Dengue Infections-An Overview

Dengue Expert Advisory Group

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 Overview
• Dengue Infection Basics

• Classification of Dengue infections

• Clinical Course of Dengue Infections

• Lab Diagnosis

• Management

• Misconceptions
 Dengue fever

is an infectious tropical disease caused by

the dengue virus.
 Dengue Virus
• Family : Flaviviridae
• Genus : Flavivirus
• Serotypes : DV1, DV2, DV3, DV4

• Enveloped virus
• 3 major proteins
• SS positive sense RNA

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Dr. S Guanasena
First New Dengue Virus Type
in 50 Years DENV 5
 Vector

Aedes Aegypti Aedes Albopictus

 Aedes Mosquito
•Only the female Aedes mosquito
feeds on blood. This is because they
need the protein found in blood to produce
eggs.
•Male mosquitoes feed only on
plant nectar.

•On average, a female Aedes

mosquito can lay about 300 eggs
during her life span of 14 to 21
days.
Life Cycle Of Aedes Mosquito

2-3 days

1-2 days
4-5 days
13
 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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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

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Dr S Guanasena
 Cytokines secreted from infected Pathogenesis of Leak
macrophages and endothelial Cytokines secreted from
cells activated T cells

Exaggerated Cytokine response

DV specific antibody interact with DV infects endothelium

the endothelium and kills cells

Endothelial dysfunction

Dr. S Guanasena 19
 Dengue Virus Infections
Classification
Dengue
Virus
Infection

Asymptomatic Symptomatic

Dengue Dengue
Undifferentiated Fever
Fever Hemorrhagic
Syndrome Fever Expanded
Dengue
Syndrome/
Isolated
organopathy/
No Dengue Unusual
Without With Unusual Shock
Hemorrhage Hemorrhage Shock manifestation
Syndrome
 Dengue Viral Infection
(10,000 patients)

Asymptomatic Symptomatic
(9,000) (1,000)

Viral Syndrome Dengue Fever DHF

(500) (400) (100)

Unusual DHF
Prolonged shock Plasma leakage
Liver failure
Encephalopathy
Renal failure
Co-infection DHF DSS
Co-morbidities (98-99) (1-2)
Case Definition for Dengue Fever

• Suspected

• Probable

• Confirmed
Reportable Dengue Fever

Any suspected
probable
or
confirmed
case of dengue should be
reported.
Case Definition for Dengue Hemorrhagic Fever
The following must all be present:

Fever, or h/o acute fever, lasting 2-7 days, occasionally biphasic

Hemorrhagic tendencies, evidenced by at least one of the following

• A positive tourniquet test
• Petechiae, ecchymoses or purpura
• Bleeding from mucosa, gastrointestinal tract, injection sites, or
other locations
• Haemetemesis or malena
Thrombocytopenia (≤100,000 per mm3)

Evidence of Plasma Leakage manifested by at least one of the following

• A rise in Hct ≥20% above average for age, sex and population
• A drop in Hct ≥20% after volume-replacement treatment
• Signs of plasma leakage such as pleural effusion, ascites and
hypoproteinemia
 Case Definition for Dengue Shock
Syndrome

All of the above four criteria of DHF must be

present, plus evidence of circulatory failure
manifested by:
• Rapid and weak pulse, and
• Narrow Pulse Pressure (<20 mmHg)
Or manifested by
• Hypotension for age, and
• Cold, clammy skin and restlessness.
 Classification of DHF
• DHF I No Shock
• DHF II

• DHF III
• DHF IV Shock
Phases of Dengue Infections

Febrile Phase

Critical Phase

Recovery/Convalescent
Phase
Natural Course of DF
Febrile phase: High fever for 2 – 7 days

No critical phase in DF!!!

