Journal of Microbiology, Immunology and Infection (2020) 53, 69e78

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journal homepage: www.e-jmii.com

Original Article

Diabetic patients suffering dengue are at risk

for development of dengue shock syndrome/
severe dengue: Emphasizing the impacts of
co-existing comorbidity(ies) and glycemic
control on dengue severity
Ing-Kit Lee a,b, Ching-Jung Hsieh c,x, Chien-Te Lee b,d,
Jien-Wei Liu a,b,*

a
Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial
Hospital, Kaohsiung 833, Taiwan
b
Chang Gung University Medical College, Tao-Yuan, Taiwan
c
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Chang Gung
Memorial Hospital, Kaohsiung 833, Taiwan
d
Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital,
Kaohsiung 833, Taiwan

Received 6 June 2016; received in revised form 18 December 2017; accepted 29 December 2017
Available online 31 January 2018

KEYWORDS Abstract Background/Purpose: The impact of type 2 diabetes mellitus (DM2) on clinical
Comorbidities; severity of dengue has not been fully understood. We aimed to assess risk factors for dengue
Dengue shock hemorrhagic fever (DHF)/dengue shock syndrome (DSS) and severe dengue (SD) (defined based
syndrome; on the World Health Organization 1997 and 2009 dengue classifications), and additionally iden-
Diabetes mellitus; tify, among DM2 patients, who are at risk for developing DHF/DSS and severe dengue.
Glycemic control; Methods: A retrospective analysis of dengue patients diagnosed between 2002 and 2010. Risk
Severe dengue factors for development of DHF/DSS/SD were identified using multivariate analysis. To eluci-
date the impacts of coexisting comorbidity(ies) (i.e., hypertension, chronic kidney disease,
old stroke, and/or ischemic heart disease) and glycemic control on clinical outcomes of dengue
in DM2 patients, the overall DM2 patients and stratified DM2 patients (HbA1c < 7% vs.
HbA1c S 7%), with or without comorbidity(ies), were separately compared to controls (pa-
tients without any morbidity).

* Corresponding author. Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital,
Kaohsiung 833, Taiwan.
E-mail address: jwliu@cgmh.org.tw (J.-W. Liu).
x
Present address: Division of Endocrinology and Metabolism, Department of Internal Medicine, Paochien Hospital, Ping Tung 90064,
Taiwan.

https://doi.org/10.1016/j.jmii.2017.12.005
1684-1182/Copyright ª 2018, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
70 I.-K. Lee et al.

Results: Of 767 (146 DM2 and 621 controls) included patients, 1.4% suffered DSS and 3.3% SD.
While DM2 was an independent risk factor for DSS (adjusted odds ratio [AOR] Z 7.473; 95% con-
fidence interval [CI] Z 2.221e25.146) and SD (AOR Z 6.207; 95% CI Z 2.464e15.636), only
DM2 patients with additional comorbidity(ies) and suboptimal glycemic control
(HbA1c S 7%) had significantly higher incidences of non-shock DHF (60.8% vs. 29%), DSS
(8.7% vs. 0.8%) and SD (34.8% vs. 1.1%).
Conclusions: These data could help narrow down the number of targets in the triage for risky
DM2 dengue patients to those with suboptimal glycemic control and co-existing comorbidi-
ty(ies).
Copyright ª 2018, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction found in some researches; this is not surprising as DM is a

