Demam Berdarah Dengue:

Manifestasi Klinis, Diagnosis, Terapi &

Tatalaksana pada Dengue Syok Sindrom

dr.Bramantono SpPD KPTI FINASIM

Divisi Tropik – Infeksi, Departemen Ilmu Penyakit Dalam
FK UA – RSUD Dr. Soetomo Surabaya

Dengue: Penyakit Arboviral yang Paling Cepat
Menyebar

Jumlah insiden DD dan DBD yg

dilaporkan ke WHO (WHO, 2011)

30x incidence increase in

50 yrs
Daerah penyebaran dengue 2008 (WHO, 2009)
Surabaya (2000 - 2009):
↑ insiden: 12.04 à 48.9
WHO 2009: Perlu upaya yg lebih intensif untuk penelitian
per 100000
tentang patogenesis, perbaikan tata laksana, dan upaya
penemuan obat/vaksin
Belum ada obat/ vaksin
2
•  2003-2005: DENV-2
•  2007-2008: DENV-2
•  2008-2010: DENV-1
•  2012: DENV-1
•  2013: DENV-1
•  Further surveillance ???
3
Infeksi virus dengue (DENV)

Merupakan penyakit
demam akut yang
disebabkan oleh virus
dengue dan ditularkan
melalui gigitan nyamuk
Aedes aegypty dan
Aedes albopictus serta
memenuhi kriteria
WHO untuk Demam
Berdarah Dengue (DBD)

4
 Replication and transmission
of dengue virus (Part 1)

1. Virus transmitted 1
to human in mosquito
saliva
2
2. Virus replicates
in target organs
4

3. Virus infects white 3

blood cells and
lymphatic tissues

4. Virus released and

circulates in blood
5
 Replication and transmission
of dengue virus (Part 2)

5. Second mosquito
ingests virus with blood 6
6. Virus replicates
in mosquito midgut
and other organs,
infects salivary 7
glands

7. Virus replicates
5
in salivary glands

6
Pathophysiology

7
 PATHOPHYSIOLOGY
Dengue InfecSon

AnSbody FormaSon

Re-infecSon

AugmentaSon of virus mulSplicaSon

Increased vascular Reduced platelets

permeability
Coagulopathy
Plasma leakage Disseminated intravascular
Hypovolemia CoagulaSon

Shock Severe bleeding

Death
8
 Dengue infection causes capillary
leak syndrome Primary target:
monocytes

Serotype cross-
reacSve Ab

Virions + non-
neutralizing Ab

Enhanced entry via

FcR

T cells acSvaSon

Cytokines +
complements
acSvaSon

Capillary Leak
(Rothman, 2004) 9
 DHF is not a continuum of DF

Dengue
Self-limited
Viral direct effect Fever

Dengue Virus
infecSon

Dengue Life-threatening
Secondary infecSon + Haemorrhagic
Enhanced anSbodies
Fever DHF is not
DF plus bleeding

10
 Manifestation of dengue virus infection
Dengue virus infecSon

AsymtomaSc SymtomaSc

UndifferenSated Dengue Fever Dengue haemorrhaegic Expanded dengue

Fever (DF) fever (DHF) syndrome / isolated
(viral syndrome) (with plasma leakage) organopathy
(unusual manifestaSon)

Without With unusual DHF DHF with shock

haemorrhage haemorrhage Non-shock DSS
Comprehensive Guidelines for PrevenSon and Control of Dengue and Dengue Haemorrhagic Fever, WHO-SEARO 2011 11
12
Course of dengue illness

Shock/Bleeding

Dengue: Guidelines for diagnosis, treatment, prevenSon and control, TDR-WH0 2009
13
Febrile phase
Febrile phase
•  Facial flushing •  (+) TT increases the
•  Skin erythema probability of dengue
•  Generalized body ache •  (+) hemorrhagic
•  Myalgia and arthralgia manifestaSons
•  Headache •  Enlarged and tender liver
•  Sorethroat, injected pharynx, •  Abnormality: progressive
and conjuncSval injecSon decrease in total wbc
•  Anorexia, nausea and
vomiSng

