100 Forum
2 February 2002
Science & Society
Epidemic dengue/dengue hemorrhagic fever as a public
health, social and economic problem in the 21st century
Duane J. Gubler
Dengue fever (DF) is an old disease that
became distributed worldwide in the
tropics during the 18th and 19th centuries
when the shipping industry and
commerce were expanding [1]. Both the
principal mosquito vector, Aedes aegypti,
and the viruses responsible for DF were
spread via sailing ships because the
mosquito used the stored water on the
ships as a breeding site and could
maintain the transmission cycle, even on
long voyages. When such a ship called at
a port, often both the mosquito and the
virus were introduced. Because of the
slow mode of transportation, epidemics
were infrequent, with intervals of 10 to
40 years. When a new dengue virus
(there are four serotypes: DEN-1, DEN-2,
DEN-3 and DEN-4) was introduced,
however, it frequently resulted in major
epidemics that affected numerous
countries in that region.
The global epidemiology and
transmission dynamics of dengue viruses
were changed dramatically in Southeast
Asia during World War II [1]. The
disruption and change in the ecology
caused by the war effort expanded the
geographical distribution and increased
the densities of Ae. aegypti, making many
countries in this region highly permissive
for epidemic transmission. Troop
movements accelerated the spread of
viruses between population centers in the
region, causing major epidemics. By the
end of the war, most countries in Southeast
Asia were hyperendemic (when multiple
dengue virus serotypes co-circulate in
a community), and a few years later
epidemic dengue hemorrhagic fever (DHF)
emerged in the region. The first recorded
epidemic of DHF occurred in Manila,
Philippines in 1953–1954, followed by
Bangkok, Thailand in 1958 and Malaysia,
Singapore and Vietnam in the 1960s [1].
With the economic boom and associated
urbanization in Southeast Asia in the post-
war years, epidemic DF/DHF spread to
the whole region during the 1970s [1,2]
Epidemic DHF was localized in
Southeast Asia during this period because
http://tim.trends.com
TRENDS in Microbiology Vol.10 No.
of the isolation of the Pacific islands and
the successful Ae. aegypti eradication
program in the Americas to control urban
yellow fever. In the 1970s, however, the
American program was disbanded and
Ae. aegypti re-invaded most countries in
the region (Fig. 1). Modern transportation
facilitated and increased the movement
of people and commodities within and
between regions of the world, leading
to increased movement of both the
mosquitoes and the viruses. As a result,
epidemic DF/DHF spread to the Pacific
and the American tropics. In the 1980s
and 1990s, both the mosquito vectors
and the viruses continued their global
geographical expansion, causing
increased frequency and magnitude of
epidemic DF, and the emergence of DHF.
Factors responsible for resurgence
There are many factors that were
responsible for this dramatic resurgence
of epidemic DF/DHF in the waning years
of the 20th century, some of which are not
well understood [3]. It is clear, however,
that demographic and societal changes
such as population growth, urbanization
and modern transportation contributed
greatly to the increased incidence and
geographical spread of dengue activity.
1930s
Fig. 1. Aedes aegypti distribution in the Americas: 1930s, 1970 and 2001.
0966-842X/01/$ – see front matter Published by Elsevier Science Ltd. PII: S0966-842X(01)02288-0
For example, Gubler and Meltzer showed
that the increase in the reported number
of cases of DF/DHF has historically been
highly correlated with human population
growth [4]. This was compounded by
complacency about infectious diseases
in general and vector-borne diseases in
particular, and a lack of public health
resources for research, surveillance,
prevention, and control programs.
Increased epidemic activity caused by
multiple virus serotypes increased the
rate of genetic change in the viruses, and
thus increased the probability of the
emergence of virus strains or genotypes
with greater epidemic potential and/or
virulence, an important risk factor for
DHF. In the past 20 years, new virus
strains have been detected with
increasing frequency in new geographical
areas, some resulting in epidemic
transmission and others resulting in
silent transmission [1,3,5,6]. This change
in the transmission dynamics of dengue
viruses also increased the probability of
secondary dengue infections, another
principal risk factor for DHF [7].
Public health impact
At the beginning of the 21st century,
DF/DHF is the most important arboviral
1970 2001
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 Forum TRENDS in Microbiology Vol.10 No.2 February 2002 101

