Original Studies

Daily Dengue Severity Score to Assess Severe Manifestations

Kanchana Tangnararatchakit, MD,* Ampaiwan Chuansumrit, MD,* Piangor Watcharakuldilok, MD,†
Nopporn Apiwattanakul, MD, PhD,* Rojjanee Lertbunrian, MD,* Jiraporn Keatkla, BSc,‡
and Sutee Yoksan, MD, PhD§

Background: The study aimed to develop dengue severity score to assess

1958 to 0.13% in 2018, and has remained unchanged (below 0.2%)
severe manifestations among hospitalized patients with dengue infection.
during the last decade.5 Nevertheless, high-risk patients with multi-
Method: Children and adolescents with serologically confirmed dengue
organ failure involving acute liver failure, acute respiratory fail-
infection admitted at Ramathibodi Hospital from 2004 to 2018 and treated
ure, acute kidney injury, active massive bleeding and fluid overload
by an expert multidisciplinary team were recruited. Medical records were
are at risk of lethal DHF/DSS with a higher mortality rate up to
retrospectively reviewed and 14 items, related to clinical parameters and
15% to 44%.1,6–12 and almost 50% to 100% in DSS with massive
managements during hospitalization, were obtained daily as dengue sever-
uncontrolled bleeding or multi-organ failure.11 In addition, studies
ity score.
among Thai children have found that infants and obese children had
Results: A total of 191 patients with a mean age of 10.7 years from 2004
a higher risk of having severe dengue infection.13–16 Also, patients
to 2013 were recruited. They were classified as dengue fever (35), dengue
with underlying diseases such as thalassemia and hemophilia are
hemorrhagic fever (DHF) I (53), II (50), III (37) and IV (16). The analy-
prone to aggravated hemolytic anemia17,18 and bleeding manifesta-
sis of 593 daily records revealed the range of daily severity score among
tions,19 respectively.
patients with DHF grades III (10–20) and IV (31–47) were significantly
The clinical diagnosis of DHF is based on four major char-
higher than those of other groups (dengue fever, 5–13; DHF I, 2–10; DHF
acteristic manifestations19: (1) high continuous fever lasting for 2 to
II, 6–11) with P-values of 0.0001. Using a validity test, a total daily score 7 days; (2) hemorrhagic tendency such as positive tourniquet test,
of ≥12 was an assessment tool for dengue shock syndrome with sensitivity, petechiae, epistaxis or intestinal bleeding; (3) thrombocytopenia
86% and specificity, 84%. An additional 51 hospitalized patients with DHF (platelet count <100,000 µ/L) and (4) evidence of plasma leakage
grades II, III and IV with similar ages from 2014 to 2018 were recruited. due to increased vascular permeability manifested by hemoconcen-
The number of patients with severe manifestations, having daily score of tration (an increase in hematocrit >20%) and pleural effusion or
≥12, was significantly higher than those without severe manifestations start- ascites. The three stages of DHF are febrile, toxic and deferves-
ing from Day −3 to Day +1 of illness. cence. The febrile stage lasts 2 to 7 days followed by an abrupt
Conclusions: Daily dengue severity score of ≥12 was an accurate assess- fall to normal or subnormal levels of temperature; the toxic stage
ment tool for severe manifestations. lasts 24 to 48 h; and finally, rapid clinical recovery without seque-
lae in the defervescence stage. The toxic stage is the most critical
Key Words: severity score, dengue hemorrhagic fever, dengue shock syn- period from prominent plasma leakage leading to DSS and requir-
drome ing intensive supportive care. Optimal fluid therapy is essential to
maintain vital organ functions during the critical period. According
(Pediatr Infect Dis J 2020;39:184–187)
to the 1997 World Health Organization (WHO) committee classi-
fication of dengue infection20 varying from DF to DHF grade I–IV
was precisely concluded after the defervescence emphasizing the

