paediatric

TROPICAL MEDICINE
Isna Nurhayati

Dengue Hemorrhagic Fever

Past, Present, and The
Future

Isna

Disebabkan virus dalam kelompok

arbovirus B, terdapat 4 stereotipe ,
yaitu tipe 1,2,3 dan 4
Vektor :
- Aedes aegypti
- Aedes albopictus
- Aedes scuttelaris
- Aedes polynesiensis
- Aedes rotumae
- Aedes hakansoni
- Aedes cooki

Dengue
Fever

The most important of

Arthropod-borne viral
diseases affecting
(pronounced DENGgay),
WHO 2007humans
From 500 000 cases of

breakbone or dandy
fever
Ex vice President Al Gore in
"An Inconvenient Truth"
Documentary Focuses on
Al Gore's Fight
Against Global Warming
Rating

Watch Live Earth On

Demand
July 8, 2007 12:48 PM
The New York Live Earth
Concert

DHF/DSS,
> 20 000 deaths occur each
year
Incidence
increased in last

50 yrs, Endemic > 100

countries,
two-fifths of the world's
population are at risk for
dengue
Global warming
Mosquitoes on the march
to America, Europe,

Australia

Dengue fever spread

dramatically as
global temperatures head
upward.
Paul R. Epstein. Pesticides and You.
Vol. 20, No. 4, 2000-2001

Dengue in the
Cook Islands

Nature; July 2001

Dengue/DHF
West Nile
Yellow fever

Japanese Encephalitis
Tick borne enchephalitis

THE VECTORS

THE VIRUS
There are four serotypes of dengue virus (DEN-1, DEN-2, DEN-3 and
DEN-4).
Dengue virus is transmitted via the bite of in particular A.aegypti &
A.albopictus.
Bite during
Adapted
to breed
around
human
Figure 1. Aedes aegypti
(left) daytime.
and Aedes
albopictus
(right)
Credits:
Michele
dwellings.
Cutwa

WORLD DISTRIBUTION OF DENGUE, CDC 2007

Aed

Aedes infested area

End

Dengue endemic area

Tab. Virus Distribution in Indonesia,

1975-2007
Locations

DEN-1

DEN-2

DEN-3

DEN-4

Jakarta

Yogyakarta

Surabaya

Pontianak

Medan

Palembang

Makasar

Manado

Merauke

DEN= the dengue viruses, serotype 1-4

Source: NIHRD, MoH, Indonesia
Erna Tresnaningsih

UNDIP 17-5-08

Problem of DHF
1.

No specific drug and vaccine

2.

Low community and inter-sectoral

participation

3.

Case fatality is still high in several

districts in Indonesia

4.

Inadequate of surveillance

5.

Unccontroled risk factors

6.

Inadequate budgeting
Erna Tresnaningsih

UNDIP 17-5-08

House Index (HI) by Province

in Indonesia, 2004

Erna Tresnaningsih

UNDIP 17-5-08

Case Fatality Rate (CFR) of DHF

by Province in Indonesia, 2007

Erna Tresnaningsih
UNDIP 17-5-08

IR (per 100,000 population)

Changes of the endothelial function

caused by virus or cytokines lead to
prothrombotic state and vascular
leakage
Release of adhesion molecules ( ICAM
& VCAM ), cytokines IL-1,IL-8, MP
Vascular leakage and prothrombotic
activity

Multistep leucocyte adhesion

cascade on EC in DSS

Secondary Inf

CCR1

Monocyte

CCR3

Eos

Basophil

M 2

TH2-m

CCR3
47
x

Adesi

MadCAM1

Migrasi

Eotaxin
RANTES
MCP

VCAM -1

3
2
1

Trombosis

Fibrinolisis

TECK

ICAM

4
3

Proinflammatory cytokines
sVCAM-1)
Neutrophyl adhesion and EC
EC leakage

Myrna Soepriadi. Allergy-Immunology Subdivision. Child

Health Department. Hasan Sadikin Hospital.

