Paediatrica Indonesiana

VOLUME 52

May 

NUMBER 3

Original Article

Peripheral blood examination to assess bleeding risk in

children with dengue infections
Irene R Huwae, Kurniawan T Kadafi

Abstract
Background Dengue viral infection may cause mild to severe
clinical manifestations, with or without bleeding. A number of
factors may cause bleeding in patients with dengue. However,
health providers may be unable to perform the examinations
required to sufficiently predict the risk of bleeding.
Objective To find risk factors for bleeding using peripheral blood
examinations in children with dengue infection.
Methods This cross-sectional study was conducted at the
3HGLDWULF :DUG RI WKH 'U 6DLIXO $QZDU *HQHUDO +RVSLWDO
0DODQJ IURP -DQXDU\  WR 'HFHPEHU  :H LQFOXGHG
FKLOGUHQ DJHG  WR  \HDUV ZLWK GHQJXH YLUDO LQIHFWLRQ DV
FRQILUPHGE\WKH:+2FULWHULDDQGVHURORJ\3HULSKHUDO
EORRGH[DPLQDWLRQVZHUHPDGHGDLO\GHSHQGLQJRQWKHSDWLHQWV
condition. We classified the bleeding status into non-bleeding,
petechial bleeding (mild hemorrhage), and mucosal bleeding
VHYHUHKHPRUUKDJH:HUHFRUGHGVXEMHFWVEOHHGLQJVWDWXVDW
WKHWLPHRIWKHLUKLJKHVWSDFNHGFHOOYROXPH3&9DQGUHFRUGHG
their leukocyte and platelet counts at that time. We computed
WKHSDUDPHWHUVPHGLDQVDQGFRPSDUHGWKHPWREOHHGLQJVWDWXV
E\ &KLVTXDUH WHVW )RU VLJQLILFDQW 3 DVVRFLDWLRQV ZH
FDOFXODWHGWKH25RGGVUDWLRZLWKDFRQILGHQFHLQWHUYDO
$OOSDWLHQWVZHUHWUHDWHGDFFRUGLQJWRWKH:+2GHQJXH
guidelines.
Results 7KHUH ZHUH DOO  VXEMHFWV ZLWK GHQJXH DQG 
VXEMHFWVKDGFRPSOHWHGDWDZLWKEOHHGLQJSHWHFKLDO
 PXFRVDO EOHHGLQJ DQG  ZLWKRXW EOHHGLQJ 7KH PHGLDQ
3&9ZDVZKLOHPHGLDQSODWHOHWFRXQWZDV/
DQGPHGLDQOHXNRF\WHFRXQWZDV/7KH25RI3&9
!IRUEOHHGLQJZDV&,WR7KH25
RISODWHOHWFRXQW/IRUEOHHGLQJZDV&,
WRFRPSDUHGWRSODWHOHWFRXQW!/7KH
25RISODWHOHWFRXQW/IRUPXFRVDOEOHHGLQJZDV
&,WR&KLVTXDUHDQDO\VLVIRUOHXNRF\WH
count showed it was not associated with bleeding in dengue
3 

Conclusion 7KH 3&9 OHYHO !  LQFUHDVHG WKH ULVN IRU

EOHHGLQJE\WLPHVIRUERWKSHWHFKLDODQGPXFRVDOEOHHGLQJ
3ODWHOHWFRXQW/LQFUHDVHGWKHULVNIRUEOHHGLQJ
times and for mucosal bleeding by 3.4 times. Leukocytes count
was not associated with bleeding. Basic laboratory examinations
RI3&9DQGSODWHOHWFRXQWPD\WKHUHIRUHEHXVHGDVDSUHGLFWRU
of bleeding in children with dengue infection. [Paediatr Indones.
2012;52:175-80].
Keywords: peripheral blood, dengue virus, bleeding

engue viral infection is the most prevalent

arboviral disease worldwide. It is caused by
infection with any one of four dengue virus
'(19 VHURW\SHV '(19 '(19
infections cause illness in tens of millions each year
throughout the tropics and subtropics and severe
morbidity in approximately 2 million persons/year,
ZLWKDSSUR[LPDWHO\GHDWKV\HDUIn Indonesia,