disease of humans, occurring in tropical

countries of the world where >2.5 billion
people are at risk of infection [1,3,7]
(Fig. 2). More than 100 tropical countries
have endemic dengue virus infections, and
DHF has been documented in >60 of these
countries [8]. Surveillance for DF/DHF is
poor in most countries, and in the past has
focused primarily on DHF [3]; the number
of DF cases that occur each year can
therefore only be estimated. In 1998,
however, major epidemics occurred
throughout Asia and the Americas, with
>1.2 million cases of DF/DHF reported to
the WHO. Global reports of DHF have
increased on average by fivefold in the
past 20 years (Fig. 3). At the beginning
of the 21st century it is estimated that
between 50 and 100 million cases of DF
and several hundred thousand cases of
DHF occur each year, depending on the
epidemic activity. The case fatality rate
(CFR) varies among countries, but can
be as high as 10 –15% in some and
<1% in others.
The majority of DHF cases are reported
from Asia where the disease has affected
most countries, and is a leading cause of
hospitalization and death among children.
In the American tropics, DHF was a rare
disease before 1981. Since that time,
epidemic DF/DHF has become one of the
most important public health problems
of the region. The only tropical region of
the world where it is not considered a
major problem is Africa, where other
disease problems are overwhelming by
comparison. The real public health impact
of DF/DHF occurs during epidemics of this
disease. Because surveillance is poor, the
early stages of epidemic transmission are
usually not detected, with cases grossly
under-reported until the epidemic is
recognized as dengue, which is usually
near peak transmission; it then becomes
grossly over reported [9]. Emergency
mosquito control is usually initiated at
that time, but these efforts are usually
Areas infested with Aedes aegypti
Areas with Aedes aegypti and dengue epidemic activity
Fig. 2. World distribution of dengue in 2001.
diseases in the 1950s and 1960s. The
resulting complacency that evolved
among government and public health
officials and the public eventually led
to the perception that DF was not an
important disease and, ultimately, to
deterioration of the public health
infrastructure needed to deal with DF
and other vector-borne diseases. When
epidemic DF/DHF began to re-emerge
and spread geographically, first in
Southeast Asia in the 1950s–1970s and
then globally in the waning years of the
20th century, it was ignored for the most
part by public health officials, and the
public had to tolerate the interruption of
their lives that occurred every few years
when the periodic but progressively more
frequent and larger epidemics occurred.
As noted above, most dengue endemic
countries have poor surveillance for
DF/DHF [3]. This is especially true
in those countries where clinical
management of the severe disease, DHF,
is not up to standard, and where there is
no triage plan for patients. The result is
TRENDS in Microbiology
within a few hours. Patients or family
members who experience this rapid
deterioration do not usually forget it,
and thus contribute to the confusion
and overload at health facilities.
A natural outcome of this type of
overwhelming situation is the demand
that government health agencies do
something to control the epidemic. Health
officials and politicians, wanting to appear
responsive, demand emergency response
measures that are visible [9]. This has
led over the years to the use of ultra low
volume (ULV) insecticide space sprays to
control epidemics [10], a highly visible
method that demonstrates action on the
part of the government [9]. Unfortunately,
it is not effective in controlling the
principal vector mosquito, Ae. aegypti,
and, therefore, in controlling the epidemic
[9,11]. Moreover, it is very expensive. The
social impact of this type of inefficient
emergency response is not well
600000
Number of cases

500000
misdirected, and are too little and too late overloading of clinics and hospitals by 400000
to have any impact on the epidemic [9]. patients with DF or with mild non-dengue 300000
Thus, the public health impact of epidemic illness, an overworked medical staff, 200000
DF/DHF is amplified because there is poor sub-standard care for patients with the 100000
surveillance, no public health planning life-threatening DHF/dengue shock 0
and no properly implemented emergency syndrome, and often increased mortality.
9

9
95

96

97

98

99

response plans. In large epidemics there is often chaos

–1

–1

–1

–1

–1
55

60

70

80

90

and confusion among the populace. This

19

19

19

19

19

Social impact is understandable because DHF can be TRENDS in Microbiology

The successful Ae. aegypti control a very dramatic disease; a patient can
program in the Americas was part of the have a non-specific viral syndrome and Fig. 3. Average annual number of cases of dengue/dengue
global success story against infectious progress to irreversible shock and death hemorrhagic fever reported to the WHO, 1955 –1999.