Inflamasi

47

ICAM-1

Vascular endothelium

Rolling Aktifasi

4 1

MadCAM1

Eotaxin

MIP-1

ICAM-1

CCR3

TH2-m

ICAM-2

L 2

CCR9

sL

CCR5

L 2

Hista m

TF expression and MP has a role in

coagulation activity lead to
consumption coagulopathy which
caused low level of coagulation factors
and natural inhibitor factors
Increase PAI-1 as anti-fibrinolysis
The end result is vascular leakage and
bleeding

17

DHF and DSS is a severe form of

dengue virus infection
The hallmark and critical condition is
hypovolemic shock and bleeding
leading to increase mortality
Endothelial dysfunction caused by
dengue virus and cytokines released by
macrophage has a pivotal role in the
pathogenesis of DHF

Dengue virus infection

19

PATHOPHYSIO
LOGY
DHF

VASCULAR PERMEABILITY
Plasma leakage

THROMBOCYTOPENIA
< 100 x 103/L

PT/APTT

DIC

HIPOVOLEMIA
( Hct )
HIPOVOLEMIC SHOCK

COAGULOPATHY

SEVERE HEMORRAGE
(normal/ Hct)
TISSUE ACIDOSIS

With appropriate
Blood/component
support

With appropriate
Fluid terapy

RECOVERY

MULTIORGAN FAILURE

INTRACTABLE SHOCK

RECOVERY

Pathophysiological changes

Increased vascular permeability

Loss of plasma from the vascular compartment
Haemoconcentration

Pathophysiological changes

Haemorrhagic tendency
Thrombocytopenia & thrombocytopathia
Vasculopathia

Endothelial cell activation

Thrombocytopenia

Disseminated intravascular
coagulation

Haemostasis
1. Defect in primary haemostasis
Thrombocytopenia & thrombocytopathia
Vasculopathia

2. Defect in secondary haemostasis

Coagulopathy?
Disseminated intravascular coagulation?

3. Defect in fibrinolysis

24

Primary haemostasis

Y.S. Ahn. J. Thromb Haemost. 2005 May; 3 (5): 884-887

25

Immune mediated

Decreased thrombopoiesis

Increased platelet consumption

Direct infection of Dengue virus

thrombocytopenia and/or
thrombocytopathia
ECs injury by the virus adherence
and consumption of platelet

Haemostasis
1. Defect in primary haemostasis
Thrombocytopenia & thrombocytopathia
Vasculopathia

2. Defect in secondary haemostasis

Coagulopathy?
Disseminated intravascular coagulation?

3. Defect in fibrinolysis

27

DIC is a disorder (syndrome),

Characterized by systemic activation of
coagulation widespread deposition
of fibrin organ failure
Consumption platelet and coagulation
bleeding.

ACTIVATION OF
INFLAMMATORY PATHWAY

Mediated by activation
coagulation protein and by
depression of the protein C
system

DIC
DIFFUSE ACTIVATION OF COAGULATION

DEPOSITION OF FIBRIN
(DISSEMINATED)

CONSUMPTION COAGULATION
FACTORS AND PLATELET

MICROVASCULAR
THROMBOSIS IN VARIOUS
ORGANS

MULTIORGAN FAILURE

BLEEDING

Secondary haemostasis

Disseminated intravascular coagulation

a platelet count <100,000/mm3; prolongation of clotting times, such as the
prothrombin time and the activated partial-thromboplastin time; the presence
of fibrin-degradation products in plasma; and low plasma levels of
coagulation inhibitors, such as antithrombin III.
Disseminated Intravascular Coagulation.
Levi M., ten Cate H. N Engl J Med 1999.

31

Secondary haemostasis
Coagulation abnormalities in
Dengue
are associated with Dengue
severity
Coagulation abnormalities in DSS
meet criteria for DIC1 , however

Levi M., ten Cate H. N Engl J Med 1999.

32

REDUCTION OF PHYSIOLOGICAL
ANTICOAGULANT:
Antithrombin
Protein C/S (demonstrated in DHF)
TFPI

FACTORS INFLUENCE:
Increased consumption
Impaired liver synthesis
Vascular leakage
Down-regulation of thrombomodulin

Haemostasis
1. Defect in primary haemostasis
Thrombocytopenia & thrombocytopathia
Vasculopathia

2. Defect in secondary haemostasis

Coagulopathy?
Disseminated intravascular coagulation?

3. Defect in fibrinolysis

35

IMPAIRED FIBRINOLYSIS
Mediated by release of plasminogen
activator from EC
Immediately followed by an increase of
PAI-1

Demam tinggi mendadak, kontinyu 2-7 hari

Perdarahan ( uji tornikuet positip, petekia,
purpura, ekimosis, epistaksis, perdarahan
gusi, hematemesis, melena )
Hepatomegali
Efusi pleura
Edema
Renjatan (nadi lemah cepat isi turun, tensi
turun, kulit dingin lembab, gelisah, sianosis)

Demam tinggi mendadak tanpa sebab

jelas, terus-menerus selama 2-7 hari.
Terdapat manifestasi perdarahan,
termasuk uji bendung (+), petekie,
ekimosis, epistaksis, perdarahan gusi,
hematemesis, dan melena.
Pembesaran hati.
Syok, ditandai nadi cepat dan lemah serta
penurunan tekanan nadi, hipotensi, kaki
dan tangan dingin, kulit lembab dan
pasien gelisah.

