Acta Tropica 216 (2021) 105823

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Acta Tropica
journal homepage: www.elsevier.com/locate/actatropica

Role of cytokines produced by T helper immune-modulators in dengue

pathogenesis: A systematic review and meta-analysis
Linh Tran a, b, 1, Ibrahim Radwan c, d, 1, Le Huu Nhat Minh c, e, Soon Khai Low c, f,
Mohammad Rashidul Hashan c, g, Mohammad Diaa Gomaa c, h, Mohamed Abdelmongy c, i,
Abdullah I. Abdelaziz c, j, Alaa Mohamed c, k, Gehad Mohamed Tawfik c, d, Shusaku Mizukami l,
Kenji Hirayama l, Nguyen Tien Huy m, *
a
Institute of Fundamental and Applied Sciences, Duy Tan University, Ho Chi Minh City 700000, Vietnam
b
Faculty of Natural Sciences, Duy Tan University, Da Nang City 550000, Vietnam
c
Online Research Club (http://www.onlineresearchclub.org/), Nagasaki, Japan
d
Faculty of Medicine, Ain Shams University, Cairo, Egypt
e
University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam
f
Department of Internal Medicine, Rochester General Hospital, NY
g
Bangladesh Civil Service, Ministry of Health and Family Welfare, Government of Bangladesh, Mohakhali, Dhaka, 1212, Bangladesh
h
Faculty of Pharmacy, Minia University, Minia, Egypt
i
Faculty of Medicine, Misr University for Science and Technology, Al-Motamayez District, 6th of October City, Egypt
j
Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, 833 S. Wood St. MC 871, Chicago, IL, 60612, USA
k
Faculty of Medicine, Alexandria University, Egypt
l
Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
m
School of Tropical Medicine and Global Health (TMGH), Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: Background and objectives: Modulation of the immune reaction is essential in the development of various diseases,
T-helper cells including dengue’s “Cytokine Tsunami”, an increase in vascular permeability with concomitant severe vascular
Immune mediator leakage. We aim to identify the role of T-helper (Th) cells, Th2 and Th7, with their related cytokines in dengue
Interleukins
pathogenesis.
Cytokines
Dengue
Material and methods: Nine electronic databases and manual search were applied to detect available publications.
A meta-analysis using a fixed- or random-effect model was performed to measure standardized mean difference
(SMD) with 95% confidence interval (CI). The National Institute of Health (NIH) tools for observational cohort,
cross-sectional, and case-control studies were used to examine the risk of bias. The protocol was recorded in
PROSPERO with CRD42017060230.
Results: A total of 38 articles were found including 19 case-control, 11 cross-sectional and 8 prospective cohort
studies. We indicated that Th2 cytokines (IL-4, IL-6, IL-8) and Th17 cytokine (IL-17) in dengue patients were
notably higher than in a healthy control group in acute phase (SMD = 1.59, 95% CI [0.68, 2.51], p = 0.001; SMD
= 1.24, 95% CI [0.41, 2.06], p = 0.003; SMD = 1.13, 95% CI [0.61, 1.66], p<0.0001; SMD = 1.74, 95% CI [0.87,
2.61], p<0.0001), respectively.

Abbreviations: Th, T-helper; DENV, dengue virus; DF, dengue fever; DHF, dengue hemorrhagic fever; DSS, dengue shock syndrome; DF w/B, dengue fever with a
bleeding tendency; DwoWS, dengue without warning signs; DwWS, dengue with warning signs; SD, severe dengue; OFI, other febrile illness; ND, non-dengue; NSD,
non-severe dengue; SDI, severe dengue infection; IFN, interferon; IgM, Immunoglobulin M; IgG, Immunoglobulin G; RT-PCR, Reverse transcription-polymerase chain
reaction; ELISA, Enzyme-linked immunosorbent assay; IL, Interleukin; TGF, Transforming growth factor; WHO, World Health Organization; PAHO, Pan American
Health Organization; SMD, standardized mean difference; CI, confidence interval; NIH, National Institute of Health.
* Corresponding author at: School of Tropical Medicine and Global Health (TMGH), Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
E-mail addresses: trantthuylinh10@duytan.edu.vn (L. Tran), iradwan43@gmail.com (I. Radwan), lehuunhatminh.md@ump.edu.vn (L.H.N. Minh), soonkhai.
low@gmail.com (S.K. Low), hasandmck66@gmail.com (M.R. Hashan), mohammaddiaagomaa@gmail.com (M.D. Gomaa), m.abdelmongy95@yahoo.com
(M. Abdelmongy), abduaziz295@gmail.com (A.I. Abdelaziz), dr.alaakhaled93@gmail.com (A. Mohamed), dr.gehadmohamed@hotmail.com (G.M. Tawfik),
mizukami@nagasaki-u.ac.jp (S. Mizukami), hiraken@nagasaki-u.ac.jp (K. Hirayama), tienhuy@nagasaki-u.ac.jp (N.T. Huy).
1
Authors equally contributed the work.

