PROGNOSTIC FACTORS OF SEVERE DENGUE INFECTIONS IN

CHILDREN

Senja Baiduri1, Dominicus Husada2, Dwiyanti Puspitasari3, Leny Kartina4, Parwati Setiono Basuki5,
Ismoedijanto6
Department of Child Health, Faculty of Medicine – RSUD Dr. Soetomo, Surabaya
RSUD Dr. Soewandhie, Surabaya
a Corresponding author: dominicushusada@yahoo.com

ABSTRACT

Dengue fever is mosquito-borne disease and caused by one of four serotype dengue viruses. Severe
dengue is characterized either by plasma leakage, fluid accumulation, respiratory distress, severe
bleeding, or organ impairment. Understanding the prognostic factors in severe dengue will give
early warning to physician thus decreasing morbidity, mortality, improvement of treatment and
disease management hence reducing of length of stay. To analyze the prognostic factors of severe
dengue infection in children. This study was observational cohort study in children (2 months-18
years) with dengue infection according to WHO 2009 criteria which admitted in Soetomo and
Soewandhie Hospital Surabaya. Analysis with univariat, bivariat and multivariat with IBM SPSS
Statistic 17. All patients were confirmed by serologic marker (NS-1 or IgM/IgG Dengue). Clinical
and laboratory examination (complete blood count, AST, ALT, albumin, APTT and PPT) were
analyzed comparing non severe dengue and severe dengue patients. There were 40 subjects in non
severe and 27 subjects with severe dengue infection. On bivariate analysis, there were significant
difference of nutritional status, abdominal pain, ptechie, pleural effusion, leukopenia,
thrombocytopenia, hypoalbuminemia, history of transfusion, increasing AST>3x, prolonged PPT
and APTT between severe and non severe dengue group. After multivariate analyzed, the
prognostic factors of severe dengue were overweight/obesity (p=0.003, RR 94), vomiting (p=0.02,
RR 13.3), hepatomegaly (p=0.01, RR=69.4), dan prolonged APTT (p=0.005, RR=43.25).
Overweight/obesity, vomiting, hepatomegaly and prolonged APTT were prognostic factors in
severe dengue infection in children.

ABSTRAK
Dengue merupakan penyakit virus yang disebabkan oleh satu dari empat serotipe virus dengue dan
ditularkan oleh nyamuk. Kasus dengue berat berdasarkan kriteria WHO 2009 didefinisikan sebagai
dengue dengan satu atau lebih kondisi berikut; kebocoran plasma yang menyebabkan syok (dengue
syok) dan atau akumulasi cairan dengan distres nafas, perdarahan berat dan yang ketiga adalah
keterlibatan organ. Diagnosa dini bermanfaat menurunkan morbiditas dan mortalitas, managemen
klinis, surveilens dan kontrol penyakit serta menurunkan durasi rawat inap. Penelitian ini
menganalisis faktor prognosis infeksi dengue berat pada anak. Kohort observasional pada pasien
usia 2bulan-18 tahun dengan infeksi dengue berdasarkan krieria WHO 2009 yang MRS ataupun di
poliklinik rawat jalan di RSUD DR. Soetomo dan RSUD Soewandhie Surabaya. Analisis data
dilakukan dengan univariat, bivariat dan multivariat menggunakan IBM SPSS Statistic 17. Semua
pasien terkonfirmasi dengan pemeriksaan serologis (NS-1 atau IgM/IgG Dengue). Data klinis dan
laboratorium (darah lengkap, AST, ALT, albumin, APTT dan PPT) dianalisis untuk
membandingkan antara kelompok dengue tidak berat dan dengue berat. Sebanyak 40 subyek pada
kelompok infeksi dengue tidak berat dan 27 subyek pada kelompok dengue berat yang memenuhi
kriteria inklusi. Didapatkan perbedaan yang bermakna berdasarkan analisis bivariat pada variabel
Overweight/obesitas, nyeri perut, efusi pleura, hepatomegali, leukopeni, trombositopenia,
hipoalbuminemia, AST meningkat >3x, PPT dan APTT meningkat serta riwayat transfusi.
Overweight/obesitas (p=0.003, 95% RR 94), muntah (p=0.02, RR 13.3), hepatomegali (p=0.01,
RR=69.4), dan pemanjangan APTT (p=0.005, RR=43.25) merupakan faktor prognosis infeksi
dengue berat berdasarkan analisis multivariat. Status nutrisi, muntah, hepatomegali dan
pemanjangan APTT merupakan faktor prognostik infeksi dengue berat pada anak.

