DOI: 10.1111/tmi.

13968

SYSTEMATIC REVIEW

Risk factors associated with severe dengue in Latin America:

A systematic review and meta-analysis

Victoria Cruz Paran
a 1,2 | Caroline Alves Feitosa 1 |

2
Greice Carolina Santos da Silva | Luana Leandro Gois 1,3 | Luciane Amorim Santos 1,2,4

1
Bahiana School of Medicine and Public Health,
Salvador, Bahia, Brazil
2
Gonçalo Moniz Institute, Oswaldo Cruz
Foundation, Salvador, Bahia, Brazil
3
Department of Biointeraction Sciences, Institute
of Health Sciences, Federal University of Bahia,
Salvador, Bahia, Brazil
4
Graduate Program in Health Sciences, College of
Medicine of Bahia, Federal University of Bahia,
Salvador, Bahia, Brazil
Correspondence
Luciane Amorim Santos, Bahiana School of
Medicine and Public Health, Street Silveira
Martins, 100, Cabula, Salvador, BA, 41150-100,
Brazil.
Email: lucianeamorim@bahiana.edu.br
Abstract
Objective: Severe dengue is a significant health problem in Latin America, with
children being the most affected. Understanding risk factors for severe dengue is
crucial for enhancing patient care. Therefore, this study aims to systematically review
the literature to identify the risk factors associated with severe dengue in Latin
America through systematic review and meta-analysis.
Methods: PubMed, SciELO, LILACS and EMBASE databases were used to search for
eligible scientific articles for the review. The outcomes considered were symptoms of
severe dengue, hospitalisation and death. The Joanna Briggs Institute Critical
Appraisal Checklist was used to assess the quality of the studies. Data analysis was
performed using STATA v 13.0 software. The degree of heterogeneity between studies
was quantified using the I2 measure, and statistically significant results were defined
as those with p values <0.05.
Results: Of the 1876 articles screened, 47 articles were included in the systematic
review and 45 articles were analysed through meta-analysis. Identified risk factors
associated with severe dengue included secondary dengue infection, female sex, white
or Caucasian ethnicity and specific signs and symptoms such as headache, myalgia
and/or arthralgia, vomiting/nausea, abdominal pain or tenderness, diarrhoea, prostra-
tion, lethargy, fatigue or similar. For the death outcome, respiratory symptoms and
age <18 years were identified as risk factors. On the other hand, in women, the
diagnosis of positive tourniquet test, platelet count <100,000 per μL and symptoms of
capillary fragility were associated with a lower probability of death. These data high-
light the importance of early screening of patients, to identify possible haemorrhagic
signs and reduce deaths from dengue. This study has limitations, including possible
publication bias, heterogeneity of results and study design biases.
Conclusion: These findings are significant for shaping strategies, management
approaches and identifying high-risk groups, which will help establish future
guidelines.

KEYWORDS
dengue, Latin America, risk factors, systematic review or meta-analysis

INTRODUCTION A. aegypti and occasionally by A. Albopictus [3]. The virus

Dengue virus (DENV) is a single-stranded RNA virus that
belongs to the Flaviviridae family and the Flavivirus genus
[1, 2]. This virus is transmitted by the bite of the female
mosquito of the genus Aedes spp., predominantly by
International Prospective Register of Systematic Reviews (PROSPERO) registration
number: CRD42021283608.
has four known serotypes (DENV 1, DENV 2, DENV 3 and
DENV 4), each with different antigenic properties [4, 5].
These serotypes are all present in Asia, Africa and the
Americas [4].
Dengue outbreaks often occur explosively and affect
urban centres because the urban environment favours the
spread and increase in A. Aegypti density [6, 7]. The likeli-
hood of dengue occurrence was associated with tropical and

Trop Med Int Health. 2024;29:173–191. wileyonlinelibrary.com/journal/tmi © 2024 John Wiley & Sons Ltd. 173

174
subtropical areas, commonly found in Latin America [8, 9].
Approximately 4 billion people, almost half of the global
population, reside in areas at high risk for infection [10].
Every year, around 400 million people are infected with
dengue, with around 100 million experiencing illness [11]. It
is estimated that an average of 9000 people worldwide die
from dengue every year [12]. In North and South America
in particular, the number of dengue cases has risen over the
last four decades, from 1.5 million cases in the 1980s to
16.2 million cases in the period 2010–2019 [9]. According to
a previous study, the combined incidence of dengue in
Latin America between 1995 and 2010 was 72.1 cases per
100,000 inhabitants [13]. In 2019, just over 3.1 million cases,
28 thousand severe cases and 1534 deaths were recorded in
the Americas [9].
A major challenge in the surveillance and diagnosis of
DENV is the wide range of clinical manifestations, including
asymptomatic infections and a spectrum of illnesses that
range from mild febrile illness to fatal haemorrhagic
disease [14]. The World Health Organisation (WHO)
classifies dengue into two broad categories: dengue (with/
without warning signs) and severe dengue [3]. In dengue,
the initial symptom is typically high fever (between 39 and
40 C) accompanied by symptoms such as headache,
adynamia, myalgias, arthralgias and/or retroorbital pain [15].
Severe dengue is characterised by severe plasma leakage
leading to shock and/or fluid accumulation with respiratory
distress [13]. Severe haemorrhage as assessed by healthcare
professionals or involvement of multiple organs may also be
observed [16]. Severe forms of the disease are commonly
referred to DHF and DSS [17].
The circulation of multiple DENV serotypes in the same
area can lead to coinfections or subsequent infections caused
by different serotypes. These infections have been associated
with an increased risk of severe dengue [18, 19]. Addition-
ally, it has been reported that the white race, secondary
dengue infection, people of younger age, especially children,
and some chronic diseases, such as diabetes, kidney disease
and hypertension, may be possible risk factors for the sever-
ity of the disease [18, 20–22]. The presence of warning signs,
such as increased haematocrit with a concomitant decrease
in platelet count, abdominal pain, lethargy, vomiting, hepa-
tomegaly, ascites, pleural effusion and melena, can also be
predictors for the development of severe dengue [22].
Due to the possibility that dengue infection can progress
to severe cases or even death, it is crucial to identify risk fac-
tors associated with the severe forms of the disease. In this
way, the population at risk should be identified promptly
and appropriate measure and interventions can be imple-
mented to prevent complications and potential deaths.
According to the Pan American Health Organisation
(PAHO), severe dengue is a significant cause of serious
illness and death in Latin American countries, especially in
children [9]. Thus, a study in Latin America is particularly
important because the tropical and subtropical climate there
provides an ideal environment for the widespread presence
of the mosquito vector [9]. Therefore, the aim of this study
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TROPICAL MEDICINE & INTERNATIONAL HEALTH
is to conduct a systematic review with meta-analysis of the
existing literature to identify risk factors associated with
severe dengue in Latin America.
METHODS
This study is a systematic review and meta-analysis which
was conducted following the recommendations of the
Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) [23]. The study followed the Population
Intervention Comparison Outcome Study Design (PICOS)
strategy to construct the research question: ‘What are the
risk factors associated with severe dengue, death and hospi-
talization due to dengue in Latin America?’. This review
protocol was registered in PROSPERO with the number:
CRD42021283608.
The National Library of Medicine (PubMed), Scientific
Electronic Library Online (SciELO), Latin American and
Caribbean Literature in Health Sciences (LILACS)
and Excerpta Medica Database (EMBASE) databases were
used to search for scientific articles eligible for the study.
Descriptors were selected using the Medical Subject Head-
ings (MeSH) tool combined with Boolean connectors
to form the same search algorithm used in the four data-
bases: ((DENGUE OR DENV*) AND (“RISK FACTORS”
OR COMORBIDITY) AND (“LATIN AMERICA*” OR
“SOUTH AMERICA*” OR “CENTRAL AMERICA*” OR
CARIBBEAN* OR CHILE* OR COLOMBIA* OR ECUADOR*
OR “FRENCH GUIAN*” OR GUYAN* OR PARAGUAY* OR
PERU* OR SURINAME* OR URUGUAY* OR “TRINIDAD
AND TOBAGO” OR “TRINIDADIAN AND TOBAGONIAN”
OR TRINBAGONIAN OR TRINI OR VENEZUELA*
OR BOLIVIA* OR BRAZIL* OR ARGENTIN* OR
BARBAD* OR BAHAM* MEXIC* OR BELIZE* OR
“COSTA RICA*” OR “EL SALVADOR” OR SALVADOR*
OR GUANAC* OR GUATEMALA* OR CHAPÍN OR
HONDURAS* OR NICARAGUA* OR PANAMA* OR
CUBA* OR “DOMINICAN REPUBLIC” OR DOMINICAN
OR QUISQUEYAN OR HAITI* OR “ANTIGUA AND
BARBUDA” OR “ANTIGUAN BARBUDAN” OR JAMAICA*
OR GRENAD* OR “SAINT VINCENT AND THE
GRENADINES” OR “SAINT VINCENTIAN” OR
VINCENTIAN OR “SAINT LUCIA*” OR “SAINT KITTS
AND NEVIS” OR KITTITIAN OR NEVISIAN OR
DOMINICA* OR GUADELOUPE* OR MARTINIQUE
OR MARTINI* OR “PUERTO RIC*” OR BURICUA
OR SAINT-MARTIN OR ST. MARTIN* OR ST. MAARTENER
OR SAINT-BARTHELEMY


