ORIGINAL PAPER
Nagoya J. Med. Sci. 83. 749–763, 2021
doi:10.18999/nagjms.83.4.749

Factors associated with severe dengue in Savannakhet
Province, Lao People’s Democratic Republic
Phetvilay Senavong1,2, Eiko Yamamoto1, Phouvilay Keomoungkhoune2,
Nouda Prasith3, Virasack Somoulay4, Tetsuyoshi Kariya1, Yu Mon Saw1,
Tiengkham Pongvongsa3 and Nobuyuki Hamajima1
Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
2
Healthcare Administration Unit, Savannakhet Provincial Hospital, Savannakhet,
Lao People’s Democratic Republic
3
Public Health Office, Savannakhet, Lao People’s Democratic Republic
4
National Central Laboratory and Epidemiology, Ministry of Health, Lao People’s Democratic Republic

1

ABSTRACTThis study aimed to describe the socio-demographic and clinical characteristics of dengue inpatients at
a provincial hospital, and to identify factors associated with severe dengue. This is a retrospective study
involving 402 dengue patients admitted to the Savannakhet Provincial Hospital, Lao People’s Democratic
Republic (Lao PDR), between January 2018 and April 2019. Socio-demographic factors, clinical signs
and laboratory data on admission, final diagnosis, use of health care services before admission, admission
date, and hospitalization period were collected from patient records. The number of dengue inpatientswas higher in the rainy season than in the dry season. Of the 402 patients, 205 patients (51.0%) were
finally diagnosed with severe dengue. Children aged <15 years had more symptoms, higher proportion ofsevere dengue (69.8% vs. 35.9%), and longer hospitalization (3.5 days vs. 3.0 days) than adults aged ≥15
years. In multivariable analyses, factors associated with severe dengue were nausea on admission (adjusted
odds ratio=3.57, 95% CI=1.05–12.09, P=0.04) in children and persistent vomiting on admission (adjusted
odds ratio=3.82, 95% CI=1.23–11.92, P=0.02) in adults. In adults, the creatinine level on admission
was significantly higher in patients with a final diagnosis of severe dengue compared to the others. The
proportion of severe dengue in our study was higher than that in other countries. Nausea and persistentvomiting on admission were suggested to be predictive factors for severe dengue. To reduce the incidenceof severe dengue in Lao PDR, improvements in access to health care, referral system, and training ofhealth care workers are needed.
Keywords: children, Lao PDR, nausea, persistent vomiting, severe dengue
Abbreviations:
AKI: acute kidney injury
ALT: alanine aminotransferase
ARDS: acute respiratory distress syndrome
AST: aspartate aminotransferase
CFR: case fatality rate
CRT: capillary refill time

Received: August 6, 2020; accepted: March 10, 2021
Corresponding author: Eiko Yamamoto, MD, PhD
Department of Healthcare Administration, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho,Showa-ku, Nagoya 466-8550, Japan
Tel: +81-52-744-1985, Fax: +81-52-744-2302, E-mail: yamaeiko@med.nagoya-u.ac.jp
749

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Phetvilay Senavong et al

Lao PDR: Lao People’s Democratic Republic
NCLE: National Central Laboratory and Epidemiology
NS1: nonstructural protein 1
TT: tourniquet test
WHO: World Health Organization
This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

INTRODUCTION
Dengue is a mosquito-borne infectious disease. It is one of the global public health issues
given its high incidence in more than 100 countries. The incidence of dengue is very high in thetropical and sub-tropical countries, especially those in the Western Pacific region and South East
Asia.1-3 Globally, the annual number of new dengue cases is 50–100 million, and approximately
500,000 people with severe dengue are hospitalized every year with a case fatality rate (CFR)of 2.5%.1,2 Globally, more than two billion people are at risk of dengue infection, mostly in
Asian countries including Lao People Democratic Republic (Lao PDR).1,2,4 The annual numberof dengue patients hospitalized from 2001 to 2010 was, on average, 816,000 patients, with 5,900
deaths in South East Asia and 18,000 cases and 41 deaths estimated in Lao PDR.5 In Thailand,
the incidence of dengue infections increased over the last 50 years, from 189 cases per 100,000
population in 1958 to 218 cases per 100,000 population in 2011.6 In June 2019, the World HealthOrganization (WHO) reported that the number of dengue cases was much higher than that in
the same period in the previous year in Asian countries, such as Lao PDR, Cambodia, Vietnam,
the Philippines, Malaysia, and Bangladesh.7
There are four serotypes of the dengue virus, namely DENV-1, DENV-2, DENV-3, and
DENV-4. All serotypes cause similar symptoms, although approximately 35% of the genome ineach serotype is different.8 High fever is the most common symptom, followed by pain, gastrointestinal symptoms, skin reactions, bleeding, fluid accumulation, and neurological symptoms.9-11
There are three phases of dengue infection: febrile phase, 2–7 days; critical phase, 24–48
hours; and recovery phase, 48–72 hours.9,10,12 A person infected with the dengue virus develops
cross-protection against other serotypes but only for 1–3 years.13 Secondary dengue infection
with another serotype and multiple infections are considered a severe condition.2,11 The WHO
classification of dengue severity defines three categories: dengue without warning signs, dengue
with warning signs, and severe dengue.9 The warning signs of dengue are persistent vomiting,mucosal bleeding, fluid accumulation, abdominal pain or tenderness, lethargy/restlessness, liverenlargement >2 cm, and hematocrit elevation >20% concurrent with a rapid decrease in platelet
count to ≤100,000/µL. Severe dengue is characterized by severe plasma leakage, severe bleeding,and severe organ impairment.2,9,14
In Lao PDR, dengue is a major public health issue.15 There have been dengue epidemics inthe past: 17,500 cases in 1998 and 2003, 22,890 cases including 46 deaths in 2010, and 44,171
cases including 95 deaths in 2013.16 The Ministry of Health collaborated with WHO to develop
the treatment guidelines for dengue patients, provide clinical training at hospitals, and establish
laboratory and surveillance systems in five provinces (Champasack, Savannakhet, Laungphrabang,
Laungnamtha, and Oudomxay).4 Savannakhet Province has the second highest number of dengue
cases in the country. The CFR increased from 0.18% (nine deaths out of 4,959 cases) in 2013
to 0.98% in the 2018 outbreak according to the report of the National Central Laboratory andEpidemiology (NCLE).16 To reduce the mortality due to dengue, it is important to recognize
patients of dengue with warning signs and manage patients of severe dengue.9 This study aimed