Trombositopenia (100.000/l atau

kurang).
Hemokonsentrasi, dilihat dari
peningkatan hematokrit 20% menurut
standar umur dan jenis kelamin.
Dua kriteria klinis pertama +
trombositopenia dan hemokonsentrasi,
serta dikonfirmasi secara uji serologi
hemaglutinasi.

Classification
DF/DHF

Grade

DF

DHF

Symptoms
Fever with two or more of the
following signs: headache,
retro-orbital pain, Myalgia,
arthralgia

Above signs plus positive

tourniquet test

DHF

II

Above signs plus spontaneous

bleeding

DHF

III

Above signs plus circulatory

failure (week pulse,
hypotention, restlessness)

DHF

WHO, 1999

IV

Profound shock with

undetectable blood pressure
and pulse
Erna Tresnaningsih

UNDIP 17-5-08

Laboratory
Leukopenia
Occationally,
Thrombocytopenia,
may be present, no
evidence of plasma loss
Thrombocytopenia
<100.000,Hct rise 20%
Thrombocytopenia
<100.000,Hct rise 20%
Thrombocytopenia
<100.000,Hct rise 20%
Thrombocytopenia
<100.000,Hct rise 20%

Laboratory diagnosis of Dengue

Serology

ELISA

Virus detection

Natural dengue virus infections

Viremia
IgM
Pr IgG
Sec IgG

Days post onset

Gubler DJ 1993, unpublished

(http://www.searo.who.int/en/Section10/Section332/Section554_2566.htm )

 primary infections:
IgM antibodies appear soon after infection/onset of symptoms,
relative short lasting
IgG antibodies appear in early convalescence, in relatively low titres
and persist for months
secondary infections:
very low or undetectable IgM antibodies
boost in IgG antibodies, appear soon after infection and may be
detected for years post infection

IMAGING
Radiology is an important
adjunct examination to confirm
the evidence of plasma leakage
and able to observe the severity
and the complications of DHF
Modality : Chest X-Ray
Ultrasonography
CT/MR

CHEST X RAY

Chest X-ray to observe :

Pleural effusion
Assess the pleural-effusion index (PEI)
ARDS, Brpn , Edema pulmonum

Pleural effusion index ( PEI ) defined as

ratio in percentage between the
maximum width of the R pleural
effusion and the maximum width of
hemithorax.

The degree of plasma leakage may be

quantified by means of the PEI

Pleural-Effusion Index
(PEI)

PEI at time of admission had the most

critical role to predict shock in DHF

PEI > 6% at time of admission had

significant correlations with the
occurance of shock

(Tatty ,
2004 )

ANTERO POSTERIOR

RIGHT LATERAL DECUBITUS

Pleural Effusion index is 5,5%

Pleural Effusion index is 5,5 %

ULTRASONOGRAP
HY
An ideal, safety, noninvasive

investigation to detect plasma leakage

(pleural - pericardial effusion &
ascites), hepatomegaly, splenomegaly.

Abdominal & chest scanning

Detect the early mild

form of DHF :

GB-wall-thickening
wall thickness > 3 mm

Pericholecystic fluid
Minimal ascites
Pleural & pericardial effusion
Hepatosplenomegaly

NORMAL

PLEURAL
EFFUSION

Management Of Dengue
Hemorrhagic Fever

Integrated Prevention and Control

Early diagnosis and promp treatment,

H
E
A
L
T
H
P
R
O
M
O
T
I
O
N

Focus response (epid. Investig. & specific response with or without

perifocal space spraying )

Source reduction (3M plus) - COMBI

Weekly case analysis and

response, and monthly
avarage DF/DHF case for
the last 3 or 5 years

Intensification control before

transmission season to prevent
outbreak

Outbreak preparedness and response

Weekly Larval inspections (by Larval inspectors)

Erna Tresnaningsih
UNDIP 17-5-08
Routine
(every 3 moths)
larval inspections by HC

S
U
R
V
E
I
L
L
A
N
C
E

Simtomatik
Cairan dan makanan adekuat
Observasi
- Tanda vital
- Hemoglobin, hematokrit,
trombosit
- Keseimbangan cairan

