA

c. PCR

d. Electron microscopy

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Adenovirus Infection

Treatment:

Supportive

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Enterovirus Infection

RNA varices

1.Coxsackievirus group A

2.Coxsackievirus group B

3.Echovirus

4.enterovirus

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Nonpolio EnterovirusesNonpolio EnterovirusesExanthemsExanthems

Coxsackievirus group ACoxsackievirus group A Coxsackievirus group BCoxsackievirus group B EchovirusesEchoviruses EnterovirusesEnteroviruses

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Enterovirus Infection

Sources: feces

oropharyngeal secretions

Mode of transmission:• Oral fecal route• Oral – oral route

Increase incidence:

1. young children

2. low socio-economic group

3. unhygienic, economically deprived population

Incubation period: 3-6 days

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Coxsackievirus

• Coxsackievirus group A 6

Various presentation of rash

Erythematous and maculopapularVesicular Urticaria and

Urticaria plus fever: r/o infectious origin

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Coxsackievirus

• Coxsackievirus group A 16

Hand-foot and mouth syndromeEnanthem: large vesicularicular lesions (1-

2cm.) on buccal surfaces, tongue, palate, uvula, anterior tonsil pillars, and gums

Exanthem: large vesicular lesions on hand feet, and buttocks

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Echovirus 9

• Associated with epidemics

• Incubation period: 4-6 days

• Clinical manifestations:

1. Noexudative pharyngitis (50%)

2. Cough, sore throat

3. Cervical lymphadenopathy

4. Abdominal pain

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Echovirus 9

Clinical manifestations:

5. Aseptic meningitis

6. Rash:

a. Erythematous

b. Maculopapular

c. Petechial/petechial component

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Echovirus 9

• Laboratory: Pleocytosis with predominance of neutrophils

• Differential diagnosis: Meningococcemia

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Thank You!