The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Symptomatic Dengue in Children in 10

Asian and Latin American Countries
Maïna L’Azou, M.Sc., Annick Moureau, M.Sc., Elsa Sarti, Ph.D.,
Joshua Nealon, M.Sc., Betzana Zambrano, M.D., T. Anh Wartel, M.D.,
Luis Villar, M.D., Maria R.Z. Capeding, M.D., and R. Leon Ochiai, Ph.D.,
for the CYD14 and CYD15 Primary Study Groups*​​

A BS T R AC T

BACKGROUND
The control groups in two phase 3 trials of dengue vaccine efficacy included two From Global Epidemiology, Sanofi Pas-
large regional cohorts that were followed up for dengue infection. These cohorts teur, Lyon (M.L., R.L.O.), and the Global
Clinical Department, Sanofi Pasteur, Marcy
provided a sample for epidemiologic analyses of symptomatic dengue in children l’Etoile (A.M.) — both in France; Sanofi
across 10 countries in Southeast Asia and Latin America in which dengue is en- Pasteur Latin America, Coyoacán, Mexico
demic. (E.S.); Sanofi Pasteur Asia Pacific Region,
Singapore, Singapore (J.N., T.A.W.); Sanofi
Pasteur Uruguay, Montevideo (B.Z.); Clin-
METHODS ical Epidemiology Unit, School of Medi-
We monitored acute febrile illness and virologically confirmed dengue (VCD) in cine, Universidad Industrial de Santander,
3424 healthy children, 2 to 16 years of age, in Asia (Indonesia, Malaysia, the Philip- Bucaramanga, Colombia (L.V.); and the
Research Institute for Tropical Medicine,
pines, Thailand, and Vietnam) from June 2011 through December 2013 and in Alabang, Muntinlupa City, Philippines
6939 children, 9 to 18 years of age, in Latin America (Brazil, Colombia, Honduras, (M.R.Z.C.). Address reprint requests to
Mexico, and Puerto Rico) from June 2011 through April 2014. Acute febrile epi- Dr. Ochiai at Global Epidemiology, Sanofi
Pasteur, 2 Ave. Pont Pasteur, 69367 Lyon,
sodes were determined to be VCD by means of a nonstructural protein 1 antigen France, or at ­leon​.­ochiai@​­sanofipasteur​
immunoassay and reverse-transcriptase–polymerase-chain-reaction assays. Dengue .­com.
hemorrhagic fever was defined according to 1997 World Health Organization * The complete list of the members of the
criteria. CYD14 and CYD15 Primary Study Groups
is provided in the Supplementary Appen-
RESULTS dix, available at NEJM.org.
Approximately 10% of the febrile episodes in each cohort were confirmed to be N Engl J Med 2016;374:1155-66.
VCD, with 319 VCD episodes (4.6 episodes per 100 person-years) occurring in the DOI: 10.1056/NEJMoa1503877
Asian cohort and 389 VCD episodes (2.9 episodes per 100 person-years) occurring Copyright © 2016 Massachusetts Medical Society.

in the Latin American cohort; no trend according to age group was observed. The
incidence of dengue hemorrhagic fever was less than 0.3 episodes per 100 person-
years in each cohort. The percentage of VCD episodes requiring hospitalization
was 19.1% in the Asian cohort and 11.1% in the Latin American cohort. In com-
parable age groups (9 to 12 years and 13 to 16 years), the burden of dengue was
higher in Asia than in Latin America.
CONCLUSIONS
The burdens of dengue were substantial in the two regions and in all age groups.
Burdens varied widely according to country, but the rates were generally higher
and the disease more frequently severe in Asian countries than in Latin American
countries. (Funded by Sanofi Pasteur; CYD14 and CYD15 ClinicalTrials.gov numbers,
NCT01373281 and NCT01374516.)