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Severe dengue inpatients in Lao PDR

to describe the socio-demographic and clinical characteristics of dengue inpatients at a provincial
hospital, and to identify factors associated with severe dengue.

MATERIALS AND METHODS
Study design and participantsThis was a retrospective study involving dengue patients who were admitted to the intensive
care unit, internal medicine ward, and pediatric ward of Savannakhet Provincial Hospital between
January 2018 and April 2019. Patients were diagnosed with dengue by detection of nonstructuralprotein 1 (NS1) antigen on reverse transcription polymerase chain reaction or immunoglobulin
M (IgM) and IgG antibodies on enzyme linked immunosorbent assay. The examinations were
performed at the Savannakhet Provincial Hospital and/or NCLE in Vientiane Capital. Patients
whose medical records were unavailable were excluded. In total, 402 dengue patients were
included in this study.
Definition of clinical symptoms and signs of dengue
The tourniquet test (TT) is used to determine capillary breakability. A patient’s arm was
fastened by a blood pressure cuff with the cuff inflated to midway between systolic and diastolicblood pressure for five minutes. When the number of petechiae in a 2.5 cm2 area in the distal
part of the cuff was more than 15, the test result was considered to be positive.9,10,17 WHO
recommends using the TT as a clinical diagnostic tool for dengue and repeating the test to
increase the sensitivity.
Persistent vomiting was defined as a patient vomiting more than two times within 24 hours.
Mucosal bleeding included bleeding in the gums, conjunctiva, skin ecchymosis or purpura. Fluid
accumulation included namely pleural effusion, pulmonary edema, and ascites, was diagnosed
using chest radiography and abdominal ultrasonography. Liver enlargement was measured using
abdominal examination (palpation and percussion) and abdominal ultrasonography.2,9,10,14
Diagnosis of severe dengue
Patients were diagnosed with severe dengue when they met at least one of three criteria:
severe plasma leakage, severe bleeding, and severe organ impairment. Severe plasma leakage
was diagnosed when a patient had plasma leakage with symptoms of shock, such as weak andrapid pulse, cold extremities, capillary refill time (CRT) greater than 2 seconds, narrow pulsepressure (≤20 mmHg) with normal or slightly high systolic blood pressure (eg, 110/95 mmHg)
in compensating shock, lower blood pressure than normal in hypotensive shock, or prolonged
shock. CRT is measured by the time it takes for color to return to an external capillary bed
after pressure is applied to cause blanching, and the CRT is usually 2 seconds or less in healthypeople.9,10,18 Severe plasma leakage is the main cause of dengue shock syndrome, which is aform of hypovolemic shock, and acute respiratory distress syndrome (ARDS).2,9,12
Severe bleeding was diagnosed with clinical symptoms, such as gastrointestinal bleeding(blood in vomit, melena) or severe vaginal bleeding, with decreasing levels of hematocrit andhemoglobin, and shock status without recovery after crystalloid resuscitation.4,9,10
Severe organ impairment occurs when a patient is in a prolonged shock status.9,12 Severeorgan impairment was diagnosed when a patient met at least one of the criteria of acute kidney
injury (AKI), ARDS, acute liver failure with encephalopathy or encephalitis, and cardiomyopathy. 9
AKI can lead to pulmonary edema and respiratory distress. AKI was diagnosed when the urine
output was less than 0.5 mL/kg/h with a rise in the creatinine level ≥2 mg/dL. To confirm the752
Phetvilay Senavong et al