OR BARTHELEMOIS OR
SAINT-BARTH)).
First, the inclusion criteria were applied for the selection
of studies: (I) patients infected with dengue, (II) studies per-
formed in humans, (III) studies that analyse risk factors
and/or comorbidities associated with severe dengue, death
and/or hospitalisation due to dengue, (IV) studies carried
out in Latin American countries, (V) studies that reported
Odds ratio (OR), Relative risk (RR), Hazard ratio (HR) or

TROPICAL MEDICINE & INTERNATIONAL HEALTH
Prevalence ratio (PR) as measures of association. There were
no restrictions related to the study language. Then, the fol-
lowing exclusion criteria were used: (I) literature reviews,
(II) case reports, (III) editorials, (IV) research protocols and
(V) comments. The search for scientific articles was carried
out on 31 December 2022. Screening of articles included in
this study was performed blindly and independently by two
authors (PARANÁ, VC and SILVA, GCS). The final deci-
sion on the inclusion of articles was made through a collec-
tive review involving all authors.
The definition of severe dengue in this study predomi-
nantly followed the WHO 2009 guideline, which includes
patients with severe plasma leakage leading to shock and/or
fluid accumulation with respiratory distress, severe haemor-
rhage or severe organ involvement. However, it should be
noted that articles published before 2009 used the WHO
1997 guideline, which classifies severe cases as dengue hae-
morrhagic fever (DHF) and dengue shock syndrome (DSS)
[16, 17]. Furthermore, the Brazilian Ministry of Health
introduced an intermediate classification known as compli-
cated dengue due to challenges in classifying severe cases, as
the classification of classic dengue was deemed inade-
quate [15]. This classification was included in the severe
category as studies conducted in Brazil consider them to be
severe cases. Additionally, outcomes such as severe manifes-
tations, deaths and hospitalisation caused by dengue infec-
tion were also classified as severe cases in this review.
The Joanna Briggs Institute Critical Appraisal Checklist
for Analytical Cross-Sectional Studies, Case–Control
Studies, Cohort Studies, Quasi-Experimental Studies (non-
randomised experimental studies) and Randomised Con-
trolled Trials was used to assess the quality of the
studies [24]. Studies were classified as low, medium and high
risk of bias if 70% or more, 50%–69% and 50% or less of
checklist responses were ‘yes’, respectively [25, 26].
The selected articles were carefully reviewed, and the
data of interest were extracted from each study. The total
number of participants in each study, cases diagnosed with
severe dengue and deaths were tabulated. The sum of the
population of each study allowed us to obtain the total num-
bers and the respective percentages for each outcome. Stud-
ies in which 100% of the population were classified as severe
dengue cases or deaths were excluded from this analysis.
To perform the meta-analysis, the type of study, popula-
tion size, analysed outcome, risk factors associated with the
outcome, and the corresponding association measures (such
as OR, RR, HR or PR) along with their confidence intervals
(CI) were collected from each article. All the collected infor-
mation was organised in a spreadsheet using Microsoft Excel
version 16.61.1.
For the meta-analysis, the collected data were pooled
using STATA/MP version 13.0 software. Articles with the
same measures of association and outcomes analysed were
combined for analysis. However, subgroup analyzes
were not performed. The degree of heterogeneity among the
included studies was quantified using the I 2 measure, with
values of ≤25% indicating low heterogeneity, 26%–74%
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175
indicating medium heterogeneity and values ≥75% indicat-
ing high heterogeneity. Pooled measures of association were
calculated along with their corresponding 95% confidence
intervals (CI) to determine the risk factors for severe den-
gue, death and hospitalisation due to dengue, based on the
available study variables. All results with p-values <0.05 were
considered statistically significant. All the results of the
meta-analysis are present in this article, but only those that
met the following criteria were analysed and discussed:
(a) the risk factor was analysed by at least tree studies,
(b) with significant results in meta-analysis and
(c) presenting an heterogeneity below 75%.
RESULTS
Articles selection
From the initial databases search, we obtained 1876 arti-
cles. After removing duplicates (n = 245) and articles
without full-text availability (n = 5), a total of 1626 arti-
cles were screened based on title and abstract. Among
these, 1406 articles did not meet the criteria and were not
included. Subsequently, the full texts of the remaining
220 articles were assessed for exclusion criteria, resulting
in the exclusion of 173 articles. Finally, 47 articles were
included in the systematic review, and 45 of them were
used for the meta-analysis (Figure 1). Two articles
[27, 28] were not included in the meta-analysis, due to
incompatibility and inconsistency in the association mea-
sures reported by the authors.
Forty-one (87%; 41/47) of the selected studies had a low
risk of bias, while four (8.5%; 4/47) and two (4%; 2/47) had
a medium and high risk of bias, respectively (Table 1).
Main characteristic of the included articles
Forty of the included articles were conducted in South
America, while two studies were carried out in multiple
countries [63, 67]. More than half of the studies were con-
ducted in Brazil (53%; 25/47), followed by Paraguay (14%;
7/47) and Colombia (11%; 5/47) (Table 1; Figure 2).
Thirty-five studies provided the total number of cases
and the number of cases of severe dengue, considering the
sum of the populations from each study, the percentage of
cases classified as severe dengue ranged from 1% to 81%
(mean: 32%), severe dengue was found in approximately 1%
of cases (n = 84,317/6,486,662). Eight articles did not pro-
vide information about the population classified as severe
dengue. In these articles, the outcomes analysed were death
or hospitalisation due to dengue (Table 1).
Thirty-one articles reported the number of deaths due to
dengue, with a percentage ranging from 0.06% to 32.4%
(mean: 6%). When considering the sum of the study popula-
tions of each article that provided death data, it was
found that 0.1% of the total cases resulted in death
 13653156, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13968 by Eduardo Missoni - CochraneItalia , Wiley Online Library on [11/03/2024]. 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
176 TROPICAL MEDICINE & INTERNATIONAL HEALTH

Identification of studies via databases and registers

Records identified from: Records removed before

Identification
SCIELO (n = 78) screening:
PubMed (n = 1378) Duplicate records removed (n
LILACS (n = 190) = 245)
*Records removed for other
EMBASE (n = 230) reasons (n = 5)

Records screened (n = 1626) Records excluded (n = 1406)

Screening

Reports excluded:
Reports assessed for eligibility Did not use OR, RR or PR in
(n = 220) the analysis (n = 83)
Did not analyze risk factors
for severe dengue, death, or
hospitalization (n = 87)
Studies conducted outside of
Latin America (n = 3)

Studies included in the

Included

systematic review (n = 47)

Studies included in the meta-
analysis (n = 45)

FIGURE 1 Flow-diagram for selecting and screening articles for inclusion in the systematic review and meta-analyses. *Articles not found.

