DENGUE

Guidelines for Diagnosis and

Treatment
Donnie Lumban Gaol

Internal Medicine , Faculty of Medicine University of

Indonesia
Ciptomangunkusumo Hospital

Global Spread of Dengue

It has been estimated that in recent years 50 million dengue
infection occur annually
2.5 billion people are at risk infected dengue 75% south
East Asia Region
Case fatality rates in some countries reach 5%

WHY IS DENGUE SUCH A BIG

PROBLEM TODAY?
Global
population
growth
Rural to urban
migration
Growth of
cities
Deterioration
of cities

Jet travel
Health
services poorly
organized/
underfunded
Lack of vector
control
professionals

Dengue
Famili :
Flaviviridae.
Genus :
Flavivirus.
Dengue is a virus
consisting of a
single-stranded
Ribonucleic Acid
(RNA)

There are four serotypes

of dengue
Life time
Den-1
immunity
follows
Den-2
infection to
Den-3
one type
Den-4
Infection of one serotype
does not ensure
immunity against the
other serotypes
The serotypes are
independent of each
other

Modes of Transmission
Vector borne
transmission
Mosquito
Non vector borne
transmission
Mother to child

Aedes
Aegypt
i

womans late term of their

pregnancy through the
placenta

Blood transfusion
Organ
transplantation
dengue infected
organ

Aedes albopictus
and Aedes
polynesiensis

Life cycle of the Aedes Mosquito

1-2 days

Larvae

Pupae

4-5 days

Stagnant water

Eggs

2-3 days

Transmission of Dengue Virus

by Aedes aegypti
Mosquito refeeds /
transmits virus

Mosquito feeds /
acquires virus
Extrinsic
incubation
period

Viremia
0

Illness
Human #1

Intrinsic
incubation
period

12
16
DAYS

20

Viremia
24

Illness
Human #2

28

Replication and Transmission

of Dengue Virus (Part 1)
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

4
3

Replication and Transmission

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
5

7. Virus replicates
in salivary glands

Viral replication involves the following steps:

a.
b.
c.
d.
e.
f.

Attachment to the cell surface

Entry into the cytoplasm
Translation of viral proteins
Replication of the viral RNA genome
Formation of virions (encapsidation)
Release from the cell

Viral load
Virulensi
Serotype
Immunity
Co-morbid
Co-infection
Obese
Age

Agent

Vecto
Host
r

Enviromen
t
Breeding
cycle

Risk Factors Reported for

DHF
Virus serotype
Severe dengue is greatest for DEN-2, followed by
DEN-3, DEN-4 and DEN-1
Pre-existing anti-dengue antibody
ANTIBODY DEPENDENT
previous infection
ENHANCEMENT
maternal antibodies in infants
Host genetics
Age (fatal cases are among children and young

adult)
Higher risk in secondary infections
Higher risk in locations with two or more serotypes
circulating simultaneously at high levels
(hyperendemic transmission)

Infected cell
higher

Disruption of
endotelial
barrier
Directly exposed of
subendothelial
matriks

Apoptosis of
endothelial cells
Cytokine
storm

Diasthesis
hemoragic
Trombocytope
nia

Non
neutralizing
antibody
Activation of
complement
system

Recruitment
of leucocyte
Leucocyte
migration

Activation
of
coagulation
cascade

Virus entry

leucopeni
a

Vascular
leakage
Intravascular plasma volume
depletion
Hemoconcentra
tion
Activated
thrombocyte

Postural gravity
Mobilisation
Type and volume of
fluid theraphy

PATHOGENESIS

 Widening of endothelial gaps Leakage

from intravascular to extravascular
Consequences: Hipovolemia,
Hemoconcentration, edema, dan visceral
congestion
Systemic leakage caused by inflammatory
cytokine related to systemic inflammation
syndrome
Inflamation Loose of Inter endothelial cell
adherens junction endothelial gaps
widening plasma leakage
This process depend on biochemical
substance ( proinflammatory cytokine),
biochemical factor (shear stress) and
individual host responses

 Degree of plasma leakage depend on:

Depend on the size of endothelial gap &
location of the organ
Perivascular
compartement
matriks
composition
Differences between hydrostatic pressure and
oncotic pressure