diagnosis of ARDS, pulmonary edema and respiratory distress were identified by wheezing or
crepitation on pulmonary examination, besides the respiratory rate measurements and chest radiography findings.9,18 Although the criteria were not clearly set, acute liver failure was diagnosedby an increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levelsof ≥1,000U/L with jaundice symptom, increase in total bilirubin with coagulopathy, and hepatic
encephalopathy with no evidence of prior liver disease. The symptoms of hepatic encephalopathy
included movement disorder, change in mood or personality, and, in the advanced stage, coma.
Cardiomyopathy was diagnosis using electrocardiogram and echocardiography.9,12,19
Data collection
The following data were collected from the medical record books of the hospital: (1) datesof admission and discharge, (2) socio-demographic data (age, sex, occupation, nationality,
ethnic group, and religion), (3) medical history (congenital disease, pregnancy, obesity, diabetic,
hypertension, renal failure, liver diseases, chronic hemolytic diseases, and peptic ulcer), (4) usageof a health facility before admission to the hospital (pharmacies, private clinics, health centers,
district hospitals, and the provincial hospital), (5) clinical symptoms and signs on admission,(6) final diagnosis of dengue (dengue without warning signs, dengue with warning signs, severe
dengue), and (7) laboratory data on admission (hemoglobin, hematocrit, platelet, creatinine,
glucose, sodium, ALT, and AST levels). Clinical symptoms and signs included general symptoms(fever, TT, or skin rash), pain and ache (headache, myalgia, general body ache, or arthralgia),
gastrointestinal symptoms (nausea, anorexia, severe abdominal pain, vomiting, persistent vomiting,or liver enlargement), plasma leakage (ascites or pleural effusion), cardiovascular signs (CRT,
weak and rapid pulse, or cold extremities), bleeding (petechiae, mucosal bleeding, severe vaginal
bleeding, melena, or blood in vomit), and neurological symptoms (lethargy/restlessness, dizziness,or convulsion).
Statistical analysis
Final diagnoses were categorized into non-severe dengue and severe dengue. Non-severe
dengue included dengue with or without warning signs. A chi-square test was performed to
examine a relationship between two categorical variables, but Fisher’s exact test was used whenmore than 20% of cells had expected frequencies <5. A t-test was performed to compare themeans of two groups. A logistic regression model was used to determine the odds ratio (OR)and 95% confidence interval (CI). In the logistic regression analyses on severe dengue, age,sex, occupation, usage of health facilities before admission, and clinical symptoms and signs on
admission were used as independent variables. In adults, 15 clinical signs on admission wereused: fever, TT, skin rash, headache, myalgia, general body ache, arthralgia, nausea, anorexia,
severe abdominal pain, vomiting, persistent vomiting, pleural effusions, mucosal bleeding anddizziness. In children, the same signs, except dizziness, were included because young children
might find it difficult to explain dizziness. Multivariable logistic regression analyses on the final
diagnosis of severe dengue were performed in the forced-entry method, and the forward andbackward stepwise selection. The criteria for variable selection were P <0.05 for adding variables,
and P >0.1 for removing variables. A p-value <0.05 was deemed to be statistically significant.
Data were analyzed using IBM SPSS statistic software version 26 (IBM SPPS Inc).
Ethical considerations
The requirement for written informed consent was waived owing to the retrospective nature of
the study, and ethical approval for this study was obtained from the National Ethics Committee
for Health Research, Ministry of Health, on August 9, 2019 (issue number 089/NECHR).

753
Severe dengue inpatients in Lao PDR

RESULTS
Fig. 1 shows that the number of dengue inpatients at the Savannakhet Provincial Hospital
was higher in the rainy season (from July to October) than in the dry season (from November
to June). The highest number of admissions per week was 36 during weeks 29 and 33.

Number of dengue inpatients

40
35

Children
Adults

30
25
20
15
10
5
0
1

5

10

15

20

25
2018

30

35
40
Epi week
Year

45

52 1

5

10

17

2019

Fig. 1

Distribution of dengue inpatients at Savannakhet Provincial Hospital from January 2018
to April 2019
The black (adults) and grey (children) bars show the number of dengue patients who were admitted to theprovincial hospital in each epi week.

A total of 402 (196 male and 206 female) dengue patients were included in this study (Table1). There were 179 children aged 1–14 years and 223 adults aged ≥15 years. Most patients were
Lao-lum (94.0%) and Buddhist (93.8%). The underlying conditions were peptic ulcers in ninepatients, hypertension in seven patients, obesity in six patients, pregnancy in three patients, andrenal failure in one patient.
Table 2 shows a comparison of characteristics and clinical factors between children andadults. The children’s group had significantly more female patients (57.0%) than the adult group(46.6%, P = 0.039). Children used health facilities before admission more often (84.9%) thanadults (47.9%, P <0.001). Of the 107 adult patients who used health facilities, most patients
visited district hospitals or the provincial hospital (n = 100). The major symptoms on admission
were pain and ache, such as headache (96.8%), myalgia (92.5%), general body ache (88.6%),
and arthralgia (74.1%). The common gastrointestinal symptoms were nausea (68.4%), anorexia(59.5%), severe abdominal pain (57.2%), vomiting (48.5%), dizziness (42.3%), and mucosal bleeding (28.9%). The TT result was positive in 85.0% of the patients. Ascites and convulsion wereobserved only in four patients and one patient, respectively. There were significant differences inmany clinical signs on admission between children and adults patients, and children had more
symptoms than adults: general body ache (95.0% vs. 83.4%, P <0.001), arthralgia (82.7% vs.