Dengue is an important mosquito-borne disease in tropical
and subtropical regions.1,2 It is estimated that 50e200
million dengue infections occur annually around the globe,
and among them, approximately 500,000 were of clinically
severe cases.2 Dengue is also one of the most common
febrile illnesses in travelers returning to the United States
from tropical and subtropical countries.3e5 There are four
dengue virus serotypes (i.e., DENV-1, DENV-2, DENV-3, and
DENV-4), and each is able to cause a broad clinical spec-
trum of dengue illness ranging from a mild-form nonspecific
febrile illness, classic dengue fever (DF), to dengue hem-
orrhagic fever (DHF).6 DF is often clinically self-limited and
patients typically present with fever, arthralgia, myalgia,
and headache, while DHF is characterized by thrombocy-
topenia, hemorrhage, and plasma leak resulting from
increased vascular permeability.6 DHF was stratified into
grades I, II, III and IV; the later 2 were grouped as dengue
shock syndrome (DSS) by the 1997 World Health Organiza-
tion (WHO) dengue classification scheme.6 Once DSS de-
velops, the patient fatality rate may sore to as high as
20%.6e8 Remarkably, clinical severities of dengue are not
always fit those delineated (i.e., DF vs. DHF and non-shock
DHF vs. DSS) by the 1997 WHO dengue classification
scheme, and severity stratification (i.e., dengue vs. severe
dengue) based on the greatly varied clinical manifestations
of dengue was addressed by the 2009 WHO dengue classi-
fication version.1 The pathogenesis of DHF/DSS is complex
and not yet fully understood.2,9 Although immunoreactions
in sequential dengue infections caused by different dengue
serotypes were reported to play important roles in the
pathogenesis of the DHF/DSS,10e12 only a small number of
dengue cases clinically progressed to DHF/DSS in some
areas with high dengue sero-prevalence, where multiple
dengue serotypes were co-circulating.13,14 Multi-factorial
involvement in the dengue pathogenesis has been re-
ported from the immunologic interplay standpoint.15e20
Comorbidities were reported to aggravate dengue
illness, suggesting that host characteristics as risk factor(s)
in the development of DHF/DSS/severe dengue.21e27 Dia-
betes mellitus (type 2 diabetes mellitus hereof [DM2]), a
globally highly prevalent disease, is one of the noteworthy
proposed host risk factors for the development of DHF/DSS/
severe dengue,1,17,24e27 although conflicting results were
multifaceted disease that implicates a wide range of
metabolic derangement and immune dysfunction. The ob-
jectives of the study were (i) to identify risk factors and to
explore the role of DM2 for the development of DHF/DSS/
severe dengue, and (2) among DM2 patients, to identify
who are at risk for the development DHF/DSS/severe
dengue, emphasizing the effects of additional comorbid-
ities, optimal and/or suboptimal blood sugar control.
Materials and methods
Patients, dengue diagnosis and classification
This is a retrospective analysis conducted at Kaohsiung
Chang Gung Memorial Hospital, a 2700-bed primary care
and tertiary referral medical center in Taiwan. Included
patients were those aged S18 years suffering acute dengue
illness admitted to the hospital between 2002 and 2010.
The diagnosis of dengue was confirmed by a positive dengue
virus-specific reverse transcriptase-polymerase chain re-
action (RT-PCR) result, a Sfour-fold increase in dengue-
specific hemagglutination inhibition titer in paired sera
respectively sampled in the acute phase and the conva-
lescent phase, and/or a detectable dengue-specific
nonstructural glycoprotein NS1 in the acute-phase
serum.20 These diagnostic serology tests were performed
by Taiwan CDC.
The included patients were separately classified into (i)
those with DF and DHF/DSS, according to the 1997 WHO
dengue case classification,6 and (ii) those suffering non-
severe dengue and severe dengue, based on the 2009
WHO dengue definitions.1 DHF was defined as the presence
of thrombocytopenia (platelet count <100  109 cells/L),
hemorrhage, and plasma leak resulting from increased
vascular permeability (i.e., presence of hemoconcentra-
tion, pleural effusion, ascites and/or hypoalbuminemia).6
The stratified DHF grades I-IV were defined as follows.6
Grade I referred to a positive tourniquet test result being
the only dengue hemorrhagic manifestation, while grade II
referred to spontaneous bleeding; grade III referred to
circulatory failure manifested by a rapid and weak pulse, as
well as a narrowing pulse pressure (&20 mmHg), whereas
grade IV referred to a profound shock, with an
Development of dengue shock syndrome/severe dengue
undetectable pulse or blood pressure.6 DHF grade III and IV
were grouped as DSS. Severe dengue referred to shock and/
or respiratory distress resulting from plasma leak, severe
bleeding and/or severe organ impairment.1
Definitions
A comorbidity was defined as any of the underlying chronic
diseases/conditions as follows: DM2, hypertension (HTN),
chronic kidney disease (CKD), end-stage renal disease
(ESRD), stroke and ischemic heart disease (IHD). Dengue
patients without any of these comorbidities were grouped
as controls. Individuals with DM2 referred to those who
have been using either oral hypoglycemic agent(s) or insulin
which was switched from previous oral hypoglycemic agents
for the control of his or her blood sugar.28 Patients with