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 The n e w e ng l a n d j o u r na l
I
n the past several decades, the bur-
den of dengue has expanded to place almost
3.9 billion people at risk for infection.1,2
From an evidence-based global map, it was esti-
mated that 390 million infections occur annu-
ally, 96 million of which are symptomatic.1
Furthermore, dengue is essentially endemic
throughout the tropics and has expanded into
128 countries as dengue virus serotypes con-
tinue to spread into new areas.2 In areas where
dengue is endemic, all populations and age
groups are at risk, and the burden of cases that
require hospitalization can be substantial, espe-
cially during outbreaks, with attendant strains
on health care resources and utilization.3-5 Den-
gue has no specific treatment, and the vaccine
that was most advanced in its clinical develop-
ment was licensed in Mexico, the Philippines,
and Brazil in 2015.6-8
Precise estimates of the burden of dengue
disease have been difficult to determine.1,2 Al-
though dengue is generally a reportable disease,
the totals that are reported by national health
authorities are likely to underestimate the true
burden of disease because medical care is not
sought for many mild-to-moderate cases.9 Fur-
thermore, national surveillance, reporting, and
laboratory-confirmation practices vary consider-
ably,10-14 and the clinical definitions recommend-
ed by the World Health Organization (WHO)
have not been used or applied consistently.15,16
Prospective longitudinal cohort studies that have
used active surveillance allow the incidence of
symptomatic dengue in a defined population to
be measured with precision and reliability.1,10-13
Disease burdens in such cohorts vary over time
but tend to be higher than nationally reported
totals. However, because locations, periods, and
methods usually differ among cohort studies,
these studies are often difficult to compare.
Sanofi Pasteur developed a recombinant live,
attenuated, tetravalent dengue vaccine (chimeric
yellow fever–dengue–tetravalent dengue vaccine
[CYD-TDV]).6,7,17 Two phase 3 clinical trials that
included more than 30,000 children, 2 to 16 years
of age, were conducted in Southeast Asia and
Latin America.6,7 Recruitment of the participants,
active surveillance, definition of episodes, clini-
cal assessment, and laboratory confirmation
were standardized across all the study sites.
Thus, the unvaccinated control groups in the two
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of m e dic i n e
studies could be considered to be two comparable
cohorts for the study of dengue disease across
10 countries in which dengue is endemic. Here,
we present data regarding the burdens of symp-
tomatic dengue and seropositivity results in the
various age groups in these two cohorts during
25 months of follow-up that occurred in the
period from June 2011 through April 2014.
Me thods
Study Population and Design
The children included in the descriptive analyses
presented here were in the control groups of two
phase 3, randomized, observer-blind, placebo-
controlled clinical trials to assess the safety and
efficacy of CYD-TDV in preventing dengue infec-
tion and reducing disease severity.6,7 Details of
the study procedures have been reported previ-
ously.6,7 In brief, the studies began in 2011 and
included healthy children 2 to 14 years of age in
Southeast Asia, with multiple centers in Indone-
sia, Malaysia, the Philippines, Thailand, and Viet-
nam (Fig. S1A in the Supplementary Appendix,
available with the full text of this article at
NEJM.org), and children 9 to 16 years of age in
Latin America, with multiple centers in Brazil,
Colombia, Honduras, Mexico, and Puerto Rico
(Fig. S1B in the Supplementary Appendix). These
countries and the age ranges of the participants
were selected because they had a high incidence
of dengue disease, which was confirmed for
most countries in two prospective cohort studies
that were conducted before the vaccine trials.18,19
Participants were randomly assigned, in a 2:1
ratio, to receive three doses of CYD-TDV (treat-
ment group) or placebo (0.9% sodium chloride;
control group) within 1 year. In addition, 20% of
the participants in Asia and 10% of those in
Latin America were randomly assigned to a sub-
group for the assessment of vaccine reactogenic-
ity, immunogenicity, and baseline seropositivity.
Participants were followed for 25 months after
the first dose of vaccine or placebo.
Each study was conducted in compliance with
Good Clinical Practice guidelines, the principles
of the Declaration of Helsinki, and the regula-
tions of the relevant country. Each study was
approved by the appropriate ethics review com-
mittee. Written informed consent was obtained
from a parent or guardian for all the partici-
 Symptomatic Dengue in Children in Asia and Latin America
pants in the two trials, with assent obtained
depending on the participant’s age.
With respect to the current analysis, the spon-
sor (Sanofi Pasteur) participated in the design of
the study and the collection, analysis, and inter-
pretation of the data. The sponsor also partici-
pated in the writing of the report and in the
decision to submit the manuscript for publica-
tion. Medical writing services were provided by
4Clinics France, with funding from the sponsor.
Study Procedures
Children were actively monitored for acute fe-
brile illness (temperature ≥38°C for ≥2 consec-
utive days) by means of weekly contact with
parents or guardians in each cohort and by
surveillance of school absenteeism in the Asian
cohort. Participants who had an acute febrile
episode were provided standard care, and routine
biologic tests were performed; children were hos-
pitalized if necessary, according to local prac-
tices. Consecutive febrile episodes were consid-
ered to be independent if they occurred more
than 14 days apart.
To confirm the presence of dengue virus in-
fection, a blood sample obtained within 5 days
after the onset of fever was tested by an enzyme-
linked immunosorbent assay for nonstructural
protein 1 antigen (Platelia, Bio-Rad Laboratories),
by a quantitative reverse-transcriptase–polymerase-
chain-reaction (PCR) screening assay for dengue,
and by a serotype-specific real-time PCR assay
(Simplexa Dengue, Focus Diagnostics). Febrile
episodes were considered to be virologically con-
firmed dengue (VCD) if any of these tests had a
positive result.
Dengue hemorrhagic fever was defined accord-
ing to the 1997 WHO criteria, which included
fever persisting for 2 to 7 days accompanied
by hemorrhage (or a positive tourniquet test),
thrombocytopenia (≤100,000 cells per cubic milli-
meter), and evidence of plasma leakage (hemato-
crit that is ≥20% above the normal value for age
or that decreased by ≥20% after fluid-replace-
ment therapy), pleural effusion, ascites, or hypo-
proteinemia.20 Dengue hemorrhagic fever was
classified in four grades of severity. Grade 1 is
defined by fever accompanied by nonspecific
constitutional symptoms; the only hemorrhagic
manifestation is a positive tourniquet test, easy
bruising, or both. Grade 2 is defined by sponta-
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neous bleeding (usually in the forms of skin or
other hemorrhages) in addition to the manifes-
tations of grade 1. Grade 3 is defined by circula-
tory failure manifested by a rapid, weak pulse
and narrowing of pulse pressure or hypotension,
with the presence of cold, clammy skin and rest-
lessness. Grade 4 is defined by profound shock
with undetectable blood pressure or pulse.20
The seropositivity analysis was performed with
baseline data from participants in the immuno-
genicity subgroup who received at least one in-
jection of vaccine or placebo. The baseline titers
of dengue-neutralizing antibodies in the blood
samples obtained before vaccination were mea-
sured with the use of a plaque-reduction sero-
neutralization assay, in which the titer was the
reciprocal of the serum dilution that reduced the
number of plaques in the control by 50%, and
seropositivity was defined as a titer of 10 or
more.21 Assays were performed under blinded
conditions at the Global Clinical Immunology
laboratories of the sponsor, at the Center for
Vaccine Development at Mahidol University in
Bangkok, Thailand, and at Focus Diagnostics.
Statistical Analysis
Descriptive analyses of the acute febrile episodes,
VCD, hospitalization, and dengue hemorrhagic
fever according to country and age group in-
cluded all the participants in the control group
of each study who received at least one injection
of placebo. All the initial and recurrent epi-
sodes of VCD were considered in the incidence-
density calculation for the entire follow-up period.
Incidence density was determined according to
age group on the basis of the age at fever onset
for the episode and the number of person-years
followed, which was determined weekly as the
cumulative time in years that each participant
contributed to each age group during the active
surveillance period.
Participants were stratified according to age
groups that were applicable to each cohort accord-
ing to the age at the onset of fever (2 to 4 years,
5 to 8 years, 9 to 12 years, 13 to 16 years, and
17 to 18 years); thus, some children were outside
the inclusion age range of each cohort, and only
the age groups of 9 to 12 years and 13 to 16 years
were comparable across the two cohorts. The
95% confidence intervals for incidence density
and percentages were computed with the exact
1157
 The n e w e ng l a n d j o u r na l of m e dic i n e