)URP WKH 'LYLVLRQ RI ,QIHFWLRXV 'LVHDVHV DQG 7URSLFDO 3HGLDWULFV

'HSDUWPHQWRI&KLOG+HDOWK0HGLFDO6FKRRO%UDZLMD\D8QLYHUVLW\'U
6DLIXO$QZDU*HQHUDO+RVSLWDO0DODQJ,QGRQHVLD
Reprint requests to: Irene Ratridewi Huwae, Division of Infectious
'LVHDVHVDQG7URSLFDO3HGLDWULFV'HSDUWPHQWRI&KLOG+HDOWK0HGLFDO
6FKRRO %UDZLMD\D 8QLYHUVLW\ 'U 6DLIXO $QZDU *HQHUDO +RVSLWDO -O
-DNJXQJ6XSUDSWR0DODQJ,QGRQHVLD7HO)D[
(PDLOiratridewi@yahoo.com

Paediatr Indones, Vol. 52, No. 3, May 2012 175

Irene R Huwae et al: 3HULSKHUDOEORRGH[DPLQDWLRQWRDVVHVVEOHHGLQJULVNLQGHQJXHLQIHFWLRQV

dengue viral infections have spread through all

SURYLQFHVDQGYLOODJHVVLQFHZLWKWKHKLJKHVW
LQFLGHQFHLQZLWKDERXWSDWLHQWV2
Dengue virus infections may be subclinical or
manifest as dengue fever (DF) or dengue hemorrhagic
IHYHU '+) '+) LV D V\QGURPH ZLWK  GD\V RI
fever, headache, myalgia, and rash, accompanied by
leukopenia and varying degrees of thrombocytopenia.3
An early clinical diagnosis of DHF is difficult because
the World Health Organization (WHO) clinical and
laboratory criteria for DHF may be manifested only
in the late phase of acute illness.4 The latest WHO
FULWHULDUHSRUWHGPXFRVDOEOHHGLQJDVDZDUQLQJ
sign of dengue, leading to severe dengue when it
presents as severe bleeding.
The pathogenesis of bleeding in dengue viral
LQIHFWLRQHQFRPSDVVHVPHFKDQLVPVYDVFXORSDWK\
thrombopathy, and coagulopathy. These 3 mechanisms
are caused by interconnected complement activation
cascades.3-5 Measuring vasculopathy, thrombopathy,
and coagulopathy is complex, expensive, and cannot
be done in all health care settings. The routine
follow-up for dengue patients includes a simple and
low-cost complete blood examination, especially
in the post-febrile defervesence period, which is a
particularly critical phase. The aim of this study
was to determine the predictive value of simple
laboratory examination on bleeding tendency in
dengue patients. The examinations include packed
FHOO YROXPH 3&9 OHXNRF\WH FRXQW DQG SODWHOHW
count, all of which are available in limited resource
settings.

Methods
This cross-sectional study was undertaken from
-DQXDU\  WR 'HFHPEHU  :H LQFOXGHG DOO
FKLOGUHQ  WR  \HDUV ROG DGPLWWHG WR 'U 6DLIXO
Anwar General Hospital, with dengue viral infection
only. The dengue diagnoses were made according to
:+2  FULWHULD DQG FRQILUPHG E\ VHURORJ\ $V
suggested in the guidelines, hematologic examinations
ZHUHSHUIRUPHGGDLO\GHSHQGLQJRQSDWLHQWVFOLQLFDO
FRQGLWLRQ LQFOXGLQJ 3&9 OHYHOV SODWHOHW FRXQWV
DQGOHXNRF\WHFRXQWV7KHKLJKHVWPHGLDQ3&9ZDV
recorded with the assumption that it represented the
critical phase (leakage period). Median leukocyte

176Paediatr Indones, Vol. 52, No. 3, May 2012

counts and platelet counts were also taken at that

time. We did not measure or observe bleeding volumes
nor outcomes of the patients. Data of patients
requiring blood or other transfusion components was
taken only up to the time of transfusion.
Laboratory examinations were performed in the
&OLQLFDO 3DWKRORJ\ /DERUDWRU\ RI 'U 6DLIXO $QZDU
General Hospital. We did not collect informed consent
in this study because the laboratory examination was
part of the dengue management.
6XEMHFWV ZLWK EOHHGLQJ ZHUH GLYLGHG LQWR 
groups, i.e. mild bleeding represented by petechial
bleeding, and mucosal bleeding with the potential
IRUVHYHUHEOHHGLQJ7KH:+2FULWHULDUHSRUWHG
mucosal bleeding to be a warning sign which may
OHDGWRVHYHUHGHQJXH+RZHYHULQWKH:+2
criteria, a spontaneous bleeding tendency was defined
as dengue hemorrhagic fever grade II. The bleeding
tendency of each patient was recorded at the same
WLPHWKHKLJKHVW3&9GDWDZDVWDNHQ
:HFDOFXODWHGWKHRGGVUDWLR25RIWKH3&9
level, leukocyte count, and platelet count relationships
to non-bleeding, petechial bleeding, and mucosal
bleeding case status.

