Dr. Halesh .L.H.

Professor and Head of the department , Microbiology

SIMS,Shimoga

*Causative agent of dengue fever, belongs to family flaviviridae,

genus flavivirus.

*It is a spherical enveloped virus

*Genomic material – single stranded RNA

*There are presently 5 serotypes identified

*Fifth serotype, identified in 2013, october follows sylvatic

cycle,and is found only in Sarawak forest, Malaysia

*Each serotype provides specific lifetime immunity, and short-term cross-immunity

*All serotypes can cause severe and fatal disease

*Genetic variation within serotypes

*Some genetic variants within each serotype appear to be more

virulent or have greater epidemic potential

oThe first record of dengue fever is in chinese medical

encyclopedia referred as water poison caused by flying insects

oReports of epidemics – 1779-80

oThen until 1940 , epidemics were infrequent

oThen there was marked spread of dengue during and after

second world war

*The incidence is dramatically increasing

*390 million dengue cases per year

*Infections are acquired in urban

environment

*Rate of dengue has increased 10folds between 1960-2010

1. Virus is 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

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

*Dengue transmitted by infected female mosquito

*Primarily a daytime feeder

*Lives around human habitation

*Lays eggs and produces larvae

preferentially in artificial

containers

*Undifferentiated fever

*Classic dengue fever

*Dengue hemorrhagic fever

*Dengue shock syndrome

4 Necessary Criteria:

1.Fever, or recent history of acute fever

2.Hemorrhagic manifestations

3.Low platelet count (100,000/mm3 or less)

4.Objective evidence of “leaky capillaries:”

*elevated hematocrit (20% or more over baseline)

*low albumin

*pleural or other effusions

criteria for DHF

1.Evidence of circulatory failure manifested indirectly by all

of the following:

*Rapid and weak pulse*Narrow pulse pressure ( 20 mm Hg) OR hypotension for age*Cold, clammy skin and altered mental status

2.Frank shock is direct evidence of circulatory failure

Grade 1

*Fever and nonspecific constitutional symptoms

*Positive tourniquet test is only hemorrhagic Manifestation

Grade 2

*Grade 1 manifestations + spontaneous bleeding

Grade 3

*Signs of circulatory failure (rapid/weak pulse, narrow

pulse pressure, hypotension, cold/clammy skin)

Grade 4

*Profound shock (undetectable pulse and BP)

*Abdominal pain - intense and sustained

*Persistent vomiting

*Abrupt change from fever to hypothermia, with sweating and

prostration

*Restlessness or somnolence

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

*Encephalopathy

*Hepatic damage

*Cardiomyopathy

*Severe gastrointestinal hemorrhage

*Higher risk in secondary infections

*Higher risk in locations with two or more serotypes circulating

simultaneously at high levels (hyperendemic transmission)

*Persons who have experienced a dengue infection develop

serum antibodies that can neutralize the dengue virus of

that same (homologous) serotype

Neutralizing antibody to Dengue 1 virus

1

1

Dengue 1 virus 1

Homologous Homologous Antibodies Form Antibodies Form Non-infectious Non-infectious ComplexesComplexes

Non-neutralizing antibody

1

1 Complex formed by neutralizing antibody and virus

*In a subsequent infection, the pre-existing heterologous

antibodies form complexes with the new infecting virus

serotype, but do not neutralize the new virus

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

*Antibody-dependent enhancement is the process in which

certain strains of dengue virus, complexed with non-

neutralizing antibodies, can enter a greater proportion of

cells of the mononuclear lineage, thus increasing virus

production

2

2

2

2

22

2

22

2

Non-neutralizing antibody

Dengue 2 virus 2

Complex formed by non-neutralizing antibody and Dengue 2 virus

2

*Infected monocytes release vasoactive mediators, resulting in

increased vascular permeability & hemorrhagic manifestations

that characterize DHF and DSS

Virus serotype

*DHF risk is greatest for DEN-2, followed by DEN-3,

DEN-4 & DEN-1

*Blood pressure

*Evidence of bleeding in skin or other sites

*Hydration status

*Evidence of increased vascular permeability-

pleural effusions, ascites

Virus Isolation:Virus Isolation:Mosquito InoculationMosquito Inoculation

*No hemorrhagic manifestations and patient is well-hydrated:

home treatment

*Hemorrhagic manifestations or hydration borderline:

outpatient observation center or hospitalization

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

hospitalize

*Patients treated at home

*Instruction regarding danger signs

*Consider repeat clinical evaluation

*Patients with bleeding manifestations

*Serial hematocrits and platelets at least daily until temperature normal for 1 to 2 days

*All patients

*If blood sample taken in first 5 days after onset, need

convalescent sample between days 6 - 30

*All hospitalized patients need samples on admission and

at discharge or death

*Fluids

*Rest

*Antipyretics (avoid aspirin & NSAIDs)

*Monitor blood pressure, hematocrit, platelet count,

level of consciousness

*Only needed until fever subsides, to prevent Aedes

aegypti mosquitoes from biting patients and acquiring

virus

*Keep patient in screened sick room or under a mosquito

net

*Absence of fever for 24 hours (without anti-fever

therapy) and return of appetite

*Visible improvement in clinical picture

*Stable hematocrit

*3 days after recovery from shock

*Platelets 50,000 / mm3

*No respiratory distress from pleural effusions / ascites

DHF is a pediatric disease

All age groups are involved

DHF is a problem of low income families

All socioeconomic groups are affected

*No licensed vaccine at present

*Effective vaccine must be tetravalent

*Field testing of an attenuated

tetravalent vaccine currently

underway

*Effective, safe and affordable vaccine is awaited

*Larvicides may be used to kill immature aquatic stages

*Ultra-low volume fumigation ineffective against adult mosquitoes

*Mosquitoes may have resistance to commercial aerosol sprays

Biological control

*Largely experimental

*Option: place fish in

containers to eat larvae

Environmental control

*Elimination of larval habitats

*Most likely method to be effective in the long term