(n = 6275/6,501,667). Two studies reported no deaths in
their respective populations (Table 1).
Of the included articles, 31 (66%; 31/47) performed mul-
tivariate analyses, while 10 (21%; 10/47) performed univari-
ate analyses. Nine articles (19%; 9/47) did not report the
type of analysis was conducted. In the articles where multi-
variate analyses were performed, age and sex (AS) emerged
as the most commonly adjusted confounder (65%; 20/31),
followed by signs and symptoms (SS) (52%, 16/31), which
included dengue-related symptoms, laboratory tests and
similar factors. Clinical variables (CV), including secondary
dengue infection, serotype, pregnancy, classification of den-
gue cases, vaccination, medication and similar aspects, were
also considered (45%; 14/31). However, the selection and
extraction methods of confounders varied from article to
article (Table 1; Table S1).
Risk factors for severe dengue
The clinical characteristic that was most frequently associ-
ated with severe dengue and had a statistically significant
association was the presence of comorbidities or underlying
diseases (Figure 3). Regarding sociodemographic charac-
teristics, age <18 years was identified as a frequent risk
factor in the articles, although the article by Luppe MJ
et al. (2019) presented this variable as a protective factor.
In this same category, being white or Caucasian was con-
sistently identified as a risk factor in all articles that
examined this variable (Figure 3). Among the signs and
symptoms statistically significantly associated with severe
dengue, the most frequent were abdominal pain or ten-
derness, bleeding/haemorrhagic manifestations, hepato-
megaly, splenomegaly or similar symptoms, and
alterations in red blood cell count. Furthermore, prostra-
tion, lethargy, fatigue or similar symptoms were consis-
tently associated with severe dengue in all articles that
investigated this variable. Some signs and symptoms also
showed some significance, but many articles did not find
significant associations, such as symptoms of capillary
fragility and vomiting/nausea (Figure 3).
The results of the meta-analysis revealed that secondary
dengue infection was a risk factor for disease severity
(OR: 1.17, 95% CI: 1.04–1.29), as well as the white or Cauca-
sian ethnicity (OR: 1.28, 95% CI: 1.14–1.42). Regarding
gender, female sex was associated with an increased chance
 TABLE 1 Main characteristic of each study.
Total
Country (study population Severe dengue Deaths, Male, Female, Confound
Author, year period) Study design Outcome Type of population (n) cases, n (%) n (%) n (%)a n (%)a analysis Age groupa Risk of bias
e
Casali CG et al. Brazil Surveillance study Severe dengue Notified cases 82.277 958 (1%)—DHF 60 (0.07%) NR NR NR Mean: 32.8 years old Low (71%)
(2004) [29] (2001–2002)
Hammond SN Nicaragua Cohort Severe dengue Patients presenting to 3.173 869 (27%)—Severe 13 (0.41%) NR NR Univariate 0–11 months: 73 (8%) Low (87.5%)
et al. (2005) [30] (1999–2011) hospitals clinical analysis 1–14 years: 666 (77%)
manifestations ≥15 years: 130 (15%)
Navarrete- Mexico Case control Severe dengue or Cases diagnosed as DF 1.415 898 (63%)—DHF 79 (5.58%) 50 (6%) 50 (6%) NR Mean: 26.9 years old Low (78%)
Espinosa J et al. (1995–2003) death or DHF
(2005) [31]
Acioli-Santos B et al. Brazil Cohort Severe dengue Patients with dengue 110 79 (72%)—DFTb NR NR NR Univariate 5–15 years: 6 (8%) Low (78%)
(2008) [32] (NR) symptoms analysis 16–25 years: 15 (19%)
26–50 years: 45 (57%)
TROPICAL MEDICINE & INTERNATIONAL HEALTH

51–76 years: 13 (16%)

Gonz
alez AL et al. Colombia Cohort Hospitalisation Hospitalised patients 328 116 (35%)—DHF 1 (0.3%) 36 (31%) 46 (40%) AS, CV Mean: 20.06 years old Low (100%)
(2008) [33] (2006–2007)
Rubio DG et al. Cuba Case control Severe dengue Adult patients 228 94 (41%)—DHF/ NR 51 (54%) 25 (27%) NR <20 years: 1 (1%) Medium (60%)
(2008) [34] (2001–2002) DSS 20–59 years: 72 (77%)
≥60 years: 3 (3%)
Cavalcanti LPG Brazil Surveillance studye Death DHF cases 291 291 (100%)—DHF 20 (6.87%) 130 (47%) 161 (55%) NR Mean (range): 33 years Low (86%)
et al. (2010) (2003) old
[27] (2–88)
Figueiredo MAA Brazil Case control Severe dengue Cases and controls that 1.345 170 (13%)—DHF 0 (0%) 75 (44%) 95 (56%) SV, C ≤15 years: 35 (21%) Low (90%)
et al. (2010) [21] (2002–2005) tested positive for ≥16 years: 135 (79%)
IgG
Thomas L et al. Martinique Cohort Severe dengue Patients admitted to the 560 95 (17%)—DHF/ 7 (1.25%) NR NR AS, CV Median (range): Low (100%)
(2010) [35] (2005–2008) adult emergency DSS DHF = 43 (17–73);
department DSS = 42 (16–75);
DHF/DSS
incomplete = 45
(16–83)d
Giraldo D et al. Brazil Cohort Severe dengue Children up to 15 years 181 30 (17%)—Severe 0 (0%) 16 (53%) 14 (47%) SS Mean: 104 months Medium (55%)
(2011) [36] (2007–2008) old admitted to the dengue
hospital
Su
arez-Ognio L Peru Case control Severe dengue Inpatients 226 73 (32%)—Severe NR 31 (42%) 42 (57%) AS, CV =15 years: 38 (53%) Low (89%)
et al. (2011) [37] (2010–2011) dengue >15 years: 34 (47%)
Monteiro SP et al. Brazil Case control Severe dengue Outpatients and 109 42 (39%)—DHF NR 19 (45%) 23 (55%) Univariate Mean (range): 35.02 Low (100%)
(2012) [38] (2002–2008) inpatients analysis (12–66)
Moraes GH et al. Brazil Case control Death Severe dengue cases 12.321 12.321 (100%)— 1.062 (8.62%) 5.059 (41%) 7.262 (59%) AS, SV, TSV 0–14 years =1.903 Low (90%)
(2013) [39] (2000–2005) Severe dengue (15%)
15–49 years = 8.596
(70%)
≥50 years = 1.815
(15%)
(Continues)
177