Trombocytopenia
Suppresion of trombocyte production in
bone marrow
in circulation
1. Trombocyte destruction Interaction antibody-antigen
Dengue viral on trombocyte surface
2. Disruption of endothelial cell Interaction between
trombocyte with subendothelial colagen Agregation &
destruction of trombocyte
3. IL-6 Antibodi IgM anti trombocyte trombocyte
destruction
4. Increased destruction or consumption (peripheral
sequestration and consumption)

Cont
A transient and reversible imbalance
of inflammatory mediators, cytokines
and
chemokines
occurs
during
severe dengue, probably driven by a
high early viral burden, and leading
to dysfunction of vascular endothelial
cells,
derangement
of
the
haemocoagulation system then to
plasma leakage, shock and bleeding

Dengue Clinical Syndromes

(WHO 1997)

Undifferentiated fever
Classic dengue fever
Dengue hemorrhagic fever
Dengue shock syndrome

Four Grades of DHF

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)

Dengue Classification WHO

2009

Probable Dengue
Live in or travel to endemic area
Fever and 2 folllowing criteria :
a) Nausea and vomiting
b)Rash
c) Aches and pain
d)Tourniquet test (+)
e) Leukopenia
f) Other warning sign

WARNING SIGN

Abdominal pain or Tenderness

Persistant vomiting
Clinical fluid accumulation
Mucosal Bleed
Lethary and restlessness
Liver enlargement > 2cm
Increase of hematocrite with a rapid
decrease from trombocyte

Hemorrhagic Manifestations
of Dengue
Skin hemorrhages petechiae,
purpura, ecchymoses
Gingival bleeding
Nasal bleeding
Gastro-intestinal bleeding:
hematemesis, melena,
Hematuria
Increased menstrual flow

Clinical Case Definition for Dengue

Shock Syndrome
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
Frank shock is direct evidence of
circulatory failure

Unusual Presentations
of Severe Dengue Fever

Encephalopathy
Hepatic damage
Cardiomyopathy
Severe gastrointestinal
hemorrhage

The Course of Dengue Illness

3 Phase of Dengue
Infection
CRITICAL PHASE
FEBRILE PHASE
RECOVERY
PHASE

- Usually on day 3-7

- After 24-48 hours critical phase
- Marked by decresed
2-7 daysthe temperature
gradual
reabsorption
of
- Symptoms
anorexia,
vomitus,
nausea,
level
extravascular
compartment
fluid take
sore
throat,
injected
pharynk,
conjungtival
- Progressive trombocytopenia, severe
in the
following
24-48
hours
-places
Physical
examination
high grade
hemorrage , organ impairment
-fever,
hepatomegaly,
manifestation
of
SYMPTOMS
general
well being
- Increase ofhemoragic
hematocrit level
improved ,appetite returns,
plasma
leakage
(+) pleyral
-Laboratory

leucopenia,mild
hemodynamic stabile, rash, pruritus,
effusion, ascites
trombocytopenia
- Laboratory hematocrit maybe low,
-- NS
1 positive
highly
suspected
Watch
Out for
the
warning
sign
trombocytedengue
gradually increase
SHOCK

WHEN U NEED TO TRANSFER THE PATIENT TO HIGH

DEPENDECY UNIT

Early presentation with shock (on

days 2 or 3 of illness)
Severe plasma leakage and/or shock
Undetectable pulse and blood
pressure
Severe bleeding
Fluid overload
Organ impairment (such as hepatic
damage, cardiomyopathy,
encephalopathy, Encephalitis and

STEPWISE APPROCH TO MANAGEMENT DENGUE

 Assetment for warning sign

abdominal pain , mucosal bleeding,

persistant
vomiting,
lethargy
,
restlessness
Additional symptoms aches , pain
(muscle, retroorbital, bone) , diarrhea
Additional information live or go to
endemic dengue , neighbour or family
member sufffering dengue
Past history dengue (+)/(-)
HISTORY

Co- existing condition

infancy,
pregnancy, obesity, diabetes mellitus,
hypertension, chronic kidney disease,
congestive heart failure
Jungle trekking and swimming in waterfall
(consider leptospirosis, typhus, malaria )
differential diagnosis
Recent unprotected sex or drug abuse
(consider acute HIV seroconversion
illness)