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102 Forum
understood, but it is clear that the highly
visible mosquito space sprays, and the
reassurance by the government that they
are controlling the epidemic, results in a
false sense of security by the public who
then continue to do nothing to control the
mosquitoes in and around their homes,
thus perpetuating the epidemic cycles.
The end result is that neither the
government nor the public do anything
to prevent the social disruption that
accompanies epidemic DF/DHF. Instead
they live from epidemic to epidemic under
the misguided belief that it is beyond
their control [12].
Economic impact
It is difficult to measure the economic
impact of epidemic DF/DHF on a
community, and few studies have been
attempted. Those that have, generally
focused on single epidemics and have not
taken into account the total burden of the
disease on a population, mainly because
it is difficult to put a dollar value on an
illness like DF that has a relatively low
CFR but causes social disruption. Even so,
some estimates have been made. The 1977
epidemic in Puerto Rico was estimated to
have cost between US $6 and $16 million
in medical costs and control measures,
and the 1994 epidemic on the same island
was estimated to have cost US $12 million
in medical costs alone [13,14]. The 1981
epidemic in Cuba was estimated to have
cost US $103 million, nearly half of that
being for mosquito control [15]. In
Thailand, the annual economic burden
of DHF on the country was estimated
to range between US $31.5 and
$51.5 million, depending on epidemic
activity [16]. Approximately 45% of these
costs are paid by the patients and their
families [17]; this economic burden
contributes greatly to the social impact
of epidemic DF/DHF.
These figures are gross underestimates
of the true economic impact of dengue
because they do not measure the total cost
of large epidemics of ‘flu-like illness on the
economy in, for example, lost work and
productivity, absence from school, lost
tourism and social disruption. Moreover,
the disease burden caused by this virus
during inter-epidemic periods has been
completely ignored because of the poor
surveillance. The World Bank has
developed a non-monetary composite
index called ‘disability-adjusted life years’
(DALYs), which attempts to measure
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TRENDS in Microbiology Vol.10 No.2 February 2002
the total impact of both morbidity and
mortality of a disease on the population
[18]. Recent studies using this approach
to measure the impact of DF/DHF have
shown that, in addition to the epidemic
periods, there is considerable disease
burden during inter-epidemic periods,
mostly in the form of unreported indirect
costs such as lost productivity and time
away from work or school owing to illness.
These studies have shown that DF/DHF
has a total impact of the same order of
magnitude as many of the major infectious
diseases such as malaria, tuberculosis,
hepatitis, bacterial meningitis and others
[4,19]. These diseases receive a great
deal of attention and funding from the
international funding agencies. For
example, in 1998, it is estimated that
US $84 million was directed at the global
malaria problem, whereas DF/DHF
received less than US $5 million [4]. In
recent years, this disparity has been
even greater.
Summary and conclusions
DF/DHF is one of the most important
emerging tropical diseases at the
beginning of the 21st century. The
resurgence of epidemic DF and the
emergence of DHF in the waning years of
the 20th century have been closely tied
with population growth, urbanization
and air travel [3,4]. Despite repeated
warnings, public health officials and
international funding agencies have
stood by and done nothing as this disease
spread rapidly on a global basis over the
past 20 years, with major epidemics
occurring primarily in the tropical
developing countries of the world.
Although DF/DHF has a public health,
social and economic impact comparable
to some of the most visible infectious
diseases, it is still perceived as
unimportant, and receives little attention
and even less funding for research,
prevention and control. This lack of