Kata kunci :
Dengue berat, infeksi dengue, peningkatan APTT, overweight/obesitas, hepatomegali

INTRODUCTION fall in the platelet count.5 The benefficial of

The worldwide prevalence of dengue fever prompt diagnose can decreasing morbidity and

estimated 50-100 billion and dengue mortality, improvement of treatment and

hemorrahgic fever about 250.000-500.000.1 surveillance, and also disease management

Dengue fever is mosquito-borne disease and hence reducing of length of stay.5,6,7,8

caused by one of four serotype dengue

viruses(DENV-1, DENV-2, DENV-3 and MATERIAL AND METHODS

This study design was cohort observational
DENV-4).2,3 Dengue infection characterized by
study. The study population was selected from
fever and constitutional symptoms to
patient in pediatric outpatient clinic and
hemorrhagic manifestations and shock, or
pediatric emergency department Dr.Soetomo
dengue hemorrhagic fever/dengue shock
and Soewandhie Surabaya Hospital. During
syndrome (DHF/DSS).4 Severe dengue is
November 2017 until Juni 2018, 67 patients
characterized either by plasma leakage, fluid
with dengue infection wich is 27 and 40 were
accumulation, respiratory distress, severe
diagnosis as severe dengue and non severe
bleeding, or organ impairment. Recognizing
dengue infection respectively. Subject eligible
the warning signs for severe disease is
between two months until 18 years old with
important for successful clinical management.
fever ≥3 days and probable dengue infection
Warning signs include abdominal pain,
symptoms such as headache, nausea-vomiting,
evidence of fluid accumulation, hepatomegaly
ptekie, atralgia and retroorbita pain were
and increases in haematocrit accompanied by a
included. Patients were assessed as severe Siemens Dimension to analized albumin, AST

dengue and non severe dengue based on WHO and ALT. while Sysmex CS2100 in order to

2009 guideline and positively serology marker analyzed PPT and APTT. This study was

(IgM or NS-1). The exclusion criteria were aproved by Institutional Review Dr. Soetomo

congenital anomaly, malignancy, autoimmune and Soewandhie Hospital for ethical clearence.

and immunodefficiency disease

RESULTS AND DISCUSSION

This study was conducted in eight months,

from November 2017 to Juni 2018. The

population of this study were patients with

dengue infection in Dr. Soetomo Surabaya and

Figure 1. Flow diagram of subjects recruitment. Soewandhie Hospital. A total of 67 patients

with dengue infection met the inclusion

Nutritional status was assessed by BMI CDC
criteria. All subjects carried out anamnesis,
growth chart 2000 for patients 2-18 years old
physical examination and laboratory. Clinical
and WHO 2007b for patient below than 2 years
and laboratory examination (complete blood
old. The data were analyzed by Statistical
count, AST, ALT, albumin, APTT and PPT)
Program for Social Science software (SPSS)
were analyzed comparing non severe dengue
IBM SPSS Statistic 17. Chi-square test was
and severe dengue patients. Characteristics of
used to assess the categorical data and logistic
67 research subjects can be seen in the table
regression carried out to assess multi variate
below (table 1).
analysis.
There were 40 subjects in non severe and 27
In this study, laboratory examination was
subjects with severe dengue infection. All
carried out from the material of venous blood
patients were confirmed by serologic marker
samples by using Hematology Analyzer
(NS-1 or IgM/IgG Dengue). On bivariate
Sysmex XN1000 and Celldyne Ruby Sysmex
analysis, there were significant difference of
CS2100 to analized complete blood count,
thrombocytopenia, hypoalbuminemia, 27 (p=0.01, RR=69.4), dan prolonged APTT

subjects with severe dengue infection. All (p=0.005, RR=43.25)

patients were confirmed by serologic marker

(NS-1 or IgM/IgG Dengue). On bivariate DISCUSSION

analysis, there were significant difference of The baseline characteristics of children with

thrombocytopenia, hypoalbuminemia, history dengue infection and controls in this study

of transfusion, increasing AST>3x, nutritional were very similar except nutritional status and

status, abdominal pain, ptechie, pleural outcome. Nutritional status was statistic

effusion, leukopenia, prolonged PPT and significantly in bivariate and multivariate