Dengue: Guidelines for diagnosis, treatment, prevenSon and control, TDR-WH0 2009

14
Critical phase

Cri?cal phase
•  Temp drops to 37.5-38 •  if (-) increase in •  Shock: criScal volume
(days 3-7) capillary permeability of plasma is lost
•  (+) increase in capillary à improve •  Temperature may be
permeability with •  if (+) increase in subnormal
increasing hematocrit
capillary permeability •  Prolonged shock à
levels
•  Significant plasma à pleural effusion and organ hypoperfusion
leakage lasts for 24-48 ascites à organ impairment,
hours •  Degree of increase metabolic acidosis, and
•  Progressive leukopenia above the baseline DIC à severe
followed by rapid hematocrit reflects the hemorrhage
decrease in platelet severity of plasma •  Severe hepaSSs,
precedes plasma leakage encephaliSs or
leakage myocardiSs

Dengue: Guidelines for diagnosis, treatment, prevenSon and control, TDR-WH0 2009
15
Recovery phase
Recovery phase
•  Gradual reabsorpSon of •  Hematocrit stabilizes or may be
extravascular compartment fluid lower due to diluSonal effect of
(48-72 hours) reabsorbed fluid
•  General well-being improves, •  Wbc starts to rise
appeSte returns, GI symptoms abate, •  Recovery of platelet count occurs
hemodynamic status stabilizes and later
diuresis ensues
•  (+) rash: “isles of white in the sea of
red”

Dengue: Guidelines for diagnosis, treatment, prevenSon and control, TDR-WH0 2009

16
Pemeriksaan penunjang

•  Pemeriksaan darah serta serologi

•  DL, LFT, RFT, BG, CoagulaSon profile, BGA, Electrolyte, lactate, NS1,
Igm/IgG anS-dengue
•  EKG
•  Pemeriksaan Radiologis
•  Foto Thoraks
•  USG
•  Penunjang lainnya sesuai indikasi

17
Diagnosis of dengue

•  AnSbody detecSon
•  HemaggluSnaSon InhibiSon
(HAI)
•  IgM & IgG
•  AnSgen detecSon
•  NS1
•  RNA detecSon
•  RT-PCR
•  Viral isolaSon

18
Antibody detection

19
Approximate timeline of primary and secondary dengue virus
infections and the diagnostic methods that can be used to detect
infection

NS1 detec?on

Virus isola?on
RNA detec?on

Viraemia

O.D
IgM primary

IgM secondary
HIA

>25
IgG secondary
O.D 60

IgG primary infec?on 80

0

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-20 21-40 41-60 61-80 90 >90 Days

Onset of symptoms 20
Differential diagnoses of dengue

•  Arboviruses: Chikungunya virus (terutama di Asia

Tenggara)
•  Other viral diseases: Measles; rubella; Epstein-Barr
Virus (EBV)
•  Enteroviruses; influenza; hepaSSs A; Hantavirus
•  Bacterial diseases: Meningococcaemia,
leptospirosis, typhoid, melioidosis, rickemsial
diseases, scarlet fever
•  ParasiSc diseases: Malaria

21
WHO Guidelines on dengue
2009

1997 2011
22
Criteria for clinical diagnosis of
DHF (2011)
•  Clinical manifestaSons
•  Fever: acute onset, high and conSnuous, lasSng two to
seven days in most cases
•  Any of the following haemorrhagic manifestaSons
including a posiSve tourniquet test (the most common),
petechiae, purpura, ecchymosis, epistaxis, gum
bleeding, and haematemesis and/or melena
•  Laboratory findings
•  Thrombocytopenia (100 000 cells per mm 3 or less)
•  HaemoconcentraSon; haematocrit increase of ≥20%
from the baseline, plasma leakage : pleura effusion,
ascites, hypoproteinemia / hypoalbuminemia

23
Classifications
1997 2009 2011
Dengue Fever Dengue without warning signs Dengue Fever
DHF grade I
DHF grade I
Dengue with warning signs
DHF grade II
DHF grade II

DHF grade III

Severe dengue: DHF grade III
§ With compensated shock
DHF grade IV § With hypotensive shock DHF grade IV