binomial distribution for percentages (Clopper–

* Plus–minus values are means ±SD. Participants were in the control groups of two phase 3, randomized, placebo-controlled clinical trials of the chimeric yellow fever–dengue–tetravalent
4168 (60.1)
2771 (39.9)
(N = 6939)
Pearson method).22 Statistical analyses were per-

12.5±2.1
9.0–17.0
Total

0.97
100

NA
NA
—
formed with the use of SAS software, version 9.2
(SAS Institute).
Puerto Rico

221 (50.2)
219 (49.8)
(N = 1149) (N = 440)

13.0±2.2
9.0–17.0
8/11– R e sult s
3/14
1.00

NA
NA
6.3

Demographic Characteristics of the Cohorts

The Asian cohort included 3424 participants, 2 to

699 (60.8)
450 (39.2)
12.4±2.1
9.0–17.0
Mexico

14 years of age, who were followed for 25 months

6/11–
3/14
16.6

0.99

NA
NA
Latin America

in the period between June 3, 2011, and Decem-

ber 16, 2013 (Table 1).6 The country subcohorts
in Asia varied in size, with the smallest in Thai-

578 (62.1)
353 (37.9)
Honduras
(N = 931)

12.3±2.1
9.0–17.0
6/11–
4/14
13.4

0.96

NA land and the largest in the Philippines. The

NA Latin American cohort included 6939 partici-
1949 (60.1) pants, 9 to 16 years of age, who were followed
1296 (39.9)
(N = 3245)
Colombia

12.5±2.2
9.0–17.0

for 25 months in the period between June 8,

6/11–
3/14
46.8

0.97

NA
NA

2011, and April 3, 2014. The smallest country

subcohort in Latin America was in Puerto Rico
and the largest was in Colombia. The mean age
(N = 1174)

721 (61.4)
453 (38.6)
12.4±2.1
9.0–16.9

of the participants was 8.8 years in the Asian

8/11–
Brazil

3/14
0.94
16.9

NA
NA

cohort and 12.5 years in the Latin American

cohort. The mean ages and the sex ratios of the
Table 1. Characteristics of the Study Populations at Inclusion in the Asian and Latin American Cohorts.*

country subcohorts were similar at inclusion

588 (17.2)
1179 (34.4)
1201 (35.1)
456 (13.3)
(N = 3424)

2.2–15.0
8.8±3.4

within each geographic region.

Total

0.94
100

Acute Febrile Episodes

In the Asian cohort, 3109 febrile episodes were
289 (37.1)
338 (43.4)
84 (10.8)
(N = 778)

2.0–14.8
Vietnam

67 (8.6)
9.3±3.0

observed during 6934 person-years (2.03 years

9/11–
12/13
22.7

0.91

per participant), for an overall incidence of

44.8 episodes per 100 person-years (Table 2, and
Table S1 in the Supplementary Appendix). In the
78 (19.9)
129 (32.9)
130 (33.2)
55 (14.0)
(N = 392)
Thailand

2.0–15.0
8.7±3.6
10/11–
12/13

Latin American cohort, 3615 febrile episodes

0.98
11.4

were observed during 13,527 person-years (1.95

years per participant), for an overall incidence of
Asia

26.7 episodes per 100 person-years. The inci-

Philippines
(N = 1166)

273 (23.4)
337 (28.9)
361 (31.0)
195 (16.7)
2.0–15.0
8.7±3.8
6/11–
12/13

dengue vaccine (CYD-TDV). NA denotes not applicable.

dence of febrile episodes in the subcohorts

0.90
34.1

ranged from 20.7 episodes per 100 person-years

(in Mexico) to 60.0 episodes per 100 person-
years (in the Philippines); the incidence decreased
74 (15.9)
155 (33.3)
168 (36.1)
68 (14.6)
(N = 465)
Malaysia

2.0–15.0
9.0±3.5
6/11–
11/13
0.98
13.6

with increasing age of the participants. The

overall incidence in each comparable age group
(9 to 12 years and 13 to 16 years) was similar in
the two cohorts, although the incidence rates
96 (15.4)
269 (43.2)
204 (32.7)
Indonesia
(N = 623)

2.1–15.0

54 (8.7)
8.5±3.0
6/11–

varied according to subcohort.