https://doi.org/10.1016/j.actatropica.2021.105823
Received 7 May 2020; Received in revised form 24 December 2020; Accepted 29 December 2020
Available online 7 January 2021
0001-706X/© 2021 Published by Elsevier B.V.
L. Tran et al.
Conclusions: This study provides evidence of the significant roles of IL-4, IL-6, IL-8, IL-10 and IL-17 in the
pathogenesis of developing a severe reaction in dengue fever. However, to fully determine the association of Th
cytokines with dengue, it is necessary to perform further studies to assess kinetic levels during the duration of the
illness.
1. Introduction
Dengue is a worldwide mosquito-borne viral infection prevalent in
urban areas of tropical countries (Enshaei et al., 2016). The infection is
caused by a Flavivirus RNA virus among four different serotypes (DENV
1–4), and is transferred by Aedes mosquitoes, principally Aedes Aegypti
(Enshaei et al., 2016). As reported by World Health Organization (WHO)
1997 guidelines, dengue is known as a vector-borne illness with three
main phases: febrile, defervescence and convalescence. Symptoms of
dengue fever (DF) range from mild to severe and consist of high fever,
rash, and musculoskeletal pain. Dengue fever can lead to the develop of
more severe complications such as dengue hemorrhagic fever (DHF) and
dengue shock syndrome (DSS). The WHO 2009 guidelines classified
dengue infection into several types including dengue infections with/­
without warning signs (DwWS/DwoWS), and severe dengue (SD) man­
ifesting with plasma leak, serious bleeding and/or acute organ
disruption ([Anonymous]. 2009).
Severity of dengue is determined by many factors, such as the host
immune response and DENV genetic aspects (Guzman et al., 2002;
Thomas et al., 2008; Graham et al., 1999). It is hypothesized that
antibody-dependent enhancement plays an important role in the SD
mechanism. Dengue virus targets mononuclear phagocytic cells during
the adaptive immune response, neutralizing antibodies to increase the
viral burden with a second different serotype (Halstead et al., 1977;
Halstead, 1988; Kliks, 1990). The infection itself, as well as
cell-mediated immune responses, activate infected monocytes to pro­
duce and release biological mediators that exert effects on the perme­
ability of the endothelial lining, thereby producing vascular leakage and
coagulopathy. Loss of plasma in dengue patients leads to increased
disease severity, as well as dengue shock. Furthermore, the variation of
cytokines or chemokines is assumed to induce endothelial cell damage
(Butthep et al., 2012; Lin et al., 2005). Such differences in cytokine
production has led to the hypothesis that the exchange between T-helper
(Th) cells, also known as CD4+ cells, has a major role in determining
dengue severity.
Many studies have revealed that mosquito saliva can enhance the
viral infection through adjusting host inflammatory responses, inhibit­
ing interferon (IFN) signaling and facilitating viral adhesion (Sun et al.,
2020; Pingen et al., 2016; Styer et al., 2011; Conway et al., 2014). A
recent study from Vogt et al. demonstrated that the protein in mosquito
saliva is highly immunogenic to the human body, can produce a mixed
Th1/Th2 response, and subsequently delay the influence of cytokine
levels in the blood (Vogt et al., 2018). Similarly, Pingen et al. observed
that several components of the Th2 immune reaction are provoked by
mosquito salivary compounds (Pingen et al., 2016). The presence of
mosquito salivary proteins has been proven to be involved in bleeding
disorders and inflammatory responses, thus principally promoting
hematophagy (Ribeiro and Francischetti, 2003; Calvo et al., 2009).
However, the role of Th cells against dengue infection remain poorly
understood.
Cytokine molecules in response to dengue were released from CD4+
Th cells with two major subgroups of immune mediators involving Th1
and Th2 cells. An in vitro study reported that the predominant Th1
immune response was induced early during the first three days after
infection while a Th2 reaction replaced this role afterwards (Chaturvedi
et al., 1999). Th1 cells generate interferon-gamma (IFNγ), tumor ne­
crosis factor-α (TNF-α), TNFβ, IL-12, promote macrophage activation
and antibody production, as well as stimulate the activation of cytotoxic
T lymphocytes all leading to efficient viral clearance (Viallard et al.,
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Acta Tropica 216 (2021) 105823
1999). Th1 activation is an important event in the activation of specific
immunity (Marchingo et al., 2020). Th2 cells, which secrete different
interleukins (ILs) including IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13,
contribute to the optimization of antibody construction. They enhance
both mast cell production and eosinophil differentiation and activation,
leading to humoral or allergic immune defenses (Chaturvedi et al.,
2000). This shift of Th1/Th2 contributes to the progression of DHF (Fink
et al., 2006). IL-8 is a chemokine created by macrophages and epithelial
cells with the main capacity of stimulating neutrophil migration. Th17
cells secrete IL-9, IL-17, IL-6 via IL-21 and IL-23, IL-22, and TNF-α,
which are indispensable to tissue immunity and trigger neutrophils to
resist primarily extracellular bacterial infections (Pingen et al., 2016;
Sallusto and Lanzavecchia, 2009). Th1 inflammatory mediators are
involved in dengue pathogenesis during the initial days after infection
and are subsequently replaced by a Th2 response. The scope of our
research includes the immune-mediators of Th2, Th17, Th23, T-reg and
IL-8 of monocyte cytokines, which showed activity in DHF in the liter­
ature (Chaturvedi et al., 1999; Helper, 2009; Raghupathy et al., 1998).
In this work, we aim to systematically review and meta-analyze data of
Th2 and Th17 cells during an acute dengue infection to determine the
severity of the infection.
2. Materials and methods
2.1. Protocol registration
Our work was performed as stated in the Preferred Reporting Items
for Systematic Reviews and Meta-Analysis (PRISMA) statement (Lib­
erati et al., 2009), which was available in supporting information
(Supplementary Table 1). The protocol of our study was recorded on the
International Prospective Register of Systematic Reviews (PROSPERO)
with identification number CRD42017060230.
2.2. Search strategy and screening
We searched nine electronic databases including PubMed, Web of
Science (ISI), POPLINE, Scopus, Google Scholar, Virtual Health Library
(VHL), New York Academy of Medicine Grey Literature Report (NYAM),
WHO Global Health Library (GHL), and the System for Information on
Grey Literature in Europe (SIGLE) for original studies using a combi­
nation of free text and controlled vocabulary in March 2017. In addition,
we performed a manual search in reference and citation lists using
PubMed and Google Scholar (Vassar et al., 2016). The search terms in
each database were described in Supplementary Table 2.
The first step began with title and abstract (when available)
screening, in which three independent reviewers were blinded to each
other’s results. The next step was downloading and screening full-text
articles individually. To enhance sensitivity, records were only
removed if both reviewers had agreed to exclude. Any inconsistency was
finalized by discussion with a senior reviewer.
2.3. Selection criteria
We included the original articles, which reported circulating levels of
IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-13, IL-17, IL-23, IL-31 and TGF-β in
dengue patients. There were no restrictions in terms of the publication
date, language, country, gender and age of patients. The exclusion
criteria were duplicates, in vitro, in vivo studies, reviews, letters, con­
ference papers, commentary articles, thesis, books, protocols or non-
L. Tran et al.
available full-texts.
2.4. Data extraction
The data extraction form was created in an Excel file to obtain the
information including the first author’s name, country of recruited pa­
tients, publication year, study design, description of the patient’s pop­
ulation, criteria of dengue infection, classification of dengue, category of
dengue infection including primary or secondary, number of included
individuals in each group, gender, age, the serotype of dengue virus and
type of blood samples. We extracted data time points according to the
authors’ definition of days (admission, fever or defervescence) or phases
of the disease.
Time and region of patient recruitment were checked to rule out
potential data duplicates for studies published by the same research
group. Data extraction was performed by three authors working inde­
pendently. When there was a disagreement, it was discussed with a third
reviewer and discrepant results were reconciled through arbitration.
Graphs were extracted from figures by PlotDigitizer (Jelicic Kadic et al.,
2016).
2.5. Quality assessment of included studies
Three reviewers individually evaluated the quality of included
publications in a double-blinded manner. Any divergence was resolved
to conclude with a third reviewer. The quality of selected articles was