type 1 diabetes mellitus were excluded from this series.
Patients with an optimal glycemic control (glycosylated
hemoglobin [HbA1c] <7%) and those with suboptimal gly-
cemic control (HbA1c S 7%) were determined by a HbA1c
detected within the 6 months prior to or at the dengue
development.29 Individuals with HTN referred to those
received anti-HTN therapy for a previously diagnosed
HTN.30 CKD was defined as a glomerular filtration rate
<60 mL/min/1.73 m2 for 3 months, for which regular
hemodialysis was clinically not indicated.31 ESRD referred
to a CKD that required regular therapeutic hemodialysis for
the involved patients. Severe organ impairment included
altered consciousness, acute hepatitis, acute or acute on
chronic kidney injury, and acute pulmonary edema.1 Acute
kidney injury referred to an increased serum creatinine
level of >0.5 mg/dL within 48 h after hospitalization.31
Acute hepatitis was defined as an elevated serum alanine
aminotransferase (ALT) level S1000 U/L (reference value,
<40 U/L).1,32 Acute pulmonary edema referred to the
accumulation of fluid in the lungs, irrespective of the
cause, leading to respiratory distress.33 Severe gastroin-
testinal bleeding was defined as the passage of large
amount of tarry/bloody stool, coupled with hemodynamic
instability and/or a rapidly decreased hemoglobin level
&8.0 g/dL.7
Statistical analyses
Potential risk factors for DHF/DSS and severe dengue were
identified using univariate analysis to compare de-
mographics, clinical manifestations and dengue serotypes
between (i) DHF/DSS patients and DF patients, and (ii) se-
vere dengue patients and non-severe dengue patients. To
eliminate confounding, significant risk factors found in
univariate analyses were entered a logistic model to iden-
tify independent risk factors for DHF/DSS and severe
dengue.
DM2 has been widely reported to be an important risk
factor for the development of severe dengue1,17,24e27 and a
substantial number of the DM2 patients had other coexist-
ing morbidity (ies). To clarify the impacts of DM2 in general
and glycemic control in DM2 patients in particular, as well
as other coexisting comorbidity(ies) on clinical outcomes of
dengue in the diabetes, we further separately analyzed the
differences between (i) the overall DM2 patients
71
(regardless of the glycemic control) with or without addi-
tional comorbidity(ies) and controls, and (ii) the stratified
DM2 patients (based on optimal or suboptimal glycemic
control) with or without additional comorbidity(ies) and
controls.
In univariate analysis between different groups, com-
parison of categorical variables was carried out using the
chi-squared test or Fisher exact test when appropriate, and
comparison of continuous variables was performed using t-
test or ManneWhitney U test, where applicable. For both
univariate analysis and multivariate analysis, a 2-tailed
P < 0.05 was regarded as statistical significance. SPSS
software package, version 17.0 (SPSS Inc., Chicago, IL) was
used for all data analyses.
Results
Cohort description
Of a total of 767 dengue patients (146 with DM2 and 621
controls) included for analysis, 586 (76.4%) were diagnosed
with dengue illness in the 2002 DENV-2 epidemic.34 Infor-
mation regarding primary or secondary dengue infection
was not available in this series. Among 544 patients (71%)
with RT-PCR data available, DENV-2 was detected in 527
(96.8%), DENV-1 and DENV-3 each in 8 (each 1.4%), and
DENV-4 in 1 (0.2%).
Of the 146 dengue patients with DM2 (mean age,
60.3  8.9 years; 34.2% aged S65 years), a majority of 107
(72.8%) were diagnosed with dengue in 2002, while 1
(0.6%) each in 2003 and 2004, 3 (2%) in 2008, 9 (6.1%) in
2009, 2 (2.9%) in 2012, and 5 (3.4%) in 2010. Among the 146
dengue patients with DM2, fever (91.7%), petechiae
(56.2%) and bone pain (45.2%) were the 3 leading clinical
manifestations; of these 146 DM2 patients, 86 (mean age,
61.8  8.2 years) had at least one additional comorbidity
other than DM2, which, in decreasing order, were HTN
(88.3%), previous stroke (19.8%), IHD (6.9%), ESRD (3.5%),
and CKD (2.3%). Only 2 (1.4%) of 146 DM2 patients clearly
reported that they received non-steroid anti-inflammatory
drug (NSAID) for fever and relief of discomforts upon their
hospital presentations. A mean HbA1c of 8.6% was found
from 57 patients with data available, and 47 (82.4%) of
these patients had a suboptimal blood glucose control.
Among the overall 146 DM2 patients, acute pulmonary
edema was found in 6 (4.1%), severe gastrointestinal
bleeding in 5 (3.4%) and acute kidney injury in 2 (1.4%).
Eighty-one percent of patients were diagnosed with DF,
40.4% with non-shock DHF, and 4.1% with DSS based on the
1997 WHO dengue classification scheme, while 12.3% were
found to suffered severe dengue according to the 2009
WHO dengue classification scheme. Two (1.4%) of the
overall 146 DM2 patients died.
Among the 621 controls (mean age 45.7  14.9 years;
9.5% aged S65 years), fever (95.8%), bone pain (56.4%) and
headache (44.8%) were the 3 leading clinical manifesta-
tions; severe gastrointestinal bleeding was found in 3
(0.5%), and acute kidney injury and acute pulmonary
edema each in 1 (0.2%). NSAID was prescribed for relief of
fever and constitutional symptoms for 12 (1.9%) patients
upon their hospital presentations. Based on the 1997 WHO
72 I.-K. Lee et al.

