DOI: 10.1111/tmi.

13797

SYSTEMATIC REVIEW

Risk factors for mortality in patients with dengue: A systematic

review and meta-analysis

Gabriel Cavalcante Lima Chagas1 | Amanda Ribeiro Rangel1 |

Luísa Macambira Noronha1 | Felipe Camilo Santiago Veloso2 | Samir Buainain Kassar2 |
Michelle Jacintha Cavalcante Oliveira2 | Gdayllon Cavalcante Meneses1 |
Geraldo Bezerra da Silva Junior1,3 | Elizabeth De Francesco Daher1

1
Post-Graduation Program in Medical Sciences,
Department of Internal Medicine, Faculty of
Medicine, Federal University of Cear
a, Fortaleza,
Brazil
2
Post-Graduation Program in Medical Sciences,
Department of Internal Medicine, Faculty of
Medicine, Federal University of Alagoas, Macei

o,
Brazil
3
Public Health and Medical Sciences Graduate
Programs, Health Sciences, School of Medicine,
University of Fortaleza, Fortaleza, Brazil
Correspondence
Gabriel Cavalcante Lima Chagas, Rua NS 03, 92,
Fortaleza, Cear
a, CEP: 60824-090, Brazil.
Email: gabrielchagas.gc@gmail.com
Funding information
Coordination of Improvement of Higher
Education Personnel—Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior
(CAPES); Brazilian Council for Scientific and
Technological Development—Conselho Nacional
de Desenvolvimento Científico e Tecnol
ogico
(CNPq)
Abstract
Objective: To investigate risk factors for mortality in dengue.
Methods: We performed a systematic review and meta-analysis searching MEDLINE,
Embase, SciELO, LILACS Bireme, and OpenGrey databases to identify eligible obser-
vational studies of patients with dengue, of both genders, aged 14 years or older, that
analysed risk factors associated with mortality and reported adjusted risk measures
with their respective confidence intervals (CIs). We estimated the pooled weighted
mean difference and 95% CIs with a DerSimonian and Laird random-effects model.
We assessed the methodological quality using the Newcastle-Ottawa Scale.
Results: Of 1,170 citations reviewed, 18 papers, with a total of 25,851 patients, were
included in the systematic review and 12 in the meta-analysis. Severe hepatitis
(OR 29.222, 95% CI 3.876–220.314), dengue shock syndrome (OR 23.575, 95% CI
3.664–151.702), altered mental status (OR 3.76, 95% CI 1.67–8.42), diabetes mellitus
(OR 3.698, 95% CI 1.196–11.433), and higher pulse rate (OR 1.039, 95% CI 1.011–
1.067) are associated with mortality in patients with dengue. All studies included were
classified as having a high quality.
Conclusions: Proper identification and management of these risk factors should be
considered to improve patient outcomes and reduce the hidden burden of this
neglected tropical disease. Future well-designed studies are needed to investigate the
association of other clinical, radiological, and laboratorial findings with mortality in
dengue, as well as to develop prognostic models based on the risk factors found in our
study.

KEYWORDS
dengue, meta-analysis, mortality, risk factors, systematic review

INTRODUCTION Dengue is the most important arboviral disease affecting

Dengue, also known as ‘breakbone fever’, is caused by RNA
viruses grouped into four serotypes (DENV1-4) belonging
to the Flaviviridae family and mainly transmitted by Aedes
aegypti [1–4]. Dengue is endemic in almost all tropical and
subtropical countries [2]. More than 3.9 billion individuals
are in danger of contracting DENV worldwide, and 390 mil-
lion infections (96 million symptomatic) and 20,000 deaths
from dengue occur every year [4, 5].
Sustainable Development Goal: Good Health and Wellbeing.
humans in terms of morbidity and mortality, with case-fatality
rates of severe dengue up to 5% [1, 2]. The clinical presentation
is highly variable. Most infections are asymptomatic [6]. Symp-
tomatic cases usually present sudden onset of fever, severe
headache, retro-ocular pain, macular rash, mild haemorrhagic
manifestations, severe myalgia and arthralgia, abdominal pain,
nausea, and vomiting [1, 2]. In a minority of cases, patients
can develop complications associated with plasma leakage,
severe bleeding, and/or organ impairment [1].
In 1997, WHO published a classification scheme group-
ing dengue into three categories: dengue fever, dengue hae-
morrhagic fever (DHF), and dengue shock syndrome (DSS)

656 © 2022 John Wiley & Sons Ltd. wileyonlinelibrary.com/journal/tmi Trop Med Int Health. 2022;27:656–668.

TROPICAL MEDICINE & INTERNATIONAL HEALTH
[7]. In 2009, the WHO revised this classification and issued
a new version as dengue without warning signs, dengue with
warning signs, and severe dengue [1].
A provisional diagnosis of dengue is usually established
clinically in patients with an acute febrile illness and relevant
epidemiological exposure with a high positive predictive
value [8]. For confirming dengue, laboratory diagnosis can
be established by serology or detection of viral antigens or
RNA by RT-PCR and viral culture [1, 2, 9]. However, the
lack of diagnostic resources in dengue-endemic countries
limits the possibility of classifying and managing dengue
patients according to WHO 2009 guidelines [1]. Thus, in
these countries, the diagnosis of dengue is mostly probable
dengue, and many febrile illnesses are still included among
the probable cases of dengue [1].
Currently, no effective antiviral agents are available for
the treatment of dengue, and management remains support-
ive. Early recognition of severe disease and prompt manage-
ment with more aggressive therapy are essential to reduce
mortality [1, 2, 5, 9]. Patients without warning signs or coex-
isting conditions should be instructed about the recognition
of warning signs and adequate rest, fluid intake, and man-
agement of fever [1, 2, 5, 9]. Inpatient management is war-
ranted for patients with warning signs, severe dengue, or
coexisting conditions. Fluid therapy for patients admitted to
the hospital includes isotonic solutions, and transfusion of
blood products may be indicated according to WHO 2009
guidelines [1, 2, 5, 9].
There is no systematic review evaluating risk factors
associated with mortality in patients with dengue. Herein,
we performed a systematic review and meta-analysis to
assess the impact of risk factors on mortality in patients with
dengue. Thus, the findings of our study will possibly support
public health and clinical decision-making.
METHODS
This systematic review and meta-analysis was performed
according to the Preferred Reporting Items for Systematic
reviews and Meta-Analyses (PRISMA) 2020 guidelines
[10]. Thus, our systematic review was registered with the
International Prospective Register of Systematic Reviews
(PROSPERO) on July 4, 2021 (registration number
CRD42021259094) [11].
Eligibility criteria
We included observational studies of patients affected by
dengue, aged 14 years or older (in accordance with the
WHO definition for adults [1]), that analysed risk factors
associated with mortality in patients with dengue and
reported adjusted risk measures with their respective confi-
dence intervals (CIs). Studies that involved non-human
experiments and/or the human paediatric population (below
14 years) were excluded. Non-observational studies were
13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
657
excluded, as well as observational studies that did not ana-
lyse risk factors associated with mortality and/or did not
report adjusted risk measures with their respective CIs.
Exposure and control were defined by the variables asso-
ciated with mortality in patients aged 14 years or older
affected by dengue. The outcome of interest was the
mortality rate.
Information sources
We searched the Medical Literature Analysis and Retrieval
System Online (MEDLINE), Excerpta Medica Database
(Embase), Scientific Electronic Library Online (SciELO),
Latin American Caribbean Health Sciences Literature
(LILACS) Bireme, and OpenGrey databases on June 6, 2021
and updated on March 23, 2022. There were no language or
publication period restrictions.
Search strategy
The search strategy used in each database is provided
in Box 1.
Selection process
Studies were independently selected by two authors (AR and
LN). Studies were excluded if there was inaccessibility of the
full text. In the case of disagreement between the two
reviewers, a third review author (GC) was involved to
resolve, by consensus, any discrepancies. In the case of
duplicate studies and multiple reports from the same cohort,
we only examined (a) the largest cohort, (b) the one with
longer follow-up, or (c) the most recent one.
Data collection
Studies were independently selected by two authors (AR and
LN) in three phases: (a) reading of titles, (b) reading of
abstracts, and (c) reading of full articles. We screened the
reference lists of eligible studies to capture additional rele-
vant citations. In case of disagreement between the two
reviewers, a third author (GC) was involved to resolve, by
consensus, any discrepancies. Literature selection and cod-
ing were performed using the Mendeley software version
1.19.8 (Elsevier, Amsterdam, NL).
Data items
Data were extracted and entered in a piloted spreadsheet in
the Microsoft Excel software version 2020 (Microsoft Cor-
poration, Redmond, WA) with the following elements: name
of the first author; title; journal of publication; publication
 13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
658 TROPICAL MEDICINE & INTERNATIONAL HEALTH

