Dengue and dengue hemorrhagic fever (DHF) are caused by
one of four closely related, but antigenically distinct,
virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4), of the
genus Flavivirus (1). Infection with one of these
serotypes does not provide cross-protective immunity, so
persons living in a dengue-endemic area can have four
dengue infections during their lifetimes. Dengue is
primarily an urban disease of the tropics, and the
viruses that cause it are maintained in a cycle that
involves humans and Aedes aegypti, a domestic, day-biting
mosquito that prefers to feed on humans. Infection with
a dengue virus serotype can produce a spectrum of
clinical illness, ranging from a nonspecific viral
syndrome to severe and fatal hemorrhagic disease.
Important risk factors for DHF include the strain and
serotype of the virus involved, as well as the age,
immune status, and genetic predisposition of the patient.
The first reported epidemics of dengue fever occurred in
1779-1780 in Asia, Africa, and North America; the near
simultaneous occurrence of outbreaks on three continents
indicates that these viruses and their mosquito vector
have had a worldwide distribution in the tropics for more
than 200 years. During most of this time, dengue fever
was considered a benign, nonfatal disease of visitors to
the tropics. Generally, there were long intervals (10-40
years) between major epidemics, mainly because the
viruses and their mosquito vector could only be
transported between population centers by sailing
A global pandemic of dengue begun in Southeast Asia after
World War II and has intensified during the last 15
years. Epidemics caused by multiple serotypes
(hyperendemicity) are more frequent, the geographic
distribution of dengue viruses has expanded, and DHF has
emerged in the Pacific region and the Americas (1,2). In
Southeast Asia, epidemic DHF first appeared in the 1950s,
but by 1975 it had become a leading cause of
hospitalization and death among children in many
countries. In the 1980s, DHF began a second expansion
into Asia when Sri Lanka, India, and the Maldive Islands
had their first major DHF epidemics; Pakistan first
reported an epidemic of dengue fever in 1994. The recent
epidemics in Sri Lanka and India were associated with
multiple dengue virus serotypes, but DEN-3 was
predominant and was genetically distinct from DEN-3
viruses previously isolated from infected persons in
those countries (3).
After an absence of 35 years, epidemic dengue fever
occurred in both Taiwan and the People's Republic of
China in the 1980s. The People's Republic of China had a
series of epidemics caused by all four serotypes, and its
first major epidemic of DHF, caused by DEN-2, was
reported on Hainan Island in 1985 (4). Singapore also had
a resurgence of dengue/DHF from 1990 to 1994 after a
successful control program had prevented significant
transmission for over 20 years (5). In other countries of
Asia where DHF is endemic, the epidemics have become
progressively larger in the last 15 years.
In the Pacific, dengue viruses were reintroduced in the
early 1970s after an absence of more than 25 years.
Epidemic activity caused by all four serotypes has
intensified in recent years with major epidemics of DHF
on several islands (6).
Despite poor surveillance for dengue in Africa, we know
that epidemic dengue fever caused by all four serotypes
has increased dramatically since 1980. Most activity has
occurred in East Africa, and major epidemics were
reported for the first time in the Seychelles (1977),
Kenya (1982, DEN-2), Mozambique (1985, DEN-3), Djibouti
(1991-92, DEN-2), Somalia (1982, 1993, DEN-2), and Saudi
Arabia (1994, DEN-2) (1,6, CDC, unpublished data).
Epidemic DHF has been reported in neither Africa nor the
Middle East, but sporadic cases clinically compatible
with DHF have been reported from Mozambique, Djibouti,
and Saudi Arabia (CDC, unpublished data).
The emergence of dengue/DHF as a major public health
problem has been most dramatic in the American region. In
an effort to prevent urban yellow fever, which is also
transmitted by Ae. aegypti, the Pan American Health
Organization organized a campaign that eradicated Ae.
aegypti from most Central and South American countries in
the 1950s and 1960s. As a result, epidemic dengue
occurred only sporadically in some Caribbean islands
during this period. The Ae. aegypti eradication program,
which was officially discontinued in the United States in
1970, gradually eroded elsewhere, and this species began
to reinfest countries from which it had been eradicated.
In 1995, the geographic distribution of Ae. aegypti was
similar to its distribution before the eradication
In 1970, only DEN-2 virus was present in the Americas,
although DEN-3 may have had a focal distribution in
Colombia and Puerto Rico (7). In 1977, DEN-1 was
introduced and caused major epidemics throughout the
region over a 16-year period (7). DEN-4 was introduced in
1981 and caused similar widespread epidemics (7). Also in
1981, a new strain of DEN-2 from Southeast Asia caused
the first major DHF epidemic in the Americas (Cuba) (7).
This strain has spread rapidly throughout the region and
has caused outbreaks of DHF in Venezuela, Colombia,
Brazil, French Guiana, Suriname, and Puerto Rico. By
1995, 14 countries in the American region had reported
confirmed DHF cases,
and DHF is endemic in many of these countries.