Tips and Trick

PROBABLE DENGUE

FEVE
R

Mixed Infection
(bacterial)

Not Dengue

-Abruptly High Fever

will slighty
decrease in the next
day

-Abruptly High Fever

and Continue Increase

Gradually increase /
step ledder increase

Identified the agent based on fever

type

VIRAL
INFECTION

Day

Day 1

Day 2

Day 3

Day 4

Day 5

Identified the agent based on fever

type

BACTERIAL
INFECTION

Day

Day 1

Day 2

Day 3

Day 4

Day 5

Identified the agent based on fever

type
Mixed viral and bacterial
infection

Day

Day 1

Day 2

Day 3

Day 4

Day 5

Physical
Examination

- General conditions mental

status, hydration status ,
hemodynamic status
- Tachypneu , acidotic breathing,
pleural effusion
- Abdominaltenderness/hepatom
egaly
ascites
- Rash and bleeding
manifestations
tourniquet test (repeat if
previously negative or if there is
no bleeding manifestation)

Petechiae

Tourniquet Test
Inflate blood pressure cuff
to a point midway
between systolic and
diastolic pressure for 5
minutes
Positive test: 20 or more
petechiae per 1 inch2
2
Pan American
Health
Dengue
(6.25
cmOrganization:
)
and Dengue Hemorrhagic Fever: Guidelines
for Prevention and Control. PAHO:
Washington, D.C., 1994: 12.

Positive Tourniquet Test

- Complete Blood Count

Hemaglobin, Haematocrit,
Trombocyte

Laborato
ry

- Tests of liver injury, glucose,

serum electrolytes, urea and
creatinine, bicarbonate or
lactate, cardiac enzymes, ECG
and urinalysis if there is a
indication ( not routinely)
- NS 1 early phase ( day 1-3)
- Serology IgM and IgG

Laboratory Methods for Dengue

Diagnosis, CDC Dengue Branch
Virus isolation to determine
serotype of the infecting virus
IgM and IgG ELISA test for
serologic diagnosis
NS 1 for early detection
dengue

Collection and Processing of

Samples for Laboratory Diagnosis
Type of
Specimen
Acute-phase
blood
1-5 days Fever

Time of
Collection

Type of
Analysis

When patient presents FEVER

Virus isolation
collect second sample and/or serology
during convalescence
NS -1

Convalescent-phase
blood
(days Fever)

Between days 6 and 21

after onset

Serology

ANTIBODY TITER

IgG
IgM

Virus

5 10 15
Early phase
Symptoms (-)
Primer
Infection

IgM

IgG
Virus

5
Early

Symptoms (+)
Secondary
infection

Immune response for dengue infection

(Days)

Management for Dengue Pasien

GROUP A

Dont have warning sign

Stable Hemodynamic
Adequate volume of oral fluid
Can pass urine at least once
every 6 hours

RECOMMENDATION
Reviewed daily by health care providers temperature
pattern, volume of
fluid intake and losses, urine output
RECOMMENDATION
Sent
(volume and frequency),
warning
home signs, signs of plasma
Antipyretic
leakage and
bleeding, haematocrit,
and white blood
Paracetamol
Aspirin,
cell andIbuprofen,
platelet counts
untilacid,
theysteroid
are outfrom
mefenemic
NOT
critical period
RECOMMENDED
Encourage
WARNING
oral intake
at oral
rehydration
solution If
SIGN
GO
TO HOSPITAL
not tolerated, start intravenous fluid therapy of 0.9%
saline or Ringers lactate with or without dextrose at
maintenance rate

Management for Dengue Pasien

GROUP B

Crystaloid
theraphy
5-7 mL/Kg/Hours
(1-2 hours)
Crystaloid
theraphy
3-5 mL/Kg/Hours
(2-4 hours)
Crystaloid
theraphy
2-3 mL/Kg/Hours
(1-2 hours)