BOX 1 Literature search strategy for the databases searched

• Medical Literature Analysis and Retrieval System Online (MEDLINE)
Search strategy: (Dengue OR Dengue Viral Infection OR Break-Bone Fever OR Break Bone Fever OR Breakbone
Fever OR Classical Dengue OR Classical Dengue Fever OR Dengue Fever OR Dengue Hemorrhagic Fever OR
Dengue Shock Syndrome OR Severe Dengue OR Non-severe Dengue OR Dengue Without Warning Signs OR
Dengue With Warning Signs OR Severe Dengue OR Fatal Dengue) AND (Risk Factors OR Health Correlates
OR Population at Risk OR Populations at Risk OR Risk Factor Scores OR Risk Scores OR Predictor OR Predictors)
AND (Mortality OR Fatality OR Death OR Age Specific Death Rate OR Age-Specific Death Rate OR Case Fatality
Rate OR Crude Death Rate OR Crude Mortality Rate OR Death Rate OR Mortality Determinants OR Differential
Mortality OR Excess Mortality OR Mortality Rate) NOT Insecticide

• Excerpta Medica Database (Embase)

Search strategy: (Dengue OR Dengue Viral Infection OR Break-Bone Fever OR Break Bone Fever OR Breakbone
Fever OR Classical Dengue OR Classical Dengue Fever OR Dengue Fever OR Dengue Hemorrhagic Fever OR
Dengue Shock Syndrome OR Severe Dengue OR Non-severe Dengue OR Dengue Without Warning Signs OR
Dengue With Warning Signs OR Severe Dengue OR Fatal Dengue) AND (Risk Factors OR Health Correlates
OR Population at Risk OR Populations at Risk OR Risk Factor Scores OR Risk Scores OR Predictor OR Predictors)
AND (Mortality OR Fatality OR Death OR Age Specific Death Rate OR Age-Specific Death Rate OR Case Fatality
Rate OR Crude Death Rate OR Crude Mortality Rate OR Death Rate OR Mortality Determinants OR Differential
Mortality OR Excess Mortality OR Mortality Rate)

• Scientific Electronic Library Online (SciELO)

Search strategy: (Dengue OR Break-Bone Fever OR Breakbone Fever) AND (Risk Factors OR Predictor OR Predictors)
AND (Mortality OR Fatality OR Death)

• Latin American Caribbean Health Sciences Literature (LILACS) Bireme

Search strategy: (Dengue OR Break-Bone Fever OR Breakbone Fever) AND (Risk Factors OR Predictor OR Predictors)
AND (Mortality OR Fatality OR Death)

• OpenGrey
Search strategy: (Dengue OR Dengue Viral Infection OR Break-Bone Fever OR Break Bone Fever OR Breakbone
Fever OR Classical Dengue OR Classical Dengue Fever OR Dengue Fever OR Dengue Hemorrhagic Fever OR
Dengue Shock Syndrome OR Severe Dengue OR Non-severe Dengue OR Dengue Without Warning Signs OR
Dengue With Warning Signs OR Severe Dengue OR Fatal Dengue) AND (Risk Factors OR Health Correlates
OR Population at Risk OR Populations at Risk OR Risk Factor Scores OR Risk Scores OR Predictor OR Predictors)
AND (Mortality OR Fatality OR Death OR Age Specific Death Rate OR Age-Specific Death Rate OR Case Fatality
Rate OR Crude Death Rate OR Crude Mortality Rate OR Death Rate OR Mortality Determinants OR Differential
Mortality OR Excess Mortality OR Mortality Rate)

year; country(ies) where the study was performed; study
design; number of study participants; aim(s); criteria used
for diagnosing dengue; criteria used for classifying
dengue; mortality; variables related to mortality in patients
with dengue; adjusted risk measures and CIs of the included
variables. We attempted to contact the original author by
email correspondence to obtain any further information if
not reported.
sectional studies. The methodological quality was deter-
mined according to the scores obtained, as follows: low qual-
ity: 0–3; intermediate quality: 4–6; and high quality: 7–9.
Two reviewers (AR and LN) independently assessed the
methodological quality in each study. The discrepancies
between the two reviewers on the methodological quality
assessment were resolved, by consensus, by consulting a
third review (GC) author.

Study methodological quality assessment Effect measures

We assessed the methodological quality of all included stud- We investigated the main outcome by analysing the adjusted
ies using the Newcastle-Ottawa Scale (NOS) [12]. The NOS risk measures along with their respective 95% CIs of vari-
adapted for cross-sectional studies was used to assess cross- ables associated with mortality in patients with dengue.