Results
7KHUHZHUHSDWLHQWVZLWKGHQJXHYLUDOLQIHFWLRQ
EXWRQO\KDGFRPSOHWHGDWD$PRQJWKHVH
KDGEOHHGLQJSHWHFKLDOEOHHGLQJPXFRVDO
EOHHGLQJ ZKLOH  KDG QR EOHHGLQJ 7KH PHGLDQ
3&9ZDVPHGLDQSODWHOHWVFRXQWZDV
/DQGPHGLDQOHXNRF\WHVFRXQWZDV/7KH
numbers of male and female patients with dengue
viral infection were not significantly different. The
incidence of petechial bleeding appeared greater than
mucosal bleeding in each of the above blood parameter
groups. The basic characteristics of subjects are shown
LQ7DEOH
Table 2 shows the OR of predicting the risk of
EOHHGLQJ 6XEMHFWV ZLWK D 3&9 ! KDG 
WLPHV WKH ULVN RI EOHHGLQJ WKDQ WKRVH ZLWK 3&9 
 7KH OHXNRF\WHV FRXQW ZDV QRW VLJQLILFDQWO\
DVVRFLDWHG ZLWK EOHHGLQJ WHQGHQF\ 6XEMHFWV ZLWK
SODWHOHWVFRXQW/KDGWLPHVWKHULVN
for mucosal bleeding than those with platelet count
!/

Irene R Huwae et al: 3HULSKHUDOEORRGH[DPLQDWLRQWRDVVHVVEOHHGLQJULVNLQGHQJXHLQIHFWLRQV

Table 1.Subjects basic characteristics
Characteristics
Male
Female

Non-bleeding
(n=80)

Petechial bleeding
(n=120)

Mucosal bleeding
(n=82)

Total
(n=282)

46
34

63
57

44
38

153
129

Median PCV
Median leucocytes count
Median platelets count

36.8%
3,400/ L
51,000/ L

PCV < 36.8%

PCV > 36.8%

52
28

53
67

37
45

142
140

Leucocytes count
< 3,400/L
Leucocytes count
>3,400/L

46

53

44

143

34

67

38

139

Platelets count
< 51,000/L
Platelets count
>51,000/L

30

63

55

148

50

57

27

134

Stage of dengue hemorrhagic

feve
DHF I
DHF II
DHF III
DHF IV

124
32
36
61
29

Table 2.#UUQEKCVKQPQHDNGGFKPIVQ2%8NGWMQE[VGUEQWPVCPFRNCVGNGVUEQWPV
NonBleeding
bleeding
n=202
n=80
PCV, n
> 36.8%
<36.7%
.GWMQE[VGEQWPVP
< 3,400/L
>3,400/L
Chi-square P=0.128
Platelet count, n
< 51,000/L
>51,000/L

28
52

112
90

46
34

97
105

30
50

118
84

OR
(95% CI)

2.31
(1.35 to 3.95)

2.34
(1.37 to 3.99)

Non- Petechial
bleeding bleeding
n=80
n=120
28
52

67
53

46
34

53
67

30
50

63
57

Discussion
Dengue has a wide spectrum of clinical presentations,
often with unpredictable clinical evolution and
outcomes. While most patients recover following
a self-limiting, non-severe clinical course, a small
proportion progress to severe disease, mostly
characterized by plasma leakage with or without
hemorrhage.6 7KH :+2  FULWHULD JXLGHOLQH
groups symptomatic dengue virus infections into three
FDWHJRULHVXQGLIIHUHQWLDWHGIHYHUGHQJXHIHYHU')

OR

2.35
(1.31 to 4.21)

1.84
(1.03 to 3.28)

Non- Mucosal
bleeding bleeding
n=80
n=82
28
52

45
37

46
34

44
38

30
50

55
27

OR
(95% CI)

2.26
(1.20 to 4.25)

3.4
(1.78 to 6.48)

and dengue hemorrhagic fever (DHF). DHF is further

classified into four severity grades, with grades III and
IV being defined as dengue shock syndrome.
There are several difficulties in applying these
criteria in that some cases cannot be classified into
RQHRIWKRVHWKUHHGHQJXHFDWHJRULHV7KH:+2
criteria guideline is more practical for clinicians. The
:+2  FULWHULD FODVVLI\ GHQJXH FDVHV LQWR WKUHH
JURXSV *URXS  FRPSULVHV SUREDEOH GHQJXH FDVHV
defined as a person who traveled or lived in an endemic
DUHDDQGKDGIHYHUZLWKRIIROORZLQJFULWHULDQDXVHD