D engue infection is one of the most common mosquito-borne

diseases of public health significance. Currently dengue
infection affects about 1% of the world’s population annually and
pathophysiologic alteration of the clinical manifestations. In the
2009 WHO classification, dengue infection was defined as either
dengue with or without warning signs, or severe dengue including
is associated with high morbidity.1–4 The clinical manifestations severe plasma leakage, severe hemorrhage and severe organ impair-
of dengue infection range from asymptomatic to undifferentiated ments.21 It has been used to aid appropriate management in decision
fever, an influenza-like symptom known as dengue fever (DF) and making regarding outpatient care and hospitalization criteria.
a severe, sometimes fatal disease characterized by massive plasma This study was designed to develop a daily dengue severity
leakage, hemorrhage and shock known as dengue hemorrhagic score to assess severe manifestations among patients with dengue
fever (DHF) and dengue shock syndrome (DSS). Due to advanced infection in a hospitalized setting.
comprehensive care technology, the mortality rate among patients
with DHF in Thailand has progressively declined from 13.7% in SUBJECTS AND METHODS
The medical records of hospitalized children admitted for
Accepted for publication October 12, 2019. dengue by serologic confirmation between 2004 and 2018 were
From the *Department of Pediatrics, Mahidol University, Bangkok, Thailand; retrospectively reviewed. The study consisted of 2 phases. Phase I
†Department of Pediatrics, Buriram Hospital, Buriram, Thailand; ‡Pathol- established the daily dengue score system and assessment tool for
ogy, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang-
kok, Thailand; and §Center for Vaccine Development, Institute of Molecular severe manifestations, followed by phase II testing the accuracy of
Biosciences, Mahidol University, Nakhon Pathom, Thailand. the severity score. This study was approved by the Ramathibodi
The authors have no funding or conflicts of interest to disclose. Hospital Ethics Committee for Human Research.
Address for correspondence: Kanchana Tangnararatchakit, MD, Department of
Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University,
Bangkok 10400 Thailand. E-mail: kanchana.tan@mahidol.ac.th. Patients
Supplemental digital content is available for this article. Direct URL citations In all, 355 children 1 month to 18 years of age with sero-
appear in the printed text and are provided in the HTML and PDF versions of logic confirmation of dengue infection (DF,102; DHF grade I, 88;
this article on the journal’s website (www.pidj.com).
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
DHF grade II, 103; DHF grade III, 46; and DHF grade IV, 16) were
ISSN: 0891-3668/20/3903-0184 hospitalized at the Department of Pediatrics, Faculty of Medicine,
DOI: 10.1097/INF.0000000000002533 Ramathibodi Hospital, Mahidol University from 2004 to 2013. All

184 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 39, Number 3, March 2020
The Pediatric Infectious Disease Journal • Volume 39, Number 3, March 2020 DengueSeverityScoretoAssessSevereManifestations

patients were treated by an expert multidisciplinary team using RESULTS

Ramathibodi Clinical Practice Guidelines.22–24 The complete medi- The baseline characteristics of the studied patients from
cal records of 191 cases (DF, 35; DHF grade I, 53; DHF grade II, 2004 to 2013 in the phase I study are shown in Table 1. Their mean
50; DHF grade III, 37; and DHF grade IV 16) from 355 patients (SD) age was 10.7 (3.8) years with 102 males and 89 females.
were included in the phase I study to establish daily dengue severity Patients with DHF grades I and II were significantly older than
score. Then, 51 additional hospitalized patients with DHF grades those with DF, DHF grades III and IV. Duration of fever in each
II, III, and IV from 2014 to 2018 were included in phase II study to group did not significantly differ but DHF grades III and IV had
test the accuracy of the severity score. significantly longer hospitalizations than those of the other groups.
Data collection included baseline characteristics (age, The initial complete blood counts at admission showed higher white
sex, duration of fever, and duration of hospitalization), complete blood cell counts and lower platelet counts among patients with
blood cell counts and bleeding sites. The 14 items related to DHF grades III and IV compared with those of the other groups.
clinical parameters and managements, shown in Table, Supple- However, the levels of initial hematocrit did not significantly dif-
mental Digital Content 1, http://links.lww.com/INF/D712, were fer between patients with DF and DHF. The levels of hematocrit
entered in the computerized program using Microsoft Access to among patients with DHF gradually increased to levels of more
obtain the daily severity score during hospitalization until dis- than 20% of their baseline except for those with massive bleed-
charge or death. ing. Importantly, patients with DHF had significantly lower platelet
According to the pathophysiology of dengue infection, the counts during hospitalization compared with those of patients with
day of defervescence was designated as Day 0 (D0). One and 2 days DF (29,000–51,000/µL vs. 86,000/µL, P = 0.002).
before defervescence were designated as Day −1 (D −1) and Day Concerning bleeding manifestations, patients with DHF
−2 (D −2) and so on. One and 2 days after defervescence were des- exhibited frequent bleeding episodes while those with DF rarely
ignated as Day +1(D +1) and Day +2 (D +2). Designating the day exhibited bleeding except for petechiae. The logistic regres-
of illness related to the day of defervescence is useful in recruiting sion analysis showed that epistaxis was commonly found among
patients in the same pathophysiology in the same group because the patients with DHF grade II (odd ratio 4.47, 95% CI 1.45–15.58,
febrile stage of dengue infection lasts 2 to 7 days. P = 0.01) but gastrointestinal hemorrhage was commonly found
among patients with DHF grades III and IV (odd ratio 102, 95% CI
Confirmation Study 10.35–1005.23, P = 0.01) compared with those of patients with DF.
The dengue nonstructural protein antigen 1 (NS1) was iden- The case-fatality rate was 4.7% (9/191) found among patients with
tified by strip test in 125 patients of a total of 242 patients and DHF grade IV only. All fatal patients had experienced prolonged
was positive in 84 of 125 patients (67.2%). All patients had posi- shock with uncontrolled massive bleeding and multi-organ failure
tive serologic studies of dengue-specific IgM/IgG performed by before being referred for comprehensive management at the Pediat-
enzyme-linked immunosorbent assay (ELISA). ric Intensive Care Unit, Faculty of Medicine Ramathibodi Hospital.
A total of 593 daily dengue severity scores from Day −4
WHO Dengue Classification to Day +2 among patients with DF and DHF grades I to IV were
Dengue infection was classified as DF and DHF according recorded and analyzed. The median number of daily score was 3.0
to the WHO (1997) criteria by two physicians (KT, AC) from clini- with an interquartile range of 2 to 4. The mean daily dengue sever-
cal data, laboratory investigation and/or a right lateral view of chest ity score during hospitalization related to defervescence is shown in
radiograph obtained after defervescence. Figure 1. The analysis revealed that the range of mean daily dengue
severity scores among patients with DHF grade III (10–20) and
Statistical Analysis DHF grade IV (31–47) were significantly higher than those of DF
Database was analyzed using the Statistical Package for (5–13), DHF grade I (2–10) and DHF grade II (6–11) with P-values
Social Sciences Software (SPSS, Version 12.0). Categorical of 0.0001. The ability of dengue severity score to assess the subse-
variables were analyzed using χ2 or Fisher exact tests. Daily quent threatened shock and profound shock in DHF grades III and
dengue severity score was assessed using the Area under the IV known as DSS using AUROC curves was the score on Day −1
Receiver Operating Characteristic (AUROC) curves. Continu- compared with other days as shown in Table 2. Using the validity
ous severity scores were compared using multilevel analysis. test, dengue severity score of ≥12 was used as an assessment tool
The predictive ability of a score for subsequent DSS was ana- for the severe manifestations of DSS with a sensitivity of 86.2%,
lyzed and presented with sensitivity, specificity and positive specificity of 84.3% and positive likelihood ratio of 5.7 as shown
likelihood ratio. in Table 3.

