Dengue Expert Advisory Group 1. Dengue – An Overview Dengue Expert Advisory Group

Introduction Dengue Fever Dengue Hemorrhagic Fever Dengue Shock Syndrome

Dengue Virus Family : Flaviviridae Genus : Flavivirus Serotypes : DV1, DV2, DV3, DV4 Enveloped virus 3 major proteins SS positive sense RNA Dr. S Guanasena

Viral Serotypes DV1 DV2 DV3 DV4 Subgroups and clades One or more virus types in circulation during an epidemic

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

Pathogenesis of Dengue Fever “Breakbone” symptoms due to adventitial and dendridic cell involvement of the marrow Cytopenias due to direct marrow involvement

Antibody Structure

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 Dr. S Guanasena

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 effective reacting T cells in eliminating the secondary infecting DV 2. T cell activation contribute to disease pathogenesis Dr S Guanasena

Exaggerated Cytokine response Pathogenesis of Leak Cytokines secreted from activated T cells Cytokines secreted from infected macrophages and endothelial cells Exaggerated Cytokine response DV infects endothelium and kills cells DV specific antibody interact with the endothelium Endothelial dysfunction Dr. S Guanasena

? DHF a misnomer DLF

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 Dr. S Guanasena

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, NSAIDS Dr. S Guanasena

Organ Involvement in Dengue Direct involvement - infection of hepatocytes or brain with the dengue virus Circulatory failure - poor organ perfusion Drugs – Paracetamol Dr. S Guanasena

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

Symptomatic to Asymptomatic Ratio 500:9500

List of Warning Signs Warrants 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

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

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 Biochemistry 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

Pulse Pressure Warning if 20 or below! BP 120/60 Pulse Pressure =60 BP 80/60 Pulse Pressure= 20

DHF and DSS Not Complications of Dengue Fever Dengue Hemorrhagic Fever < 5%- leak Dengue Shock Syndrome-big leak

Capillary Refill Time

Dengue Shock Syndrome Profound Shock (No BP, No Pulse) Decompensated Shock (feeble pulse, pulse pressure <20) Compensated Shock (pulse pressure 20-30)

Suitable Fluids in DSS Normal Saline Hemaccel 6% Starch Dextran 40 in saline

Convalescent Phase Lasts 5 – 7 days. Management: 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, discharge

Recovery

Misconceptions Platelet Transfusions Steroids Misinterpretation of low WBC/TLC Antibiotics Growth Factors Empiric Anti Malarials

Laboratory Diagnosis Epidemic/ Inter epidemic Health care worker location (field worker vs tertiary care facility)

Dr. S Guanasena

Dr. S Guanasena

Laboratory Diagnosis Detection of Dengue viral antigen Detection of the Dengue viral genome Isolation of the Dengue virus Detection of Dengue specific IgG, IgM Dr. S Guanasena

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

Laboratory diagnostic criteria One of the following: 1. PCR + NS1 + 2. Virus culture + 3. IgM seroconversion in paired sera 4. IgG seroconversion in paired sera or fourfold IgG titer increase in paired sera 1. IgM + in a single serum sample 2. IgG + in a single serum sample with a HI titre of 1280 or greater Confirmed Highly suggestive

IgM antibody to the secondary infecting DV serotype 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) Dr. S Guanasena

The WHO does not recommend serologic tests by screening method ELISA is the preferred mode