TROPICAL MEDICINE & INTERNATIONAL HEALTH
Synthesis methods
The meta-analysis was performed by two review authors
independently (FV and GM) using the Stata software ver-
sion 13.0 (StataCorp, College Station, TX). In the case of dis-
agreement between the two reviewers on meta-analysis, a
third review author (GC) was involved to resolve, by con-
sensus, any discrepancies.
The data used were the natural logarithms of the
adjusted risk measures of the included variables and their
95% CIs. We estimated the pooled weighted mean difference
(WMD) and 95% CIs with a DerSimonian and Laird
random-effects model [13]. We regarded a p value of <0.05
as statistically significant.
We assessed the heterogeneity of included studies with
Cochran’s Q test [14] and Higgins and Thompson I 2
index [15]. We regarded a p value of <0.10 as statistically
significant when using Cochran’s Q test [14]. We consid-
ered I 2 index values of 0% to <25%, 25% to <40%, ≥40%
as not important, moderate, and substantial heterogene-
ity, respectively.
Analysis of subgroups
If heterogeneity were relevant, we aimed to perform sub-
group analyses to investigate the origin of this heterogeneity.
Sensitivity analyses
We aimed to perform sensitivity analyses to assess the robust-
ness of our findings for the outcome of interest by
(a) excluding studies that were judged to be at overall low
quality on methodological quality assessment and
(b) excluding studies that were judged to be at overall low and
intermediate quality on methodological quality assessment.
Reporting bias assessment
We aimed to evaluate the potential for publication biases
using Begg’s [16] and Egger’s [17] tests, statistical
methods, and funnel plot, a graphic method, when the
analysed exposure factor had at least 10 included studies
(k ≥ 10) [18].
RESULTS
Study selection
Our search yielded overall 1,170 records (Figure 1). After
duplicate removal, we screened 1,007 records, from which
we reviewed 68 full articles and included 15 papers. Then,
we searched the references for eligible studies, and three
extra articles were found in these searches. Finally, 18 studies
were included in our analysis (Table 1) [19–36].
13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
659
Study characteristics
The included studies were performed between 1998 and
2020, with a total of 25,851 patients. Eight studies [19, 26–
29, 31–33] used a retrospective observational design, five
[20, 23–25, 34] used prospective observational design, and
five [22, 24, 25, 29, 36] used a retrospective case–control
design. Studies were undertaken in Taiwan (n = 7) [19,
21, 22, 26–28, 35], India (n = 6) [23–25, 32–34], Singapore
(n = 2) [30, 36], Malaysia (n = 1) [29], Pakistan (n = 1)
[31], and Puerto Rico (n = 1) [20]. Seventeen studies [19–
32, 34–36] used a laboratory-confirmed criteria for the diag-
nosis of dengue, with one report [33] using clinical features
only. Eight studies [19, 20, 23, 26, 27, 30, 32, 33] used the
WHO 1997 classification, seven [21, 22, 25, 28, 29, 34, 35]
used the WHO 2009 classification, one [36] used both the
WHO 1997 and 2009 classifications, and two [24, 31] did
not report the criteria used. The median mortality rate was
5.13% (range 0.01%–38.68%). Pertinent information about
reported risk factors associated with mortality are shown in
Table 2.
Methodological quality of studies
All studies included were classified as high-quality (Table 3).
Results of synthesis
Figure 2 shows the overall association between the analysed
risk factors and mortality in patients with dengue. The results
of the association between each analysed risk factor and mor-
tality in patients with dengue are described separately.
Age
Four studies [20, 23, 26, 31] reported age as a risk factor
associated with mortality in dengue. Only studies that
reported a cut-off value were included in the quantitative
analysis. Thus, a total of 19,043 patients from three studies
[20, 23, 31] were included in the meta-analysis of age as a
risk factor for mortality in dengue. There was a positive
association between age >19 years and mortality [Pooled
OR (95% CI): 2.546 (0.431–15.034)], however not statisti-
cally significant. Heterogeneity was considered substantial,
although not statistically significant (I 2 = 81.9%; p = 0.302).
Diabetes mellitus
Two studies [26, 31], with a total of 1,527 patients,
reported diabetes mellitus (DM) as a risk factor associ-
ated with mortality in dengue. Both were included in the
meta-analysis. Overall, there was a statistically significant
positive association between DM and mortality [Pooled
OR (95% CI): 3.698 (1.196–11.433)]. Heterogeneity was

660
FIGURE 1 PRISMA 2020 flow diagram of the literature search and selection
statistically significant and not important (I 2 = 0.0%;
p = 0.023).
Altered mental status
Three studies [19, 23, 29], with a total of 744 patients, reported
altered consciousness, altered sensorium, and lethargy as risk
factors associated with mortality in dengue. All studies [19,
23, 29] were included in the meta-analysis unified as altered
mental status. Overall, there was a statistically significant positive
association between AMS and mortality [Pooled OR (95% CI):
3.76 (1.67–8.42)]. Heterogeneity was considered substantial,
although not statistically significant (I 2 = 81.9%; p = 0.302).
Bleeding manifestations
Three studies [28, 29, 33], with a total of 1,383 patients,
reported bleed, ecchymosis, and gastrointestinal bleeding as
13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TROPICAL MEDICINE & INTERNATIONAL HEALTH
risk factors associated with mortality in dengue. All studies
[28, 29, 33] were included in the meta-analysis unified as
bleeding manifestations. Overall, there was a positive associa-
tion between bleeding manifestations and mortality [Pooled
OR (95% CI): 3.313 (0.276–39.733)], however not statistically
significant. Heterogeneity was considered substantial,
although not statistically significant (I 2 = 88.5%; p = 0.345).
Dengue shock syndrome
Two studies [27, 34], with a total of 444 patients, reported
DSS, defined as DHF grades III and IV according to the
WHO 1997 classification [7], as a risk factor associated
with mortality in dengue. Both studies [27, 34] were
included in the meta-analysis. Overall, there was a statisti-
cally significant positive association between DSS and
mortality [Pooled OR (95% CI): 23.575 (3.664–151.702)].
Heterogeneity was statistically significant and considered
moderate (I 2 = 37.6%; p = 0.001).
 13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TROPICAL MEDICINE & INTERNATIONAL HEALTH 661

TABLE 1 Characteristics of included studies

Criteria used for diagnosing Criteria used for

Studies Country Study type n the dengue infection classifying dengue Mortality

Chang et al., 2017 [19] Taiwan Retrospective observational 206 Viral isolation, RT-PCR, NS1 WHO 1997 24.3%
ELISA, serology
García-Rivera et al., 2003 [20] Puerto Rico Prospective observational 17,666 IF, NS1 ELISA WHO 1997 0.249%
Huang et al., 2017 [21] Taiwan Retrospective case–control 627 Clinical, NS1 ELISA, serology WHO 2009 4.3%
Huang et al., 2018 [22] Taiwan Retrospective case–control 2358 Clinical, NS1 ELISA, serology WHO 2009 0.01%
Jain et al., 2017 [23] India Prospective observational 369 NS1 ELISA, serology WHO 1997 5.96%
Jog et al., 2015 [24] India Prospective observational 113 RT-PCR, NS1 ELISA, Not reported 26.55%
serology
Juneja et al., 2011 [25] India Prospective observational 198 NS1 ELISA, serology WHO 2009 6.1%
Kuo et al., 2008 [26] Taiwan Retrospective observational 519 Viral isolation, RT-PCR, WHO 1997 2.3%
serology
Lee et al., 2008 [27] Taiwan Retrospective observational 307 RT-PCR, NS1 ELISA, WHO 1997 7.57%
serology
Ill perform sensitivity, Taiwan Retrospective observational 1086 RT-PCR, NS1 ELISA, WHO 2009 0.04%
Lee et al., 2018 [28] serology
Md-Sani et al., 2018 [29] Malaysia Retrospective observational 199 NS1 ELISA, serology WHO 2009 10.05%
Ong et al., 2007 [30] Singapore Retrospective case–control 42 Clinical, RT-PCR, NS1 WHO 1997 16.7%
ELISA, serology
Rehman et al., 2020 [31] Pakistan Retrospective observational 1008 NS1 ELISA Not reported 1.6%
Schmitz et al., 2011 [32] India Retrospective observational 184 Serology WHO 1997 0.19%
Sharma et al., 1998 [33] India Retrospective observational 98 Clinical WHO 1997 8.1%
Shastri et al., 2020 [34] India Prospective observational 137 NS1 ELISA WHO 2009 38.68%
Tan et al., 2020 [35] Taiwan Retrospective case–control 626 Clinical, NS1 ELISA, serology WHO 2009 4.3%
Thein et al., 2013 [36] Singapore Retrospective observational 108 RT-PCR, NS1 ELISA WHO 1997, WHO 2009 0.26%
Abbreviations: ELISA, enzyme-linked immunosorbent assay; HIA, haemagglutination inhibition assay; IF, indirect fluorescent; n, number of participants; NS1, non-structural
protein 1; RT-PCR, reverse transcriptase-polymerase chain reaction.