APTT between severe and non severe dengue analysis (RR 2.93, 95% CI 2.18-6.20) while the

group. After multivariate analyzed, the previous study, Excess nutrition does not

prognostic factors of severe dengue were appear to be a risk factor for severe dengue

overweight /obesity (p=0.003, RR 94), infection.9,10,11 In addition, normal nutritional

vomiting (p=0.02, RR 13.3), hepatomegaly status had negative corelation with DHF and

Table 2. prognostics factors based on biv

Kelompok
Prognostic factors Severe Dengue Non Severe
n 27 (%) Dengue
n 40(%)

Abdominal pain 23 (85) 18 (45)

Nausea 24 (88.9) 28 (70)
DSS.12 However, meta analysis and sistematic severe dengue group (2-8 days). Mortality rate

review recently in this study was 5.9% in all

Table 3. prognostics factors based on multivariate analysis

Faktor Prognosis B p RR 95% CI

Hepatomegali 2.77 0.01* 69.4 2.18-287.4

Increase of APTT 3.42 0.005* 43.25 2.6-699
Obesitas/Overweight 4.5.3 0,003* 94 4.47-1989
vomiting 2.59 0.02* 13.3 1.5-118.8
Leukopenia -29.95 0.9 000 0.000
AST >3x 0.000
Abdominal pain 2.87 0.27 17.68 0.09-3221
Melena -2.65 0.14 0.071 0.002-2.28
Albumin <3.5 g/dL 1.26 0.22 3.5 0.47-26.54
Pleural effusiion -0.56 0.72 0.57 0.028-11.73
Increase of PPT -1.6 0.25 4.9 0.3-77.3
Transfusion 30.09 1 0.99 ~
Hb -1.34 0.42 0.26 0.009-7.23
Ptechie 2.27 0.16 9.7 0.42-226
Vomiting -2.36 0.31 0.095 0.001-8.81
Thrombocytopenia (≤ -7.8 0.81 0.46 0.001-291
50.000/µL)
Constanta -6.95 0.001* 0.001

* p significantly < 0.05*, Chi square test

subjects and 50% were severe dengue patients

enroled 15 studies from 2000 until 2016
with obesity, while other study reported
reported obesitas as a risk factor of severity in
mortality rate were 6.25%.14 Kamath et al
children with dengue infection (OR = 1.38;
reported mortality of DHF or DSS estimated
95% CI:1.10, 1.73).12 Study of obesity in
40-50% in pitfall management.15 However
severe dengue infection still rare. Dengue virus
WHO stated management properly can save
infection can make edothelium disruption due
lives and mortality rates from more than 20%
to chronic inflamation thus leading to
to less than 1%.5
endothelial disfuction and plasma leakage.13
The proportion of severe dengue and non
Severe dengue group in this study had
severe dengue with vomiting were 88.9% and
prolonged length of stay (1-11 days) than non
70% respectively. Vomiting more common in
DSS and expanded dengue syndrom than non phase as prognostic factor severe dengue in

severe dengue with frequent variously range 3- children.10,11 Phongphan reported in dengue

5x/day. In previous study reported the severity score, hepatomegaly had highest score

prevalence of vomiting symptom was higher in of predictive severe dengue in children (OR

severe dengue group than dengue 12.31, 95% CI = 8.84–17.15, P <0.001) than

infection/dengue infection with warning sign other variable e.x hematocrit, age>6 years,

group.16 Persistent vomiting is one of warning platelets ≤50000 µL, WBC>5000 µL and

sign according to WHO 2009.5 Ledika et al systolic blood pressure <90 mmHg.20

held study in patients with severe dengue Hepatomegaly is one of liver involvement

showed persistent vomiting had corelation in dengue infection and most commonly in

with severe dengue.11 Meta analysis study by children than adult patients.21 Clinical evidence