754
Phetvilay Senavong et al

67.3%, P <0.001), nausea (88.3% vs. 52.5%, P <0.001), anorexia (84.9% vs. 39.0%, P <0.001),
severe abdominal pain (72.1% vs. 45.3%, P <0.001), vomiting (51.8% vs. 48.2%, P = 0.004),
persistent vomiting (32.4% vs. 10.3%, P <0.001), cold extremities (28.5% vs. 9.4%, P <0.001),
and lethargy/restlessness (10.0% vs. 2.7%, P = 0.002). The objective signs that children showed
more than adults were weak pulse (17.3% vs. 5.4%, P <0.001), liver enlargement (21.8% vs.
0.4%, P <0.001), and CRT >2s (21.2% vs. 11.2%, P = 0.006). Severe vaginal bleeding was
found in nine of 104 female adult patients (6.4%).
The final diagnosis was severe dengue in 205 patients (51.0%), and the incidence of severe
dengue in children (69.8%) was significantly higher than that in adults (35.9%) (P <0.001,
Table 2). The mean hospitalization duration was 3.2 days (standard deviation 1.3), and it wassignificantly longer in children than adults (3.5 days vs 3.0 days, P = 0.006). There was nocase of death in our study population.

Table 1Socio-demographic characteristics of patients according to children and adults

Total(N=402)

VariablesChildren(N=179)Adults(N=223)

n

(%)

n

(%)

n

(%)

1–4

11

(2.7)

11

(6.1)

-

-

5–14

168

(41.8)

168(93.9)--

Age (years)

15–24

125

(31.1)--

125(56.1)

25–44

85(21.2)--

85(38.1)

45–82

13

(3.2)

-

-

13

(5.8)

Male

196

(48.8)

77(43.0)

119(53.4)

Female206(51.2)

102(57.0)

104(46.6)

None

80(19.9)

52(29.0)

28(12.6)

Sex

Occupation
Student

193(48.0)

126(70.4)

67(30.0)

Officer

16

(4.0)

-

-

16

(7.2)

Farmer/self-employed

113(28.1)

1

(0.6)

112

(50.2)

398(99.0)

178(99.4)

220(98.7)

4

(1.0)

1

(0.6)

3

(1.3)

Lao-lum

378(94.0)

158(88.3)

220(98.7)

Other

24

(6.0)

21

(11.7)

3(1.3)

Buddhist377(93.8)

158(88.3)

219(98.2)

Other

25

(6.2)

21

(11.7)

4(1.8)

Nationality
Lao
Other

a

Ethnic groupb

ReligioncOther includes Vietnamese and Chinese.
Other includes Khemu and Hmong.
cOther includes Ghost and Christian.
a

b

755
Severe dengue inpatients in Lao PDR

Table 2
Variables

Comparison of clinical factors between children and adults
Total(N=402)
n
(%)

Sex
Male
196
Female206
Use of health facilities before admission
No
143
Pharmacy
26
Hospitalb
213
Otherc20
Clinical symptoms and signs on admission
General
Fever
89
Tourniquet test (+)
342
Skin rash
32
Pain and ache
Headache
389
Myalgia
372
General body ache356
Arthralgia
298
Gastro intestinal system
Nausea275
Anorexia
239
Severe abdominal pain
230
Vomiting
195
Persistent vomiting
81
Liver enlargement
40
Plasma leakage
Pleural effusions
11
Ascites4
Cardiovascular system
CRT >2s
63
Weak pulse
43
Cold extremities
72
Bleeding
Petechia
7
Mucosal bleeding
116
Sever vaginal bleeding
9
Melena14
Blood in vomit
7
Central nervous system
Lethargy/restless
24
Dizziness
170
Convulsion
1
Final diagnosis
Non-severe dengue
197
Severe dengue
205
Hospitalization period (days)
Mean (SD)
3.2

Children(N=179)n(%)

Adults(N=223)n(%)(48.8)(51.2)

77102(43.0)(57.0)

119104(53.4)(46.6)

0.039(35.6)(6.5)(53.0)
(5.0)

27
24
113
15

(15.1)(13.4)(63.1)
(8.4)

116
2
100
5

(52.0)(0.9)(44.8)(2.2)<0.001(22.1)(85.0)
(8.0)

39
158
17

(21.8)(88.3)
(9.5)

50
184
15

(22.4)(82.5)
(6.7)

0.879
0.107
0.308

(96.8)(92.5)(88.6)(74.1)

173
167
170
148

(96.6)(93.3)(95.0)(82.7)

216
205
186
150

(96.9)(91.9)(83.4)(67.3)

0.905
0.604<0.001<0.001(68.4)(59.5)(57.2)(48.5)(20.1)(10.0)

158
152
129
101
58
39

(88.3)(84.9)(72.1)(51.8)(32.4)(21.8)

117
87
101
94
23
1

(52.5)(39.0)(45.3)(48.2)(10.3)(0.4)<0.001<0.001<0.001
0.004<0.001<0.001

(2.7)
(1.0)

3
1

(1.7)
(0.6)

8
3

(3.6)
(1.3)

0.359
0.632

(15.7)(10.7)(17.9)

38
31
51(21.2)(17.3)(28.5)

25
12
21(11.2)
(5.4)
(9.4)

0.006
<0.001<0.001(1.7)(28.9)
(2.2)
(3.5)
(1.7)