Higher pulse rate Serum creatinine

Two studies [29, 36], with a total of 307 patients, reported
higher pulse rate as a risk factor associated with mortality in
dengue. Both studies [29, 36] were included in the meta-
analysis. Overall, there was a statistically significant positive
association between higher pulse rate and mortality [Pooled
OR (95% CI): 1.039 (1.011–1.067)]. Heterogeneity was sta-
tistically significant and not important (I 2 = 0.0%;
p = 0.007).
Platelet count
Four studies [28, 29, 34, 36] reported platelet count as a risk
factor associated with mortality in dengue. Only studies that
reported a cut-off value were included in the quantitative anal-
ysis. Thus, a total of 1,331 patients from 3 studies [28, 34, 36]
were included in the meta-analysis of platelet count as a risk
factor for mortality in dengue. There was a positive association
between platelet count <100  109/L and mortality [Pooled
OR (95% CI): 1.003 (0.960–1.048)], however not statistically
significant. Heterogeneity was considered substantial, although
not statistically significant (I 2 = 78.7%; p = 0.882).
Four studies [21, 29, 31, 34] reported serum creatinine (SCr) as
a risk factor associated with mortality in dengue. Only studies
that reported a cut-off value were included in the quantitative
analysis. Thus, a total of 1,772 patients from three studies [21,
31, 34] were included in the meta-analysis of SCr as a risk fac-
tor for mortality in dengue. There was a positive association
between SCr >1.3 mg/dl and mortality [Pooled OR (95% CI):
4.573 (0.929–22.507)], however not statistically significant.
Heterogeneity was considered substantial, although not statis-
tically significant (I 2 = 87.3%; p = 0.062).
Severe hepatitis
Two studies [19, 21], with a total of 833 patients, reported
severe hepatitis, defined as aspartate aminotransferase
(AST) or alanine aminotransferase (ALT) ≥1000 IU/L
according to the WHO 2009 classification [1], as a risk fac-
tor associated with mortality in dengue. Both studies [19,
21] were included in the meta-analysis. Overall, there was a
statistically significant positive association between severe
hepatitis and mortality [Pooled OR (95% CI): 29.222
 13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
662 TROPICAL MEDICINE & INTERNATIONAL HEALTH

TABLE 2 Reported risk factors associated with mortality and adjusted risk measures with their 95% confidence intervals of included studies

Adjusted risk measures with their 95% CIs

Study Variables associated with mortality OR LCL UCL

Chang et al., 2017 [19] Acute renal failure 98.76 10.85 899.2
Altered consciousness 2.47 0.65 9.33
Charlson score ≥5 4.07 1.24 13.31
Different year 2014 versus 2015 2.71 0.95 7.79
Haematuria 2.21 0.82 5.96
ICH or cerebral infarction 2.45 0.44 13.77
Myocarditis 2.45 0.55 10.93
Severe hepatitis 11.97 3.83 37.4
García-Rivera et al., 2003 [20] Elderly versus adults (19–64 years) 3.45 1.49 8.05
Huang et al., 2017 [21] Bedridden 10.46 1.58 69.16
Renal failure 6.03 1.50 24.246
Severe coma 11.36 1.89 68.19
Severe hepatitis 96.08 14.11 654.39
Huang et al., 2018 [22] Group B versus Group Aa 7.2 0.8 64.5
a
Group C versus Group A 1475 194.3 11,197.9
Jain et al., 2017 [23] Age >24 years 15.8 2.1 119.0
Altered sensorium 11.1 1.2 102.6
Dyspnea at rest 7.5 1.1 52.1
Jog et al., 2015 [24] Highest arterial lactate (mmol/L) 1.27 1.13 1.43
Mechanical ventilation (non-invasive/invasive) 0.25 0.06 1.09
Serum albumin >3 g/dl 0.30 0.09 0.97
SOFA score on day 1 1.23 1.00 1.51
Juneja et al., 2011 [25] APACHE II 1.781 0.967 3.281
Kuo et al., 2008 [26] Age 1.0 1.0 1.1
Cancers 1.8 0.2 18.5
Cardiovascular diseases 0.8 0.1 6.1
Diabetes 2.1 0.1 11.6
Gastrointestinal diseases 2.2 0.5 9.8
Gender (male) 1.1 0.3 4.3
Hypertension 0.6 0.1 3.0
Pulmonary diseases 15.1 2.2 102.1
Renal failure 33.9 7.0 164.1
Rheumatologic diseases 4.2 0.8 22.2
Lee et al., 2008 [27] DSS 77.33 6.479 923.112
Lee et al., 2018 [28] Gastrointestinal bleeding 20.728 5.089 84.426
Haemoconcentration during hospitalisation 55.674 13.110 236.422
Leucocytosis during hospitalisation 12.763 3.788 43.003
Platelet count <50  109/L at presentation 5.422 1.398 21.025
Md-Sani et al., 2018 [29] ALT 1.001 1 1.002
AST 1.001 1 1.001
Bleed 8.88 2.91 27.15
Lethargy 3.84 1.23 12.03
Multiple co-morbidities 1.28 0.32 5.15
Platelet 0.981 0.97 1.00
Pulse rate 1.04 1.01 1.07
Serum bicarbonate 0.79 0.7 0.89
Serum creatinine 1.008 1 1111
(Continues)
 13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TROPICAL MEDICINE & INTERNATIONAL HEALTH 663

TABLE 2 (Continued)
Adjusted risk measures with their 95% CIs
Study Variables associated with mortality OR LCL UCL

Serum lactate 1.27 1.09 1.47

Ong et al., 2007 [30] Tachycardia 3.56 2.76 4.87

Rehman et al., 2020 [31] Age >35 years 0.43 0.12 1.54
Creatinine >1.3 mg/dl 14.738 4.19 51.85
Diabetes 4.36 1.21 15.74
Gender (female) 1.67 0.51 5.5
Pleural effusion 2.35 0.64 8.64
Potassium levels <3.5 mEq/L 0.29 0.04 2.43
Sodium levels <135 mEq/L 1.4 0.44 4.49
Schmitz et al., 2011 [32] CNS and cardiovascular failure versus no organ failure 4.0 2.7 6.0
Sharma et al., 1998 [33] Ecchymoses 0.14 0.02 1.04
Respiratory rate 0.84 0.73 0.96
Shock 0.12 0.02 0.85
Shastri et al., 2020 [34] APACHE II score >10 0.6016 0.47 0.77
ALT (IU/L) 1 1 1
Coagulopathy 3.32 0.01 10.95
Creatinine >1.5 mg/dl 1.416 1.03 1.94
DSS 11.03 1.98 61.23
Platelet count <100  109/L 11.015 1.002 1.027
Total bilirubin >2/dl 70.027 1.52 32.23
Tan et al., 2020 [35] SI ≥1 8.49 1.76 17.92
Thein et al., 2013 [36] Abdominal pain/tenderness 0.571 0.045 7.289
Fever 0.519 0 93,135
Myalgia 0.087 0.012 0.625
Platelet count <100  10 /L 9
0.986 0.959 1.014
Pulse rate 1.026 0.943 1.116
White cell count 2.938 1.264 6.829
Abbreviations: ALT, alanine aminotransferase; ALT, aspartate aminotransferase; APACHE II, Acute Physiology And Chronic Health Evaluation II (http://www.medicinaintensiva.com.
br/ApacheScore.htm); CIs< confidence intervals; CNS, central nervous system; DSS, dengue shock syndrome; ICH, intracranial haemorrhage; LCL, lower confidence limit; OR, odds
ratio; SI, shock index; SOFA, Sequential Organ Failure Assessment (https://www.mdcalc.com/sequential-organ-failure-assessment-sofa-score); UCL, upper confidence limit.
a
Group A, Group B, and Group C were defined according to the WHO 2009 classification management groups.