Dengue patient with warning

sign
co-existing conditions that
may make dengue or its
management more
Complicated
Reduce
intravenous fluids
certain
social
circumstances
gradually
when
the
rate
of plasma
If the
haematocrit
remains
leakage
towards
the end
the samedecreases
or rises only
minimally,
of
Ifthe
thecritical
vital
signs
phase
are worsening
continue
with
the same
rate (23
and haematocrit is rising
ml/kg/hr)
IMPORTANT
in critical
the
rate
phase
to 5

rapidly,
Give theincrease
minimum
intravenous
close
10
ml/kg/hour
monitor
for 12 to
hours
,
fluid
volumehaemodynamic
required
maintain
vital
signs,
hydration
urine
good
perfusion
and status,
urine output
output
and0.5
haematocrit,
of about
ml/kg/hr. bleeding
manifestation
Reasses clinical
status ,
Repeat hematocrit
Cek urine output

Management for Dengue Pasien

GROUP C

Require emergency treatment

and urgent referral when they
are in the critical phase of
disease

RECOMMENDATION
RECOMMENDATION
GOALS
of RESUSCITATION
Condition
that, you
MUST shock
REFFERED
a) Plasma losses
preshock,
Give

B) There should be continued replacement of further

immediately
intravenous
fluid
resucitation

Improving
central
and
peripheral
circulation
plasma
losses
to
maintain
effective
at
severe plasma leakage leading to denguecirculation
shock

FIRST
pressure,
10-20
(decreasing
tachycardia,
improving blood
least
for
2448
hours CRYSTALOID
and/or
fluidCHOICE
accumulation
and pink extremities,
withvolume,
respiratory
distress
mL/Kg
BW (warm
in
30-120)
see
the and
C)pulse
Close
monitoring
haemodynamic
status,
hydration
severe
haemorrhages
capillary
refill
time
<2
seconds)
status,
urine
output
, mental
status,
bleeding
responses

if
good
continue
to
maintain
severe organ impairment (hepatic damage, renal
manifestation
,cardiomyopathy,
haematocrite
level
fluid
,
if
worse
give
the
crytaloid again
10impairment,
encephalopathy
or

end-organ
perfusion
i.e. stable
D)Improving
Blood
transfusion
should
be given
only inconscious
encephalitis)
20 (more
mL/Kgalert
BWor, and
if still nourine
response
Give
level
less
restless),
output

cases with suspected/severe bleeding

Koloid
ml/kg/hour,
metabolic
) no
E)0.5
DONT
GIVE decreasing
TROMBOCYTE
if acidosis
there is
indication

Severe bleeding can be recognized by:

Persistent and/or severe overt bleeding in the
presence of unstable
Haemodynamic
status,
regardless
of
the
haematocrit level;
A decrease in haematocrit after fluid resuscitation
together with unstable haemodynamic status;
Refractory shock that fails to respond to
consecutive fluid resuscitation of 40-60 ml/kg;
Hypotensive shock with low/normal haematocrit
before fluid resuscitation;
Persistent or worsening metabolic acidosis a
well-maintained systolic bloodpressure, especially
in those with severe abdominal tenderness and
distension

Treatment of haemorrhagic complications

Give 510ml/kg of fresh-packed red

cells or 1020 ml/kg of fresh whole
Consider repeating the blood
transfusion if there is further blood
loss or no appropriate rise in
haematocrit after blood transfusion
There is little evidence to support the
practice of transfusing platelet
concentrates and/or fresh-frozen
plasma for severe bleeding.

Complication

Fluid overload
DIC
Hyperglycemiaatau hypoglycemia
Metabolic ascidosis
Electrolit imbalance
Renal failure and liver failure

NO VACCINE
AVAILABLE
Vaccines are being created and are in clinical
studies so that they can be tested and researched
for safety and effectiveness (Guzman, Vazquez &
Kouri, 2009)
Some issues with creating vaccines include the
differences between the four serotypes which may
require different types of vaccine instead of one
and the lack of an animal research subject
(Guzman et al. 2009)

Prevention
The best preventive measure is vector
control
Personal protection against mosquito biting
Screening doors and windows
Protective clothing
Application of mosquito repellents on exposed
skin

Vector Control Methods:

Biological control
Largely experimental
Option: place fish in containers to eat larvae

Environmental control
Elimination of larval habitats; Cover water
holding containers, Discard artificial containers
It is the most likely method to be effective in
the long term.