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 TABLE 1 (Continued)
178

Total
Country (study population Severe dengue Deaths, Male, Female, Confound
Author, year period) Study design Outcome Type of population (n) cases, n (%) n (%) n (%)a n (%)a analysis Age groupa Risk of bias
e
Machado CR et al. Brazil Surveillance study Severe dengue Women of childbearing 546 129 (24%)—DHF/ 8 (1.47%) 0 (0%) 129 (100%) CV, AS Mean (range): 25.5 Low (75%)
(2013) [40] (2007–2008) age with DSS (15–49)
information about
pregnancy
Lora AJM et al. Dominican Cross-sectional Severe dengue or Paediatric population 796 207 (26%)—Severe 41 (5.15%) 100 (48%) 107 (52%) SS <1 year = 38 (18%) Low (75%)
(2014) [41] Republic death aged less than 1– dengue ≥1 year = 169 (82%)
(2008–2009) 16 years old
Branco MRFC et al. Brazil Case control Death Age under 13 years and 95 77 (81%)—Severe 18 (18.95%) 34 (44%) 43 (56%) Univariate Mean (range): 4.04 (0– Low (90%)
(2014) [42] (2006–2007) hospital admission dengue analysis 12)
Gibson G et al. Brazil Surveillance studye Severe dengue Confirmed cases of 18.341 5.721 (31%)— NR NR NR TSV, SV ≤5 years = 410 (7%) Low (75%)
(2014) [28] (2008) severe dengue fever Severe dengue 6–15 years = 2632
(46%)
16–20 = 365 (6%)
21–60 = 1927 (34%)
>60 years = 387 (7%)
Campos KB et al. Brazil Cohort Death DHF, DSS and 2.214 2.214 (100%)— 156 (7.05%) 1070 (48%) 1144 (52%) SS, CV, AS, 0–5 years = 141 (6%) Medium (55%)
(2015) [43] (2008–2010) complicated dengue Severe dengue TSV 6–14 years = 366
cases (17%)
15–49 years = 979
(44%)
50–60 years = 428
(19%)
>60 years = 300 (14%)
Teixeira MG et al. Brazil Case control Severe dengue Recruited in hospitals 1.806 490 (27%)—DHF NR 211 (43%) 279 (57%) SV ≥15 years = 316 (64%) Low (100%)
(2015) [44] (2009–2012) ≤15 years = 174 (36%)
Amâncio FF et al. Brazil Multicenter case Death adult (≥15 years) 97 68 (70%)—Severe 19 (19.59%) NR NR Univariate NR Low (80%)
(2015) [45] (2008–2013) series admitted to ICU dengue analysis
Lugo S et al. Paraguay Case control Severe dengue Paediatric hospital 217 57 (26%)—Severe NR 25 (44%) 32 (56%) SS Mean: 133 months Low (100%)
(2015) [46] (2012) population up to dengue
18 years old
Lugo S et al. Paraguay Cohort Severe dengue Hospitalised children 60 15 (25%)—Severe NR 6 (40%) 9 (60%) NR ≤6 months = 15 Low (87.5%)
(2015) [47] (2013) from 1 week to dengue (100%)
12 months of age
Negrete AFA et al. Paraguay Case control Death Adults over 18 years old 258 NR 61 (23.64%) NR NR Univariate NR Low (78%)
(2015) [48] (2012–2013) who died from analysis
dengue
Lovera D et al. Paraguay Case control Severe dengue Children under 15 years 471 354 (75%)—DSS 6 (1.27%) 183 (52%) 171 (48%) AS, CV, SS <24 months = 26 (7%) Low (90%)
(2016) [49] (2011–2013) old 2–5 years = 25 (7%)
>5 years = 303 (86%)
Burattini MN et al. Brazil Surveillance studye Hospitalisation Notified cases 5.444.285 NR NR NR NR AS, CV, TSV, NR Low (71%)
(2016) [50] (2000–2014) SV
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 TABLE 1 (Continued)
Total
Country (study population Severe dengue Deaths, Male, Female, Confound
Author, year period) Study design Outcome Type of population (n) cases, n (%) n (%) n (%)a n (%)a analysis Age groupa Risk of bias

Pinto RC et al. Brazil Cohort Death Severe dengue cases and 105.459 1.605 (2%)— 62 (0.06%) NR NR AS, SS NR Low (100%)
(2016) [51] (2011–2013) dengue-related Severe dengue
deaths
Dias Júnior JJ et al. Brazil Surveillance studye Severe dengue Notified cases 14.780 1.229 (8%)— 58 (0.39%) 570 (46%) 660 (54%) NR <15 years = 812 (66%) Low (71%)
(2017) [52] (2002–2011) Severe dengue ≥15 years = 417 (34%)
Tukasan C et al. Brazil Surveillance studye Severe dengue Confirmed cases of 14.756 368 (2%)—Severe NR NR NR NR NR Low (100%)
(2017) [53] (1998–2012) dengue dengue
Teixeira LAS et al. Brazil Cohort Severe dengue or Patients older than 113 368 (5%)—Severe NR NR NR Univariate Mean: 55,3 Low (89%)
(2017) [54] (2012–2015) hospitalisation 14 years dengue analysis
hospitalised and/or
receiving outpatient
TROPICAL MEDICINE & INTERNATIONAL HEALTH

care
Cuellar CM et al. Paraguay Surveillance studye Death or Patients younger than 57.483 NR 35 (0.06%) NR NR NR NR Low (71%)
(2017) [55] (2010–2013) hospitalisation 15 years
Ferreira RAX et al. Brazil Cross-sectional Severe dengue Hospitalised patients 419 296 (71%)—DHF 6 (1.43%) NR NR AS, SS <5 years = 27 (9%) Low (75%)
(2018) [56] (2008) under then 16 years ≥5 years = 270 (91%)
old
Nunes PCG et al. Brazil Cross-sectional Death Fatal cases of dengue 5.391 NR 1047 (19.42%) NR NR Univariate NR High (43%)
(2018) [57] (1986–2015) analysis
Silva NS et al. Brazil Surveillance studye Hospitaliation Dengue cases 7.613 NR 28 (0.37%) NR NR AS, SV, SS NR High (37.5%)
(2018) [58] (2002–2012)
Delgado-Enciso I Mexico Cross-sectional Severe dengue Patients with fever who 31 6 (19%)—Severe 1 (3.23%) NR NR Univariate NR Low (71%)
et al. (2018) (2007–2008) consulted the dengue analysis
[59] Health Services
Lovera D et al. Paraguay Cross-sectional Severe dengue, death Patients ≤15 years 784 361 (46%)—DSS 5 (0.64%) NR NR SS, AS NR Low (71%)
(2019) [60] (2007–2018) or hospitalised
hospitalisation
Luppe MJ et al. Brazil Case control Severe dengue Inpatients and 11.448 4.268 (37%)— NR 1526 (36%) 2742 (64%) SS, CV, AS >15 years = 4033 Low (100%)
(2019) [61] (1998–2006) outpatients Severe dengue (94%)
0–15 years = 244 (6%)
Kumar A et al. Barbados Cohort Severe dengue, death Confirmed cases of 4.344 190 (4%)—Severe 18 (0.41%) 102 (54%) 88 (46%) NR NR Low (89%)
(2020) [62] (2006–2015) or dengue dengue
hospitalisation
Elenga N et al. Martinique, Cohort Severe dengue Children hospitalised 106 33 (31%)—Severe 6 (5.66%) 15 (45%) 18 (55%) AS, SS, CV Median (interquartile Low (78%)
(2020) [63] Guadeloupe with sickle cell dengue range): 10.5 (5; 15)
and French disease under then
Guiana 15 years old
(2005–2013)
Barry MR et al. Colombia Cross-sectional Hospitalisation Children up to 15 years 2.446 NR NR NR NR AS NR Medium
(2020) [64] (2015) and adults (62.5%)
Pimentel J, Colombia Case control Death Patients who died from 179 179 (100%)— 58 (32.4%) 88 (49%) 91 (51%) SS, C, CV, SV <15 years = 106 (59%) Low (100%)
2020 [65] (2013–2014) severe dengue and Severe dengue 15–19 = 17 (9%)
patients who 20–49 = 40 (22%)
survived ≥50 = 16 (9%)
179