(3.876–220.314)]. Heterogeneity was statistically significant Risk of reporting biases in synthesis

and considered substantial (I 2 = 70.1; p = 0.001).
Analysis of subgroups
Subgroup analyses were not possible as there was a small
number of studies included in our meta-analysis (k < 10) to
perform it meaningfully.
Sensitivity analyses
As all studies included were classified as having a high qual-
ity in methodological quality assessment, sensitivity analyses
were not applicable.
Reporting bias assessment was not possible as our meta-
analyses included a small number of studies.
DISCUSSION
This is the first systematic review and meta-analysis to
comprehensively identify and critically evaluate the risk
factors for mortality in dengue. This systematic review
included 18 studies [19–36], which indicates that there is a
paucity of studies in the literature investigating the risk fac-
tors for mortality in dengue. Eleven studies were published
in the last decade, which suggests that there is increasing
interest in researching the complications of this disease
 13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
664 TROPICAL MEDICINE & INTERNATIONAL HEALTH

TABLE 3 Methodological quality assessment of included studies

Newcastle-Ottawa
Study type Authors Selection Comparability Outcome Total Classification

Cohort Chang et al., 2017 [19] ★★★ ★ ★★★ ★★★★★★★ High quality
García-Rivera et al., 2003 [20] ★★★ ★★ ★★★ ★★★★★★★★ High quality
Jain et al., 2017 [23] ★★★ ★ ★★★ ★★★★★★★ High quality
Jog et al., 2015 [24] ★★★ ★ ★★★ ★★★★★★★ High quality
Juneja et al., 2011 [25] ★★★ ★ ★★★ ★★★★★★★ High quality
Kuo et al., 2008 [26] ★★★ ★★ ★★★ ★★★★★★★★ High quality
Lee et al., 2008 [27] ★★★ ★★ ★★★ ★★★★★★★★ High quality
Lee et al., 2018 [28] ★★★ ★★ ★★★ ★★★★★★★★ High quality
Md-Sani et al., 2018 [29] ★★★ ★★ ★★★ ★★★★★★★★ High quality
Rehman et al., 2020 [31] ★★★ ★★ ★★★ ★★★★★★★★ High quality
Schmitz et al., 2011 [32] ★★★ ★ ★★★ ★★★★★★★ High quality
Sharma et al., 1998 [33] ★★★ ★ ★★★ ★★★★★★★ High quality
Shastri et al., 2020 [34] ★★★ ★ ★★★ ★★★★★★★ High quality
Case–control Huang et al., 2017 [21] ★★★ ★★ ★★★ ★★★★★★★★ High quality
Huang et al., 2018 [22] ★★★ ★ ★★★ ★★★★★★★ High quality
Ong et al., 2017 [30] ★★★ ★ ★★★ ★★★★★★★ High quality
Tan et al., 2020 [35] ★★★ ★★ ★★★ ★★★★★★★★ High quality
Thein et al., 2013 [36] ★★★ ★★ ★★★ ★★★★★★★★ High quality

F I G U R E 2 Overall association between the analysed risk factors and mortality in patients with dengue. CIs, confidence intervals; DSS, dengue shock
syndrome; ID, identification; OR, odds ratio

and its burden. The median mortality rate of all series evidence of the scientific literature included in our system-
included was 5.13% (range 0.01%–38.68%). This wide atic review is high as all studies included were classified as
range may reflect the broad spectrum of disease severity having a high quality. The results of this study suggest that
and the heterogeneity of included studies. The strength of DM, AMS, DSS, higher pulse rate, and severe hepatitis are