9/13
1.00
18.2

Age group — no. (%)

Virologically Confirmed Dengue

Male:female ratio

The overall incidence of VCD in the Asian cohort

participants
Characteristic

was 4.6 episodes per 100 person-years (range,

Surveillance
Percent of

period

Age — yr

2.2 [in Malaysia] to 6.6 [in the Philippines]);

13−16 yr
9−12 yr
Range

2−4 yr
5−8 yr
Mean

the incidence in the Latin American cohort was

2.9 episodes per 100 person-years (range, 1.5 [in

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 Symptomatic Dengue in Children in Asia and Latin America
Puerto Rico] to 4.1 [in Honduras]) (Table 2, and
Table S1 in the Supplementary Appendix). The
age groups that were most affected varied ac-
cording to subcohort, with no clearly observable
trends.
The percentages of VCD episodes among fe-
brile episodes in each cohort were similar (10.3%
in Asia and 10.8% in Latin America), with per-
centages in the subcohorts ranging from 6.3%
(in Malaysia) to 12.3% (in Indonesia) in Asia and
from 7.0% (in Puerto Rico) to 14.7% (in Brazil) in
Latin America. Overall, and within most coun-
tries, this percentage tended to increase with
increasing age, but in the two comparable age
groups (9 to 12 years and 13 to 16 years), the
percentage was slightly higher in the Asian co-
hort than in the Latin American cohort.
Hospitalization and Dengue Hemorrhagic
Fever
The overall incidence of hospitalization for VCD
episodes was 0.9 hospitalizations per 100 per-
son-years (range, 0.2 [in Vietnam] to 1.6 [in Indo-
nesia and Thailand]) in the Asian cohort and 0.3
hospitalizations per 100 person-years (range, 0.1
[in Mexico and Puerto Rico] to 0.4 [in Colombia
and Honduras]) in the Latin American cohort
(Table 3, and Table S2 in the Supplementary Ap-
pendix). The percentage of VCD episodes requir-
ing hospitalization was 19.1% (range, 5.9 [in Viet-
nam] to 45.5 [in Indonesia]) in the Asian cohort
and 11.1% (range, 4.9 [in Brazil] to 17.0 [in Co-
lombia]) in the Latin American cohort. There
was no age-group trend for either the incidence
or the percentage of VCD episodes that required
hospitalization. However, both these values in
the two comparable age groups tended to be
higher in the Asian cohort than in the Latin
American cohort.
A total of 30 episodes of VCD were diagnosed
as dengue hemorrhagic fever, as defined accord-
ing to the 1997 WHO criteria, with 20 episodes
occurring in the Asian cohort and 10 in the
Latin American cohort (Table 3, and Table S2 in
the Supplementary Appendix). Most episodes of
dengue hemorrhagic fever (28 of 30) were classi-
fied as grade 1 or 2. The overall incidence of
episodes of dengue hemorrhagic fever was 0.3 epi-
sodes per 100 person-years (range, 0.1 [in Malay-
sia and Vietnam] to 0.6 [in Indonesia]) in the
Asian cohort and 0.1 episodes per 100 person-
years (range, 0.0 [in Mexico and Brazil] to 0.1
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[in Colombia, Honduras, and Puerto Rico]) in
the Latin American cohort, with no episodes of
dengue hemorrhagic fever occurring in Brazil or
Mexico. The percentage of VCD episodes that
were diagnosed as dengue hemorrhagic fever was
6.3% (range, 3.9 [in Vietnam] to 18.2 [in Indo-
nesia]) in Asia and 2.6% (range, 0.0 [in Mexico
and Brazil] to 7.7 [in Puerto Rico]) in Latin
America. The percentage in Indonesia (18.2%)
was much higher than that in any other country
(all other countries, <7.7%). There were no age-
group trends with respect to the incidence of
dengue hemorrhagic fever or the percentage of
episodes of VCD that were diagnosed as dengue
hemorrhagic fever. No deaths due to dengue oc-
curred in either cohort.
Serotype Distribution
All four dengue virus serotypes cocirculated in
the five Asian countries during the study period,
although the distributions and predominant
serotypes differed among countries (Fig. 1A).
Shifts in serotype predominance occurred in
Indonesia (serotype 2 to serotype 1), the Philip-
pines (serotype 1 to serotype 4), and Thailand
(serotype 2 to serotype 3) (Fig. S2 in the Supple-
mentary Appendix).
In the Latin American cohort, serotype dis-
tributions also varied according to country
(Fig. 1B). Single serotypes predominated in
Brazil (serotype 4) and Puerto Rico (serotype 1),
whereas two or more serotypes predominated in
Mexico, Honduras, and Colombia (which was
the only Latin American subcohort affected by
all four serotypes). No clear changes in serotype
predominance occurred in the Latin American
subcohorts (Fig. S3 in the Supplementary Ap-
pendix).
Dengue Seropositivity
In the Asian immunogenicity subgroup, 1345 of
1999 participants (67.3%) were seropositive at
baseline. In the Latin American subgroup, 1585
of 2000 participants (79.2%) were seropositive
(Table 4). Overall rates of seropositivity varied
according to country and were between 47.0%
(Malaysia) and 80.9% (Indonesia) in the Asian
cohort and between 52.6% (Mexico) and 92.3%
(Colombia) in the Latin American cohort. The
rates of seropositivity according to age group
were similar overall in the Asian cohort and the
Latin American cohort: in the group of partici-
1159
 1160
Table 2. Incidences of Febrile Episodes and Episodes of Virologically Confirmed Dengue (VCD) in the Asian and Latin American Cohorts.*