(Continues)

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 TABLE 1 (Continued)
180

Total
Country (study population Severe dengue Deaths, Male, Female, Confound
Author, year period) Study design Outcome Type of population (n) cases, n (%) n (%) n (%)a n (%)a analysis Age groupa Risk of bias

Hern
andez JPR Colombia Case control Severe dengue Patients younger than 200 24 (12%)—Dengue 3 (1.50%) 15 (63%) 9 (38%) AS, SS NR Low (80%)
et al. (2020) (2016) 18 years admitted to with warning
[66] a paediatric ICU signs or severe
denguec
Macias AE et al. Mexico, Brazil, Surveillance studye Death or Hospitalised cases 678.836 65.203 (10%)— 3.225 (0.48%) NR NR C, CV, AS, 0–8 years = 12,318 Low (75%)
(2021) [67] Colombia hospitalisation Severe dengue TSV (19%)
(2008–2017) 9–45 years = 42,072
(65%)
46–60 years = 6763
(10%)
≥60 years = 4050 (6%)
Sol

orzano VEF et al. Brazil Cohort Severe dengue Adults with suspected 225 63 (28%)—Dengue NR 25 (40%) 38 (60%) CV, SS Median (interquartile Low (77%)
(2021) [68] (2013) dengue infection with warning range): 36 (23–50)
signs or severe
denguec
Mosqueira R et al. Paraguay Case control Severe dengue Hospitalised patients 146 43 (29%)—Severe 6 (4.11%) 19 (44%) 24 (56%) Univariate 18–30 years = 13 Low (89%)
(2021) [69] (2019–2020) over then 18 years dengue analysis (30%)
old 31–60 years = 21
(49%)
≥60 years = 9 (21%)
Fonseca-Portilla R, Mexico Cohort Death or Patients diagnosed with 24.595 NR 143 (0.58%) NR NR AS, C, CV NR Low (83%)
2021 [70] (2020–2021) hospitalisation dengue fever (DF)
and treated in a
public or private
setting
de Sousa SC, Brazil Case control Death Patients admitted to the 75 NR 19 (25%) NR NR AS, SS, C NR Low (80%)
2022 [71] (2016) hospital with
dengue infection
Simpson BN, Dominican Cohort Severe dengue Children who tested 488 80 (16%) 4 (1%) 38 (48%) 42 (53%) GV Median (IQR) Low (80%)
2022 [72] Republic positive for DENV = 59 months (67)
(2018–2020)

Note: Numbers may vary depending on the availability of data in the articles.
Abbreviations: AS, age and sex (all ages and sex); C, comorbidities (diabetes, hypertension, kidney disease, immunosuppression and similar); CV, clinical variables (secondary dengue infection, serotype, pregnancy, dengue case classification,
vaccination, medications and similar); DF, dengue fever; DHF, dengue haemorrhagic fever; DSS, dengue shock syndrome; GV, genetic variables (number of minor alleles); ICU, intensive care units; NR, not reported; SSV, signs and symptoms
variables (symptoms related to dengue, laboratory tests and similar); SV, socioeconomic and/or sociodemographic variables (skin colour, race, income, educational level and similar); TSV, time-spatial variables (notification period, location of
notification, number of inhabitants and similar).
a
Gender and age from the severe dengue population.
b
Data from patients with dengue haemorrhagic fever and dengue with complications, both with manifestation of thrombocytopenia, were analysed together as the ‘Dengue fever with thrombocytopenia’ (DAFT) group.
c
Dengue with warning signs and severe dengue were analysed together, it was not possible to distinguish these two groups.
d
Incomplete DHF/DSS means missing bleeding or thrombocytopenia data.
e
Surveillance study are studies based on notified cases in a surveillance system.
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TROPICAL MEDICINE & INTERNATIONAL HEALTH
FIGURE 2 Country distribution map of studies included in the systematic review (n = 47). There are studies carried out in more than one country.
of disease severity (OR: 1.14, 95% CI: 1.04–1.25) while a
protective association was found for males (OR: 0.67, 95%
CI: 0.45–0.90) (Table 2; Figure S1). Furthermore, a statis-
tically significant association was found between certain
signs and symptoms and severe dengue, such as headache
(OR: 1.20, 95% CI: 1.07–1.34), myalgia and/or arthralgia
(OR: 1.30, 95% CI: 1.19–1.41), vomiting/nausea (OR:
1.48, 95% CI: 126–1.70), abdominal pain or tenderness
(OR: 1.64, 95% CI: 1.40–1.89), diarrhoea (OR: 1.79, 95%
CI: 1.45–2.14) and prostration, lethargy, fatigue or similar
symptoms (OR: 2.46, 95% CI: 1.33–3.58) (Table 2). In the
case of abdominal pain or tenderness, the analysis with
RR/RP measures showed a similar result (Table 3;
Figure S2). None of the included articles used PR as an
association measure for the outcome severe dengue
outcome.
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181
Risk factors for death due to dengue
The presence of comorbidity or underlying diseases was the
clinical characteristic most often significantly associated with
death in the studies (Figure 4). Additionally, age >60 years was
significantly associated with death in all articles that analysed
this variable, whereas age <18 years was significantly associated
with a lower risk of death in half of the studies (Figure 4). The
most frequent signs and symptoms significantly associated with
death were bleeding/haemorrhagic manifestation and shock,
warning signs or severe dengue. However, the articles by
Moraes GH et al. (2013) and Aldama Negrete AF et al. (2015)
presented bleeding/haemorrhagic manifestation as a protective
factor (Figure 4).
The meta-analysis for the death outcome found that the
female sex (OR: 0.82, 95% CI: 0.74–0.91) and age <18 years
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182 TROPICAL MEDICINE & INTERNATIONAL HEALTH

F I G U R E 3 Risk factors for the severe dengue outcome: sociodemographic characteristics (brown), signs and symptoms (pink), clinical characteristics
(blue), non-statistically significant (grey). Risk factors are displayed as circles. The digits inside the circles are the relevant reference numbers. The size of each
circle is proportional to the amount of articles that analysed the risk factor. In white are articles that were statistically significant, but as a protective factor. If
the article analysed the same variable or variables in the same group more than once, if one of the analyzes was statistically significant, the entire article was
marked as significant.

(OR: 0.79, 95% CI: 0.70–0.88) were associated with a lower
probability of death due to dengue. Additionally, the
detection of a positive tourniquet test (OR: 0.56, 95% CI:
0.39–0.73), platelet count <100,000 μL (OR: 0.69, 95% CI:
0.51–0.88) and symptoms of capillary fragility (OR: 0.60,
95% CI: 0.40–0.79) were also associated with a lower risk of
death (Table 4; Figure S3). The articles included in this
study that presented this data emphasised the importance of
early diagnosis. Few signs and symptoms showed significant
association with death outcome or exhibited high heteroge-
neity. However, a significant association was observed for
respiratory symptoms (OR: 5.55, 95% CI: 4.02–7.07)
(Table 4; Figure S3). For the RR/PR association measure,
age <18 years was identified as a risk factor for death (RR:
3.31, 95% CI: 1.70–4.93) (Table 5; Figure S4). None of the
included articles used PR as an association measure for
the outcome death.
Risk factors for hospitalisation due to dengue
Eleven studies analysed the outcome of hospitalisation due
to dengue, and the most frequently observed age groups
associated with hospitalisation were <18 years old and
>60 years old (Figure 5). However, only a limited number of
articles examined the hospitalisation outcome, resulting in
few variables showing statistically significant associations.
Among the analysed variables, only the age group of
19–60 years (OR: 1.07, 95% CI: 1.02–1.11) had a statistically
significant association with hospitalisation (Table 6;
Figure S5). Only one of the included articles used PR as an
association measure for the outcome hospitalisation.
DISCUSSION
This systematic review and meta-analysis evaluated risk fac-
tors associated with severe dengue, death and hospitalisation
due to dengue infection. Given the diverse clinical manifes-
tations and unpredictable clinical course of dengue, identifi-
cation of risk factors contributing to these outcomes is
crucial [16]. The risk factors for severe dengue found by this
meta-analysis were secondary dengue infection, female sex,
white or Caucasian ethnicity and some signs and symptoms.
The literature consistently reports a higher risk of severe
dengue in secondary dengue infection [3, 19, 73, 74]. The
higher severity observed in secondary infections may be due
to the response of T cells and antibodies produced during a
primary DENV infection that cross recognise DENV anti-
gens from the current infection, resulting in intense immune
activation and inflammation responsible for more severe
symptoms [75].
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TROPICAL MEDICINE & INTERNATIONAL HEALTH 183

