1. Dengue – An Overview

Dengue Expert Advisory Group

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Introduction

• Dengue Fever

• Dengue Hemorrhagic Fever

• Dengue Shock Syndrome

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Dengue Virus

• Family : Flaviviridae

• Genus : Flavivirus

• Serotypes : DV1, DV2, DV3, DV4

• Enveloped virus

• 3 major proteins

• SS positive sense RNA

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Viral Serotypes

• DV1

• DV2

• DV3

• DV4

• Subgroups and clades

• One or more virus types in circulation during an epidemic

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Pathogenesis

• Virus enters blood-reticuloendothelial system and bone marrow-blood

• Incubation period 3-10 days

• Viremia for 7 days after the entry

• Immune response ONLY for the infecting serotype

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Pathogenesis of Dengue Fever

• “Breakbone” symptoms due to adventitial and dendridic cell involvement of the marrow

• Cytopenias due to direct marrow involvement

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Antibody Structure

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Pathogenesis of DHF – Role of cross reactive DV antibodies

Cross reactive antibody binds to the infecting virus

Form v- ab complexes. V- ab complexes attach to cells bearing receptors for the Fc portion of the ab

Facilitates entry of the virus into these cells and the viral replication. Therefore, more cells are infected

Increased immune response & release of cytokines

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Pathogenesis of DHF Role of cross reactive T cells

Cross reactive T cells reacts with dengue virus of subsequent infection. Causes activation of these T cells

Activated cross 1. Are less effectivereacting T cells in eliminating the

secondary infecting DV

2. T cell activation contribute to

disease pathogenesis

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Cytokines secreted from infected macrophages and endothelial cells

Pathogenesis of Leak

Cytokines secreted from activated T cells

Exaggerated Cytokine response

Endothelial dysfunction

DV specific antibody interact with the endothelium

DV infects endothelium and kills cells

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? DHF a misnomerDLF

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Thrombocytopenia

• Low production due to temporary bone marrow suppression (DV infection, effect of cytokines)

• Increased consumption (activation of coagulation system, DIC)

• Direct infection of platelets with the virus: kills platelets

• Increased destruction of platelets by activated macrophages

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Bleeding

• Thrombocytopenia

• Activation of the coagulation system due to endothelial dysfunction, cytokines

• Disseminated intravascular coagulation

• Poor perfusion of GIT: can lead to mucosal bleeding

• Drugs: Steroids, NSAIDS16Dr. S Guanasena

Organ Involvement in Dengue

• Direct involvement - infection of hepatocytes or brain with the dengue virus

• Circulatory failure - poor organ perfusion

• Drugs – Paracetamol

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Organ Involvement

• Like other viruses many organ involvement has been reported (myositis, pancreatitis, myocarditis etc.)

• GB syndrome

• Stevens Johnsons

• Features may vary from one year to another and one epidemic to another

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Symptomatic to Asymptomatic Ratio

• 500:9500

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List of Warning SignsWarrants Admission

• No clinical improvement / worsening clinical parameters

• Persistent vomiting • Severe abdominal pain• Lethargy and or restlessness• Bleeding: severe epistaxis, black stools,

hematemesis, extensive menstrual bleeding, hematuria

• Giddiness• Pale cold clammy extremities• Less / no urine output for 4 – 6 hours

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Clinical Features – DF

• Fever > 2 and < 10 days (essential criterion)• Headache• Retro orbital pain• Myalgia• Arthralgia/ severe backache/ bone pains• Rash• Bleeding manifestations (epistaxis, hematemesis, bloody

stools, menorrhagia, hemoptysis)• Abdominal pain• Decreased urinary output despite adequate fluid intake• Irritability in infants

Tourniquet Test

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Management Dengue Fever

• Symptomatic

• Monitoring

Highly Suggestive of DHF Confirmed DHF**

Disproportionate tachycardia

Narrowing of pulse pressure < 20 mm

CRFT > 2 secs Tender hepatomegaly (DHF likely) Haemoconcentration HCT 20% rise from baseline or rise

approaching 20% if patient already on IV fluids

Biochemistryo Serum albumin < 3.5 g/dl or 0.5

gm/dl fall during illness Non fasting serum cholesterol < 100

mg/dl or 20mg/dl fall during illness Oedematous gall bladder wall on U/S

Ascites on U/S Pleural effusions (CXR Right lateral

decubitus or chest U/S to detect minimal effusion)

** Definitive evidence of plasma leakage

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Pulse PressureWarning if 20 or below!

• BP 120/60 Pulse Pressure =60

• BP 80/60 Pulse Pressure= 20

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DHF and DSSNot Complications of Dengue Fever

• Dengue Hemorrhagic Fever < 5%- leak

• Dengue Shock Syndrome-big leak

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Capillary Refill Time

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Dengue Shock Syndrome

• Profound Shock (No BP, No Pulse)

• Decompensated Shock (feeble pulse, pulse pressure <20)

• Compensated Shock (pulse pressure 20-30)

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Suitable Fluids in DSS

• Normal Saline

• Hemaccel

• 6% Starch

• Dextran 40 in saline

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Convalescent Phase• Lasts 5 – 7 days.

– Good appetite– Convalescent rash– Pruritus– Heamodynamic stability– Bradycardia– Diuresis– Stabilization of HCT– Rise in WBC– Rise in platelet count.

• Management:– Maintain oral intake, antihistamines, rest,

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Recovery

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Misconceptions

• Platelet Transfusions

• Steroids

• Misinterpretation of low WBC/TLC

• Antibiotics

• Growth Factors

• Empiric Anti Malarials

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Laboratory Diagnosis

• Epidemic/ Inter epidemic

• Health care worker location (field worker vs tertiary care facility)

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Laboratory Diagnosis

• Detection of Dengue viral antigen

• Detection of the Dengue viral genome

• Isolation of the Dengue virus

• Detection of Dengue specific IgG, IgM

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Dengue serology

• IgM detection (qualitative)In a suspected case of dengue, presence of

dengue IgM indicates recent infection IgM capture ELISA (blood collected after 5th

day)50% + in 3-5 day, 70% on 7th day, 100% day 10-14

• IgG detection (quantitative) Diagnostic sero-conversion is defined as a four

fold rise (or fall) in antibodies in paired sera (collected in the first 7 days & 10 – 14 days later)

HI assay / ELISA / Neutralization assay

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Laboratory diagnostic criteria

One of the following:1. PCR + NS1 +2. Virus culture +3. IgM seroconversion in

paired sera4. IgG seroconversion in

paired sera or fourfold IgG titer increase in paired sera

One of the following:1. IgM + in a single serum

sample2. IgG + in a single serum

sample with a HI titre of 1280 or greater

ConfirmedHighly suggestive

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IgG antibody - specific to the initial infecting DV serotype + cross reacting antibody

IgM antibody to the secondary infecting DV serotype

Following primary infection –

Specific antibody response + CMI (memory T cells)

Cross reactive antibody response + CMI (memory T cells)

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• The WHO does not recommend serologic tests by screening method

• ELISA is the preferred mode

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