TABLE 1. Comparison of Baseline Characteristics, Initial Complete Blood Cell Count and the
Lowest Platelet Count During Hospitalization Among Patients with DF, DHF Grades I, II, III and
IV from 2004 to 2013

DF DHF I DHF II DHF III DHF IV

Parameters N = 35 N = 53 N = 50 N = 37 N = 16 P

Age (years) 9.3 ± 3.8 12.3 ± 3.1* 12.0 + 2.8* 9.5 + 4.1 7.4 + 3.7 <0.001
Duration of fever (day) 5.5 ± 1.5 5.1 ± 1.2 4.9 ± 1.6 5.2 ± 1.9 5.0 ± 1.7 0.929
Duration of hospitalization (day) 4.2 ± 2.8 4.4 ± 1.6 4.4 ± 2.3 6.2 ± 4.3* 10.0 ± 9.9* <0.001
Initial hematocrit (%) 38.2 ± 3.4 39.9 ± 6.8 40.5 ± 5.0 37.0 ± 7.4 40.2 ± 10.3 0.22
Initial WBC (103/µL) 3.5 ± 2.6 3.4 ± 1.9 3.3 ± 2.1 4.8 ± 3.3 12.8 ± 9.2* <0.001
Initial platelet count (×103/µL) 130 ± 57 113 ± 64 118 ± 79 86 ± 64 65 ± 89* 0.002
Lowest platelet count (×103/µL) 86 ± 38 48 ± 22* 51 ± 24* 38 ± 28* 29 ± 14* <0.001
* The value indicate statistical significant with P-value <0.05.