TABLE 2 Meta-analysis results for the outcome of severe dengue (Odds ratio).

Results Meta-analysis, pooled Heterogeneity

Variables meta-analysed (n)a data OR (95% CI) (measure I 2)

Sociodemographic characteristics
Male gender 3 0.67 (0.45–0.90) 65.7%
Female gender 4b 1.14 (1.04–1.25) 20.5%
Age <18 years 9b 1.35 (1.22–1.49) 89.7%
Live in urban area 2 0.84 (0.66–1.03) 14.3%
White or Caucasian ethnicity 3 1.28 (1.14–1.42) 28.9%
Black or mixed ethnicity 6b 1.02 (0.84–1.20) 6.3%
b
<10 years of schooling or secondary education 4 0.76 (0.51–1.00) 34.1%
1–3 minimum salaries or low income 2 1.28 (0.82–1.74) 28.3%
Signals and symptoms
Respiratory symptoms 3b 2.76 (2.09–3.43) 0.0%
Headache 3 1.20 (1.07–1.34) 0.0%
Myalgia and/or arthralgia 7b 1.30 (1.19–1.41) 49.1%
Vomiting/nausea 9b 1.48 (1.26–1.70) 41.3%
Bleeding/haemorrhagic manifestations 8b 2.17 (1.74–2.61) 97.6%
b
Prostration, lethargy, fatigue or similar 4 2.46 (1.33–3.58) 0.0%
Symptoms of capillary fragilityc 9b 1.39 (1.22–1.55) 96.1%
Abdominal pain or tenderness 6 1.64 (1.40–1.89) 16.2%
Alterations in the red series 6b 0.65 (0.45–0.84) 85.0%
Pleural, cavity and/or pericardial effusion 3 1.52 (0.98–2.06) 73.9%
Ascitis 2 1.43 (0.89–1.97) 80.4%
Hepatomegaly, splenomegaly or similar 5 1.87 (1.28–2.46) 80.3%
Tourniquet test + 2 0.95 (0.84–1.06) 55.9%
Fever 2 1.30 (1.15–1.44) 58.6%
Ocular pain 2 1.07 (0.93–1.22) 79.7%
Diarrhoea 3 1.79 (1.45–2.14) 0.0%
Platelet count <100,000/μL 5b 1.16 (0.82–1.50) 41.0%
Clinical characteristics
Secondary dengue infection 10b 1.17 (1.04–1.29) 25.4%
Hypertension 4b 1.31 (0.96–1.66) 0.0%
Note: Results in bold are those that met the following criteria for analysis and discussion: (a) the risk factor was analysed in at least three studies, (b) with significant results in the
meta-analysis and (c) the heterogeneity was below 75%.
Abbreviation: OR, Odds ratio.
a
Some studies stratified their analysis in different groups or situations (i.e., different countries, different ages groups, male/female) reporting more than one measure of association
for each risk factor.
b
The study analysed the risk factor in different groups or situations.
c
Rash, petechiae, exanthema, haematomas and/or ecchymoses.

Previous meta-analyses showed that female sex was not
associated with the development of severe dengue [76, 77].
This meta-analysis was conducted in Latin America, which
includes several countries. Differences in results between
meta-analyses may be due to regional differences in genetic
background, environmental and social factors, circulating
virus serotypes and access to health services. In addition, a
recent article found an association between female sex and
dengue. It is important to have a view of Latin America as a
whole, because it is one of the most dengue-affected regions
in the world [9]. In addition, there are other studies that also
show a positive association between female sex and severe
dengue. This can be explained by the fact that women use
more medical care services than men, which leads to the
diagnosis of the disease, as well as the difference in immuno-
logical response between the sexes. [78–82]. Studies con-
ducted in Latin America and Asia have also found a higher
frequency of severe dengue disease in females [78, 83, 84].
In contrast, for the outcome of death, this meta-analyse
found that women have a lower risk of death, with the study
by Moraes GH et al. (2013) in Brazil carrying the most
weight in this analysis [39]. It is worth noting that statistics
and analysis suggest that Brazilian women tend to use
healthcare services more frequently than Brazilian men,
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184 TROPICAL MEDICINE & INTERNATIONAL HEALTH

TABLE 3 Meta-analysis results for the outcome of severe dengue (relative risk).

Results Meta-analysis, pooled Heterogeneity

Variables meta-analysed (n)a data RR (95% CI) (measure I 2)

Sociodemographic characteristics
Male gender 2 0.90 (0.66–1.14) 85.9%
Female gender 2 0.73 (0.54–0.92) 0.0%
Age <18 years 2 1.25 (1.03–1.47) 88.8%
Signals and symptoms
Vomiting/nausea 2 1.35 (0.80–1.91) 0.0%
Bleeding/haemorrhagic manifestations 4b 1.82 (1.75–1.90) 0.0%
Symptoms of capillary fragilityc 5b 1.58 (1.45–1.70) 92.5%
Abdominal pain or tenderness 3 1.30 (1.20–1.40) 0.0%
Alterations in the red series 2 4.30 (0.21–8.81) 32.0%
Altered leukocytes 2 1.05 (0.75–1.35) 0.0%
Altered AST 4b 0.99 (0.76–1.22) 64.9%
Hepatomegaly, splenomegaly or similar 2 1.20 (1.05–1.35) 0.0%
Clinical characteristics
Note: Results in bold are those that met the following criteria for analysis and discussion: (a) the risk factor was analysed by at least tree studies, (b) with significant results in meta-
analysis and (c) the heterogeneity was below 75%.
Abbreviation: RR: relative risk.
a
Some studies stratified their analysis in different groups or situations (i.e., different countries, different ages groups, male/female) reporting more than one measure of association
for each risk factor.
b
The study analysed the risk factor in different groups or situations.
c
Rash, petechiae, exanthema, haematomas and/or ecchymoses.

F I G U R E 4 Risk factors for the outcome of death due to dengue: sociodemographic characteristics (brown), signs and symptoms (pink), clinical
characteristics (blue), non-statistically significant (grey). Risk factors are displayed as circles. The digits inside the circles are the relevant reference numbers.
The size of each circle is proportional to the amount of articles that analysed the risk factor. In white are articles that were statistically significant, but as a
protective factor. If the article analysed the same variable or variables in the same group more than once, if one of the analyzes was statistically significant, the
entire article was marked as significant.

which could contribute to the lower likelihood of dying from
dengue in women [85]. However, it is important to note that
there are also studies that provide contradictory results.
Some studies have shown that more women die from den-
gue, while others report the opposite [78, 86, 87]. For exam-
ple, Thein TL et al. (2013) found that 68% of cases that
resulted in death were male [88]. These differences could be
due to variations in access to healthcare systems across
countries or regions.
Regarding the white or Caucasian ethnicity, a study con-
ducted in Cuba found a higher risk of severe dengue in indi-
viduals of white ethnicity. The authors of this study
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TROPICAL MEDICINE & INTERNATIONAL HEALTH 185

TABLE 4 Meta-analysis results for the outcome of death (Odds ratio).