Variable Asia Latin America

Indonesia Malaysia Philippines Thailand Vietnam Total Brazil Colombia Honduras Mexico Puerto Rico Total
(N = 623) (N = 465) (N = 1166) (N = 392) (N = 778) (N = 3424) (N = 1174) (N = 3245) (N = 931) (N = 1149) (N = 440) (N = 6939)
Person-yr — no. 1232 937 2370 792 1603 6934 2290 6313 1799 2280 845 13,527
Age group — person-yr
2−4 yr 110  81 348  95  82  716 NA NA NA NA NA NA
5−8 yr 431 288 701 263 468 2151 NA NA NA NA NA NA
9−12 yr 520 326 703 241 717 2507 1034 2887 884 1048 309 6,162
The

13−16 yr 171 242 618 193 336 1560 1129 3029 802 1101 440 6,501
17−18 yr NA NA NA NA NA NA  127  398 113  130  96 864
Febrile episodes — no. 357 332 1421 397 602 3109  552 1486 919  473 185 3,615
Incidence — no./100 person-yr
Overall 29.0 35.4 60.0  50.1 37.6 44.8 24.1 23.5 51.1 20.7 21.9 26.7
Age group
2−4 yr 52.7 70.4 98.9 116.8 82.9 89.1 NA NA NA NA NA NA
5−8 yr 36.9 49.0 75.7  57.8 48.3 56.2 NA NA NA NA NA NA
9−12 yr 22.9 31.0 48.8  37.8 30.4 34.8 27.2 27.1 54.5 23.0 24.9 30.2
n e w e ng l a n d j o u r na l

The New England Journal of Medicine

13−16 yr 12.3 13.6 32.8  22.3 26.8 25.0 22.2 20.8 47.3 19.3 22.7 24.2
of

17−18 yr NA NA NA NA NA NA 15.7 18.3 51.3 14.6  8.3 20.6

Tested for dengue — 357 332 1420 388 602 3099 551 1486 919 472 185 3613

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no.

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VCD episodes — no.  44  21  156  47  51  319  81  165  73  57  13 389
m e dic i n e

Incidence — no./100 person-yr

Overall 3.6 2.2 6.6 5.9 3.2 4.6 3.5 2.6 4.1 2.5 1.5 2.9
(95% CI) (2.6−4.8) (1.4−3.4) (5.6−7.7) (4.4−7.8) (2.4−4.2) (4.1−5.1) (2.8−4.4) (2.2−3.0) (3.2−5.1) (1.9−3.2) (0.8−2.6) 2.6−3.2)
Age group
2−4 yr 4.5 2.5 6.3 5.3 2.4 5.0 NA NA NA NA NA NA
5−8 yr 5.6 1.7 7.4 6.8 3.0 5.3 NA NA NA NA NA NA
9−12 yr 2.5 3.1 7.3 6.2 3.5 4.5 3.5 2.9 4.6 2.1 1.3 3.0

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13−16 yr 1.2 1.7 5.0 4.7 3.0 3.6 3.5 2.4 3.7 2.8 1.6 2.8
17−18 yr NA NA NA NA NA NA 4.7 2.0 1.8 3.1 2.1 2.5
 Symptomatic Dengue in Children in Asia and Latin America

pants 9 to 12 years of age, the rates were 75.7%

(N = 6939)

(9.8−11.8)
in the Asian cohort and 76.4% in the Latin
Total

10.8

10.0
11.4
12.4
NA
NA
American cohort, and in the group of those 13
to 16 years of age, the rates were 87.4% and
84.0%, respectively.
Puerto Rico

(3.8−11.7)
(N = 440)

 5.2
 7.0
25.0
NA
NA
7.0
Discussion
These two studies, conducted across 10 coun-
tries in which dengue is endemic, were similarly
(N = 1149)

(9.3–15.4)
Mexico
Latin America

12.1

 9.1
14.6
21.1
designed and used the same methods and case
NA
NA
definitions, which enabled the capture of data
regarding symptomatic dengue episodes as well
Honduras

as comparisons across countries, regions, and

(N = 931)

(6.3−9.9)

NA
NA
7.9

8.5
7.9
3.4
age groups. We found that dengue-specific bur-
dens varied extensively within each geographic
region and that all pediatric age groups were
(N = 3245)

(9.6−12.8)
Colombia

affected.
11.1

10.7
11.6
11.0
NA
NA

The overall incidences of febrile episodes var-

ied according to country and decreased with
increasing age. Although the overall incidence
(9.0−15.8) (6.4−11.0) (9.3−11.4) (11.9−17.9)
(N = 3424) (N = 1174)
Brazil

appeared to be higher in the Asian cohort than

14.7

12.9
15.5
30.0
NA
NA

in the Latin American cohort, this disparity was

probably due in part to the younger age range of
the participants included in this cohort, among
Total