3
58
0
8
5

(6.0)
(32.4)
(0.0)
(4.5)
(2.8)

4
58
9
6
2

(20.0)(26.0)
(4.0)
(2.7)
(0.9)

1.000
0.160
0.334
0.250

(6.0)
(42.3)
(0.2)

18
101
0

(10.0)(56.4)
(0.0)

6
69
1

(2.7)
(40.6)(0.4)

0.002<0.0011.000(49.0)(51.0)

54125(30.2)(69.8)

14380(64.1)(35.9)<0.001

(1.3)

3.5

(1.2)

3.0

(1.3)

0.006

P-valuea

CRT >2s, capillary refill times more than 2 seconds.
SD: standard deviationa
A t-test was used for comparison of the mean of hospitalization period. A chi-square test and Fisher’s exact test were used forthe other variables.
b
Hospital includes district hospitals and the provincial hospital.
cOther includes health centers and private clinics.

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Phetvilay Senavong et al

Table 3 Association between socio-demographic factors and clinical signs on admission with severe dengue
in children
Variables

Non-severe
dengue (N=54)

Severedengue (N=125)

n (%)

n (%)

Crude OR(95% CI)

Adjusted OR(95% CI)a

PvalueAge group (years)
0–4

1 (9.1)10 (90.9)

1 (Reference)

1 (Reference)

5–14

53 (31.5)

115 (68.5)

0.22 (0.03–1.74)

0.10 (0.01–1.32)

0.08

Male

26 (33.8)

51 (66.2)

1 (Reference)

1 (Reference)

Female28 (27.5)

74 (72.5)

1.35 (0.71–2.56)

1.34 (0.65–2.78)

Student

39 (31.0)

87 (69.0)

1 (Reference)

1 (Reference)None

15 (28.3)

38 (71.7)

1.15 (0.10–13.06)

0.75 (0.31–1.81)

No

7 (25.9)

20 (74.1)

1 (Reference)

1 (Reference)

Pharmacy

9 (37.5)

15 (62.5)

0.58 (0.18–1.93)

0.39 (0.83–1.81)

0.23

Hospitalb

35 (31.0)

78 (69.0)

0.78 (0.30–2.01)

0.60 (0.17–2.16)

0.43

Otherc3 (20.0)

12 (80.0)

1.40 (0.30–6.47)

1.33 (0.21–8.25)

0.76

0.66

Sex
0.43

Occupation
0.52

Use of health facilities before admission

Clinical symptoms and signs on admission
Fever
No

43 (30.7)

97 (69.3)

1 (Reference)

1 (Reference)Yes

11 (28.2)

28 (71.8)

1.13 (0.52–2.47)

1.26 (0.45–3.50)(–)

5 (23.8)

16 (76.2)

1 (Reference)

1 (Reference)(+)

49 (31.0)

109 (69.0)

0.70 (0.24–2.01)

0.50 (0.15–1.70)

No

49 (30.2)

113 (69.8)

1 (Reference)

1 (Reference)Yes

5 (29.4)

12 (70.6)

1.04 (0.35–3.11)

0.62 (0.17–2.31)

No

3 (50.0)

3 (50.0)

1 (Reference)

1 (Reference)Yes

51 (29.5)

122 (70.5)

2.39 (0.47–12.25)

1.69 (0.21–13.46)

No

4 (33.3)

8 (66.7)

1 (Reference)

1 (Reference)Yes

50 (29.9)117 (70.1)

1.17 (0.34–4.06)

1.29 (0.21–8.02)

No

2 (22.2)

7 (77.8)

1 (Reference)

1 (Reference)Yes

52 (30.6)

118 (69.4)

0.65 (0.13–3.23)

0.48 (0.07–3.56)

No

12 (38.7)

19 (61.3)

1 (Reference)

1 (Reference)Yes

42 (28.4)

106 (71.6)

1.59 (0.71–3.57)

2.10 (0.68–6.46)

No

11 (52.7)

10 (47.6)

1 (Reference)

1 (Reference)Yes

43 (27.2)

115 (72.8)

2.94 (1.17–7.42)*

3.57 (1.05–12.09)No

9 (33.3)

18 (66.7)

1 (Reference)

1 (Reference)Yes

45 (29.6)

107 (70.4)

1.19 (0.50–2.85)

0.91 (0.25–3.38)

No

16 (32.0)

34 (68.0)

1 (Reference)

1 (Reference)Yes

38 (29.5)

91 (70.5)

1.13 (0.56–2.28)

0.69 (0.27–1.72)

No

29 (37.2)

49 (62.8)

1 (Reference)

1 (Reference)Yes

25 (24.8)

76 (75.2)

1.80 (0.95–3.43)

1.33 (0.37–3.08)

No

41 (33.9)

80 (66.1)

1 (Reference)

1 (Reference)Yes

13 (22.4)

45 (77.6)

1.77 (0.86–3.66)

2.56 (0.97–6.75)

No

45 (32.1)

95 (67.9)

1 (Reference)

1 (Reference)Yes

9 (23.1)

30 (76.9)

1.58 (0.69–3.60)

1.90 (0.75–4.85)

No

36 (29.8)

85 (70.2)

1 (Reference)

1 (Reference)Yes

18 (31.0)