Zhang et al reported nausea-vomiting, as of liver involvement in dengue infections

predictor of severe dengue in children.17 includes the presence of hepatomegaly and

The propotion of hepatomegaly in this increased serum liver enzymes. Hepatomegaly

study was 92.6% in severe dengue group and is frequent and more common in patients with

statistic significantly in bivariate (RR 37.18, DHF than in those with DF.21 Currently, the

95% CI : 3.6-352 ) and multavariate analysis exact mechanism by which the host immunity

(RR 1.97 , 95% CI = 3.1-47.2). This was damages liver is unknown. Hepatomegaly

similar to previous study held in 110 children generally occurs via five mechanisms:

with dengue viral infection acompanied with inflammation, excessive storage, infiltration,

liver involvement reported hepatomegaly was congestion, and obstruction.22 Dengue virus can

79%18 and the most common symptom while infects hepatocite by attachment and

Roy et al 2013 reported 120 subjects with penetration in hepatocytes then internalization

dengue virus infection and proportion of liver through endocytosis and direct fusion. After

involvement was 80.8%.19 Several study infection can made apoptosis of hepatocyte.23

reported hepatomegaly >2cm in defervescence Several mechanism may be involved in

dengue-induced liver cell apoptosis. These aspartate aminotransferase (AST)/alanine

include direct cytophatic effects of the virus, aminotransferase (ALT) and APTT shows a

mithocondrial dysfunction due to low hypoxia strong association between AST/ALT elevation

and the influence of cellular and humoral and APTT prolongation in DHF patients.

immune factors.24 Dysfunction of the damaged liver might be

In this study, increased of APTT in severe responsible for the decreased synthesis of

dengue more than non severe dengue group specific factors in the intrinsic pathway.25

with propotion 88.9%. increasing of APTT Another hypothesis is NS-1 protein excreted

range from 1.5x until more than 100seconds during early stage infection will binding to

from normal level. Chi square analysis protrombine may inhibit its activation.26

revealed statistic significantly (RR 6.9 95% CI The limitations of this study are width

2.3-20.6) and also multivariate analysis caried confidence interval due to sample limitation.

out with logistic regression as prognostic This condition caused by dengue infection

factor of severe dengue in children (RR 43.25, commonly occurred in rainy season (in

95% CI: 2.6-699). September-February) and rarely to be found in

Prolongation of APTT in acute phase other season so that impacted small number

corelate with severity of infection and can subjects obtained. This study conducted with

made as early indicator DSS/DHF.25 Plasma cohort observational wich fever ≥3 days as

leakage in dengue patients also directly related inclusion criteria hence subjects came with

to APTT level.26 Coagulophaty can induced by various phase of illness.

hepatitis viral infection due to decreasing of

coagulation factors. This can be caused by

either downregulation of the synthesis of

specific factors or by increased consumption of CONCLUSION

specific factors. An analysis of the linear In conclusion, overweight/obesity, vomiting,

correlation and regression between the levels of hepatomegaly and prolonged APTT were
prognostic factors in severe dengue infection in 3. Gubler DJ. Dengue and dengue hemorrhage

children. It’s important to conduct largest study fever : its history and resurgen as a global

in order to validation this study. public health problem.1997:1-22.

4. Singhi S, Kissoon N, Bansal A. Dengue and

ACKNOWLEDGEMENT dengue hemorrhagic fever: management

Writer gratefully and sincerely thanks for issues in an intensive care unit. J Pediatr

patients of Dr. Soetomo general hospital which (Rio J). 2007;83:S22-35.

always become the first consideration, dean of 5. WHO. Dengue, guidelines for diagnosis,

Faculty of Medicine of Airlangga University, treatment, prevention and control. Genewa.

Director of Dr. Soetomo general hospital for 2009:1-160.

motivating, inspiring and spending their 6. Potts JA, Gibbon RV dan Rothman AL, et

precious time to guide and direct this al, 2010. Prediction of dengue disease

experiment until this study is done. severity among pediatric Thai patients

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