TROPICAL MEDICINE & INTERNATIONAL HEALTH
significantly and positively associated with mortality in
dengue.
The main risk factor for dengue-related mortality in this
study was severe hepatitis. Hepatitis commonly occurs in
DENV infection during the second week of illness, and the
liver is the most commonly affected organ in fatal cases [37].
The pathophysiology of liver involvement is not clear [37].
Direct cytopathic effects and host immune response, as well
as hypoxic damage secondary to microvascular leakage
and/or shock, may be related to liver injury in dengue [37].
Acute liver failure has been reported in association with pro-
longed shock, but it may also develop without obvious
plasma leakage or shock [1, 37]. Frequently used medica-
tions for symptomatic relief, such as acetaminophen, may
also contribute to liver injury [37]. Age <40 years, >10%
ratio of atypical lymphocytes, and platelet count
<50  109/L are independent risk factors for acute liver fail-
ure secondary to dengue [38]. Usually, there is a moderate
increase, greater than two to five times the upper limit of
normality, of hepatic aminotransferases levels [39], with the
rise in AST greater than that of ALT [37]. However, the
degree of elevation in the aminotransferase levels alone does
not accurately discriminate between non-severe and severe
dengue, as defined by the WHO 2009 classification [37].
Similar to our findings, Huang et al. demonstrated in a ret-
rospective case–control study in Taiwan that severe hepatitis
was the most important predictor of mortality in geriatric
patients with dengue [21]. Chang et al. conducted a retro-
spective observational study in Taiwan and showed that
severe hepatitis was the second most common complication
in fatal dengue cases [19].
The second most important risk factor in this study
was DSS, as defined by the WHO 1997 classification. Den-
gue shock syndrome is a severe life-threatening complica-
tion of dengue and occurs most often in white patients, in
older patients, during infection with certain DENV sero-
types, and during a second heterotypic DENV infection
[9]. The cardinal feature of DSS is plasma leakage and coa-
gulopathy that leads to circulatory collapse [9]. Plasma
leakage is due to increased vascular permeability secondary
to endothelial dysfunction and is usually observed through-
out the disease spectrum, being more relevant in patients
with severe disease [9]. Coagulopathy occurs due to throm-
bocytopenia, secondary to transient suppression of haema-
topoiesis and, above all, platelet destruction [9, 40];
associated with loss of coagulation factors, promoted by
increased vascular permeability [2]. The definition of DSS
encompasses a wide spectrum of disease manifestations,
from DHF grade III (defined as circulatory failure, mani-
fested by rapid and weak pulse, with narrowing of pulse
pressure or hypotension) to grade IV (defined as profound
shock, with undetectable pulse or blood pressure), with dis-
tinct prognoses [7]; however, no included study analysed
the impact of DHF grades III and IV on mortality indepen-
dently. Previously, Shastri et al. and Lee et al. demonstrated
that DSS was the most important risk factor for mortality
in patients with dengue [27, 34].
13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
665
Central nervous system (CNS) involvement in the form
of AMS showed to be a risk factor for mortality. The inci-
dence of neurological manifestations in patients with dengue
ranges from 1% to 5%, and the mortality rate of patients
who develop neurological complications ranges between 5%
and 30% [41]. Neuropathogenesis seems to be related to
direct CNS invasion, post-infectious autoimmune reactions,
and systemic complications, such as hepatic and renal fail-
ure, electrolyte abnormalities, haemorrhages, and release of
toxic products [41–43]. The most common neurological pre-
sentations are encephalopathy and encephalitis [41, 42].
High body temperature, rash, elevated haematocrit, throm-
bocytopenia, and liver dysfunction are independent risk fac-
tors for neurological complications [42]. Dengue-related
encephalopathy can be reflected by reduced sensitivity, cog-
nitive impairment, convulsions, and personality and beha-
vioural disorders, while encephalitis usually presents with
altered consciousness, headaches, and seizures [41, 42]. Neu-
roimaging features of patients with dengue are diverse, with
cerebral oedema the most commonly reported finding [44].
Cerebrospinal fluid (CSF) analyses of patients with encepha-
lopathy are usually normal, while patients with encephalitis
may present abnormalities in CSF, such as lymphocytic
pleocytosis and elevated protein [44]. The findings of Chang
et al. contrast with the incidence of neurological manifesta-
tions reported in the literature, as 8.7% (22% of patients in
the fatal group vs. 4.5% in the non-fatal group) of patients
in this cohort presented altered consciousness [19]. Jain
et al. and Md-Sani et al. demonstrated that altered senso-
rium and lethargy were the second most important risk fac-
tors for mortality in patients with dengue, only after
age ≥24 years and bleed, respectively [23, 29]. These results
should draw attention to critically evaluating the neurologi-
cal functions of dengue patients.
Diabetes mellitus showed to be a risk factor for mortality
in dengue, demonstrating the importance of co-morbidities.
In 2021, the global diabetes prevalence in adults aged 20–
79 years was estimated to be 10.5% (537 million people),
and this number is expected to increase by 19.7% in 2030
and 45.8% in 2045 [45]. This diabetes pandemic dispropor-
tionately affects low- and middle-income countries, many of
which are also classified as tropical countries, where there is
usually challenging diabetes care and also a very high den-
gue burden [46]. Direct impairment of immune functioning
and possibly indirect impairment, due to obesity, vitamin D
deficiency, oxidative stress, and diabetes drugs, contribute to
increased incidence and severity of infectious diseases in
diabetic patients [46]. Diabetes was associated with
increased severity of dengue-induced thrombocytopenia
[47], increased risk of acute kidney injury [48], increased
risk of more severe disease [49–52], and increased admission
to intensive care units [53]. Kuo et al. demonstrated in a ret-
rospective observational study in Taiwan that diabetes was
the most important predictor of mortality in patients with
dengue [21]. Thus, given that diabetes has reached pan-
demic proportions and its effects on morbidity and mortal-
ity in patients affected by dengue, it is imperative to step up

666
global efforts to improve prevention and care for patients
with this disease.
Cardiovascular involvement in the form of a higher
pulse rate showed to be a risk factor for mortality in patients
with dengue. Sinus tachycardia is an important catecholamine-
driven compensatory mechanism for increasing the cardiac
output in the setting of physiologic, pharmacologic, or path-
ologic stress [54]. Pathologic causes, such as infections,
bleeding, and shock, are usually related to increased sympa-
thetic activity and hypoxia [54]. Sinus tachycardia in febrile
viral illnesses is known to be caused by several factors,
including fever, hypoxia, hypotension, anaemia, inflamma-
tory response, and anxiety [55]. In patients with dengue, as
vascular permeability and haemorrhagic phenomena ensue,
hypovolemia may result in circulatory collapse and shock.
Inadequate fluid replacement and transfusion of blood prod-
ucts may also play a role in the development of circulatory
failure. In this setting, adequate tissue perfusion may be
maintained by haemodynamic compensation, resulting in
tachycardia, increased peripheral vascular resistance, and
narrowing pulse pressure [1]. Thein et al. demonstrated that
fatal cases of dengue when compared to non-fatal cases pre-
sented a higher median pulse rate of 102 beats per minute
(bpm) (range 61–160 bpm) vs. 86.5 bpm (range 60–
135 bpm) [36]. Later, Md-Sani et al. exhibited similar
findings (110 bpm [IQR 102–120 bpm] vs. 96 bpm [IQR
86–109 bpm]) [29]. In a retrospective case–control study at
a tertiary care centre in Singapore, Ong et al. showed that
tachycardia on hospital admission was an independent risk
factor for mortality in dengue [30]. Therefore, our findings
should draw attention to the critical importance of monitor-
ing pulse rate in patients with dengue for identifying those
at higher risk for mortality and promptly managing the
underlying causes of tachycardia.
Limitations
This study has limitations. First, as for any systematic review
and meta-analysis, our study is subject to the biases present
in the original studies included. Second, heterogeneity was
significant in our meta-analyses, as study design, inclusion
and exclusion criteria, methods for diagnosis, cut-offs of
variables, such as age, platelet count, and SCr; and definition
of variables, such as AMS—reported altered consciousness,
altered sensorium, and lethargy—and bleeding manifestations—
reported as bleeding, ecchymosis, and gastrointestinal
bleeding—, varied widely among the different studies. Due
to this diversity, we had to define cut-offs and change the
name of some variables to group them homogeneously.
Third, data on the adjusted risk measures along with their
respective 95% CIs of variables associated with mortality
were not reported in certain studies included. To retrieve
information on missing data, we contacted the correspond-
ing authors of the original studies; however, none of the
authors replied, suggesting that future original studies may
want to include such information and that corresponding
13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TROPICAL MEDICINE & INTERNATIONAL HEALTH
authors should be encouraged to take a critical role in data
sharing and collaborative research. Despite these limitations,
we feel confident in our study findings because of stringent
predefined methods, consistency with published studies, and
biologic plausibility.
Conclusions
In conclusion, the results of our meta-analyses demon-
strated a statistically significant and positive association of
DM, AMS, DSS, higher pulse rate, and severe hepatitis with
mortality in dengue. Particular attention to identifying and
managing these risk factors in patients with dengue should
be considered to improve patient outcomes and reduce the
hidden burden of this neglected tropical disease. Future
well-designed studies are needed to investigate the associa-
tion of other clinical, radiological, and laboratorial charac-
teristics with mortality in dengue, as well as to develop
prognostic models based on the risk factors found in our
study.
ACKNOWLEDGMENTS
None.
FUNDING INFORMATION
This study was supported by the Brazilian Council for Scien-
tific and Technological Development—Conselho Nacional
de Desenvolvimento Científico e Tecnol
ogico (CNPq)—and
by the Coordination of Improvement of Higher Education
Personnel—Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior (CAPES). The funding sources did not par-
ticipate in study design; collection, management, analysis,
and interpretation of data, and preparation, review, and
approval of this manuscript.
OR CI D
Gabriel Cavalcante Lima Chagas https://orcid.org/0000-
0002-7398-9070
REFERENC ES
1. World Health Organization. Dengue guidelines for diagnosis, treat-
ment, prevention and control: new edition. Published online 2009:1–
160 [cited Feb 5, 2022]. Available from: https://apps.who.int/iris/
handle/10665/44188
2. Simmons CP, Farrar JJ, van Vinh CN, Wills B. Dengue. N Engl J Med.
2012;366(15):1423–32. https://doi.org/10.1056/NEJMra1110265
3. Guzman MG, Kouri G. Dengue and dengue hemorrhagic fever in the
Americas: lessons and challenges. J Clin Virol Off Publ Pan Am Soc
Clin Virol. 2003;27(1):1–13. https://doi.org/10.1016/s1386-6532(03)
00010-6
4. World Health Organization. Dengue and severe dengue. Published
2022 [cited Feb 5, 2022]. Available from: https://www.who.int/news-
room/fact-sheets/detail/dengue-and-severe-dengue
5. Pan American Health Organization. Dengue: guidelines for patient
care in the region of the Americas. Published online 2016:1–136.
ISBN:978-92-75-11890-0.
6. Endy TP, Chunsuttiwat S, Nisalak A, Libraty DH, Green S,
Rothman AL, et al. Epidemiology of inapparent and symptomatic
acute dengue virus infection: a prospective study of primary school