Paediatr Indones, Vol. 52, No. 3, May 2012 177

Irene R Huwae et al: 3HULSKHUDOEORRGH[DPLQDWLRQWRDVVHVVEOHHGLQJULVNLQGHQJXHLQIHFWLRQV

vomiting, rash, aches and pain, positive tourniquet

test, leukopenia, or any warning signs. Group (2)
comprises dengue cases with warning signs, such as
abdominal pain and tenderness, persistent vomiting,
clinical fluid accumulation, mucosal bleeding, lethargy,
UHVWOHVVQHVVOLYHUHQODUJHPHQW!FPDQGLQFUHDVLQJ
3&9 FRQFXUUHQW ZLWK UDSLGO\ GHFUHDVLQJ SODWHOHW
count. Group (3) comprises severe dengue, defined as
cases with severe plasma leakage (leading to shock or
fluid accumulation with respiratory distress), severe
bleeding (evaluated by clinician), and severe organ
LQYROYHPHQW OLYHU $67 !  EUDLQ GHFUHDVHG
level of consciousness, heart and/or other organs).
These criteria require a basic and simple hematologic
examination to classify each case as probable dengue
with or without warning signs. The hematological exam
VKRXOGLQFOXGHKHPRJORELQ+EOHYHO3&9OHXNRF\WH
and platelet counts. Monitoring for bleeding is required
in dengue cases with warning signs that require hospital
admission.
:HREVHUYHGWKDWSDWLHQWVZLWK3&9!
KDGDWLPHVJUHDWHUULVNIRUEOHHGLQJWKDQWKRVH
ZLWK3&9:HXVHGWKHKLJKHVW3&9YDOXH
for each subject in our calculations in this study with
the assumption that patients were in the critical phase
at that time. The critical phase is characterized by
LQFUHDVLQJ3&9FRQFXUUHQWZLWKGHFUHDVLQJSODWHOHW
count. Although a bleeding tendency usually occurs
as a manifestation of plasma leakage and shock,it may
occur in cases without plasma leakage (previously
classified as dengue fever), usually manifested as
thrombocytopenia. Among the bleeding cases,
WKHUHZDVQRVWDWLVWLFDOHYLGHQFHWKDW3&9!
was a potential risk factor for mucosal bleeding, only
compared to petechial bleeding.
,QFUHDVHG3&9UHSUHVHQWVWKHKHPRFRQFHQWUDWLRQ
in dengue, which is caused by vascular leakage. One
possible cause of vascular leakage is platelet activating
IDFWRU 3$) ZKLFK FDQ SURGXFH PDQ\ IHDWXUHV RI
V\VWHPLF LQIODPPDWRU\ UHVSRQVH V\QGURPH 6,56
such as hypotension, increased vascular permeability,
cytokine release, and shock.
Thrombocytopenia and plasma leakage are
the main characteristics of severe dengue disease. It
has been postulated that autoimmunity is involved
in dengue pathogenesis, especially through the
generation of autoantibodies against platelets,
endothelial cells, and coagulatory products. The cross-