attention is not well understood, but is
probably the result of the ‘magic-bullet’
funding mentality of most international
agencies [20]; they want or demand a
quick-fix solution to the disease control
programs they support. Unfortunately,
there is no magic-bullet solution for
epidemic DF/DHF. Although funding for
dengue vaccine development has been
sparse, good progress has been made
over the past 10 years [21]. However, a
pediatric vaccine that can be used in
endemic countries to prevent epidemic
DF/DHF is still 10 or more years away. In
the meantime, we have the tools to
prevent epidemic DF/DHF by controlling
the principal vector mosquito, Ae. aegypti.
Thus, one of the most important public
health problems facing the tropical
developing world at the beginning of
the 21st century could be effectively
prevented if countries had the resources
and the political will to develop and
implement integrated community-based
prevention and control programs, as
recommended by the WHO and others
for more than 15 years [8,9].
References
1 Gubler, D.J. (1997) Dengue and dengue
hemorrhagic fever; its history and resurgence
as a global public health problem. In Dengue
and Dengue Hemorrhagic Fever (Gubler, D.J.
and Kuno, G., eds), pp. 1–22,
CAB International Press
2 Halstead, S.B. (1992) The XXth century dengue
pandemic: need for surveillance and research.
Rapport Trimestriel de Statistique Mondiales
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3 Gubler, D.J. (1998) Dengue and dengue
hemorrhagic fever. Clin. Microbiol. Rev.
11, 480–496
4 Gubler, D.J. and Meltzer, M. (1999) The impact of
dengue/dengue hemorrhagic fever on the
developing world. Adv. Virus Res. 53, 35–70
5 Rosen, L. (1977) The emperor’s new clothes
revisited, a reflection on the pathogenesis of
dengue hemorrhagic fever. Am. J. Trop. Med. Hyg.
26, 337–343
6 Rico-Hesse, R. et al. (1997) Origins of dengue
type 2 viruses associated with increased
pathogenicity in the Americas. Virology
230, 244–251
7 Halstead, S.B. (1997) Epidemiology of dengue and
dengue hemorrhagic fever. In Dengue and Dengue
Hemorrhagic Fever (Gubler, D.J. and Kuno, G.,
eds), pp. 23–44, CAB International Press
8 World Health Organization (2000)
Strengthening implementation of the global
strategy for dengue fever/dengue haemorrhagic
fever prevention and control. Report of the
Informal Consultation, 18–20 October 1999,
WHO, Geneva
9 Gubler, D.J. (1989) Aedes aegypti and Aedes
aegypti-borne disease control in the 1990s: top
down or bottom up. Am. J. Trop. Med. Hyg.
40, 571–578
10 Gratz, N.G. (1991) Emergency control of Aedes
aegypti as a disease vector in urban areas. J. Am.
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11 Newton, E.A.C. and Reiter, P. (1992) A model of
the transmission of dengue fever wth an
evaluation of the impact of ultra-low volume
(ULV) insecticide applications on dengue
epidemics. Am. J. Trop. Med. Hyg. 47, 709–720
12 Kendall, C. et al. (1993) Urbanization, dengue,
and the health transition: anthropological
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13 Von Allmen, S.D. et al. (1979) Epidemic dengue
fever in Puerto Rico, 1977: a cost analysis. Am. J.
Trop. Med. Hyg. 28, 1040–1044
 Forum
14 Rodriguez, E. (1997) Dengue outbreak in Puerto
Rico (1994–95): hospitalization cost analysis.
Centro de Investigaciones Socio Economicas, Inc.,
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fever/dengue shock syndrome: lessons from the
Cuban epidemic, 1981. Bull. WHO 67, 375–380
16 Sornmani, S. et al. (1995) Social and Economic
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Book Review
HIV therapy:
a complex issue
Antiretroviral Therapy
edited by Erik D.A. DeClercq
ASM Press, 2001.
$99.95 (hbk) (x + 359 pages)
ISBN 1 55581 156 6
Less than a decade
ago, a book on HIV
therapy would
either have been
very short or a
largely speculative
affair. Today, the
scope of issues
related to this topic
is extremely broad,
encompassing at
least 14 commercially available drugs and
numerous novel targets for therapy.
Issues of drug resistance, drug–drug
interactions, therapy toxicity, and
adherence are also vitally important.
In the preface of Antiretroviral Therapy,
Erik DeClercq defines the crucial issues as