EXPANDED DENGUE
SYNDROME
 WHO 2011 Classification of Dengue Infections
and Grading of Severity of DHF
DF/DHF Grade Symptoms Laboratory
DF Fever with two of the following:
Headache, etro-orbital pain, Myalgia,
Arthtralgia/bone pain,
Rash,Haemorrhagic manifestations, No
evidence of plasma leakage.
DHF I Fever and haemorrhagic manifestation
(positive tourniquet test) and evidence of
plasma leakage
DHF II As in Grade I plus
Spontaneous bleeding.
DHF III As in Grade I or II plus
Circulatory Failure (weak pulse, narrow
pulse pressure(≤20 mmHg),
hypotension,restlessness).
DHF IV As in Grade III plus profound shock
with undetectable BP and pulse
Leucopenia (wbc ≤5000
cells/mm 3 ), Thrombocytopenia
(Platelet count <150 000 cells/
mm 3 ), Rising haematocrit (5%
– 10% ),
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%
25 25
 Expanded dengue syndrome
NEUROLOGICAL
Febrile seizures in young children. CARDIAC
Encephalopathy. Conduction abnormalities.
Encephalitis/aseptic meningitis. Myocarditis.
Intracranial haemorrhages/thrombosis. Pericarditis.
Subdural effusions.
Mononeuropathies/polyneuropathies/GBS
Transverse myelitis.
RESPIRATORY
GASTROINTESTINAL/HEPATIC Acute respiratory distress
Hepatitis/fulminant hepatic failure. syndrome.
Acalculous cholecystitis. Pulmonary haemorrhage.
Acute pancreatitis.
Hyperplasia of Peyer’s patches.
OTHERS
Acute parotitis.

MUSCULOSKELETAL
RENAL Myositis with raise CPK
Acute renal failure. Rabdomyolysis
Hemolytic uremic syndrome.

Maheshwari A. Atypical manifestaSons of dengue. Trop Med Int Health. 2007 Sep.; 12(9):1087 – 95 26
Warning signs (2009)

•  Abdominal pain or tenderness

•  Persistent vomiSng
•  Clinical fluid accumulaSon
•  Mucosal bleed
•  Lethargy, restlessness
•  Liver enlargment >2 cm
•  Laboratory: increase in HCT concurrent with rapid
decrease in platelet count

27
High-risk patients (2011)
The following host factors contribute to more severe disease and
its complicaSons:
•  Infants and the elderly
•  Obesity
•  Pregnant women
•  PepSc ulcer disease
•  Women who have menstruaSon or abnormal vaginal bleeding
•  HaemolySc diseases
•  Thalassemia and other haemoglobinopathies
•  Congenital heart disease
•  Chronic diseases such as diabetes mellitus, hypertension, asthma,
ischaemic heart disease
•  Chronic renal failure, liver cirrhosis
•  PaSents on steroid or NSAID treatment

28
Clinical management

•  Complex pathogenesis and manifestaSons à

BUT, relaSvely simple and inexpensive treatment
•  No spesific treatment à rely on fluid management
•  The most effecSve way to reduce incidence and
morbidity à vector control
•  PotenSal manegement: vaccine and anS-viral
drugs

29
DF & DHF in Febrile Phase

•  Parcetamole
•  Physical methods of controlling fever
•  Don’t use Aspirin and NSAID
•  Fluid to maintain nutriSon and hydraSon
Recognize the Time of Entry to the Critical Phase
( when blood vessels become leaky)
•  Dropping platelet count below 100 000/dl
•  Rising HCT & Evidence of plasma leakage

30
Choice of fluids
Crystalloid Colloid
Ringer’s lactate Dextran 40 in saline
Ringer’s acetate Hydroxyethyl strach (HES)
0.9% saline GelaSn soluSons
5% dextrose 0,9%
5% dextrose 1/2 saline

•  Suspected dengue fever

-  Isotonic crystalloid : normal saline, Ringer’s lactate, Ringer’s acetate,
Ringer’s dextrose
•  Dengue hemorrhagic fever (DHF I and II)
- Isotonic crystalloid : glucose contained soluSon?
•  DSS Crystalloid vs colloid ?
31
The general principles of fluid
therapy in DHF
•  Isotonic crystalloid soluSons should be used
throughout the criScal period
•  Hyper-oncoSc colloid soluSons (osmolarity of >300
mOsm/l) such as dextran 40 or starch soluSons
may be used in paSents with massive plasma
leakage, and those not responding to crystalloid
•  A volume of about maintenance +5% dehydraSon