Cairan kristaloid, koloid

Komponen darah
- FFP
- PRP
- TC
- PC
Monitoring

Atasi syok dengan kristaloid 20

cc/kgbb/bolus 30 menit
Setelah renjatan teratasi diberikan IVFD
10cc/kgBB/jam dalam 24 jam
Turunkan cairan bertahap 7 cc/kgbb 5
cc/kgbb 3 cc/kgbb dalam tiap jam
Bila renjatan berat/berulang pasang CVP
Bila belum teratasi berikan RL 20 cc/kgbb
dan koloid 20-30 cc/kgbb/jam
Monitoring dan evaluasi

Macrocirculation:

END-POINT
FLUID RES.
IN DSS

Conciousness,
BP,
PP/MAP
SaO2 >92%, SvcO2 >70%,
Cap.refill time <2,
Diuresis
Data B : t = 38oC; HR= 120 x/min;
MAP= 60 mmHg

Microcirculation:
Lactate serum < 2mmol/l

Data A : t = 36,8 oC; HR= 65 x/min;

MAP= 82 mmHg

Microcircula
tion
Hypoperfusion

deBaker, Am J Respir Crit Care Med 166:98104,2002

Reperfusion

SHOCK PHASES

THE INFLUENCE OF VOLUME REPLACEMENT ON TISSUE

PERFUSSION AND ORGAN FUNCTION
body
control
tissue
perfusion
O2 supply
cardiac
output

metabolism

volume
replacement

Summary

diuresis

Volume replacement flow chart for a patient with DSS

WHO, 1997

UNSTABLE VITAL SIGNS

THE HOLY BOOK OF DENGUE

urine output falls, signs of shock

Immediate, rapid volume replacement*: 10 20 mlkg -1
Ringers lactate, Ringers acetate or 5% glucose diluted in
physiological saline, as intravenous bolus

(repeat if necessary)
IMPROVEMENT

Adjust intravenous therapy

NO IMPROVEMENT

Oxygen

HAEMATOCRIT FALLS
Guidelines management of
DHF/DSS (WHO, 1997) used widely
(empirical
Few studies to determine
Blood transfusion (10 mlkg-1,
if haematocrit is still >35%)
optimal fluid resc for DSS
Bridget Wills. Dengue Bulletin Vol 25, 2001;

?
HAEMATOCRIT RISES

10-20 mlkg-1plasma, plasma

substitutes or 5% albumin, as
intravenous bolus
(repeat if necessary)

* In cases of acidoses, hyperosmolar or Ringers lactate solution should not be used.

Plasma Volume Replacement

Crystalloid and or Colloid
Normal saline (NaCl 0,9%) (!)
lactate Ringer atau acetate Ringer (!)
glukosa 5% dalam normal saline 1:2 or 1:1(?)
plasma substitution (dexstran 40, plasma, or albumin 5% (?)
(WHO 1997)

Management of Dengue Virus Infection

Ministry of Health 2005
HES 130/4 (Voluven), HES 200/5 (Haes Steril 6%, Haes
Steril 10%, Wida HES), HES 40 (Expafusin),
Gelatin (Gelofusin, Gelafundin, Haemaccel),
Dextran (Dextran L, Dextran 70, Plasmafusin)

Tatalaksana SSD pada Anak (Depkes, 2005)

Based on the pathophysiology

FLUID RESUSCITATION
COLLOID and or CRYSTALOID : 20-60 ml/kg
CRYST + COLLOID
60-100 ml/kg or more
( 6 hrs )

Treatment of underlying disease (DHF)

Supportive and replacement therapy
Control of coagulation mechanism

Fluids

Reduction of fever

Nutritional support

Evaluate signs of bleeding and

shock, etc

Replacement
therapy

Plasma and Platelet

substitution

Anticoagulants

Heparin (?)
Recombinant tissue
factor pathway
inhibitor (?)

Restoration of
anticoagulant
pathway

Antithrombin
Recombinant
human activated
protein C (rAPC)

PLATELET TRANSFUSION:

Platelet concentrates (random

donor)

Single donor (apheresis platelets)

Dose for an average adult I unit /10Kg

BW

Increase approximately 5.000/L

1 unit platelet=5.5x1010 platelets

Single donor platelet = 4-6 unit random

donor

Single donor platelet = 3x1011 platelets

Threshold for prophylactic platelet

transfusion, varies based on underlying
condition and likelihood of hemorrhage.

Stable non-oncologic patients: <10.000/L

Patients undergoing invasive procedures

<50.000/L

Monitoring: platelet count 1-24 h after

transfusion

Shelf-life of platelet concentrates: 5 days

FFP contain most plasma proteins at the

time of thaw at about the same
concentration as the time of collection.

1 unit 200ml

Adults: to increase factor levels by 20%, the

dose 10-20ml/Kg 4-6 units FFP

INR > 1.6 or aPTT >1.5 times upper range of

normal indication for treatment