dengue classification scheme, 70.2% of patients were
diagnosed with DF, 20% with non-shock DHF, and 5% with
DSS; 7 (1.1%) patients were found to suffer severe dengue
according to the 2009 WHO dengue definition. Four (0.6%)
of the overall controls died.
Independent risk factors for non-shock DHF, DSS
and severe dengue
Table 1 summarizes demographic, clinical and dengue
serotype information of patients with non-shock DHF, DSS,
dengue fever, severe dengue and non-severe dengue, and
univariate analyses for (i) non-shock DHF vs. DF, (ii) DSS vs.
DF, and (iii) severe dengue vs. non-severe dengue. After
eliminating confounding, identified risk factor(s) included
(i) older age and abdominal pain for the development of
non-shock DHF, (ii) DM2 for DSS, and (iii) older age and DM2
for severe dengue (see Table 2 for details).
Comparisons between the overall DM2 patients
with (n Z 86) or without (n Z 61) additional
comorbidity(ies) and controls (n Z 621) (Table 3)
Significant findings in DM2 patients with additional comor-
bidity(ies) included: older age, higher incidences of non-
shock DHF, DSS, severe dengue, acute hepatitis, acute
kidney injury, severe gastrointestinal bleeding, acute pul-
monary edema and petechiae, lower incidence of bone
pain, as well as lower platelet count and hematocrit levels.
Significant findings in DM2 patients without any addi-
tional comorbidity included: older age, higher incidence of
petechiae and lower mean platelet nadir.