178Paediatr Indones, Vol. 52, No. 3, May 2012

reactive antibodies may cause platelet dysfunction,

endothelial cell damage, coagulation defects, and
macrophage activation.
The platelets count and the platelets usage for
sealing the vascular breakage may be considered as the
cause of bleeding. The OR of platelets in non-bleeding
and petechial cases (mild bleeding) was only 2.34,
LQGLFDWLQJWKDWVXEMHFWVZLWKSODWHOHWFRXQW
/RQO\KDGWLPHVJUHDWHUULVNIRUEOHHGLQJERWK
petechial and mucosal) than subjects with platelet
FRXQW ! / 6XEMHFWV ZLWK D SODWHOHWV FRXQW
 / KDG D  WLPHV JUHDWHU ULVN RI KDYLQJ
PXFRVDOEOHHGLQJWKDQWKRVHZLWK!/DQG
VXEMHFWVZLWKDSODWHOHWVFRXQW/ KDGD
times greater risk of having petechial bleeding than
WKRVH ZLWK ! / 7KLV REVHUYDWLRQ VXSSRUWV
the notion that petechial bleeding may be considered
as a milder and less dangerous bleeding tendency
than mucosal bleeding. However, we did not evaluate
other parameters to assess bleeding tendency in this
study, such as hemostatic states by activated partial
WKURPERSODVWLQWLPH$377DQG337
:H REVHUYHG VHYHUDO FDVHV Q   ZLWK
SODWHOHWFRXQW/ZLWKVHYHUHKHPRUUKDJH
(mucosal bleeding). This hemorrhaging may be caused
by a thrombopathy (platelet dysfunction), in addition
to the decrease of platelets in peripheral blood. Thus,
the decrease in platelets count (thrombocytopenia)
may not be the only cause of bleeding, but may be
one risk factor for bleeding tendency during dengue
infection.
7KHEOHHGLQJWHQGHQF\LQ'+)'66SDWLHQWV
involves the role of both vascular endothelial cells
and platelets, although the pathogenic mechanism
LV QRW IXOO\ XQGHUVWRRG 6WXGLHV RQ RWKHU YLUXVHV
such as CMV, HIV, and hepatitis C virus has shown
the presentation of platelet autoantibodies to be
the cause of thrombocytopenia. In dengue viral
infection these auto anti-platelet antibodies induce
complement-mediated cell lysis, which may play
role in thrombocytopenia. During blood vessel
injury, activated platelets adhere to the injury site,
aggregating together through fibrin formation. 
Carlos et al concluded that thrombocytopenia was
not the only cause of bleeding in dengue, but that the
SURORQJDWLRQRI$377DQGUHGXFWLRQLQILEULQRJHQ
concentration were strongly associated with severity
of vascular leakage, leading to hypotension, shock

Irene R Huwae et al: 3HULSKHUDOEORRGH[DPLQDWLRQWRDVVHVVEOHHGLQJULVNLQGHQJXHLQIHFWLRQV

and finally bleeding.3 Other studies have reported

that viremia may play a role in determining clinical
parameters, as is the case of secondary infection.
Higher viral load may be used as an independent
predictor for more severe thrombocytopenia, but
may also be associated with a small increase in
hemoconcentration.Examinations to determine
viral load are expensive and not available in all
settings.
The leukocyte count of our subjects was not
significantly associated with a bleeding tendency.
Hence, it should not be considered as a risk factor
for predicting bleeding. However, several studies have
reported contrasting result on leukocyte counts in
dengue. A Thai study showed that leukopenia was
a good predictor of dengue infection in children,
whilea study in Nicaragua stated that leukopenia was
significantly associated with dengue in adults, but not
LQFKLOGUHQ$VWXG\LQ3XHUWR5LFRZDVLQFRQFOXVLYH
about the role of leukopenia in dengue, but their
results showed that leukocyte counts in dengue cases
ZHUHORZHUPHDQ/WKDQWKRVHRIQRQGHQJXH
cases.$QRWKHUVWXG\RQULVNIDFWRUVIRU'66LQ
FKLOGUHQFRQFOXGHGWKDWOHXNRSHQLD/ was a
significant risk factor for shock in dengue. However,
the authors did not mention an association between
leukopenia and hemorrhage.
6XEMHFWVZLWK3&9OHYHOVRIKLJKHUWKDQ
KDG D  WLPHV KLJKHU ULVN IRU EOHHGLQJ HLWKHU
petechial or mucosal. Furthermore, a platelet count
RI OHVV WKDQ / VKRZHG D  WLPHV KLJKHU
risk for mucosal bleeding. Leukocyte count was
notsignificantly correlated to bleeding in our dengue
cases. As such, a basic laboratory examination of
3&9DQGSODWHOHWFRXQWPD\EHXVHGDVDSUHGLFWRU
of bleeding in pediatric dengue cases.

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$P-7URS0HG+\J
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 'X\HQ +7/ 1JRF 79 +D GR 7 +DQJ 977 .LHX 177
<RXQJ 35 HW DO .LQHWLFV RI SODVPD YLUHPLD DQG VROXEOH
QRQVWUXFWXUDOSURWHLQFRQFHQWUDWLRQVLQGHQJXHGLIIHUHQWLDO
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 'H5LYHUD,/3DUKDP/0XULOOR:0RQFDGD:9D]TXH]
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HQGHPLF DUHD  3XHUWR 5LFR  $P - 7URS +\J

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findings in children and adults with dengue virus infection.
-&OLQ9LURO
 *XSWD9<DGDI733DQGH\506LQJK$*XSWD0.DQDXML\D
3HWDO5LVNIDFWRUVRIGHQJXHVKRFNV\QGURPHLQFKLOGUHQ
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