40 (69.0)

0.94 (0.48–1.86)

0.67 (0.30–1.48)

Tourniquet test
0.27

Skin rash
0.48

Headache
0.62

Myalgia
0.78

General body ache
0.47

Arthralgia
0.19

Nausea0.04

Anorexia
0.89

Severe abdominal pain
0.42

Vomiting
0.51

Persistent vomiting
0.06

Liver enlargement
0.18

Mucosal bleeding

OR: odds ratio
CI: confident interval
Adjusted for all variables listed in the table.
b
Hospital includes district hospitals and the provincial hospital.
cOther includes private clinics and health care centers.
*P <0.05
a

0.32

757
Severe dengue inpatients in Lao PDR

Table 4 Association between socio-demographic factors and clinical signs on admission with sever dengue in
adults
Non-severe
dengue(N=143)Severedengue(N=80)

n (%)

n (%)

15–24

74 (59.2)

51 (40.8)

1 (Reference)

25–44

57 (67.1)

28 (32.9)

0.71 (0.41–1.27)

0.85 (0.42–1.71)

0.65

45–82

12 (92.3)

1 (7.7)0.12 (0.01–0.96)*

0.09 (0.01–1.06)

0.06

Male

79 (66.4)

40 (33.6)

1 (Reference)

1 (Reference)

0.44

Female64 (61.5)

40 (38.5)

1.23 (0.71–2.13)

1.28 (0.69–2.38)

Variables

Crude OR(95% CI)

Adjusted OR(95% CI)a

PvalueAge group (years)
1 (Reference)Sex

Occupation
Student

74 (66.1)

38 (33.9)

1 (Reference)

1 (Reference)

Otherb69 (62.2)

42 (37.8)

1.71 (0.96–3.09)

1.01 (0.50–2.05)

0.97

Use of health facilities before admission
No

77 (66.4)

39 (33.6)

1 (Reference)

1 (Reference)Yes

66 (61.7)

41 (38.3)

1.22 (0.71–2.12)

1.44 (0.74–2.81)

0.28

Clinical symptoms and signs on admission
Fever
No

112 (64.7)

61 (35.3)

1 (Reference)

1 (Reference)Yes

31 (62.0)

19 (38.0)

1.12 (0.59–2.15)

1.41 (0.55–3.57)(–)

22 (56.4)

17 (43.6)

1 (Reference)

1 (Reference)(+)

121 (65.8)

63 (34.2)

0.67 (0.33–1.36)

0.67 (0.30–1.46)

No

132 (63.5)

76 (36.5)

1 (Reference)

1 (Reference)Yes

11 (73.3)

4 (26.7)

0.63 (0.19–2.05)

0.42 (0.10–1.79)

No

6 (85.7)

1 (14.3)

1 (Reference)

1 (Reference)Yes

137 (63.4)

79 (36.6)

3.46 (0.34–2.44)

5.73 (0.48–69.27)

No

12 (66.7)

6 (33.3)

1 (Reference)

1 (Reference)Yes

131 (63.9)

74 (36.1)

1.13 (0.40–3.13)

0.74 (0.20–2.72)

No

21 (56.8)

16 (43.2)

1 (Reference)

1 (Reference)Yes

122 (65.6)

64 (34.4)

0.69 (0.34–1.41)

0.46 (0.18–1.14)

No

49 (67.1)

24 (32.9)

1 (Reference)

1 (Reference)Yes

94 (62.7)

56 (37.3)

1.22 (0.67–2.19)

0.87 (0.44–1.74)

0.47

Tourniquet test
0.31

Skin rash
0.24

Headache
0.17

Myalgia
0.64

General body ache
0.09

Arthralgia
0.70

758
Phetvilay Senavong et al

NauseaNo

67 (63.2)

39 (36.8)

1 (Reference)

1 (Reference)Yes

76 (65.0)

41 (35.0)

0.93 (0.53–1.60)

0.55 (0.25–1.29)

No

91 (66.9)

45 (33.1)

1 (Reference)

1 (Reference)Yes

52 (59.8)

35 (40.2)

1.36 (0.77–2.38)

1.21 (0.62–2.38)

No

80 (65.6)

42 (34.4)

1 (Reference)

1 (Reference)Yes

63 (62.4)

38 (37.6)

1.14 (0.66–2.00)

0.54 (0.22–1.31)

No

85 (65.9)

44 (34.1)

1 (Reference)

1 (Reference)Yes

58 (61.7)

36 (38.3)

1.20 (0.70–2.08)

1.44 (0.62–3.37)

No

135 (67.5)

65 (32.5)

1 (Reference)

1 (Reference)Yes

8 (34.8)

15 (65.2)

3.89 (1.57–9.65)**

3.82 (1.23–11.92)

No

140 (65.1)

75 (34.9)

1 (Reference)

1 (Reference)Yes

3 (37.5)5 (62.5)

3.11 (0.72–13.37)

2.47 (0.41–14.89)

No

111 (67.3)

54 (32.7)

1 (Reference)

1 (Reference)Yes

32 (55.2)

26 (44.8)

1.67 (0.90–3.07)

1.34 (0.66–2.74)

No

105 (68.2)

49 (31.8)

1 (Reference)