assessed using NIH tool ([Anonymous] 2017) (Supplementary Table 3).
2.6. Data analysis
Meta-analysis was performed by Comprehensive Meta-analysis
software version 3.3.070 (Biostat, NJ, USA). Continuous data was
analyzed to compute the standardized mean difference. All available
data were extracted and missed data, such as mean or standard deviation
was estimated according to Wan et al. (2014). Also, we converted
log-transformed data into raw using the methods developed by Higgins
et al. (2008).
Subgroups were carried out based on clinical classification of WHO
1997, 2009 and other equivalent classifications. We combined dengue
with/without warning signs (DwWS/DwoWS) respectively as non-
severe dengue (NSD). Also, we combined dengue shock syndrome
(DSS) with SD as a severe dengue infection (SDI) group to compare with
other forms of diseases, such as DF, DHF, DwoWS and DwWS as NSD
infection.
Heterogeneity was evaluated among all included studies, and
inconsistency (I2) of effect estimates measured following Higgins et al.
suggested method. Heterogeneity was determined as statistically sig­
nificant if p-value was smaller than 0.1 (p < 0.1) or I2 > 50%. A fixed-
effects model was conducted without a considerable heterogeneity be­
tween studies meanwhile a random-effects model was performed in case
of major heterogeneity (Higgins et al., 2003). The I2 interpretation was
found based on Cochrane Handbook of systematic reviews and
meta-analysis. The scoring system was determined as follows: 0–40: not
important, 30–60: moderate heterogeneity, 50–90: substantial hetero­
geneity, 90–100: considerable heterogeneity.
To characterize the publication bias, Begg’s funnel plot (Begg and
Mazumdar, 1994) and Egger’s regression test (Egger et al., 1997) were
applied, in case ten or more studies were present (Terrin et al., 2003).
Publication bias was determined as significant if p value < 0.1. Any
presence of publication bias was addressed by the trim and fill method,
which involved the addition of publications that were assumed to be
missing (Duval and Tweedie, 2000) to improve equality (Thompson and
Higgins, 2002). We also performed a sensitivity analysis using one
publication removed in the pooled meta-analysis (with more than three
studies). Removal of any study with (p > 0.05) leads to loss of significant
difference.
3
Acta Tropica 216 (2021) 105823
3. Results
3.1. Systematic review and search results
We identified 2681 records using the search strategy, in addition to
seven records that were retrieved from the manual search (Fig. 1). Of
which, 1784 records were included after excluding duplicates. After
examining the title, abstract, 1684 references were removed. We
examined the full-text screening of the remaining 104 studies, among
them, 36 reports were excluded based on exclusion criteria. We included
68 articles in qualitative synthesis and 38 articles that were eligible for
meta-analysis. The reasons for exclusion from the meta-analysis were
mismatched sample times from patients, undetectable ILs in the blood of
participants, unable to extract data from figures, and insufficient data.
Table 1 demonstrated the main characteristics of all included studies.
3.2. Meta-analysis of Th2 cytokines
IL-4 presented a significant increase in dengue group in contrast to
the healthy control at acute phase with standardized mean difference
(SMD), 95% CI (SMD = 1.59, 95% CI [0.68, 2.51], p = 0.001) pooled
studies show considerable heterogeneity (p<0.0001, I2 = 93.18%).
Meta-analysis between DHF vs. DF, DSS vs. DHF and combined groups of
severe dengue (DSS/SD) vs. mild and moderate disease (DF/DHF/
DwoWS/DwWS) showed no difference between groups at acute phase
(Fig. 2).
IL-6 was importantly increased in SD compared to NSD (WHO 2009
classification) in acute phase (SMD = 0.69, 95% CI [0.30, 1.08], p =
0.001), as well as, in complicated disease (DwWS/SD) in comparison
with non-complicated disease (SMD = 0.85, 95% CI [0.18, 1.52], p =
0.01) with a moderate heterogeneity (p = 0.16, I2 = 50.33%; p = 0.08, I2
= 67.40%), respectively (Fig. 3). According to WHO 1997 classification,
no differences were found in IL-6 levels between dengue groups. In
contrast with other febrile illness (OFI), significant increase was
observed in the dengue group and subgroups (DF, DHF and DSS)
compared to healthy control (SMD = 1.24, 95% CI [0.41, 2.06], p =
0.003; SMD = 1.74, 95% CI [0.63, 2.85], p = 0.002; SMD = 1.189, 95%
CI [0.44, 1.94], p = 0.002; SMD = 0.68, 95% CI [0.27, 1.07], p = 0.001)
with substantial heterogeneity with dengue and (DF, DHF) subgroups
(p<0.0001, I2 = 93.80%; p<0.0001, I2 = 89.66%; p<0.0001, I2 = 82%),
respectively. While non-heterogeneity with DSS subgroup (p = 0.71, I2
= 0%) was shown in Fig. 2. A funnel plot showed a symmetrical funnel in
Supplementary Figure 1. Furthermore, sensitivity analysis was done;
with all studies (p<0.05) in dengue and (DF, DHF) subgroups vs. healthy
control, removing any study does not change the significance. With DSS
subgroup one study (p = 0.10) and removing this study could lose the
significance (Juffrie et al., 2000).
Unlike IL-4 and IL-6, IL-10 was highly different between DHF and DF
at acute phase (SMD = 0.73, 95% CI [0.31, 1.15], p = 0.001) with
substantial heterogeneity (p = 0.002, I2 = 71.18%). Also, the difference
was significant between the DHF/DSS group and DF (SMD = 0.69, 95%
CI [0.30, 0.98], p<0.0001) with non-heterogeneity (p = 0.95, I2 = 0%).
Significant increase was observed in DHF compared to healthy control
(SMD = 1.18, 95% CI [0.64, 1.73], p<0.0001) with non-heterogeneity
(p = 0.48, I2 = 0%). Significant decrease was observed in dengue
compared to OFI (SMD = − 0.59, 95% CI [− 0.99, − 0.19], p = 0.004);
pooled studies showed substantial heterogeneity (p = 0.008, I2 =
74.80%) (Figs. 2 and 3). Sensitivity analysis showed all studies in DHF
vs. DF and DHF/DSS vs. DF with (p<0.05), while two studies in dengue
vs. OFI with (p>0.05), removing either could lose the significance
(Feitosa et al., 2016; Halsey et al., 2016).
IL-8 was considerably increased in dengue and subgroups (DF, DHF
and DSS) in comparison with healthy control (SMD = 1.13, 95% CI
[0.606, 1.66], p<0.0001; SMD = 1.64, 95% CI [1.09, 2.19], p<0.0001;
SMD = 3.24, 95% CI [1.47, 5.01], p<0.0001; SMD = 1.52, 95% CI [1.07,
1.96], p<0.0001), pooled studies showed moderate to considerable
L. Tran et al.
Fig. 1. PRISMA flow diagram showing the method of the search, abstract screening, systematic review and meta-analysis.
heterogeneity (p<0.0001, I2 = 86.85%; p = 0.07, I2 = 57.90%;
p<0.0001, I2 = 95.76%), respectively (Fig. 3). While in DSS there was no
heterogeneity (p = 0.38, I2 = 0%). Sensitivity analysis showed all studies
with (p<0.05) (Fig. 2).
Included studies of IL-5, IL-23, IL-31 and TGF-β were too limited for
further meta-analysis. Also, data of IL-9 and IL-13 were too limited to
conclude since there were not enough included studies of IL-9 and IL-13
with dengue classification according to WHO 2009 or WHO 1997.
3.3. Meta-analysis of Th17 cytokines
IL-17 increased in difference between SDI compared to non-SDI
(SMD = 0.94, 95% CI [0.33, 1.54], p = 0.002) with major heterogene­
ity (p = 0.03, I2 = 70.8%) (Fig. 3). Sensitivity analysis showed one study
with (p = 0.95), removing this study could lose the significance (Furuta
et al., 2012). Also, there was a significant increase between dengue
compared to healthy control (SMD = 1.74, 95% CI [0.87, 2.61],
p<0.0001) with substantial heterogeneity (p = 0.059, I2 = 71.90%)
(Fig. 2). A significant increase in SD than NSD was observed during the
5th-6th days of fever (Fig. 4).
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Acta Tropica 216 (2021) 105823
Among included publications, no study was found that reported IL-
22 and only one study mentioned IL-23, which showed no difference
between sera of DF and DHF during the febrile phase (Oliveira et al.,
2017).
3.4. Quality assessment
Using the scoring system for each study design including cohort,
case-control and cross-section was shown in Supplementary Table 3. A
quality assessment of 13 and 14 items was used for case-control,
observational cohort and cross-sectional studies respectively. The
overall quality score varied from 0.57 to 0.79 with a median of 0.69. All
studies clearly stated the research question, well-defined participants
with appropriate eligibility, except in Patra et al. with 40% eligible
participants (Patra et al., 2015). Only three studies recruited patients
from different populations (Rathakrishnan et al., 2014; Restrepo et al.,
2008b; Singla et al., 2016). All observational cohort and cross-section
studies did confirm exposure (dengue infection) before the measure­
ment of ILs. Also, exposure and outcome were defined and implemented
with all included participants. Cross-section studies did not allow
 L. Tran et al.
Table 1
Study and patient characteristics of the included studies.
Author/Year/ Country Range age (years) Total Study groups (Group sample No.) Dengue T helper immune- DENV No. DENV No.
study classification modulators serotype infection
No.