Table 1 Characteristics of patients with non-shock dengue hemorrhagic fever, dengue shock syndrome, dengue fever and
severe dengue.a
Non-shock DHFb DSSb DFb Severe denguec Non-severe denguec
(n Z 249) (n Z 11) (n Z 506) (n Z 25) (n Z 742)
(A) (B) (C) (D) (E)
Median age (range), yrs 54 (18e84)*** 63 (30e78)** 49 (18e82) 63 (30e78)*** 51 (18e84)
Female 131 (52.6) 5 (45.5) 242 (47.8) 13 (52) 365 (49.2)
Comorbidity conditiond
DM2 70 (28.1) 6 (54.5)** 70 (13.8) 17 (68)*** 129 (17.4)
Hypertension 33 (13.2) 5 (45.5) 38 (7.5) 12 (48) 64 (8.6)
Chronic kidney disease 2 (0.8) 0 0 1 (4) 1 (0.1)
End stage renal disease 2 (0.8) 0 1 (0.2) 1 (4) 2 (0.3)
Previous stroke 4 (1.6) 3 (27.2) 10 (2) 5 (20) 12 (1.6)
Ischemic heart disease 3 (1.2) 1 (9) 2 (0.4) 2 (8) 4 (0.5)
Dengue serotype, n/N (%)
Serotype 1 2/178 (1.1) 0 6/366 (1.6) 0 8/525 (1.5)
Serotype 2 174/178 (97.7) 9/10 (90) 353/366 (96.4) 18/19 (94.7) 509/525 (97)
Serotype 3 2/178 (1.1) 1/10 (10) 6/366 (1.6) 1/19 (5.3) 7/525 (1.3)
Serotype 4 0 0 1/366 (0.3) 0 1/525 (0.2)
Symptoms/signs at hospital presentatione
Fever 238 (95.6) 11 (100) 478 (94.5) 22 (88) 705 (95)
Myalgia 71 (28.5) 5 (45.5) 142 (28.1) 9 (36) 209 (28.2)
Bone pain 146 (58.6) 8 (72.7) 262 (51.8) 13 (52) 402 (54.7)
Rash 93 (37.3) 3 (27.3) 204 (40.3) 9 (36) 294 (39.6)
Abdomen pain 117 (47)*** 5 (45.5) 110 (21.7) 9 (36) 225 (30.3)
Nausea/vomiting 100 (40.2) 3 (27.3) 141 (27.9) 13 (52) 231 (31.1)
Headache 108 (43.4) 4 (36.4) 222 (43.9) 9 (36) 324 (43.7)
Orbital pain 26 (10.4) 1 (9.1) 63 (12.5) 2 (8) 88 (11.9)
Diarrhea 69 (27.7)** 2 (18.2) 61 (12.1) 6 (24) 127 (17.1)
Petechiae 123 (49.3) 8 (72.7)* 180 (35.6) 16 (64)* 295 (39.8)
GI bleeding 51 (20.4) 6 (54.5)** 71 (14) 11 (44) 118 (15.9)
Gum bleeding 62 (24.9) 3 (27.3) 64 (12.6) 5 (20) 124 (16.7)
Hemoptysis 18 (7.2) 0 15 (3) 1 (4) 32 (4.3)
a
Comparisons between (1) A and C, (2) B and C, or (3) D and E; * indicating a p < 0.05, **p < 0.01, and ***p < 0.001. Statistically
significant data are in bold font.
b
Based on 1997 WHO dengue classification scheme.6
c
Based on 2009 WHO dengue classification scheme.1
d
An individual might have more than one underlying condition.
e
An individual might have more than one symptom/sign.
Data are presented as number (%) unless otherwise indicated.
DHF Z dengue hemorrhagic fever; DSS Z dengue shock syndrome; DM2 Z type 2 diabetes mellitus; GI Z gastrointestinal; n/
N Z number of specific dengue serotype/number of all dengue serotypes.
Development of dengue shock syndrome/severe dengue
Table 2 Independent risk factor(s) derived from logistic
regression analyses for the development of non-shock
dengue hemorrhagic fever, dengue shock syndrome and
severe dengue.
Independent Odds 95% confidence p
risk factor ratio interval
Non-shock Older age 1.012 1.001e1.023 0.034
DHF vs. DFa Abdominal 2.858 2.033e4.019 <0.001
pain
DSS vs. DFa DM2 7.473 2.221e25.146 0.001
SD vs. non-SDb Older age 1.044 1.004e1.085 0.031
DM2 6.207 2.464e15.636 <0.001
a alter.41 One of the prominent histopathologic features of
Based on 1997 WHO dengue classification scheme.6
b patients with advanced DM2 is micro- and macro-vascular
Based on 2009 WHO dengue classification scheme.1
DF Z dengue fever; DHF Z dengue hemorrhagic fever;
DSS Z dengue shock syndrome; DM2 Z type 2 diabetes mellitus;
SD Z severe dengue.
Comparisons between DM2 patients stratified by
glycemic control (HbA1c < 7% [n Z 10] and
HbA1c S 7% [n Z 47]) and controls (Table 4)
Older age and higher frequency of nausea/vomiting were
significantly found among 10 overall optimal-glycemic-
control patients; of them, 7 had additional
comorbidity(ies).
Older age, higher incidence of non-shock DHF, DSS, se-
vere dengue, severe gastrointestinal bleeding and acute
pulmonary edema, as well as lower incidence of bone pain
were found in the overall 47 suboptimal-glycemic-control
patients; of them, 23 did and 24 did not have additional
comorbidity(ies). Significant findings in patients without
any additional comorbidity included younger age and lower
incidence of nausea/vomiting. Of note, older age and
higher incidences of non-shock DHF, DSS, severe dengue
and acute pulmonary edema were significantly found in
suboptimal-glycemic-control DM2 patients, irrespective of
additional comorbidity(ies).
Discussion
Our data showed that for the overall dengue patients, the
underlying DM2 was an independent risk factor for the
development of DSS and severe dengue alike (Table 2);
further analyses of the stratified patients disclosed that
only DM2 patients with additional comorbidity(ies) and DM2
patients with suboptimal glycemic control irrespective of
comorbidity(ies) were significantly at higher risk for the
development of DHF/DSS/severe dengue.
When it comes to pathogenesis, the aberrant immune
over-activation with cytokine overproduction in dengue
patients leads to the development of a great array of
manifestations.20,35,36 Some of the activated cytokines are
pro-inflammatory, while others are anti-inflammatory, and
together they cause leukocytes to activate synergistically
or antagonistically.20,35,36 Clinical, histopathological and
laboratory manifestations in dengue-affected patients are
the net effect of the interactions between one another
among these activated cytokines.20,37 Remarkably,
73
increased vascular permeability leading to plasma leak is
histopathologically unique in DHF/DSS/severe dengue.7,38
As dengue clinically features dynamic changes over
time, identification of predictors weighing the chances that
the dengue in its early clinical stage evolves into severe
dengue is therefore pragmatically important. DM2, a
multifaceted disease implicating chronic metabolic
derangement and immunologic dysfunction and thus lead-
ing to a broad range of clinical complications,39,40 is one of
the most frequently proposed predictors for potential
clinical deterioration of dengue.1,17,24e27 When compared
to their non-DM counterparts, DM2 patients have similar
leukocyte count, but their leukocyte may functionally
damage, making circulation compromised in major or-
gans.39,40 How the underlying DM2 leads dengue-affected
patients to be at higher risk for the development of DHF/
DSS/severe dengue is not fully understood; however, it is
reasonable to speculate that the mechanism involves
further damage of the impaired vasculature functions in
DM2 patients suffering dengue.26
Of note, our data suggested that dengue patients with
DM2 and optimal sugar control, regardless of additional
comorbidity(ies), were not at higher risk for the develop-
ment of DHF/DSS/severe dengue. These findings highlight
the importance of optimizing blood sugar level by keeping
a HbA1c < 7% as was recommended by the American Dia-
betes Association for diabetic patients in general.29 Be-
sides DM2, the comorbidities (i.e., HTN, CKD, ESRD, stroke
and IHD) in our patients are also associated with damaged
vasculature in major organs. HTN was the predominant
comorbidity (>90%) other than DM2 in our suboptimal
glycemic control patients. Dengue patients with a coex-
isting DM and HTN were previously reported to be at higher
risk for developing DHF in general; these investigators,
however, did not address the effects of controlled glyce-
mic levels on the clinical severity in dengue.25 Taken
together, it is likely that the advanced vascular damage
explains why DM2 patients suffered dengue having both
suboptimal glycemic control and the above-mentioned
comorbidities were significantly at higher risk for devel-
opment of DHF/DSS/severe dengue.
Though not statistically significant, our data suggest that
there was a trend of increase in fatality in DM2 dengue
patients with suboptimal glycemic control and additional
comorbidity(ies) when compared with controls (8.7% vs.
0.6%) (Table 4).
Our findings that as compared to controls, DM2 dengue
patients with additional comorbidity(ies) were subject to
significantly higher incidences of severe gastrointestinal
bleeding (5.8% vs. 0.2%; P < 0.001) and profound throm-
bocytopenia (nadir of platelet count, 35.8  45.5 vs.
58.5  53.7  109 cells/L; P < 0.001), and suggest that
they should be target candidates for strict monitoring the
emergence of warning signs that require urgent
treatment.
Acute pulmonary edema resulting from plasma leak
with/without fluid overload is not uncommonly found in
dengue patients.42 In comparison to controls, our DM2
dengue patients with additional comorbidity(ies) experi-
encing a significantly higher incidence of pulmonary edema
74 I.-K. Lee et al.