Convalescent phase:
2-5 days
Longer in adults
 Febrile Phase
• High continued fever (less than 10 days)
• Skin erythema(flushed face and extremities)
• Myalgia
• Arthralgia
• Headache
• Petechie
• Leucopenia
• Positive Torniquet Test
• Thrombocytopenia
• Tender hepatomegaly – DHF > DF
Torniquet test
 Convalescent Phase
• Good appetite

• Convalescent rash

• Pruritus
Palms & soles

• Bradycardia
Arrythmias -blocks

• Rise in WBC rise in platelet count

Convalscent rash
Itching on palms and soles
Natural Course of DHF
Febrile phase: High fever for 2 – 7 days

Critical phase: can start from Day 3..

(LEAKAGE PHASE)
Lasts only 24- 48 hrs
Usually on D5/ D6, but earliest on D3

Convalescent phase:
2-5 days
Longer in adults
 DHF vs DF
Febrile Phase
Febrile
2 – 7 days Phase

Critical Phase Critical

3-7 days Phase
Lasts only for 24 – 48 hours

Recovery Phase
Recovery
5 - 7 days Phase
DF or DHF ?
 DF vs DHF
• Important to differentiate

• Two different clinical conditions from the beginning of

the illness; Though they look very similar on the first
2 days

• However badly managed DF will never become

DHF
(DF does not progress to DHF)
Difference between DF & DHF
Dengue Fever(DF)
– Headache, muscle/ joint/ bone pain,
– BLEEDING  seen in some (not all)
– Haemorrhagic manifestations seen
in both DF & DHF (Torniquet Test)
– Leucopenia
– Plt <100,000 in about 50% of
patients(may be normal initially)
– No plasma leakage
 Critical Phase
Plasma Leakage
 Dengue Haemorrhagic Fever(DHF)
Key feature is PLASMA LEAK
– Plasma leakage:
• Rising Hct  20% or More OR even less but
towards 20% if on IV fluids or on excess oral
fluids,
• Se Cholesterol <100mg/dl
(or drop of 20mg/dl)
• Se Albumin <3.5 g/dl
(or drop of 0.5g/dl)
 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 44
 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 45
 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 46
 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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 Diagnosis
Clinical

Lab Test
 Laboratory Diagnosis
• Virus isolation
– Serotypic/genotypic characterization

• Virus nucleic acid detection

• Virus antigen detection

• Immunological response based tests

– IgM and IgG antibody assays

• Analysis for haematological parameters

 Viral Nucleic Acid Detection

Sample of viremic phase

 Tissue, Whole blood, Serum, Plasma

 Dengue viral genome-RNA by PCR

 Time to result; 1-2 days

WHO Guidelines 2011

 Viral Antigen Detection
Non Structural (NS)-1

Glycoprotein

Essential for replication & viability

First 5-6 days

Serum and tissue

Time to result; 1day

WHO Guidelines 2011

Immunological Response Based
Tests
• Acute Phase – IgM & IgG
– After 5 days

• Convalescent Phase – IgM & IgG

– After 2-3 weeks
IgM/IgG Ratio

• WHO does not recommend serologic tests by screening

method
• ELISA is the preferred mode
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Dr. S Guanasena 54
 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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 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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Dr. S Guanasena
 Highly Suggestive Confirmed

One of the following: One of the following:

1)IgM+ive in a single 1)RT-PCR +ive

serum sample
2)Virus culture +ive
1)IgG+ive in a single serum
sample with titre ≥1280 3)IgM seroconversion in
paired sera

4)IgG seroconversion in
paired sera or four-fold
IgG titre increase in
paired sera
 Analysis of Haematological
Parameters

• Hb

• Haematocrit

• TLC with differentials

• Platelets
 Haematological Change

• WBCs

– Leukopenia
– Normal/ predominant neutrophils in early febrile phase

– Ratio of neuto/lympho as predictor of critical phase.

 Haematological Change
• Platelets
– <100000
– Rapid drop – indicator of critical phase

• Hct
– Normal
– 10% rise
– ≥20% rise
 Haematocrit

• Rise of Hct by 20% over the

baseline indicates leakage

• Eg: if baseline PCV 35% 42% =

20% rise

• 35%10% is increase by 3.5 

20% is increase by 7
 Plasma Leakage Indicators

• Right lateral decubitus CXR

• USG Chest & Abdomen

• Serum Albumin- <3.5 g%

• Serum Cholesterol- <100 mg%

WHO Guidelines 2011

 Investigations for Complications-
ABCS

Acidosis –ABGs

Bleeding – G/C, PT, APTT

Calcium

Sugar
WHO Guidelines 2011
 Additional Investigations

• Serum electrolytes and BUN, creatinine

• Liver function tests.