Results Meta-analysis, pooled Heterogeneity

Variables meta-analysed (n)a data OR (95% CI) (measure I 2)

Sociodemographic characteristics
Male gender 6b 1.04 (0.83–1.25) 0.0%
Female gender 6b 0.82 (0.74–0.91) 64.4%
Age >60 years 7b 5.21 (4.73–5.69) 87.2%
b
Age 19–60 years 10 1.69 (1.51–1.87) 89.7%
Age <18 years 14b 0.79 (0.70–0.88) 61.8%
Live in rural area 2 1.93 (1.42–2.45) 0.0%
Signals and symptoms
Respiratory symptoms 9b 5.55 (4.02–7.07) 71.1%
b
Warning signs or severe dengue 21 1.46 (1.30–1.63) 95.1%
Edema 3 0.66 (0.01–1.30) 0.0%
Vomiting/nausea 7b 1.21 (0.60–1.82) 0.0%
Bleeding/haemorrhagic manifestations 28b 0.84 (0.68–1.00) 54.8%
c
Symptoms of capillary fragility 10b 0.60 (0.40–0.79) 47.8%
Myalgia and/or Arthralgia 3b 0.66 (0.32–1.00) 0.0%
b
Abdominal pain or tenderness 6 0.88 (0.41–1.36) 0.0%
Alterations in the red series 9b 0.91 (0.67–1.16) 72.2%
Pleural, cavity and/or pericardial effusion 5b 1.11 (0.66–1.56) 69.9%
Ascitis 2 1,14 (0.84–3.12) 0.0%
Hepatomegaly, splenomegaly or similar 4 0.80 (0.29–1.30) 0.0%
b
Tourniquet test+ 4 0.56 (0.39–0.73) 0.9%
Restlessness 5b 2.32 (0.99–3.65) 0.0%
Platelet count <100,000/μL 9b 0.69 (0.51–0.88) 38.9%
Fever 2 1.01 (0.91–2.93) 0.0%
Prostration, lethargy, fatigue or similar 8b 1.07 (0.51–1.62) 0.0%
Ocular pain 2 0.27 (0.22–0.76) 2.9%
Clinical characteristics
Secondary dengue infection 9b 0.77 (0.64–0.89) 35.0%
b
Pregnancy 3 1.76 (0.31–3.21) 66.1%
Hypertension 7b 1.04 (0.62–1.47) 64.5%
Note: Results in bold are those that met the following criteria for analysis and discussion: (a) the risk factor was analysed in at least three studies, (b) with significant results in the
meta-analysis and (c) the heterogeneity was below 75%.
Abbreviation: OR, Odds ratio.
a
Some studies stratified their analysis in different groups or situations (i.e., different countries, different ages groups, male/female) reporting more than one measure of association
for each risk factor.
b
The study analysed the risk factor in different groups or situations.
c
Rash, petechiae, exanthema, haematomas and/or ecchymoses.

suggested that individuals of white ethnicity could have a
more robust dengue virus-specific cellular immune response
and higher cross-reactivity to heterologous dengue antigens
compared to individuals of black ethnicity [22]. However,
further studies are needed to investigate this mechanism. In
addition, the study of ethnic groups in the Latin American
population can be challenging due to the wide genetic diver-
sity and different mixed ancestry.
Signs and symptoms such as headache, myalgia and/or
arthralgia, vomiting/nausea, abdominal pain or tenderness,
diarrhoea and prostration, lethargy, fatigue or similar have
been identified as risk factors for severe dengue. Persistent
vomiting and severe abdominal pain are considered warning
signs, as they can progress to severe cases and even lead to
death [3, 16]. One study showed that abdominal pain or ten-
derness may be associated with various conditions such as
acute hepatitis, acalculous cholecystitis, acute pancreatitis,
appendicitis and spontaneous bacterial peritonitis [89].
Severe headache is a commonly reported symptom of den-
gue fever [3, 90]. However, it may not necessarily be associ-
ated with the severity of the disease, other studies show
results that do not demonstrate headache as a risk factor for
severe dengue [77, 90]. Future studies are needed to deter-
mine the headache feature.
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186 TROPICAL MEDICINE & INTERNATIONAL HEALTH

TABLE 5 Meta-analysis results for the outcome of death (relative risk).

Meta-analysis, pooled Heterogeneity

Variables Results meta-analysed (n)a data RR (95% CI) (measure I 2)

Sociodemographic characteristics
Age <18 years 5b 3.31 (1.70–4.93) 30.0%
Age >60 years 4b 6.45 (5.28–7.62) 0.0%
Signals and symptoms
Clinical characteristics
Note: Results in bold are those that met the following criteria for analysis and discussion: (a) the risk factor was analysed in at least three studies, (b) with significant results in the
meta-analysis and (c) the heterogeneity was below 75%.
Abbreviation: RR, relative risk.
a
Some studies stratified their analysis in different groups or situations (i.e., different countries, different ages groups, male/female) reporting more than one measure of association
for each risk factor.
b
The study analysed the risk factor in different groups or situations.

Female
DENV 2 infection
58,
50, 62 Plasma leakage, shock, Warning
60 70 signs or Severe Dengue
67
Secondary Dengue 58
infection
58, 60 Age < 60
years
67, 70 58, 62, 67,
50 70

Age < 18 50, 64

58, 64 years Age 19 - 60 years

50, 55, 62
Comorbidities or
67, 70
underlying diasease
67,
70

F I G U R E 5 Risk factors for the outcome of hospitalisation due to dengue: sociodemographic characteristics (brown), signs and symptoms (pink), clinical
characteristics (blue), non-statistically significant (grey). Risk factors are displayed as circles. The digits inside the circles are the relevant reference numbers.
The size of each circle is proportional to the amount of articles that analysed the risk factor. In white are articles that were statistically significant, but as a
protective factor. If the article analysed the same variable or variables in the same group more than once, if one of the analyzes was statistically significant, the
entire article was marked as significant.

Aches and pains are typical symptoms of dengue,
especially in the initial phase of the disease, but neuro-
muscular complications can also occur and even lead to
the development of Guillain–Barré syndrome [16, 91].
Diarrhoea has been reported as the second most common
gastrointestinal symptom in dengue, although it is a
nonspecific symptom that can occur in several febrile
illnesses [92]. However, the presence of gastrointestinal
symptoms was associated with the haemorrhagic type of
dengue [93]. In addition, symptoms related to physical
and mental tiredness have shown a positive association
with severe dengue. Lethargy and fatigue are considered
warning signs by the WHO, as they can be indicators of
the development of severe dengue [3, 16]. Indeed, studies
demonstrated that lethargy or restlessness are associated
with the development of the severe form and are the most
common symptoms in severe patients [76, 94].
In this meta-analysis, the variables of positive tourniquet
test, platelet count <10,000 μL and symptoms of capillary
fragility were found to be associated with a lower risk of
death. Since these test results are indicative of the develop-
ment of a haemorrhagic syndrome, this may suggest that the
early identification of these results and/or symptoms may
contribute to early appropriate diagnosis and management
of the patient, potentially preventing fatal outcome [39].
One study highlighted the impact of not using the tourni-
quet test on the diagnosis of severe dengue, which can make
it difficult to treat patients effectively [95]. In addition, other
studies have demonstrated that tourniquet test, leukopenia
and symptoms of capillary fragility are associated with an