Abhishek et al., 2017a, N/A 300 NSD 38 SD18 ND94 Healthy150 WHO 2009 IL-2, IL-4, IL-10 N/A - N/A -
India
Bethell et al., 1998, Children; 1.2–8 443 DHF; No shock 182 DHF; Pre-shock 71 DHF; Shock DHF; Fatal shock WHO 1986 IL-6, IL-8 N/A - N/A -
Vietnam survivor 182 6
Bozza et al., 2008, Adults; 23–53 59 Mild denv 39 SD 20 - - WHO 1997 IL-4, IL-5, IL-6, DENV-1 28 N/A -
Brazil modified IL-8, IL-10, IL-13 DENV-3 31
Brasier et al., 2012, Children, adults 55 DF; male 20 DF; female 22 DHF; male 3 DHF; female 10 WHO 1997 IL-6, IL-10 DENV-1 23 N/A -
Venezuela DENV-2 14
DENV-3 12
DENV-4 5
Chau et al., 2008, Infants, children; 117 DHF II 63 DSS 6 OFI 29 Late WHO 1997 IL-6, IL-8, IL-10 N/A - Primary 71
Vietnam 2–18 months convalescence
19
Chen et al., 2006, Adults 49 DF 12 DHF; survivors 13 DHF; non-survivors Healthy 17 WHO 1997 IL-6, IL-10 DENV-2 32 Primary 13
Taiwan 7 Secondary 19
Chen et al., 2005, Adults; 20–81 99 DF 66 DHF/DSS 33 - - WHO 1997 IL-10 DENV-2 99 N/A -
Taiwan
Chen et al., 2007, Adults; 20–78 250 DF 110 DF w/B 50 DHF 90 - WHO-SEARO IL-10 DENV-2 250 Primary 142
Taiwan 1993 Secondary 108
de la Cruz Hernández Infants, children, 176 DF 101 DHF 70 Healthy 5 - WHO 1997 IL-6, IL-8 DENV-1 116 Primary 171
et al., 2016, Mexico adults DENV-2 55 Secondary 0
Cui et al., 2016b, Adults; 20–67 116 DF 60 DHF 56 - - WHO 1997 IL-4, IL-5, IL-6, DENV2 is the 40–52% of DF &
Singapore IL-8, IL-9, IL-10, predominant 22–41% of DHF
IL-13 DENV type are primary cases
5