32
Fluid management in DHF gr I & II

Kalayanarooj S. and Nimmannitya S. In: Guidelines for Dengue and Dengue Haemorrhagic Fever Management. Bangkok
Medical Publisher, Bangkok 2003.
33
 Fluid management in DHF gr III Dengue: Guidelines for diagnosis,
treatment, prevenSon and control,
(systolic pressure maintained + signs of reduced perfusion) TDR-WH0 2009

Start isotonic crystaloid

5-10 ml/kg/hr for 1 hour
Yes
No
IMPROVEMENT
Check ABCS
HCT HCT
IV crystaloid, reduce or High
Check
gradually HCT
5-7 ml/kg/hr for 1-2 hours No
Yes
3-5 ml/kg/hr for 1-2 hours Severe
2-3 ml/kg/hr for 1-2 hours overt
Crystaloid (2nd bolus) or
colloid bleed
As clinical improvement is 10-20 ml/kg/hr for 1 hour
noted, reduced fluids
accordingly Urgent Colooid 10-20
blood ml/kg/hr
IMPROVEMENT transfusion Evaluate to
Further boluses may be No
Yes
Consider
needed for the next 24-48 Blood
hours
Transfusion if
Reduce IV crystaloids 7-10 No clinical
Stop IV fluids at 48 hours ml/kg/hr for 1-2 hours improvement
34
 Pemeriksaan laboratorium syok berat atau
tidak ada perbaikan dengan resusitasi cairan
Singkatan Pemeriksaan Kepen?ngan
Laboratorium
A-Asidosis Analisa gas Menandakan syok yang sedang berlangsung. Keterlibatan
darah (kapiler organ juga harus dievaluasi ; fungsi haS, BUN dan kreaSnin
dan vena)
B-Bleeding Hematokrit Jika terjadi penurunan nilai HCT dibandingkan dengan nilai
sebelumnya atau jika Sdak berubah, lakukan cross-match
untuk transfusi darah secepatnya
C-Calsium Elektrolit, Ca++ Hipokalsemia terjadi pada kebanyakan DBD namun tanpa
gejala. Pemberian suplementasi kalsium pada kondisi yang
lebih berat/kompleks dapat diindikasikan. Dosis yang
dianjurkan 1 ml/kg maksimal 10cc kalsium glukonas, dilarutkan
dengan perbandingan 1:2, diberikan secara IV perlahan (dapat
diulang Sap 6 jam jika diperlukan)
S-Blood Kadar gula Kebanyakan kasus DBD disertai penurunan selera makan dan
Sugar darah muntah. Hipoglikemia dapat terjadi pada pasien dengan
(fingersGck) gangguan fungsi haS, namun pada kondisi lain dapat terjadi
hiperglikemia
Comprehensive Guidelines for PrevenSon and Control of Dengue and Dengue Haemorrhagic Fever, WHO-SEARO 2011
35
Dengue shock sydrome
Kriteria DHF dengan tanda tanda syok
•  Takikardia, ekstremitas dingin, waktu pengisian kapiler
memanjang, nadi lemah, lesu atau gelisah, yang mungkin
merupakan tanda dari penurunan perfusi otak

•  Tekanan nadi ≤20 mmHg dengan peningkatan tekanan

diastolik , misalnya 100/80 mmHg

•  Hipotensi yang disesuaikan dengan usia, yakni tekanan

sistolik < 80 mmHg untuk mereka yang berusia < 5 tahun
atau 80 - 90 mmHg untuk anak-anak dan orang dewasa



36
Fluid management in DSS
Fluid bolus 10- 20 ml/kg crystalloid/ 15 mt
NO IMPROVEMENT IMPROVEMENT DHF gr III

A Check HCT before fluid bolus or awer fluid bolus

B
C If HCT is dropping Rising HCT
S < 40 for Children and female
< 45 for adult male 2nd bolus - Colloids
10 – 20 ml/kg/1 hr

