Dengue Fever

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.

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 vessels.
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.

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.

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. 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.

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.

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
program.

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. 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. 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. 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 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.

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.

Although some specimens collected were not adequate for laboratory
diagnosis, preliminary data indicate that 481 (21%) cases were confirmed
as dengue. 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 aegypti
is found, are at risk for dengue transmission and sporadic outbreaks.

The reasons for this dramatic global emergence of dengue/DHF as a major
public health problem are complex and not well understood. 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.

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 cases.