Duran et al., 2013, Infants, children; 48 DNWS 20 SD 9 Healthy 10 - WHO 2009 IL-17 DENV-1 4 Primary 22
Venezuela 1–14 DENV-2 5
DENV-3 15 Secondary 16
DENV-4 7
Feitosa et al., 2016, Adults 279 Den +ve 80 Den –ve 100 Healthy 99 - N/A IL-6, IL-8, IL-10 DENV-1 19 N/A -
Brazil DENV-2 8
DENV-3 53
Fernando et al., 2016, Children, adults 55 NSD 33 SD 22 - - WHO 2009 IL-10, IL-17 DENV-2 55 N/A -
Sri Lanka
Fialho et al., 2017, Adults; 23–60 45 DF with WS 10 DF without WS 25 Healthy 10 - WHO 2009 IL-10 DENV-4 35 N/A -
Brazil
Halsey et al., 2016, Children, adults 112 DF 51 Co-infected 17 Plasmodium 44 - N/A IL-4, IL-6, IL-8, DENV-1 8 Primary 25
Peru IL-10, IL-13, IL- DENV-3 60 Secondary 43
17, TGF-β1
Houghton-Trivino Infants, children, 55 DF 21 DHF I/II 4 OFI 9 Healthy 8 WHO 2005 IL-4, IL-5, IL-8, DENV-1 16 Primary 7
et al., 2010, adults; 0.3–55 IL-10 DENV-2 3
Colombia DHF III/IV 13 DENV-3 5 Secondary 31
DENV-4 5
Nguyen et al., 2004, Infants< 12 months 107 DHF 85 DSS 22 - - WHO 1997 IL-4, IL-6, IL-10 N/A - Primary 102
Vietnam Secondary 5