10.3

 5.7
 9.4
13.1
14.4
NA

whom the incidence of acute febrile disease is

* All age groups were defined according to age at episode onset. CI denotes confidence interval.

expected to be higher.23,24 The similar overall

incidence in the comparable age groups (9 to 12
(N = 778)
Vietnam

years of age and 13 to 16 years of age) suggests

 2.9
 6.2
11.5
11.1
NA
8.5

that the burden of febrile disease among chil-

dren 9 to 16 years of age was similar in the two
(N = 392)
Thailand

cohorts.
 4.5
12.1

12.2
17.2
20.9
NA

We found substantial burdens of dengue dis-

ease in all 10 countries; however, the incidence
Asia

of VCD overall and in the two comparable age

Philippines
(N = 1166)

(9.4−12.7)

groups across the subcohorts was generally

 6.4
 9.8
14.9
15.3
11.0

NA

higher in the Asian cohort than in the Latin

American cohort. Although the incidence rates
Percent of VCD episodes among febrile episodes

of dengue differ according to location and fluc-

(N = 465)

(4.0−9.5)
Malaysia

 3.5
 3.5
 9.9
12.1
NA

tuate according to year and season, our results

6.3

(4.6 episodes per 100 person-years in the Asian

cohort and 2.9 per 100 person-years in the Latin
(9.1−16.2)
Indonesia
(N = 623)

American cohort) fall within the incidence rang-

 8.6
15.1
10.9
 9.5
12.3

NA

es observed in other dengue cohort studies con-

ducted in some of the same countries.18,19,25-27 For
example, the incidence of VCD among children
(95% CI)

was reported to be 1.77 to 5.74 episodes per 100

person-years in Thailand in the period from
13−16 yr
17−18 yr
9−12 yr
Age group
2−4 yr
5−8 yr

2006 through 2009,26 1.69 to 4.04 episodes per

Overall

100 person-years in Vietnam in the period from

Variable

2005 through 2007,25 and 1.34 episodes per 100

person-years in Puerto Rico in the period from

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 1162
Table 3. Incidences of Hospitalization and Dengue Hemorrhagic Fever (DHF) among Participants with VCD in the Asian and Latin American Cohorts.*

Variable Asia Latin America

Indonesia Malaysia Philippines Thailand Vietnam Total Brazil Colombia Honduras Mexico Puerto Rico Total
(N = 623) (N = 465) (N = 1166) (N = 392) (N = 778) (N = 3424) (N = 1174) (N = 3245) (N = 931) (N = 1149) (N = 440) (N = 6939)
Hospitalization
Total no. 20 8 17 13 3 61 4 28 7 3 1 43
Incidence — no./100 person-yr
The

Overall 1.6 0.9 0.7 1.6 0.2 0.9 0.2 0.4 0.4 0.1 0.1 0.3
(95% CI) (1.0−2.5) (0.4−1.7) (0.4−1.2) (0.9−2.8) (0.0−0.6) (0.7−1.1) (0.1−0.5) (0.3−0.6) (0.2–0.8) (0.0−0.4) (0.0−0.7) (0.2−0.4)
Age group
2−4 yr 1.8 0.0 0.0 1.1 0.0 0.4 NA NA NA NA NA NA
5−8 yr 2.1 1.0 0.7 1.5 0.0 1.0 NA NA NA NA NA NA
9−12 yr 1.3 1.2 1.3 2.1 0.3 1.1 0.3 0.5 0.6 0.1 0.0 0.4
13−16 yr 1.2 0.4 0.5 1.6 0.3 0.6 0.1 0.4 0.1 0.2 0.0 0.3
17−18 yr NA NA NA NA NA NA 0.0 0.3 0.9 0.0 1.0 0.3
Percent of hospitalizations among VCD episodes
Overall 45.5 38.1 10.9 27.7 5.9 19.1 4.9 17.0 9.6 5.3 7.7 11.1
n e w e ng l a n d j o u r na l

(95% CI) (30.4−61.2) (18.1−61.6) (6.5−16.9) (15.6−42.6) (1.2−16.2) (15.0−23.9) (1.4−12.2) (11.6−23.6) (3.9−18.8) (1.1−14.6) (0.2−36.0) (8.1−14.6)

The New England Journal of Medicine

of

Age group
2−4 yr  40.0  0.0  0.0 20.0  0.0  8.3 NA NA NA NA NA NA

n engl j med 374;12 nejm.org  March 24, 2016

5−8 yr  37.5 60.0  9.6 22.2  0.0 18.6 NA NA NA NA NA NA

Copyright © 2016 Massachusetts Medical Society. All rights reserved.

9−12 yr  53.8 40.0 17.6 33.3  8.0 23.7 8.3 16.7 12.2 4.5  0.0 12.3
m e dic i n e

13−16 yr 100.0 25.0  9.7 33.3 10.0 17.9 2.6 17.8  3.3 6.5  0.0  9.4
17−18 yr NA NA NA NA NA NA 0.0 12.5 50.0 0.0 50.0 13.6
DHF
No. of episodes 8 1 7 2 2 20 0 7 2 0 1 10
Incidence — no./100 person-yr
Overall 0.6 0.1 0.3 0.3 0.1 0.3 0.0 0.1 0.1 0.0 0.1 0.1
(95% CI) (0.3−1.3) (0.0−0.6) (0.1−0.6) (0.0−0.9) (0.0−0.5) (0.2−0.5) (0.0−0.2) (0.0−0.2) (0.0−0.4) (0.0−0.2) (0.0−0.7) (0.0−0.1)

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 Table 3. (Continued.)