TROPICAL MEDICINE & INTERNATIONAL HEALTH
children in Kamphaeng Phet, Thailand. Am J Epidemiol. 2002;156(1):
40–51. https://doi.org/10.1093/aje/kwf005
7. World Health Organization. Dengue haemorrhagic fever diagnosis,
treatment, prevention and control. Published online 1997:1–92. ISBN:
92-4-154500-3.
8. Kalayanarooj S, Chansiriwongs V, Nimmannitya S. Dengue patients
at the Children’s hospital, Bangkok: 1995–1999 review. Dengue Bull.
2002;26:33–43.
9. Guzman MG, Gubler DJ, Izquierdo A, Martinez E, Halstead SB. Den-
gue infection. Nat Rev Dis Prim. 2016;2:1–25. https://doi.org/10.1038/
nrdp.2016.55
10. Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC,
Mulrow CD, et al. PRISMA 2020 explanation and elaboration:
updated guidance and exemplars for reporting systematic reviews.
BMJ. 2021;372:160. https://doi.org/10.1136/bmj.n160
11. Chagas G, Rangel A, Noronha L, Veloso F, Kassar S, Oliveira M, et al.
Risk factors for mortality in patients with dengue: systematic review and
meta-analysis. NIHR Prospero. Published online 2021:1–4 [cited Feb 5,
2022]. Available from: https://www.crd.york.ac.uk/prospero/display_
record.php?ID=CRD42021259094
12. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al.
The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-
randomised studies in meta-analyses [cited Feb 11, 2022]. Available
from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
13. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control
Clin Trials. 1986;7(3):177–88. https://doi.org/10.1016/0197-2456
(86)90046-2
14. Cochran WG. The comparison of percentages in matched samples.
Biometrika. 1950;37(3–4):256–66. https://doi.org/10.1093/biomet/37.
3-4.256
15. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring incon-
sistency in meta-analyses. BMJ. 2003;327(7414):557–60. https://doi.
org/10.1136/bmj.327.7414.557
16. Begg CB, Mazumdar M. Operating characteristics of a rank correla-
tion test for publication bias. Biometrics. 1994;50(4):1088–101.
17. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-
analysis detected by a simple, graphical test. BMJ. 1997;315(7109):
629–34. https://doi.org/10.1136/bmj.315.7109.629
18. Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, et al.
Recommendations for examining and interpreting funnel plot asym-
metry in meta-analyses of randomised controlled trials. BMJ. 2011;
343:d4002. https://doi.org/10.1136/bmj.d4002
19. Chang K, Huang C-H, Lee I-K, et al. Differences in mortality and clin-
ical manifestations of dengue hemorrhagic fever in Taiwan in different
years: a comparison for cases in 2014 and 2015 epidemics. Am J Trop
Med Hyg. 2017;97(2):361–8. https://doi.org/10.4269/ajtmh.16-1018
20. García-Rivera EJ, Rigau-Pérez JG. Dengue severity in the elderly in
Puerto Rico TT—Gravedad del dengue en adultos mayores de Puerto
Rico. Rev Panam Salud Pública. 2003;13(6):362–8. https://doi.org/10.
1590/s1020-49892003000500004
21. Huang H-S, Hsu C-C, Ye J-C, Su S-B, Huang C-C, Lin H-J. Predicting
the mortality in geriatric patients with dengue fever. Medicine
(United States). 2017;96(37):e7878. https://doi.org/10.1097/MD.
0000000000007878
22. Huang W-T, Hsu C-C, Su S-B, Lin H-J, Huang C-C. Validation of
decision groups in patients with dengue fever: a study during 2015
outbreak in Taiwan. Am J Trop Med Hyg. 2018;99(5):1294–8. https://
doi.org/10.4269/ajtmh.18-0289
23. Jain S, Mittal A, Sharma SK, Upadhyay AD, Pandey RM, Sinha S,
et al. Predictors of dengue-related mortality and disease severity in a
tertiary care center in North India. Open Forum Infect Dis. 2017;4(2):
ofx056. https://doi.org/10.1093/ofid/ofx056
24. Jog S, Prayag S, Rajhans P, Zirpe K, Dixit S, Pillai L, et al. Dengue
infection with multiorgan dysfunction: SOFA score, arterial lactate
and serum albumin levels are predictors of outcome. Intensive
Care Med. 2015;41(11):2029–30. https://doi.org/10.1007/s00134-
015-4024-6
13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
667
25. Juneja D, Nasa P, Singh O, Javeri Y, Uniyal B, Dang R. Clinical profile,
intensive care unit course, and outcome of patients admitted in inten-
sive care unit with dengue. J Crit Care. 2011;26(5):449–52. https://doi.
org/10.1016/j.jcrc.2011.05.007
26. Kuo M-C, Lu P-L, Chang J-M, Lin MY, Tsai JJ, Chen YH, et al.
Impact of renal failure on the outcome of dengue viral infection. Clin
J Am Soc Nephrol. 2008;3(5):1350–6. https://doi.org/10.2215/CJN.
00020108
27. Lee IK, Liu JW, Yang KD. Clinical and laboratory characteristics and
risk factors for fatality in elderly patients with dengue hemorrhagic
fever. Am J Trop Med Hyg. 2008;79(2):149–53. https://doi.org/10.
4269/ajtmh.2008.79.149
28. Lee I-K, Huang C-H, Huang W-C, Chen YC, Tsai CY, Chang K, et al.
Prognostic factors in adult patients with dengue: developing risk scor-
ing models and emphasizing factors associated with death ≤7 days
after illness onset and ≤3 days after presentation. J Clin Med. 2018;
7(11):396. https://doi.org/10.3390/jcm7110396
29. Md-Sani SS, Md-Noor J, Han W-H, Gan SP, Rani NS, Tan HL, et al.
Prediction of mortality in severe dengue cases. BMC Infect Dis. 2018;
18(1):232. https://doi.org/10.1186/s12879-018-3141-6
30. Ong A, Sandar M, Chen MI, Sin LY. Fatal dengue hemorrhagic
fever in adults during a dengue epidemic in Singapore. Int J
Infect Dis. 2007;11(3):263–7. https://doi.org/10.1016/j.ijid.2006.
02.012
31. Rehman FU, Omair SF, Memon F, Amin I, Rind BJ, Aziz S. Electrolyte
imbalance at admission does not predict the length of stay or mortal-
ity in dengue-infected patients. Cureus. 2020;12(9):1–12. https://doi.
org/10.7759/cureus.10419
32. Schmitz L, Prayag S, Varghese S, Jog S, Bhargav-Patil P, Yadav A,
et al. Nonhematological organ dysfunction and positive fluid balance
are important determinants of outcome in adults with severe dengue
infection: a multicenter study from India. J Crit Care. 2011;26(5):441–
8. https://doi.org/10.1016/j.jcrc.2011.05.008
33. Sharma S, Sharma S, Mohan A, et al. Clinical profile of dengue hae-
morrhagic fever in adults during 1996—outbreak in Delhi, India. Den-
gue Bull. 1998;22:20–30.
34. Shastri P, Gupta P, Kumar R. A prospective 3 year study of clinical
spectrum and outcome of dengue fever in ICU from a tertiary care
hospital in North India. Indian J Anaesth. 2020;64(3):181–6. https://
doi.org/10.4103/ija.IJA_865_19
35. Tan T-H, Huang H-K, Hsu C-C, Lin H-J, Chung J-Y, Huang C-C.
Validation of shock index for predicting mortality in older patients
with dengue fever. Aging Clin Exp Res. 2021;33(3):635–40. https://doi.
org/10.1007/s40520-020-01563-7
36. Thein T-L, Leo Y-S, Fisher DA, Low JG, Oh HML, Gan VC, et al. Risk
factors for fatality among confirmed adult dengue inpatients in
Singapore: a matched case–control study. PLoS One. 2013;8(11):
e81060. https://doi.org/10.1371/journal.pone.0081060
37. Chia PY, Thein TL, Ong SWX, Lye DC, Leo YS. Severe dengue and
liver involvement: an overview and review of the literature. Expert Rev
Anti Infect Ther. 2020;18(3):181–9. https://doi.org/10.1080/14787210.
2020.1720652
38. Kye Mon K, Nontprasert A, Kittitrakul C, Tangkijvanich P,
Leowattana W, Poovorawan K. Incidence and clinical outcome of
acute liver failure caused by dengue in a Hospital for Tropical Dis-
eases, Thailand. Am J Trop Med Hyg. 2016;95(6):1338–44. https://doi.
org/10.4269/ajtmh.16-0374
39. Kalayanarooj S, Vaughn DW, Nimmannitya S, Green S,
Suntayakorn S, Kunentrasai N, et al. Early clinical and laboratory indi-
cators of acute dengue illness. J Infect Dis. 1997;176(2):313–21.
https://doi.org/10.1086/514047
40. Bierman HR, Nelson ER. Hematodepressive virus diseases of
Thailand. Ann Intern Med. 1965;62:867–84. https://doi.org/10.7326/
0003-4819-62-5-867
41. Puccioni-Sohler M, Orsini M, Soares CN. Dengue: a new challenge for
neurology. Neurol Int. 2012;4(3):e15. https://doi.org/10.4081/ni.
2012.e15