Table 3 Comparisons of demographic, clinical, and laboratory characteristics and outcomes between dengue patients with
type 2 diabetes mellitus (regardless of glycemic control) with or without comorbidities and controls.a
Variable Overall DM2 DM2 with additional DM2 without additional Controls
(N Z 146) comorbidities comorbidities (N Z 621)
(n Z 86) (n Z 60) (C)
(A) (B)
Demographic characteristics
Median age (range), yrs 61(28e82) 62.5(28e82)*** 57(36e78)*** 46(18e84)
Female 87 (59.6) 49 (57) 38 (63.3) 329 (53)
Comorbid conditionb
Hypertension 76 (52) 76 (88.3) 0 0
Chronic kidney disease 2 (1.4) 2 (2.3) 0 0
End-stage renal disease 3 (2.1) 3 (3.5) 0 0
Previous stroke 17 (1.2) 17 (19.8) 0 0
Ischemic heart disease 6 (4.1) 6 (6.9) 0 0
Dengue classifications
DFc 81 (55.5) 43 (50) 38 (63.3) 436 (70.2)
Non-shock DHFc 59 (40.4) 37 (43)** 22 (36.7) 180 (29)
DSSc 6 (4.1) 6 (7)*** 0 5 (0.8)
Severe dengued 18 (12.3) 17 (19.7)*** 1 (1.7) 7 (1.1)
Clinical features and outcome
Pleural effusion, no./No. (%) 38/110 (34.5) 23/69 (33.3) 15/41 (37) 85/365 (23.3)
Ascites, no./No. (%) 19/81 (23.5) 11/49 (22.4) 8/32 (25) 81/270 (30)
Acute hepatitis (ALT > 1000 U/L), 3/116 (2.6) 3/68 (4.4)* 0/48 (0) 1/400 (0.3)
no./No. (%)
Acute kidney injury 2 (1.4) 2 (2.3)* 0 1 (0.2)
Severe gastrointestinal bleeding 5 (3.4) 5 (5.8)** 0 3 (0.5)
Acute pulmonary edema 6 (4.1) 5 (5.8)*** 1 (1.7) 1 (0.2)
Fatality 2 (1.4) 2 (2.3) 0 4 (0.6)
Symptom/sign at hospital presentatione
Fever 134 (91.7) 83 (96.5) 51 (85) 595 (95.8)
Abdominal pain 49 (33.6) 27 (31.4) 22 (36.7) 184 (29.6)
Orbital pain 16 (10.9) 11 (12.8) 5 (8.3) 74 (11.9)
Bone pain 66 (45.2) 35 (40.7)** 31 (51.7) 350 (56.4)
Myalgia 40 (27.4) 24 (27.9) 16 (26.7) 179 (28.8)
Headache 56 (38.4) 32 (37.2) 24 (40) 278 (44.8)
Rashes 53 (36.3) 30 (34.9) 23 (38.3) 248 (39.9)
Vomiting/nausea 46 (31.5) 32 (37.2) 14 (23.3) 198 (31.9)
Diarrhea 24 (16.4) 14 (16.3) 10 (16.7) 108 (17.4)
Petechiae 82 (56.2) 48 (55.8)** 34 (56.7)** 229 (36.9)
Gastrointestinal bleeding 35 (23.9) 22 (25.6) 13 (21.7) 93 (14.9)
Gum bleeding 36 (24.6) 20 (23.3) 16 (26.7) 93 (15)
Hemoptysis 10 (6.8) 7 (8.1) 3 (5) 23 (3.7)
Laboratory characteristics
Mean glycosylated hemoglobin (%) 8.6  1.9 8.5  2.1 8.8  1.7 (n Z 27) e
(n Z 57) (n Z 30)
Leukocytosis 11/144 (7.6) 10/85 (11.7) 1/59 (1.7) 25/599 (4.2)
(WBC > 12.0  109 cells/L), n/N (%)
Median nadir of platelet count 20.5 (1.0e303) 21 (1.0e303)*** 17.5 (2.0e170)** 38.0 (1.0e306)
(range) (  109 cells/L) (no.) (n Z 146) (n Z 86) (n Z 60) (n Z 610)
Median peak hematocrit (range) (%) 39.4 (26.8e52.6) 38.2 (26.8e52.6)*** 40.2 (29.2e49.4) 40.6 (25e57.2)
(no.) (n Z 146) (n Z 86) (n Z 60) (n Z 608)
a
Comparisons between A and C and between B and C; * indicating a p < 0.05, **p < 0.01, and ***p < 0.001. Statistically significant
figures are in bold font.
b
An individual might have more than one underlying condition.
c
Based on 1997 WHO dengue classification scheme.6
d
Based on 2009 WHO dengue classification scheme.1
e
An individual might have more than one symptom/sign.
Data are presented as number (%) unless otherwise indicated.
DF Z dengue fever; DHF Z dengue hemorrhagic fever; DSS Z dengue shock syndrome; DM2 Z type 2 diabetes mellitus; ALT Z alanine
aminotransferase; WBC Z white blood cell; WHO Z World Health Organization; n/N Z number of cases/number of overall cases with
data available for evaluation.
 Development of dengue shock syndrome/severe dengue
Table 4 Comparisons of demographic, clinical and laboratory characteristics between dengue patients with type 2 diabetes mellitus patients (stratified by HbA1C < 7% and
HbA1C  7%) and controls.a
Variable DM2 with HbA1C < 7% DM2 with HbA1C  7% Controls
Cases regardless of Cases with Cases regardless of Cases with Cases with (n Z 621)
additional additional additional additional DM only (F)
comorbidities comorbidities comorbidities comorbidities (n Z 24)
(n Z 10) (n Z 7) (n Z 47) (n Z 23) (E)
(A) (B) (C) (D)
Demographic characteristics
Median age (range), yrs 58 (42e78)* 62 (53e78)** 61 (39e78)* 65 (41e77)*** 57.5 (39e78)*** 46 (18e84)
Female 6 (60) 5 (71.4) 26 (55.3) 14 (60.9) 12 (50) 329 (53)
Comorbid conditionb
Hypertension 7 (70) 7 (100) 21 (44.7) 21 (91.3) 0 0
Chronic kidney disease 0 0 1 (2.1) 1 (4.3) 0 0
Previous stroke 1 (10) 1 (14.3) 5 (10.6) 5 (21.7) 0 0
Ischemic heart disease 1 (10) 1 (14.3) 2 (4.3) 2 (8.7) 0 0
Dengue classifications
DFc 7 (70) 5 (71.4) 23 (49)** 7 (30.4)*** 16 (66.7) 436 (70.2)
Non-shock DHFc 3 (30) 2 (25.6) 22 (47)** 14 (60.8)** 8 (33.3) 180 (29)
DSSc 0 0 2 (4.3)* 2 (8.7)*** 0 5 (0.8)
Severe dengued 0 0 8 (17)*** 8 (34.8)*** 0 7 (1.1)
Clinical features and outcome
Pleural effusion, no./No. (%) 3/9 (33.3) 2/7 (28.6) 12/35 (34.3) 8/20 (40) 4/15 (26.7) 85/365 (23.3)
Ascites, no./No. (%) 1/5 (20) 0/3 (0) 6/28 (21.4) 4/15 (26.7) 2/13 (15.4) 81/270 (30)
Acute hepatitis (ALT > 1000 U/L), 0/8 (0) 0/6 (0) 1/40 (2.5) 1/21 (4.8) 0/19 (0) 1/400 (0.3)
no./No. (%)
Acute kidney injury 0 0 1 (4.2) 1 (4.3) 0 1 (0.2)
Severe gastrointestinal bleeding 0 0 2 (4.3)* 2 (8.7) 0 3 (0.5)
Acute pulmonary edema 0 0 3 (6.3)** 3 (13)*** 0 1 (0.2)
Fatality 0 0 2 (4.3) 2 (8.7) 0 4 (0.6)
Symptom/sign at presentatione
Fever 10 (100) 7 (100) 41 (87.2) 22 (95.7) 19 (79.2) 595 (95.8)
Abdominal pain 3 (30) 1 (14.3) 15 (31.9) 6 (26.1) 9 (37.5) 184 (29.6)
Orbital pain 1 (10) 1 (14.3) 5 (10.6) 3 (13) 2 (8.3) 74 (11.9)
Bone pain 7 (70) 4 (57.1) 18 (38.3)* 9 (39.1) 9 (37.5) 350 (56.4)
Myalgia 2 (20) 2 (28.6) 16 (34) 10 (43.5) 6 (25) 179 (28.8)
Headache 4 (40) 3 (42.9) 17 (36.2) 10 (43.5) 7 (29.2) 278 (44.8)
Rashes 6 (60) 3 (42.9) 18 (38.3) 9 (39.1) 9 (37.5) 248 (39.9)
Vomiting/nausea 7 (70)* 6 (85.7)** 10 (21.3) 8 (34.8) 2 (8.3)* 198 (31.9)
Diarrhea 1 (10) 1 (14.3) 4 (8.5) 3 (13) 1 (4.2) 108 (17.4)
Petechial 6 (60) 3 (42.9) 21 (44.7) 9 (39.1) 12 (50) 229 (36.9)
Gastrointestinal bleeding 1 (10) 0 13 (27.6) 6 (26) 7 (29.2) 93 (14.9)
Gum bleeding 3 (30) 2 (28.6) 12 (25.5) 6 (26) 6 (25) 93 (15)