• Cardiac enzymes or ECG if indicated,

especially in adults.

• Serum amylase
 Criteria for CBC
• All febrile patients at the first visit to get the
baseline HCT, WBC and PLT

• All patients with warning signs

• All patients with fever >3 days

• All patients with circulatory

disturbance/shock (+glucose check).
Mico hamematocrit machine
 Management Dengue Fever
• Symptomatic

• Monitoring
 Management—Febrile Phase
Restricted Physical Activity
• Reduction of fever
– Paracetamol
– Tepid sponge
– Do NOT give NSAIDs NOT even suppositories
• Nutritional support
– Soft diet
– Electrolyte solution, fruit juice
• Follow up
• Advice on review & admission

• Advise warning signs of leaking* 68

 Warning Signs
• No clinical improvement or worsening of the
situation just before or during the transition to
afebrile phase or as the disease progresses
• Persistent vomiting
• Severe abdominal pain
• Lethargy and/or restlessness
• Bleeding
• Giddiness
• Pale, cold and clammy extremities
• Less/no urine output for 4–6 hours
Highly Suggestive of DHF
 Disproportionate tachycardia
 Narrowing of pulse pressure < 20
mm
 CRFT > 2 secs
 Tender hepatomegaly (DHF likely)
Confirmed DHF**
 Ascites on U/S
 Pleural effusions (CXR Right lateral
decubitus or chest U/S to detect
minimal effusion)
** Definitive evidence of plasma leakage

 Haemoconcentration
HCT 20% rise from baseline or rise
approaching 20% if patient already
on IV fluids
 Biochemistry
o 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

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 Pulse Pressure
Warning if 20 or below!

• BP 120/60 Pulse Pressure =60

• BP 80/60 Pulse Pressure= 20

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 DHF and DSS
Not 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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• Once the patient is detected to be in the
critical phase…..

…A STRICT FLUID REGIMEN IS NEEDED

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 Difference from Septic Shock

No fever

Responds to Fluid Therapy

 DENGUE FEVER/DHF
Differential Diagnosis
• Arboviruses Chikungunya

• Other viral Measles; rubella and other viral

Diseases exanthems; Epstein-Barr Virus,
Enteroviruses, Influenza;
hepatitis A, Hantavirus
• Bacterial diseases
Meningococcemia, leptospirosis,
typhoid, melioidosis, rickettsial
diseases, Scarlet fever

• Parasitic diseases
Malaria
 Criteria for Admission

• Warning signs
• Platelet count < 100,000 cells/c.mm
• Pregnancy
• Elderly patients & infants
• Obese
• Co morbidity
• Diabetes
• IHD
• Chronic renal failure
Refer to Hospital Emergency
“Ignorance is the most serious disease of
mankind and is the cause of all its ills.
Healing is achieved through knowledge”-
Buddha.
 Misconceptions

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

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 When platelets are low may need but only in
very exceptional circumstances

– Each platelet pack is 50-150ml  contribute to

fluid overload

– No prophylaxis plt. Transfusion

– At the initial phase the platelet drop >.100,000 is

due to BM suppression but later when it drops
<100,000 the cause is increase platelet
consumption and the BM become hypercellular
with increase production
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 Blood & blood component used
in DHF/DSS patients

Crystalloid
100%

Platelet 0.4%

Colloid
Blood 20-25%
10-15%

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Courtesy of Prof Siripen- Thailand
 Myths Associated with Dengue
1. Dengue is a contagious disease

2. Secondary infection in Dengue is always fatal

3. Unjustified use of fluids and blood products

4. Myths and alternative medication

DENGUE BATTLE WON, WAR NOT OVER !!!