1 (Reference)Yes

38 (55.1)

31 (44.9)

1.75 (0.98–3.13)

1.97 (0.81–4.81)

0.14

Anorexia
0.57

Severe abdominal pain
0.17

Vomiting
0.40

Persistent vomiting
0.02

Pleural effusions
0.33

Mucosal bleeding
0.42

Dizziness
0.14

OR odds ratio
CI: confident intervalaAdjusted for all variables.
b
Other includes farmer, self-employee, officer, and no work.
*P <0.05, **P <0.01

To identify factors associated with the final diagnosis of severe dengue, age, sex, and clinicalsigns on admission were analyzed in children and adults. Regarding pediatric patients, bivariate
logistic regression analysis showed that the diagnosis of severe dengue was significantly higher
in those who had nausea on admission (crude OR = 2.94, P = 0.041) than in those who didnot (Table 3). Multiple logistic regression analysis adjusted for all factors showed that nausea(adjusted OR = 3.57, 95% CI = 1.05–12.09, P = 0.04) on admission was significantly associated with the final diagnosis of severe dengue. In the forward and backward stepwise selection
methods, only nausea was associated with the final diagnosis of severe dengue.
Among patients aged ≥15 years, those aged 45–82 years (crude OR = 0.12, P = 0.046) had
significantly less severe dengue than those aged 15–24 years, and persistent vomiting symptom(crude OR = 3.89, P = 0.003) on admission was significantly associated with severe dengue(Table 4). After adjusting for all variables, only persistent vomiting on admission (adjusted OR =3.82, 95% CI = 1.23–11.92, P = 0.02) was found to have a significant impact on the incidence

759
Severe dengue inpatients in Lao PDRof severe dengue among adult patients. The result of forward stepwise regression was the sameas that of the forced-entry method. In the backward stepwise method, two variables were associated with the final diagnosis of severe dengue: the age group of 45–82 years compared to
15–24 years (adjusted OR = 8.14, 95% CI = 1.00–66.13, P = 0.0497) and persistent vomiting(adjusted OR = 3.79, 95% CI = 1.49–9.61, P = 0.005) showed significant differences in the
final diagnosis of severe dengue.
All patients underwent complete blood count tests, but only nine children and 97 adults
underwent biochemical tests (Table 5). The t-test was performed to compare the results of blood
tests of patients who were finally diagnosed with non-severe and those diagnosed with severe
dengue. Children with severe dengue had a higher level of hemoglobin and lower level ofplatelet than children with non- severe dengue, but the differences were not significant. Adults
with severe dengue were more likely to have a lower level of platelet than those with non-severe
dengue, but the difference was not significant. The levels of hemoglobin and hematocrit were
almost the same among the two groups of patients. As per the biochemistry tests, the level ofcreatinine in adult patients was significantly higher in the severe dengue than in the non-severe
dengue group (P = 0.04). The levels of ALT and AST were lower in the severe dengue than in
the non-severe dengue group, but not at a significant level.

Table 5Comparison of laboratory data on admission in children and adults

Laboratory examination

Non-severe dengue

Severe dengue

P-value

N

Mean

(SD)

N

Mean

(SD)

Hemoglobin (g/dL)

179

11.4

(2.1)

125

12.8

(4.3)

0.90

Hematocrit (%)

179

37.0

(5.1)

125

38.9

(7.0)

0.13

Platelet (×10 /µL)

179

91.0

(55.7)

125

77.2(54.5)

0.91

Glucose (mg/dL)

9

97.0

8

102.6

(19.7)-Creatinine (mg/dL)

3

1.0

2

1.1

(0.5)

-

ALT (U/L)

4

97.0

3

130.2

(142.9)-

AST (U/L)

4

337.0

3

113.2

(66.0)-

Hemoglobin (g/dL)

223

13.0

(7.3)

80

13.0

(3.9)

0.82

Hematocrit (%)

223

40.0

(7.5)

80

39.6

(6.7)

0.47

Platelet (×10 /µL)

223

92.5

(69.0)

80

84.7(78.8)

0.93

Glucose (mg/dL)

97

103.7

(25.7)

36

105.6(28.6)

0.90

Creatinine (mg/dL)

82

1.0

(0.3)

36

2.0

(6.7)

0.04

Children3

Adults3

ALT (U/L)

31

108.9

(94.3)

18

102.3(83.0)

0.89

AST (U/L)

31

153.7

(142.2)18

114.0(82.5)

0.22

SD: standard deviation
ALT: alanine aminotransferase
AST: aspartate aminotransferase