follows: ‘…What are the optimal dosage
and drug combination schedules?…Could
and should total suppression of virus
replication be achieved? Should virus
eradication from sanctuary sites be
aimed for? How long must treatment be
continued, and could it be interrupted, or
even stopped altogether…Could drug
treatment schedules be improved so as to
minimize toxic side effects and optimize
the patient’s compliance? Should drug
treatment regimens be strictly guided by
geno- and phenotypic monitoring of the
virus…should we envisage molecular
targets other than reverse transcriptase
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TRENDS in Microbiology Vol.10 No.2 February 2002
18 Murray, C.J.L. and Lopez, A.D. (1996) The Global
Burden of Disease: Global Burden of Disease and
Injury Series (Vol. 1), Harvard School of Public
Health
19 Meltzer, M.I. et al. (1998) Using disability-
adjusted life years to assess the economic impact
of dengue in Puerto Rico: 1984–1994. Am. J. Trop.
Med. Hyg. 59, 265–271
20 Gubler, D.J. (2001) The President’s address. Prevention
and control of tropical diseases in the 21st century:
back to the field. Am. J. Trop. Med. Hyg. 65, v–xi
21 Kinney, R.M. and Huang, C.Y.H. (2001)
Development of new vaccines against dengue
and protease…? Should we put more
emphasis on the prevention of HIV
infection…? And should these efforts be
extended to make the anti-HIV agents that
are presently available…accessible for
therapeutic and prophylactic use in those
countries that are in the highest need?’
This is a succinct statement of the state of
current HIV therapy research, and the
thought that all issues could be addressed
in a single text is an ambitious goal.
DeClercq assembles an impressive
panel of opinion-leaders in HIV therapy
to address many of these questions, or at
least to provide an up-to-date review of
the state of HIV research. The focus of the
discussion of drug targets is their pre-
clinical pharmacology and mechanisms
of action, and the book includes very
comprehensive discussions of these areas
in chapters covering the nucleoside
analogs, non-nucleoside reverse
transcriptase inhibitors, protease
inhibitors, integrase inhibitors and
other, less familiar compounds including
inhibitors of transcription and
transactivation, oligonucleotides and
therapeutic vaccines. A review of the
state of research on cellular factors and
glycoprotein-processing enzymes as
targets is also presented in a very lucent
fashion. Discussions of clinical toxicities,
results of clinical trials and adherence
issues are presented, although in a more
cursory manner. Although an individual
chapter is devoted to combination
therapy, this discussion is, because of the
breadth of the topic, a summary review.
Important topics such as the timing of
treatment, the choice of initial regimen
and reducing toxicity are each covered in
only a paragraph. Two chapters are
devoted to the subject of drug resistance,
with an extremely well-stated review of
103
fever and Japanese encephalitis. Interviology
44, 176–197
Duane J. Gubler
Division of Vector-Borne Infectious Diseases,
National Center for Infectious Diseases,
Centers for Disease Control and Prevention,
Public Health Service, US Dept of Health and
Human Services, PO Box 2087, Fort Collins,
CO 80522, USA.
e-mail: dgubler@cdc.gov
the literature regarding the clinical
utility of resistance testing. The final
chapter, devoted to pharmacological
interactions, contains excellent reference
tables for drug interactions and a lucid
discussion of the interaction of the
cytochrome P450 and p-glycoprotein
systems and their relationship to
HIV therapy.
Clearly, no book can be all things to
all people. Antiretroviral Therapy is no
exception. At its best, it is an excellent
state-of-the-art review of the research
data in several HIV therapy-related
topics. That it fails to address fully many
of the questions posed by DeClercq in the
preface is not necessarily a fault, but
rather a reflection of the state of the field
of HIV research itself.
S. Wegner
Dept of Clinical Interventions
US Military HIV Research Program,
1600 E. Gude Drive, Rockville,
MD 20850, USA.
e-mail: swegner@hivresearch.org
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