Variable Asia Latin America

Indonesia Malaysia Philippines Thailand Vietnam Total Brazil Colombia Honduras Mexico Puerto Rico Total
(N = 623) (N = 465) (N = 1166) (N = 392) (N = 778) (N = 3424) (N = 1174) (N = 3245) (N = 931) (N = 1149) (N = 440) (N = 6939)
Age group
2−4 yr 0.9 0.0 0.0 0.0 0.0 0.1 NA NA NA NA NA NA
5−8 yr 0.9 0.3 0.3 0.4 0.0 0.4 NA NA NA NA NA NA
9−12 yr 0.4 0.0 0.4 0.4 0.3 0.3 0.0 0.1 0.0 0.0 0.0 0.0
13−16 yr 0.6 0.0 0.3 0.0 0.0 0.2 0.0 0.1 0.1 0.0 0.0 0.1
17−18 yr NA NA NA NA NA NA 0.0 0.0 0.9 0.0 1.0 0.2
Percent of DHF episodes among VCD episodes
Overall 18.2 4.8 4.5 4.3 3.9 6.3 0.0 4.2 2.7 0.0 7.7 2.6
(95% CI) (8.2−32.7) (0.1−23.8) (1.8−9.0) (0.5−14.5) (0.5−13.4) (3.9−9.5) (0.0−4.5) (1.7−8.6) (0.3−9.6) (0.0−6.3) (0.2−36.0) (1.2−4.7)
Age group
2−4 yr 20.0 0.0 0.0 0.0 0.0 2.8 NA NA NA NA NA NA
5−8 yr 16.7 20.0 3.9 5.6 0.0 7.1 NA NA NA NA NA NA
9−12 yr 15.4 0.0 5.9 6.7 8.0 7.0 0.0 3.6  0.0 0.0  0.0 1.6
13−16 yr 50.0 0.0 6.5 0.0 0.0 5.4 0.0 5.5  3.3 0.0  0.0 2.8
17−18 yr NA NA NA NA NA NA 0.0 0.0 50.0 0.0 50.0 9.1

* Age groups were stratified according to age at episode onset.

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Symptomatic Dengue in Children in Asia and Latin America

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1163
 The n e w e ng l a n d j o u r na l of m e dic i n e

fever were observed in the studies. The incidence

A Asian Cohort
in the Asian cohort (0.3 episodes per 100 per-
Serotype 1 Serotype 2 Serotype 3 Serotype 4
son-years) was similar to the incidence of severe
100
dengue that has been found in other Asian co-
hort studies (0.1 to 0.7%).27 Owing to the active
80 nature of the surveillance used in our studies,
we consider these incidence rates of dengue
Participants (%)

60 hemorrhagic fever to be accurate measures of

this disease in these otherwise-healthy, pediatric
40 community-based cohorts.
Although the indicators of dengue severity
(i.e., incidences of hospitalizations for VCD or
20
dengue hemorrhagic fever and the percentages
of VCD episodes for which the participant was
0
Indonesia Malaysia Philippines Thailand Vietnam
hospitalized or was found to have dengue hem-
(N=42) (N=20) (N=159) (N=46) (N=48) orrhagic fever) varied according to country, they
were generally higher in Asia than in Latin
B Latin American Cohort America, both overall and in the comparable age
Serotype 1 Serotype 2 Serotype 3 Serotype 4 groups. Whether this means that VCD is more
100 severe in Asia than in Latin America continues
to be a topic of discussion that involves complex
80 factors, including differences in disease burden
and virus genotype.29,30 Finally, since more than
Participants (%)

60
40
20
0 regional cohort was more clearly affected than
Brazil Colombia Honduras Mexico Puerto Rico
(N=81) (N=167) (N=65) (N=57) (N=13)
Figure 1. Serotype Distributions in Episodes of Virologically Confirmed
Dengue, According to Country Subcohort in Asia and Latin America.
Dengue virus serotypes in blood samples that were obtained during episodes
of virologically confirmed dengue were determined by means of reverse-
transcriptase–polymerase-chain-reaction assay with the use of serotype-
specific primers. The overall serotype distributions during the surveillance
period are shown for each country. Results include five episodes in the Asian
cohort (one in Indonesia and four in the Philippines) and eight in the Latin
American cohort (four in Colombia, one in Honduras, two in Mexico, and
one in Puerto Rico) that were coinfections with two dengue virus serotypes.
2005 through 2006.28 VCD accounted for ap-
proximately 10% of the febrile episodes across
the two cohorts. This percentage tended to in-
crease with age in the two cohorts and within
most countries; in some of the oldest age groups,
it was more than 20%.
A total of 30 episodes of dengue hemorrhagic
70% of the hospitalizations for VCD episodes
(74 of 104 episodes overall) were not associated
with dengue hemorrhagic fever, it appears that
this milder presentation exerts a substantial hos-
pitalization burden in some countries.
All the age groups in the subcohorts were af-
fected by dengue. Overall, no age group in either
any other, although some age groups had higher
incidence rates in some countries. In the Asian
subcohorts, the incidence of VCD appeared to be
highest in either the group of participants who
were 5 to 8 years of age or the group of those
who were 9 to 12 years of age (depending on
country). In the Latin American cohort, the
highest incidence rates occurred in different age
groups (the group that was 17 to 18 years of age
in Brazil, Mexico, and Puerto Rico and the group
that was 9 to 12 years of age in Colombia and
Honduras). These findings are consistent with
recent reviews of reports that were based on
national surveillance.3,10-13,31-33 There were no ob-
servable trends according to age group with re-
spect to the percentages of VCD episodes that
either required hospitalization or were found to
be dengue hemorrhagic fever.
Between 60 and 98% of the children who
were older than 13 years of age in these coun-
tries had been exposed to dengue before the