75
Hemoptysis 1 (10) 1 (14.3) 1 (2.1) 0 1 (4.2) 23 (3.7)
(continued on next page)
 76
Table 4 (continued )
Variable DM2 with HbA1C < 7% DM2 with HbA1C  7% Controls
Cases regardless of Cases with Cases regardless of Cases with Cases with (n Z 621)
additional additional additional additional DM only (F)
comorbidities comorbidities comorbidities comorbidities (n Z 24)
(n Z 10) (n Z 7) (n Z 47) (n Z 23) (E)
(A) (B) (C) (D)
Laboratory characteristics
Leukocytosis 0/10 (0) 0/7 (0) 4/47 (8.5) 3/23 (13) 1/24 (4.2) 25/599 (4.2)
(WBC > 12.0  109 cells/L), no./
No. (%)
Median nadir of platelet count 37 (4e137) 37 (4e137) 27 (1e303) 26 (1e303) 36.5 (5e153) 38 (1e306)
(range) (  109 cells/L) (no.) (n Z 10) (n Z 7) (n Z 47) (n Z 23) (n Z 24) (n Z 610)
Median peak hematocrit (range) (%) 38.9 (33.8e48.4) 37.6 (33.8e48.4) 39.9 (26.8e49.9) 39.6 (26.8e49.9) 40.3 (32e47.5) 40.6 (25e57)
(no.) (n Z 10) (n Z 7) (n Z 47) (n Z 23) (n Z 24) (n Z 608)
a
Comparisons of (1) A vs. F, (2) B vs. F, (3) C and F, (4) D vs. F, or (5) E vs. F, with * indicating a P < 0.05, **P < 0.01, and ***P < 0.001.
Statistically significant data are in bold font.
b
An individual might have more than one underlying condition.
c
Based on 1997 WHO dengue classification scheme.6
d
Based on 2009 WHO dengue classification scheme.1
e
An individual might have more than one symptom/sign.
Data are given as number (%) unless otherwise indicated.
HbA1C Z glycosylated haemoglobin; DM2 Z type 2 diabetes mellitus; DF Z dengue fever; DHF Z dengue hemorrhagic fever; DSS Z dengue shock syndrome; ALT Z Alanine amino-
transferase; WBC Z white blood cell; WHO Z World Health Organization; no./No. Z number of cases/number of overall cases with data available for evaluation.