Acta Tropica 216 (2021) 105823

Jain et al., 2013, India Infants, children, 281 NSD 90 SD 121 Healthy 70 - WHO 2009 IL-17 DENV-1 26 N/A -
adults; 0–35 (121 DENV-2 84
patients), >35 (49 DENV-3 28
patients)
Juffrie et al., 2001, Infants, children; 229 DF 115 DHF II 20 DHF IV 11 Healthy 33 WHO 1997 IL-6 N/A - N/A -
Indonesia <1–15 DHF I 21 DHF III 18 OFI 11
Juffrie et al., 2000, Children 227 DF 113 DHF I 21 DHF III 18 OFI 11 WHO 1997 IL-8 N/A - N/A -
Indonesia DHF II 20 DHF IV 11 Healthy 33
(continued on next page)
 L. Tran et al.
Table 1 (continued )
Author/Year/ Country Range age (years) Total Study groups (Group sample No.) Dengue T helper immune- DENV No. DENV No.
study classification modulators serotype infection
No.

Kumar et al., 2012, Adults 62 DF 44 DHF 18 - - WHO 1997 IL-4, IL-5, IL-6, DENV-1 36 N/A -
Singapore IL-8, IL-9, IL-10, DENV-2 4
IL-13, IL-17 DENV-3 21
Kuno and Bailey, 1994, Children (<15), 233 Children with Children without Adults with Children WHO 1986 IL-6 N/A - N/A -
Puerto Rico adults hemorrhage hemorrhage hemorrhage (outpatients) 44
(hospitalized) 8 (hospitalized) 48 (hospitalized) 42
Adults without Adults
hemorrhage (outpatients) 44
(hospitalized) 47
Lee et al., 2008, Children, adults 44 DF 16 DHF 15 DSS 5 Normal control 8 WHO 1997 IL-6, IL-10 N/A - N/A -
Vietnam & Taiwan
Liao et al., 2015, China Adults 51 DF 30 SD 21 - - WHO 2009 IL-6, IL-10 N/A - N/A -
Libraty et al., 2002, Children; 6.3–10.7 54 DF 12 DF/DHF 13 DHF/DSS 29 - WHO 1997 IL-10 DENV-3 54 Secondary 54
Thailand
Malavige et al., 2013, Children, adults 274 NSD 219 SD 40 Healthy 15 - WHO 2009 IL-10 N/A - N/A -
Sri Lanka
Malavige et al., 2012, Children, adults 112 DHF without shock DSS 29 - - WHO 1997; IL-6, IL-10, IL- N/A - N/A -
Sri Lanka 83 WHO 2009 for 17, TGF-β1
DHF
Mangione et al., 2014, Children 67 DF 6 DHF 18 DSS 33 OFI 5 WHO 1997 IL-6, IL-8 DENV-1 8 Primary 14
Vietnam DENV-2 7
Healthy 5 DENV-3 5 Secondary 43
Mendonça et al., 2015, Adults; 20.8–52.25 112 DF 30 Co-infected 30 Plasmodium 52 - N/A IL-4, IL-5, IL-6, DENV-1 4 N/A -
Brazil IL-8, IL-10, IL-13 DENV-2 39
DENV-3 5
6

DENV-4 12
Patra et al., 2015, India N/A 89 DF 29 DHF 11 Healthy 49 - WHO-SEARO IL-8 N/A - N/A -
2011
Rathakrishnan et al., Children, adults 504 DwoWS 64 DwWS 388 SD 5 ND 47 WHO 2009 IL-5, IL-8, IL-10, N/A - N/A -
2014, Malaysia IL-13
Rathakrishnan et al., Children, adults; 44 DwoWS 11 DwWS 29 SD 4 - WHO 2009 IL-4, IL-5, IL-6, N/A - Primary 16
2012a, Malaysia 14–67 IL-8, IL-9, IL-10, Secondary 28
IL-13, IL-17
Restrepo et al., 2008a, Infants 41 DF 18 DHF 9 ND 14 - PAHO 1995 IL-6 N/A - Primary 11
Colombia Secondary 16
Restrepo et al., 2008b, Adults 78 Mestizo; DF 33 Mestizo; DHF 10 Afro-Colombian; DF Afro-Colombian; PAHO 1995 IL-6 N/A - N/A -
Colombia 31 DHF 4
Singla et al., 2016, Children 97 DwWS 30 DI 21 SD 46 - WHO 2009 IL-6, IL-8, IL-10, DENV-1 3 Primary 39
India IL-17 DENV-2 84
DENV-3 1 Secondary 58
2 2
serotypes
Levy et al., 2010, Children, adults; 80 DF 36 DHF 34 Control 10 - WHO 1997 IL-6 DENV-2 6 Primary 28
Venezuela 3–53 DENV-3 4
DENV-4 4 Secondary 32

Acta Tropica 216 (2021) 105823

Furuta et al., 2012, Infants, children; 310 DF 19 DSS 41 OFI 18 Healthy 189 WHO 1997 IL-4, IL-9, IL-17 DENV-1 21 Primary 30
Vietnam 0.5–15 DENV-2 21
DHF 43 DENV-3 6 Secondary 73
Nguyen et al., 2005, Infants; 1–11 months 778 DHF I/II 182 DSS 63 Healthy 533 - WHO 1997 IL-4, IL-6, IL-10 N/A - Primary 174
Vietnam Secondary 8