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 Symptomatic Dengue in Children in Asia and Latin America

start of the study. However, a link between the

955 (76.4)
630 (84.0)
(77.4−81.0)
(N = 6939)
various seropositivity rates in the subcohorts

2000

1585
Total

79.2

NA
NA
and the incidence of VCD was not evident, which
further highlights the extensive geographic and
temporal variability of dengue epidemiology.

Puerto Rico
All four virus serotypes cocirculated in all

(47.7−64.0)
(N = 440)

42 (51.2)
43 (61.4)
55.9
five Asian countries, with variations according

152

85

NA
NA
to country and over time. Serotype distributions
in the Latin American countries usually con-

(47.0−58.1)
sisted of one or two predominant serotypes,

(N = 1149)

97 (48.3)
75 (59.5)
Mexico

52.6

* Age groups were stratified according to age at inclusion. The value in parentheses is the seropositivity rate in the age group of the country subcohort.
327

172
with minor changes over time. The different

NA
NA
Latin America
serotype-distribution profiles in these two geo-
graphic regions have been linked to their differ-

(81.9−90.0)

154 (82.4)
105 (92.9)
Honduras
ent histories of dengue, with sustained hyperen-

(N = 931)

86.3
300

259

NA
NA
demicity in Southeast Asia since World War II
versus widespread eradication of the Aedes aegypti
vector in Latin America in the 1950s, followed by

(90.4−93.9)
(N = 3245)

526 (90.9)
324 (94.7)
Colombia
progressive reintroduction of the mosquito and

92.3
921

850

NA
NA
of dengue viruses.29 As serotypes continue to
spread in Latin America, serotype distributions
and the epidemiologic features of dengue may

(76.3−84.9) (41.2−52.8) (74.6−81.3) (62.5−72.7) (49.2−59.1) (65.2−69.3) (67.6−77.9)

(N = 1174)

136 (67.7)
83 (83.8)
eventually resemble those in Asia. Brazil

73.0
300

219

NA
NA
Our analysis has a few limitations. First, since
the countries were chosen for their high burdens
of dengue,20,21 generalization of these findings
(N = 3424)

235 (50.0)
372 (62.1)
482 (75.7)
256 (87.4)
to other countries in the region may be limited.
Total

1999

1345
67.3
Furthermore, the cohorts included only healthy
children whose parents were willing to have
their children participate in a vaccine trial; the
(N = 778)

43 (44.3)
70 (49.3)
90 (62.1)
17 (77.3)
Vietnam
Table 4. Dengue Seropositivity at Inclusion in the Asian and Latin American Cohorts.

54.2
406

220

disease-burden estimates in these children may

differ from those in other children in these
countries. Second, the ages of the participants
(N = 392)

33 (48.5)
73 (61.9)
93 (79.5)
32 (84.2)
Thailand

were selected on the basis of the highest inci-

67.7
341

231

dence of dengue in each cohort but did not in-

clude the youngest children (<2 years of age) in
Asia

either geographic region and were not the same

Philippines
(N = 1166)

87 (58.0)
125 (74.9)
139 (88.5)
119 (93.0)
78.1

across the two regions, which limited some

602

470

comparisons. Finally, with only 30 episodes of

dengue hemorrhagic fever observed in the two
(N = 465)

22 (32.4)
28 (34.1)
59 (57.8)
32 (66.7)
Malaysia

cohorts, interpretations of the incidence of this

47.0
300

141

disease should be made with caution.

Our analysis of these pediatric cohorts showed
substantial and varied burdens of dengue dis-
50 (57.5)
76 (84.4)
101 (87.1)
56 (98.2)
Indonesia
(N = 623)

ease among participants 2 to 16 years of age in

80.9
350

283

five Asian countries and among participants 9 to

Seropositive specimens

18 years of age in five Latin American countries.

Age group — no. (%)*
Blood samples — no.

The disease burden was severe enough to cause

considerable rates of hospitalization and ac-
counted for up to approximately 15% of the epi-
13−16 yr
% (95% CI)

9−12 yr
2−4 yr
5−8 yr
Total no.

sodes of febrile disease in some countries.

Variable

Supported by Sanofi Pasteur.

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 Symptomatic Dengue in Children in Asia and Latin America

Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank all the parents and children who agreed to partici-
pate in these trials; the trial staff in the countries; the clinical
research organization staff who contributed to the successful
completion of the trials; Sandra Besada-Lombana, Paul Com-
mander, Valentine Delore, Laure Durand, Michael Greenberg,
Chris Nelson, and Jo-Ann West for critical review of an earlier
version of the manuscript; and Kurt Liittschwager, 4Clinics
France, for medical writing services.

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