Vector Control Methods:

Chemical Control
Larvicides may be used to kill immature aquatic
stages
Ultra-low volume fumigation is ineffective
against adult mosquitoes as Aedes aegypti is
fully domesticated
Mosquitoes may have resistance to commercial
aerosol sprays

Community Participation
Prevention and mosquito control through
active

community

involvement

and

participation to reduce larval breeding

sources is the key.
Educate the public in the basics of
dengue, such as:
Where the mosquito lays the eggs
The link between larvae and adult
mosquitoes

Patient Education

Dengue fever is NOT contagious

through person-to-person contact
Early hospitalization
Reduce Aedes aegypti vector
populations
Reduce exposure to Aedes
aegypti.
Use insect repellent.
Sleep under a mosquito net in
affected areas.
Wear protective clothing.

Take Home Messages

Dengue isnt a horrible disease
History of Fever is very Important
Early diagnose and early treatment
have a good prognosis
The main theraphy is fluid theraphy and
bed rest
No vaccine for dengue
Dont be a Fever Maniac and
Trombocytopenia Phobia

THANK YOU

Tips and Trick for

Dengue

Tips and Trick

PROBABLE DENGUE

FEVE
R

Mixed Infection
(bacterial)

Not Dengue

-Abruptly High Fever

will slighty
decrease in the next
day

-Abruptly High Fever

and Continue Increase

Gradually increase /
step ledder increase

Identified the agent based on fever

type

VIRAL
INFECTION

Day

Day 1

Day 2

Day 3

Day 4

Day 5

Identified the agent based on fever

type

BACTERIAL
INFECTION

Day

Day 1

Day 2

Day 3

Day 4

Day 5

Identified the agent based on fever

type
Mixed viral and bacterial
infection

Day

Day 1

Day 2

Day 3

Day 4

Day 5

Tips and Trick

If day 1 or 2 fever already have a
severe manifestion or shock NOT
DENGUE, think about bacterial
infection (SEPTIC or TOXIC SHOCK)
Additional symptoms in dengue
headache, retroorbital pain, vomit,
epigastric pain, fibromyalgia,
arthalgia

Viral Rash / Exanthema

Acute Phase
-Appear in febrile
phase
- Usually in the site
of port d entry of
the dengue virus

Convalence Phase
- Appear after 48
hours critical phase
- it means
recovery phase
- Site palms and
soles (1st) , other
part of the body
- Itchy , hyperemic

Bleeding manifestation
Past history of bleeding
manifestation ( epistaksis , purpura,
petechie ) for other differential
diagnosis such as ITP
Bleeding manifestation after
spontaneous fever relieve
PATOGNOMONIC for DENGUE

Hemodynamic
Hypotensive VS Shock
Pre shock low blood pressure ,
tachicardia, weak pulse , pulse
pressure < 20 mmHg +
restlessness , cold extrimities ,
tachpneu
In Dengue infection usually happen when the fever had
already release

If happen when there is still fever SEPTIC

SHOCK caused by bacterial infection

Organ Involvement
Liver

Kidney

- Increasing of ALT , AST ( 4-5 xULN)

- AST or ALT >>>> more severe of dengue
infection
- If bilirubin level also increase still other
posibility diagnose Leptospirosis , HELLP
SYNDROME in pregnant women
-- Usually we can found proteinuria , but without
increasing of ureum and creatinine level
- EXCEPTION in Severe Dengue Shock Increasing
ureum and creatinine level + Symptoms and Signs
of shock + urine output <1 cc/Kg BW
IF no Shock , but still have increasing in ureum
and creatinine level differential diagnose was
LEPTOSPIROSIS

Organ Involvement
Lung

Central
Nervous
System

Cardivascu
lar

- Edema intertitial of pulmary tissue make

hypoxia in pulmonary tissue the manifestation
are Acute Lung Injury or Acute Respiratory
Distress Syndrome (ARDS)

--Although Dengue Virus is neurotrophic virus, but

just a few case showed neurological manifestation
like unconciousness, neurological deficit, seizure

- The possibilty of cardiac manifestation are

arrythmia and cardia ischemic
- Be careful in giving fluid theraphy in patient with
history of cardiac disease