Blood transfusion 3rd bolus - Colloids

whole blood 10 -20 ml/kg 10 – 20 ml/kg/1 hr
Packed RBC 5-10 ml/kg
Dengue: Guidelines for diagnosis, treatment, prevenSon and control, TDR-WH0 2009 37
 Algorithm for fluid management in hypotensive shock/DSS

Hypotensive shock
Fluid resuscitaSon with 20ml/kg isotonic crystaloid or colloid
over 15 minutes
Try to obtain a HCT level before fluid resuscitaSon

IMPROVEMENT
No
Yes
Review 1st HCT
Crystaloid/colloid 10 ml/kg/hr for 1 HCT or High HCT
hour, then conSnue with :
In cristaloid 5-7 ml/kg/hr for 1-2 hours Administer 2nd bolus fluid (colloid) Consider significant occult/overt bleed
Reduce to 3-5 ml/kg/hr for 2-4 hours 10-20 ml/kg over 1/2 hour IniSate transfusion with fresh whole
Reduce to 2-3 ml/kg/hr for 2-4 hours blood

If paSent is not stable, act according to
IMPROVEMENT
HCT levels No
If HCT increase, consider bolus fluid
administraSon or increase fluid Yes
administraSon; Repeat 2sd HCT
If HCT decreases, consider transfusion
with fresh whole transfusion HCT or High HCT
Administer 3rd bolus fluid
Stop at 48 hours (colloid) 10-20 ml/kg over 1 hour

IMPROVEMENT
No
38
Yes Repeat 3sd HCT
 Fluid management in DSS
IV Adjust on shock grade III, IV
Name…………………..BW……………….kg. M=………….CC/days………..cc/hr M+5%=……….….CC/days………..cc/hr

10 6 hrs…….cc
9 10-5 ml/kg/hr
(200-120 ml/hr)
8
7 8 hrs…….cc
IV Transfusion
(ml/kg/hr)

6 5-3 ml/kg/hr
5 (120-80 ml/hr) 18 hrs…….cc
4 3-1.5 ml/kg/hr
3 (80-40 ml/hr) 24 hrs…….cc

2 1.5 ml/kg/hr-KVO
(40 ml/hr-KVO)
1
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
shock Rate of KV fluid for children (Rate for adults) hour
Hour 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
1
Time
Type IV
Intake
Urine (mL)
Hct (%)
Kalayanarooj S. and Nimmannitya S. In: Guidelines for Dengue and Dengue Haemorrhagic Fever Management. 39
Bangkok Medical Publisher, Bangkok 2003.79
Tatalaksana perdarahan masif

•  Sumber pedarahan diidenSfikasi, mis : epitaxis

dikontrol dgn nasal packing
•  Perdarahan saluran cerna diberikan H-2 antagonis
atau PPI, monitor HCT
•  Tranfusi darah segera diberikan, 10 ml/kg WB atau
PRC
•  Trombosit konsentrat / fresh frozen plasma (FFP)
meningkatkan resiko kelebihan cairan

40
Fase pemulihan

•  Perbaikan parameter klinis serta hemodinamik

•  HCT kembali ke base line atau lebih rendah
•  Cairan intravena dihenSkan cegah overload
•  Pada pasien dengan efusi masif dan ascites,
hypervolemia dapat terjadi dan terapi diureSk
dapat diperSmbang untuk mencegah edema paru

41
Criteria for transfer IGD Soetomo

•  Early presentaSon 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 hepaSc damage,
cardiomyopathy, encephalopathy, encephaliSs and
other unusual complicaSons) Expanded dengue
syndrome

42
Kriteria KRS

•  Tidak ada demam dalam 24 jam terakhir, tanpa

anSpireSk
•  Kembalinya nafsu makan
•  Perbaikan klinis yang nyata
•  Produksi urin yang baik
•  SeSdaknya 2-3 hari setelah sembuh dari syok
•  Tidak ada distres nafas
•  Tidak ada asites
•  Trombosit lebih dari 50000 sel/mm3

43
TERIMA KASIH