760
Phetvilay Senavong et al

DISCUSSION
The number of inpatients with dengue was higher in the rainy season than in the dry season.
The hot and humid weather of the monsoons is a condition favorable for mosquito (Aedes species)
breeding, which is associated with dengue outbreaks.7,20
In this study, the proportion of final diagnosis of severe dengue was 51.0% among dengue
patients admitted to the Savannakhet Provincial Hospital between January 2018 and April 2019,
which was higher than that in previous studies in other Asian countries: 35% in inpatients in
India,21 and 28% in Singapore.22 In a systematic review comprising 198 studies, the proportionof severe dengue was 28.5%.23 This is probably because all dengue patients in severe conditions
in all 14 districts of Savannakhet Province were referred to the provincial hospital. There might
have been a delay in visiting the health care facilities owing to the rainy season or lack oftransportation in rural areas,24,25 although patients seemed to understand that they should visit
health facilities when they were suffered.26 The limited number of health care workers and thelow level of health care at health centers and district hospitals might have led to severe condition. Furthermore, the referral system from lower levels to high levels in public health facilities
might have been another reason for the high incidence of severe dengue because some districts
have no ambulance service.
Children showed significantly more clinical symptoms and signs on admission than adults. The
mean hospitalization and incidence of severe dengue were also significantly longer and higher inchildren than in adults, respectively. These results were consistent with those of previous studies
in Asian countries as well as a systemic review.23 This finding could be attributed to the fact thatthe protective immune responses to secondary infections are less developed and microvascularfragility is higher in children than in adults.21-23,27
In pediatric patients in this study, nausea on admission was significantly associated with thefinal diagnosis of severe dengue. This result was consistent with the results of previous studies.22,23,28 In adult patients, young age and persistent vomiting on admission were significantly
associated with the final diagnosis of severe dengue. This result was consistent with those ofprevious studies, which reported that persistent vomiting was a good predictor of severe plasma
leakage and a factor associated with severe dengue.21-23,27 Laboratory data in this study showedthat the creatinine level was significantly higher in severe dengue than in non-severe dengue
patients. AKI is a common complication of severe dengue and patients with AKI have longer
hospitalization and higher mortality than non-AKI patients.28,29
To treat severe dengue patients appropriately, a treatment team for dengue in hospitals must
carefully monitor and assess dengue patients who exhibit plasma leakage. However, it seemed thatmembers of the treatment team in the provincial hospital did not accurately follow the guideline
because the number of admitted patients was high but the nursing staff were not enough. It isalso reported that healthcare workers do not follow the guidelines when they do not understandabout the guidelines.30,31 Severe dengue patients should be monitored in the intensive care unit
rather than in the general wards.12,32 These results suggest that strict adherence to guidelines byhealthcare workers and sufficient medical staff are necessary for treating severe dengue patients.
To reduce the incidence of severe dengue and CFR of dengue in Lao PDR, the Ministry of
Health and WHO recommend daily reporting of suggested cases to the Emergency Operating
Center and retraining treatment teams in health facilities at the provincial, district, and healthcenter levels. The recommended training program includes (1) physiology of dengue according
to the three phases of dengue and (2) diagnosis, classification, and treatment indicators, e.g.,
dengue patients can stay at home with symptomatic treatment when they have no warning signs,
but patients with warning signs are recommended to be hospitalized, observed carefully in the761
Severe dengue inpatients in Lao PDR

hospital, and must be referred to a provincial hospital. Severe dengue patients should be admitted
to the intensive care unit in provincial hospitals. (3) Patient follow-up and assessment should be
carried out according to the standard guidelines. (4) Treatment should be based on the WHO
guidelines on dengue classification, diagnosis, treatment, and control. Training should be provided
to healthcare teams every year, and the surveillance and referral systems should be improved.
This study had some limitations. First, the incidence of severe dengue might be underestimated.
Some patients were discharged against medical advice and their outcomes were unknown. It
was reported that there were 12 dengue-related deaths in Savannakhet Province from January
2018 to April 2019. However, death cases could not be included because medical records ofall death cases had been sent to the Ministry of Health for further analyses and not available
for inclusion in this study. If the outcome and data of these patients were collected, the factors
associated with death due to dengue could have been studied. Second, the clinical signs anddiagnosis might not have been diagnosed correctly. Only four children and 82 adults underwent
blood examinations for liver and kidney functions on admission for diagnosis of acute liver failureand AKI. In the hospital, magnetic resonance imaging for the diagnosis of encephalopathy orencephalitis was not available. However, this study included many clinical symptoms and resultsof complete blood count tests. Therefore, risk factors for severe dengue outlined in this study
may be useful for doctors in provinces of Lao PDR and other developing countries. Third, thisstudy did not include a history of dengue and the serotype of dengue in variables of analyses,
although these factors were suggested to be associated with severe dengue. Further studies on
outcomes, laboratory data, treatment during hospitalization, and history of dengue are warranted
to determine the factors associated with severe dengue and dengue outbreaks in Lao PDR.
In conclusion, the incidence of severe dengue was 51.0% among inpatients at the Savannakhet
Provincial Hospital and it was higher than that in other Asian countries. Children had more
symptoms, longer hospitalization duration, and higher incidence of severe dengue than adults. In
children, nausea was associated with severe dengue. In adults, persistent vomiting on admission
was associated with severe dengue and the creatinine level on admission was higher in severe
dengue than non-severe dengue. These results suggest that nausea and persistent vomiting are
predictive factors for severe dengue. To reduce the incidence of severe dengue, training programson management of dengue patients should be provided to healthcare workers and the referral
system should be improved in Lao PDR.

ACKNOWLEDGMENTS
We would like to thank Dr. Bongshouvanh Phanthavongsa and staff of Communicable Diseases
Control Unit of Savannakhet Public Health Office, and Family medicine residency in Savannakhet
Province for their support to conduct this study.

CONFLICTS OF INTEREST
The authors have nothing to disclose.

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