DEN-3 virus recently reappeared in the Americas after an
absence of 16 years. This serotype was first detected in
association with a 1994 dengue/DHF epidemic in Nicaragua
(8). Almost simultaneously, DEN-3 was confirmed in Panama
and, in early 1995, in Costa Rica (8, CDC, unpublished
data). In Nicaragua, considerable numbers of DHF were
associated with the epidemic, which was apparently caused
by DEN-3. In Panama and Costa Rica, the cases were
classic dengue fever.
Viral envelope gene sequence data from the DEN-3 strains
isolated from Panama and Nicaragua have shown that this
new American DEN-3 virus strain was likely a recent
introduction from Asia since it is genetically distinct
from the DEN-3 strain found previously in the Americas,
but is identical to the DEN-3 virus serotype that caused
major DHF epidemics in Sri Lanka and India in the 1980s
(R. Lanciotti; unpublished data). The new DEN-3 strain,
and the susceptibility of the population in the American
tropics to it, suggests that DEN-3 will spread rapidly
throughout the region and likely will cause major
epidemics of dengue/DHF in the near future.
In 1995, dengue is the most important mosquito-borne
viral disease affecting humans; its global distribution
is comparable to that of malaria, and an estimated 2.5
billion people are living in areas at risk for epidemic
transmission (Figure 3. [cannot be viewed in ASCII].) Each
year, tens of millions of cases of dengue fever occur
and, depending on the year, up to hundreds of thousands
of cases of DHF. The case-fatality rate of DHF in most
countries is about 5%: most fatal cases are among children.
There is a small, but significant, risk for dengue
outbreaks in the continental United States. Two competent
mosquito vectors, Ae. aegypti and Aedes albopictus, are
present and, under certain circumstances, each could
transmit dengue viruses. This type of transmission has
been detected twice in the last 15 years in south Texas
(1980 and 1986) and has been associated with dengue
epidemics in northern Mexico (7). Moreover, numerous
viruses are introduced annually by travelers returning
from tropical areas where dengue viruses are endemic.
From 1977 to 1994, a total of 2,248 suspected cases of
imported dengue were reported in the United States (9,
CDC, unpublished data). Although some specimens collected
were not adequate for laboratory diagnosis, preliminary
data indicate that 481 (21%) cases were confirmed as
dengue (9, CDC, unpublished data). Many more cases
probably go unreported each year because surveillance in
the United States is passive and relies on physicians to
recognize the disease, inquire about the patient's travel
history, obtain proper diagnostic samples, and report the
case. These data underscore the fact that southern Texas
and the southeastern United States, where Ae. aegypti is
found, are at risk for dengue transmission and sporadic
The reasons for this dramatic global emergence of
dengue/DHF as a major public health problem are complex
and not well understood (10). However, several important
factors can be identified. First, effective mosquito
control is virtually nonexistent in most dengue-endemic
countries. Considerable emphasis for the past 20 years
has been placed on ultra-low-volume insecticide space
sprays for adult mosquito control, a relatively
ineffective approach for controlling Ae. aegypti. Second,
major global demographic changes have occurred, the most
important of which have been uncontrolled urbanization
and concurrent population growth. These demographic
changes have resulted in substandard housing and
inadequate water, sewer, and waste management systems,
all of which increase Ae. aegypti population densities
and facilitate transmission of Ae. aegypti-borne disease.
Third, increased travel by airplane provides the ideal
mechanism for transporting dengue viruses between
population centers of the tropics, resulting in a
constant exchange of dengue viruses and other pathogens.
Lastly, in most countries the public health
infrastructure has deteriorated. Limited financial and
human resources and competing priorities have resulted in
a "crisis mentality" with emphasis on implementing
so-called emergency control methods in response to
epidemics rather than on developing programs to prevent
epidemic transmission. This approach has been
particularly detrimental to dengue control because, in
most countries, surveillance is very inadequate; the
system to detect increased transmission normally relies
on reports by local physicians who often do not consider
dengue in their diagnoses. As a result, an epidemic has
often reached or passed the peak of transmission before
it is detected.
No dengue vaccine is available. Recently, however,
attenuated candidate vaccine viruses have been developed
in Thailand. These vaccines are safe and immunogenic when
given in various formulations, including a quadrivalent
vaccine for all four dengue virus serotypes.
Unfortunately, efficacy trials in human volunteers have
yet to be initiated. Research is also being conducted to
develop second-generation recombinant vaccine viruses;
the Thailand attenuated viruses are used as a template.
However, an effective dengue vaccine for public use will
not be available for 5 to 10 years.
Prospects for reversing the recent trend of increased
epidemic activity and geographic expansion of dengue are
not promising. New dengue virus strains and serotypes
will likely continue to be introduced into many areas
where the population densities of Ae. aegypti are at high
levels. With no new mosquito control technology
available, in recent years public health authorities have
emphasized disease prevention and mosquito control
through community efforts to reduce larval breeding
sources (11). Although this approach will probably be
effective in the long run, it is unlikely to impact
disease transmission in the near future. We must,
therefore, develop improved, proactive, laboratory-based
surveillance systems that can provide early warning of an
impending dengue epidemic. At the very least,
surveillance results can alert the public to take action
and physicians to diagnose and properly treat dengue/DHF
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