TROPICAL MEDICINE & INTERNATIONAL HEALTH
TABLE 6 Meta-analysis results for the outcome of hospitalisation (Odds ratio).
Variables
Sociodemographic characteristics
Female gender
Sociodemographic characteristics
Age <18 years
Age 19–60 years
Age >60 years
Signals and symptoms
Warning signs or severe dengue
Clinical characteristics
Hypertension
Note: Results in bold are those that met the following criteria for analysis and discussion: (a) the risk factor was analysed in at least three studies, (b) with significant results in the
meta-analysis and (c) the heterogeneity was below 75%.
Abbreviation: OR, Odds ratio.
a
Some studies stratified their analysis in different groups or situations (i.e., different countries, different ages groups, male/female) reporting more than one measure of association
for each risk factor.
b
The study analysed the risk factor in different groups or situations.
increased likelihood of identifying and diagnosing dengue
cases [96, 97]. Early diagnosis can reduce mortality rates to
less than 1% [9].
In this meta-analysis, respiratory symptoms were
identified as a risk factor for death. Furthermore, it has
been observed in other studies that respiratory symptoms
are associated with mortality in dengue infection
[98–101]. Moreover, a study has shown that allergic
symptoms such as asthma can contribute to the increased
severity of the disease [102]. This could be attributed to
the release of cytokines and inflammatory cells in asthma,
which can exacerbate vascular leakage phenomena and
increase the risk of severe dengue, potentially leading to
death [102, 103].
In addition, this meta-analysis identified age <18 years
as a risk factor for death in using RR/PR measure. This
result is consistent with information from WHO and
PAHO, which indicate that dengue is one of the leading
causes of death in children in certain parts of Asia and Latin
America [9, 16]. Studies have shown that death from dengue
can occur across all age groups, but it is more frequently
observed in children and the elderly [2, 93, 104–106]. How-
ever, in this meta-analysis using the OR measure, age
<18 years was found to be a protective factor for death. In
this analysis, the study conducted by Macias AE et al. (2021)
in Brazil was the only one that reported this protective
effect, and it had the greatest weight (72%), which influ-
enced the overall analysis in this direction [67]. Further
research is needed to investigate specific factors in children
and/or adolescents that may contribute to their better prog-
nosis. Furthermore, with respect to the RR measures, it
should also be emphasised that the only variable that
showed a statistically significant difference was age
<18 years. This is due to the fact that only a few articles used
the RR association measure. Since a meta-analysis usually
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187
Meta-analysis, pooled Heterogeneity
Results meta-analysed (n)a data OR (95% CI) (measure I 2)
3b 1.35 (1.11–1.58) 0.0%
9b 1.69 (1.61–1.77) 96.7%
b
9 1.07 (1.02–1.11) 59.5%
6b 1.51 (1.41–1.61) 76.6%
3b 7.58 (6.90–8.27) 98.4%
4b 2.51 (2.04–2.98) 92.0%
requires at least three studies, this measure of association is
not frequently analysed. This could be because cohort stud-
ies are expensive and difficult to conduct.
This systematic review and meta-analysis have some
limitations that should be acknowledged. First, the inclusion
of studies published in journals indexed on major research
platforms may introduce publication bias, statistically signif-
icant or ‘interesting’ results are more likely to be published
than studies with non-significant or less impactful results,
which may influence the scientific literature and our
results [107]. This bias could affect the overall results and
potentially overestimate the significance of certain risk fac-
tors. This review included only observational studies of risk
factors and not clinical trials. Due to the small number of
studies examining each risk factor and the large variability
in design, variables and measures, it was not possible to
investigate this further using funnel plots. Furthermore, the
meta-analysis showed a large heterogeneity between some of
the results, suggesting substantial variability in the measures
reported by the included studies. This heterogeneity makes
it difficult to understand the precision of the association
between risk factors and outcomes, as well as its direction,
either risk or protection.
Furthermore, study design plays a crucial role in inter-
preting the results of a systematic review and can influence
the validity of the conclusions reached. Each type of study
has its respective biases, which can influence the results of
that study. This meta-analysis had few cohort studies with
the RR association measure, which are ideal for assessing
temporality and minimising memory bias. But cohort stud-
ies are expensive and difficult to carry out in low-income
countries. Case–control studies have some biases, such as
selection and self-report, which can lead to biased results. It
is important to highlight that there is a great number of
case–control studies included in our analysis. It is well

188
documented that most severe patients tend to recall more
severe signs and symptoms and to record more and better
data. Furthermore, given that most of the statistically signifi-
cant polled ORs in this review were related to signs and
symptoms, it is possible that those results are overestimating
the association with the dengue outcomes, due to differential
recall bias. Another limitation is the variability of confound-
ing factors included in the multivariable analysis. The inclu-
sion of different confounders across studies may affect the
estimated associations and potentially introduce bias.
Conducting meta-regression analyses could provide a more
comprehensive understanding of the impact of additional
variables on the association between the risk factors and
dengue outcomes.
This study aimed to investigate the main risk factors
associated with severe dengue in Latin America, a region
characterised by high dengue incidence and comprising
countries with significant social inequalities, as well as
different strategies for dengue management, control and
prevention. Based on our findings, we identified several
risk factors for the outcome of severe dengue, including
secondary dengue infection, female sex, white or Cauca-
sian ethnicity, headache, myalgia and/or arthralgia,
vomiting/nausea, abdominal pain or tenderness, diar-
rhoea and prostration, lethargy, fatigue or similar symp-
toms. These results provide valuable insights for defining
risk groups, establishing guidelines to prevent complica-
tions and developing future strategies for dengue manage-
ment in Latin American countries. Moreover, this study
highlights the importance of early diagnosis and accurate
interpretation of diagnostic tests such as the tourniquet
test, and platelet count to prevent death from dengue.
Additionally, recognition of specific symptoms such as
rash, petechiae, exanthema, haematoma and/or ecchymo-
sis is crucial to identify severe cases and take appropriate
measures to prevent fatalities due to dengue. While our
study contributes to the understanding of risk factors for
severe dengue in Latin America, it is important to note
that further research is needed to confirm these findings
and identify additional risk factors that may not have
been captured in our meta-analysis. Standardisation of
risk factors and guidelines based on robust evidence will
ultimately lead to improved management of high-risk
patients and improved outcomes. Future studies should
aim to address these gaps and provide a comprehensive
understanding of the factors influencing severe dengue
cases in the region.
ACKNOWLEDGEMENTS
We are grateful to Escola Bahiana de Medicina e Saúde Púb-
lica have encouraged this study. Furthermore, we thank
Instituto Gonçalo Moniz (IGM), Fiocruz/BA and Instituto
de Saúde Coletiva for making the software available for data
analysis.
CONFLICT OF INTEREST STATEMENT
The authors declare to have no conflicts of interest.
13653156, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tmi.13968 by Eduardo Missoni - CochraneItalia , Wiley Online Library on [11/03/2024]. 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
OR CI D
Victoria Cruz Paran
a https://orcid.org/0000-0002-8582-
2518
Caroline Alves Feitosa https://orcid.org/0009-0000-1891-
1337
Greice Carolina Santos da Silva https://orcid.org/0000-
0002-6066-6344
Luana Leandro Gois https://orcid.org/0000-0002-7538-
3558
Luciane Amorim Santos https://orcid.org/0000-0003-
0261-3495
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How to cite this article: Paran
a VC, Feitosa CA, da
Silva GCS, Gois LL, Santos LA. Risk factors associated
with severe dengue in Latin America: A systematic
review and meta-analysis. Trop Med Int Health. 2024;
29(3):173–91. https://doi.org/10.1111/tmi.13968