© 2019 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | 185
Tangnararatchakit et al The Pediatric Infectious Disease Journal • Volume 39, Number 3, March 2020

FIG. 1. Compaarison of the

mean daily dengue severity
scores among patients with
DF, DHF grade I, II, III and IV.
Day 0 (D 0) was the day of
defervescence; Day-1 (D-1) to
Day-4 (D-4) were one to four
days before defervescence.
Day+1 (D+1) and Day+2 (D+2)
were one and two days after
defervescence.

obesity (n = 7) and having the daily score of ≥12, was significantly

TABLE 2. Discriminative Performance of Daily Dengue higher than those of DHF grade II without severe manifestations (n
Severity Score Among Patients with DF, DHF Grades I– = 23). This included from Day −3 to Day +1 (Day −3, 3/5 vs. 0/5,
II and Patients with DSS (DHF III-IV) Using Area Under P = 0.038; Day −2, 8/10 vs. 0/12, P < 0.0001; Day −1, 11/17 vs.
the Receiver Operating Characteristic (AUROC) Curves 1/18, P < 0.0001, Day 0, 24/28 vs. 2/23, P < 0.0001 and Day +1,
11/26 vs. 0/21, P = 0.001). Therefore, the daily dengue severity
Day of illness* AUROC 95%CI scores of ≥12 was proven as an accurate assessment tool for severe
Day −4 0.65 0.28–1.00 manifestations among patients with DHF starting from the febrile
Day −3 0.70 0.52–0.87 to the toxic stage.
Day −2 0.79 0.66–0.92
Day −1 0.93 0.87–0.99
Day 0 0.88 0.82–0.95 DISCUSSION
Day +1 0.75 0.65–0.85 Dengue virus infection is a clinical diagnosis and is sub-
Day +2 0.66 0.48–0.84 sequently confirmed by virus isolation, the dengue NS1 antigen
* Day 0 was the day of defervescence; Day −1 to Day −4 were 1–4 days before defer- and serologic testing requiring a single sample or paired sera from
vescence. Day+1 and Day+2 were 1–2 days after defervescence acute and convalescent stages. Dengue virus isolation or dengue
virus amplification will be positive during the first 1–2 days of
fever requiring advanced technology and is unavailable in general
TABLE 3. Score-Classified Dengue Severity Level hospital services. Recently, determining the dengue nonstructural
to Predict Subsequent DSS at Day −1 (1 Day Before protein 1 (NS1) antigen in the serum and urine is helpful to initially
Defervescence) confirm dengue virus infection during the febrile stage.25,26 How-
ever, patients with positive dengue NS1 may exhibit mild manifes-
Score Positive tations of DF or the more severe manifestations of DHF.
classified Sensitivity Specificity Correctively likelihood Several attempts were made to find out a suitable marker
severity level (%) (%) classified (%) ratio to predict patients at risk of subsequent severe manifestations of
8 96.55 57.14 65.67 2.25 bleeding, plasma leakage, threatened shock and profound shock
10 89.66 75.24 78.35 3.62 during the febrile and toxic stages. In 2006, Butthep et al27 studied
12 86.21 84.26 85.07 5.66 111 patients (25 DF, 78 DHF and 8 with other febrile illnesses) 4
15 75.86 94.29 90.30 13.27 to 16 years of age revealed that elevated soluble thrombomodulin
acted as an early predictor of DSS during the febrile stage. However,
Then the phase II study recruited a total of 149 hospitalized testing to determine soluble thrombomodulin is routinely unavail-
patients (DF 77, DHF grade I, 21; II 29; III 18 and IV 4) from 2014 able in hospital services. The routine laboratory tests of complete
blood counts and coagulation tests of activated partial thrombo-
to 2018 treated by a multidisciplinary expert team using Ramathi-
plastin time, prothrombin time and thrombin time were analyzed
bodi Clinical Practice Guidelines. Their mean (SD) age was 10.1
among the same group of 111 patients. The results revealed any
(4.4) years. The case-fatality rate was 2.0% (3/149) found among 1 of the following abnormal laboratory findings during the febrile
patients with DHF grade IV only. A total of 190 daily dengue sever- stage served as predictors for risk of DSS: increased hematocrit
ity scores from Day −3 to Day +2 from patients with DHF grades >25%, platelet count <40,000/µL, activated partial thromboplastin
II, III and IV (35 males, 16 females,) were recruited to test the time >44 seconds, prothrombin time >14 seconds and thrombin
accuracy of daily dengue severity scores. The median number of time >16 seconds with the relative risk ranging from 6.7 to 13.6.28
daily scores was 4 with an interquartile range of 3 to 5. The num- In 2013, Pongpan et al29 developed a dengue infection sever-
ber of patients, who exhibited severe manifestations including DHF ity score using the data of 777 patients with dengue infection (391
grades III and IV (n = 21) and DHF grade II with severe hem- DF, 296 DHF, 90 DSS) from 3 hospitals located in northern Thai-
orrhage, severe plasma leakage and risk factor of age ≤1 year or land. The results revealed that the significant clinical predictors of

186 | www.pidj.com © 2019 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 39, Number 3, March 2020 DengueSeverityScoretoAssessSevereManifestations

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