I.-K. Lee et al.

Development of dengue shock syndrome/severe dengue
(5.8% vs. 0.2%; P < 0.001) (Table 3) suggest that, to avoid
preventable cardiopulmonary failure, cautious hydration
should be given at an appropriate speed and under close
monitoring, especially when hydration is given for in-
dications other than DSS.
Previous studies reported that DENV-2 of southeast
Asian genotype correlated increased incidence of DHF.43,44
The genomic information of the DENV-2, the predominant
dengue serotype in our series, were not available. How-
ever, the findings that the absence of significant differ-
ence in incidences of DHF/DSS and severe dengue in this
series suggest that factor(s) other that dengue serotypes
play a role in determining clinical severity in dengue
patients.
There are a few limitations in this study. First, this study
was conducted at a single medical centre, which might be
biased by patient referral patterns. Second, data regarding
primary and secondary dengue infection were not avail-
able. Third, the small number of included patients with
comorbidity(ies) other than DM2 made it impossible to
assess the risk of each of these non-DM comorbidity(ies) for
the development of DHF/DSS/severe dengue. Nevertheless,
this is the first study addressed clinical evolvements into
DHF/DSS/severe dengue in diabetic patients, shedding light
on the pathophysiologic roles of coexisting comorbidities
other than DM2 and optimal glycemic control.
These data highlight the importance of measuring the
HbA1c of all diabetics suffering dengue. DM2 is highly
prevalent, and our findings help minimize the number of
candidates in the triage for risky dengue victims by nar-
rowing down targets to those with either (i) DM2 and other
co-existing comorbidity(ies) or (ii) DM2 with suboptimal
glycemic control. This is extremely important in large-
scale dengue outbreaks that usually occur in rural areas
where medical resources are limited. Even in developed
countries struck by a large dengue outbreak, the regular
facility capacities are not necessarily able to offer an
abrupt increase in hospitalization for monitor purposes/
aggressive treatments to the overwhelming number of
dengue patients.
Conflict of interest
The authors declare that they have no competing interests.
Funding
This work was supported by a grant (document no. 104-
2314-B-182A-061) from the Ministry of Science and Tech-
nology, Taiwan, ROC. The funder had no role in study
design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Ethical approval
As the data were anonymized and de-identified prior to
analysis, the study was conducted with a waiver of patient
consent approved by the Institutional Review Board of
Chang Gung Memorial Hospital (Document no. 98-2957B).
77
Acknowledgments
We thank the staff members of Emergency Services of
Kaohsiung Chang Gung Memorial Hospital for the manage-
ment of patients.
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