DENV: dengue virus N/A: not applicable DF: dengue fever; DHF: dengue hemorrhagic fever; DSS: dengue shock syndrome; DF w/B: dengue fever with bleeding tendency DwoWS: dengue without warning signs; DwWS:
dengue with warning signs; SD: severe dengue OFI: other febrile illness; ND: non-dengue, NSD: non-severe dengue IgM: Immunoglobulin M; IgG: Immunoglobulin G; RT-PCR: Reverse transcription polymerase chain
reaction; ELISA: Enzyme-linked immunosorbent assay IL: Interleukin; TGF-β1: Transforming growth factor beta 1.
WHO: World Health Organization; PAHO: Pan American Health Organization.
L. Tran et al.
Fig. 2. Meta-analysis of immune-mediators of dengue during acute phase.
sufficient timeframe for studying the effect (Abhishek et al., 2017a;
Bethell et al., 1998; de la Cruz Hernández et al., 2016; Cui et al., 2016b;
Halsey et al., 2016; Malavige et al., 2013; Malavige et al., 2012; Men­
donça et al., 2015; Patra et al., 2015; Restrepo et al., 2008a; Levy et al.,
2010). Most of the studies did not report blinding during assessing
outcomes, except for Cui et al. (2016b), in which blood samples were
anonymous. No study justified the reason for the selected sample size,
except (Halsey et al., 2016). Also, no studies performed power calcula­
tions. Details of quality assessment for each study were presented in
(Supplementary Table 3).
4. Discussion
Despite lacking data of Th1 immune-modulators extracted from the
included studies, several efforts have been made to summarize the
findings of Th1 cytokines detected (Lan and Hirayama, 2011). Th1 cy­
tokines enhance viral epitope profiling by antigen-specific CD8+ T cells
(Schroder et al., 2004). A recent finding stated that TGFβ1, TNF-α, and
IFN-γ polymorphisms could be important in the development of SD
(Fernandez-Mestre et al., 2004). TGF-β exhibits pro-inflammatory and
anti-inflammatory mediator activity depending on its concentration. It
decreases the free radicals, restricts Th1 cytokines, and triggers Th2
cytokine production consisting of IL-10 (Hernandez-Pando et al., 1997).
Previous efforts evaluated cytokine levels between dengue patients and
healthy individuals at different time points. For instance, a high level of
TGF-β was observed in SD patients, however, it was undetected in the
healthy control group, which obtained the highest signal on the day of
defervescence and then remained at a high level on later days of illness
(Chaturvedi et al., 1999; Malavige et al., 2012; Azeredo et al., 2006;
Pandey et al., 2015; Djamiatun et al., 2011; Laur et al., 1998). Halsey
et al. found that TGF-β in a DENV mono-infected group was considerably
higher than the one in a Plasmodium mono-infected or co-infected
groups (Halsey et al., 2016). The level of IL-10 declined in DwoWS pa­
tients but remained high in DwWS patients during the disease (Pérez
et al., 2004). IL-4, IL-5, and IL-12 levels in dengue patients were detected
at lower levels than the healthy control group during the period of illness
(Rathakrishnan et al., 2012b).
Our main results generally found a significantly higher level of IL-4,
IL-6, IL-8, IL-10, and IL-17 in dengue patients compared to healthy pa­
tients. In dengue patient groups, there were significant differences in
Th2 cytokines IL-6, IL-10 and Th17 cytokine IL-17 during the acute
phase. This indicated that Th2 and Th17 cytokines play significant roles
7
Acta Tropica 216 (2021) 105823
in developing severe response to dengue infection. Therefore, the
pathway of severe hemorrhagic disease is probably different from mild
disease. The difference in pro-inflammatory and anti-inflammatory
levels in severe disease is considered to be responsible for inducing
several immuno-pathological mechanisms, causing “cytokine storm”
with uncontrolled immune cell activation and endothelial cell
dysfunction (Costa et al., 2013; Rothman, 2011; Rosen, 1986; Basu and
Chaturvedi, 2008). A study found that pro-inflammatory cytokines from
adipose tissue in infants resulted in a high viral load that induced severe
diseases (Libraty et al., 2015). An increase in specific anti-inflammatory
cytokines in the febrile phase is a physiological reflex counter-response
to pro-inflammatory cytokines and associated with an increased prob­
ability of DHF (Gagnon et al., 2002; Adikari et al., 2016; Tauseef et al.,
2014; Gurugama et al., 2010).
Several studies presented a major growth of IL-4 serum in SD patients
during the febrile phase (Butthep et al., 2012; Chaturvedi et al., 1999;
Bozza et al., 2008; Houghton-Trivino et al., 2010; Abhishek et al.,
2017b; Cui et al., 2016a; Manoharan et al., 2016) and remained at high
levels during defervescence between the 4th to 8th days of illness
(Chaturvedi et al., 1999; Bozza et al., 2008). The higher level of IL-4
increases the viral binding affinity of lectins molecule-3–grabbing non­
integrin and mannose receptor, which subsequently release TNF-α to
trigger an inflammatory cascade leading to DHF and supporting viral
replication (Abhishek et al., 2017a; Schaeffer et al., 2015). Also, high
viral load early in the infection and at defervescence can be risk factors
of SD (Martina, 2014). A dengue study with the exclusion of severe cases
reported a low level of IL-4, IL-5 and IL-12 (Rathakrishnan et al., 2012a).
Nevertheless, it was detected that the IL-4 level in febrile and conva­
lescence with DHF/DSS in infected infants was not greatly different
compared to healthy infants (Nguyen et al., 2004; Nguyen et al., 2005).
The major difference was reported in IL-6 between SD and NSD
during the febrile phase in the meta-analysis, while it was only in IL-10
between DHF and DF. It is important to further investigate these cyto­
kines and kinetic changes in their levels during dengue infection as
potential markers to screen severe disease early before serious compli­
cations (Lee and Ooi, 2013). Besides, IL-6 showed no difference between
different groups of dengue and was positively detected in 77% sera of
dengue patients during the first three days of fever and the fourth to the
eighth day of illness (Chaturvedi et al., 1999). A study on NSD showed
that DwWS had a higher level of IL-6 than DwoWS, except during
defervescence when the groups had no difference (Rathakrishnan et al.,
2012a).
L. Tran et al.
Fig. 3. Subgroup meta-analysis of immune-mediators of dengue during acute phase.
The CD4+ T cells differentiate into Th17 cells in correspondence to
connected signals from TGF-β, IL-6, IL-21, IL-1β and IL-23 (Bettelli and
Kuchroo, 2005). IL-22 is known to be secreted from Th17 cells (Di
Cesare et al., 2009) and produced by Th1 cells as well (Volpe et al.,
2008). The function of IL-17 is not elucidated in dengue pathogenesis