668
42. Li G-H, Ning Z-J, Liu Y-M, Li X-H. Neurological manifestations of
dengue infection. Front Cell Infect Microbiol. 2017;7:449. https://doi.
org/10.3389/fcimb.2017.00449
43. Verma R, Sahu R, Holla V. Neurological manifestations of dengue
infection: a review. J Neurol Sci. 2014;346(1–2):26–34. https://doi.org/
10.1016/j.jns.2014.08.044
44. Carod-Artal FJ, Wichmann O, Farrar J, Gasc
on J. Neurological com-
plications of dengue virus infection. Lancet Neurol. 2013;12(9):906–
19. https://doi.org/10.1016/S1474-4422(13)70150-9
45. International Diabetes Federation Diabetes Atlas 10th Edition Com-
mittee. IDF Diabetes Atlas 10th Edition. Vol 64; 2021 [cited Feb 11,
2022]. Available from: https://diabetesatlas.org/
46. van Crevel R, van de Vijver S, Moore DAJ. The global diabetes epi-
demic: what does it mean for infectious diseases in tropical countries?
Lancet Diabetes Endocrinol. 2017;5(6):457–68. https://doi.org/10.
1016/S2213-8587(16)30081-X
47. Chen C-Y, Lee M-Y, Lin K-D, Hsu WH, Lee YJ, Hsiao PJ, et al. Diabe-
tes mellitus increases severity of thrombocytopenia in dengue-infected
patients. Int J Mol Sci. 2015;16(2):3820–30. https://doi.org/10.3390/
ijms16023820
48. Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F.
Incidence, characteristics and risk factors of acute kidney injury
among dengue patients: a retrospective analysis. PLoS One. 2015;
10(9):e0138465. https://doi.org/10.1371/journal.pone.0138465
49. Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F.
Clinico-laboratory spectrum of dengue viral infection and risk fac-
tors associated with dengue hemorrhagic fever: a retrospective study.
BMC Infect Dis. 2015;15:399. https://doi.org/10.1186/s12879-015-
1141-3
50. Pang J, Salim A, Lee VJ, Hibberd ML, Chia KS, Leo YS, et al. Diabetes
with hypertension as risk factors for adult dengue hemorrhagic fever
in a predominantly dengue serotype 2 epidemic: a case control study.
13653156, 2022, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13797 by Cochrane Colombia, Wiley Online Library on [01/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
TROPICAL MEDICINE & INTERNATIONAL HEALTH
PLoS Negl Trop Dis. 2012;6(5):e1641. https://doi.org/10.1371/journal.
pntd.0001641
51. Htun NSN, Odermatt P, Eze IC, Boillat-Blanco N,
D’Acremont V, Probst-Hensch N. Is diabetes a risk factor for a
severe clinical presentation of dengue?—review and meta-analysis.
PLoS Negl Trop Dis. 2015;9(4):e0003741. https://doi.org/10.1371/
journal.pntd.0003741
52. Figueiredo MAA, Rodrigues LC, Barreto ML, Lima JWO, Costa MCN,
Morato V, et al. Allergies and diabetes as risk factors for dengue hem-
orrhagic fever: results of a case control study. PLoS Negl Trop Dis.
2010;4(6):e699. https://doi.org/10.1371/journal.pntd.0000699
53. Pang J, Thein T-L, Leo Y-S, Lye DC. Early clinical and laboratory risk
factors of intensive care unit requirement during 2004–2008 dengue
epidemics in Singapore: a matched case–control study. BMC Infect
Dis. 2014;14:649. https://doi.org/10.1186/s12879-014-0649-2
54. Yusuf S, Camm AJ. The sinus tachycardias. Nat Clin Pract Cardiovasc
Med. 2005;2(1):44–52. https://doi.org/10.1038/ncpcardio0068
55. Hsieh JYC, Kan JYL, Mattar SAM, Qin Y. The clinical implications of
sinus tachycardia in mild COVID-19 infection: a retrospective cohort
study. SAGE Open Med. 2021;9:20503121211054972. https://doi.org/
10.1177/20503121211054973
How to cite this article: Chagas GCL, Rangel AR,
Noronha LM, Veloso FCS, Kassar SB, Oliveira MJC,
et al. Risk factors for mortality in patients with
dengue: A systematic review and meta-analysis. Trop
Med Int Health. 2022;27(8):656–68. https://doi.org/
10.1111/tmi.13797