although it involves adaptive immunity (Becquart et al., 2010). Th-17
cells exhibit an immunostimulatory response, by promoting the secre­
tion of Th1 and Th2 pro-inflammatory cytokines. While T-reg cells have
an immunosuppressive function, they were higher in mild dengue than
8
Acta Tropica 216 (2021) 105823
moderate cases during later illness. The positive correlation with
platelet counts could strengthen the protective function of T-reg cells in
dengue transmission (Tillu et al., 2016).
IL-9, which could be secreted by both Th2 and Th7, presented no
critical difference during the febrile phase but was higher during
defervescence in DHF (Kumar et al., 2012; Rathakrishnan et al., 2012a).
Some studies reported high level of IL-13 in severe disease during the
febrile phase (Bozza et al., 2008; Mustafa et al., 2001) but decreased
IL-13 level in mild dengue patients comparing to healthy
L. Tran et al.
Fig. 4. Meta-analysis of IL-17 serum level from the 4th day to 7th day of illness.
(Rathakrishnan et al., 2012a), and a significant increase in convales­
cence phase in DwWS (Rathakrishnan et al., 2014).
5. Limitations
Since many cytokines are secreted by multiple cell types, findings of
elevated levels in the sera cannot indicate which cell subset is respon­
sible for the cytokine detected. Though these cytokines are mainly
produced by Th2 or Th17, they are also produced by other cells,
therefore, the interpretation should be cautious.
There are also limitations in our study due to the diverse range of cell
types and influences in cytokine signaling of IL-6 and IL-8. From our
results, IL-6 cytokine and IL-8 chemokine were considered to be secreted
from Th2 cells since IL-6 can regulate Th2 immune responses (Heijink
et al., 2002). Consistently, IL-6 was demonstrated to initially promote
IL-4 secretion in CD4+ T cells polarizing these cells into Th2 cells
(Heijink et al., 2002; Tanaka et al., 2014). Also, IL-6 is highly important
in the final maturation of B-cells for antibody production and regulation
of Th2 phenotypes (Smith and Maizels, 2014; Turner et al., 2014). For
instance, Chaturvedi and co-workers stated that IL-6 was secreted from
Th2 cells, meanwhile, Th1 cells secrete IFN-γ, IL-2 and TNF-α (Cha­
turvedi et al., 2000). IL-6 enhances Th2 differentiation by up-regulating
IL-4 secretion (Diehl et al., 2002). IL-6 also limits IFN-γ production and
Th1 differentiation (Diehl et al., 2000). In combination with TGF-β, IL-6
also contributes to the differentiation of Th17 cells (Di Cesare et al.,
2009; Bettelli et al., 2006; Ivanov et al., 2006). The Th17 subset is
characterized by the production of IL-8, IL-17, IL-21 and IL-22 (San­
tarlasci et al., 2013). Besides which, IL-17 can induce IL-6 cytokines and
IL-8 chemokine and thus plays an essential role in inducing inflamma­
tory responses (Yao et al., 1995). In general, IL-6 and IL-8 were not only
primarily derived from monocytes/macrophages and endothelial cells,
but they were also produced by Th cells (Osugi et al., 1997). Taken
together, we hypothesized in our study that both IL-6 and IL-8 belong to
the Th2 cells axis.
Insufficient extracted data on IL-5, IL-9, IL-13 IL-23, IL-31 and TGF-β
limited our meta-analysis. IL-5 has been known for its activity on pro­
liferation and activation of Th2 cells as well as memory CD8+ Th dif­
ferentiation. IL-5 obtained higher trends in dengue during defervescence
and convalescence (Kumar et al., 2012; Rathakrishnan et al., 2014;
Rathakrishnan et al., 2012a). Also, significant associations were found
during defervescence between IL-5 and platelet levels in patients with
warning signs (Rathakrishnan et al., 2012a). Further studies demon­
strated that IL-5 was lower in dengue patients than in the healthy control
(Rathakrishnan et al., 2012a; Appanna et al., 2012).
Other limitations in our study were the effects of primary/secondary
dengue disease, data extraction during epidemics, the influence of other
comorbid diseases, and early treatment, which could not be assessed due
to limited data from the included studies. Furthermore, differences in
study designs, clinical diagnostics, population selection, and heteroge­
neous severity definitions may limit the interpretation of our results.
Also, different sampling time in dengue patient and cytokine levels were
reported to be highly dynamic, which could lead to different results if
not adjusted or noted by the authors of the included studies. It is
important to take into consideration the sampling time as SD usually
9
Acta Tropica 216 (2021) 105823
occurs around the time of defervescence.
6. Conclusions
Our study demonstrated the significant associations between dengue
infections and several IL levels. Among the positively associated ILs,
some associations were especially prominent in SD infection including
IL-4, IL-6, IL-8, IL-10 and IL-17. The association of severe dengue
infection with these elevated levels of ILs might help to predict the
development of SDF, allowing better diagnosis and management to
avoid the dreadful complications attributed to dengue infection.
Nevertheless, future research is needed to provide better insight into the
mechanisms of pathogenesis responsible for the association between Th
cells and their cytokines during dengue infection.
Funding statement
None.
CRediT authorship contribution statement
Linh Tran: Conceptualization, Methodology, Validation, Visualiza­
tion, Writing - original draft, Writing - review & editing. Ibrahim
Radwan: Formal analysis, Data curation, Methodology, Validation,
Writing - review & editing. Le Huu Nhat Minh: Methodology, Investi­
gation, Writing - review & editing. Soon Khai Low: Methodology,
Investigation. Mohammad Rashidul Hashan: Methodology, Investi­
gation. Mohammad Diaa Gomaa: Methodology, Investigation.
Mohamed Abdelmongy: Methodology, Investigation. Abdullah I.
Abdelaziz: Methodology, Investigation. Alaa Mohamed: Methodology,
Investigation. Gehad Mohamed Tawfik: Visualization. Shusaku Miz­
ukami: Visualization, Validation, Writing - review & editing. Kenji
Hirayama: Supervision, Funding acquisition, Project administration.
Nguyen Tien Huy: Conceptualization, Data curation, Visualization,
Validation, Writing - review & editing, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
We would like to thank Dr. Morgan Turnage (American University of
Caribbean, School of Medicine, Sint Maarten), a native speaker of En­
glish, for proofreading the manuscript.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.actatropica.2021.105823.
L. Tran et al. Acta Tropica 216 (2021) 105823

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