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Perspectives
Dengue
(DF) 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 provides immunity to only that serotype for life, so persons
living in a dengue-endemic area can have more than one dengue infection
during their lifetime. DF and DHF are primarily diseases of tropical and
sub tropical areas, and the four different dengue serotypes are maintained
in a cycle that involves humans and the Aedes mosquito. However, Aedes aegypti,
a domestic, day-biting mosquito that prefers to feed on humans, is the
most common Aedes species. Infections 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
of the infecting virus, as well as the age, and especially the prior dengue
infection history of the patient.
The first reported epidemics of DF 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, DF was considered a mild, nonfatal disease of
visitors to the tropics. Generally, there were long intervals (10-40 years)
between major epidemics, mainly because the introduction of a new serotype
in a susceptible population occurred only if viruses and their mosquito
vector could survive the slow transport between population centers by
sailing vessels.
A pandemic of dengue began in Southeast Asia after World War II and has
spread around the globe since then. Epidemics caused by multiple
serotypes (hyperendemicity) are more frequent, the geographic distribution
of dengue viruses and their mosquito vectors has expanded, and DHF has
emerged in the Pacific region and the Americas. In Southeast Asia, epidemic
DHF first appeared in the 1950s, but by 1975 it had become a frequent
cause of hospitalization and death among children in many countries in
that region.
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 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 reemerged 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, 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). Epidemic DHF has not been reported in
Africa or 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 started 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
weakened elsewhere, and the mosquito began to reinfest countries from
which it had been eradicated. As a result, the geographic distribution
of Ae. aegypti in 2002 was much wider than that before the eradication
program (Figure 1).
Figure
1. Distribution of Aedes aegypti (red shaded areas) in the Americas
in 1970, at the end of the mosquito eradication program, and in 2002.
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. DEN-4 was introduced in 1981 and caused similar
widespread epidemics. Also in 1981, a new strain of DEN-2 from Southeast
Asia caused the first major DHF epidemic in the Americas (Cuba). 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 2003, 24 countries in the American region had reported confirmed
DHF cases (Figure 2), and DHF is now endemic in many of these countries.
Figure
2. American countries with laboratory-confirmed dengue hemorrhagic fever
(red shaded areas), prior to 1981 and from 1981 to 2003.
DEN-3 virus 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. Almost simultaneously, DEN-3 was confirmed in Panama and,
in early 1995, in Costa Rica.
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. As suggested by the finding of a new DEN-3 strain,
and the susceptibility of the population in the American tropics to it
DEN-3 spread rapidly throughout the region causing major epidemics of
dengue/DHF in Central America in 1995.
Figure
3. Presence of DEN-3 in the Americas from 1994 to 2003
In 2005, 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 live in areas at risk for epidemic transmission
(Figure 4). Each year, tens of millions of cases of DF 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%, but this can be reduced to
less than 1% with proper treatment. Most fatal cases are among children
and young adults.
Figure
4. World distribution of dengue viruses and their mosquito vector, Aedes
aegypti, in 2005.
There is a small 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 six times in the
last 25 years in south Texas (1980 -2004) and has been associated with
dengue epidemics in northern Mexico by Aedes aegypti and in Hawaii
(2001-02) due to Ae. albopictus. Moreover, numerous viruses
are introduced annually by travelers returning from tropical areas where
dengue viruses are endemic. From 1977 to 2004, a
total of 3,806 suspected cases of imported dengue were reported in the
United States. Although some specimens collected were not adequate for
laboratory diagnosis, 864 (23%) 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 suggest that states
in southern and southeastern United States, where Ae. aegypti is
found, are at risk for dengue transmission and sporadic outbreaks.
Although
travel-associated dengue and limited outbreaks do occur in the continental
United States, most dengue cases in US citizens occur as endemic transmission
among residents in some of the US territories. CDC conducts laboratory-based
passive surveillance in Puerto Rico in collaboration with the Puerto Rico
Department of Health. The weekly surveillance report from this collaboration can be found at: Dengue
Surveillance Report
The reasons for the dramatic global emergence of DF/DHF as a major public
health problem are complex and not well understood. However, several important
factors can be identified.
- First,
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.
- 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 (just as in the U.S.) passive; the system to detect increased transmission
normally relies on reports by local physicians who often do not consider
dengue in their differential diagnoses. As a result, an epidemic has
often reached or passed its peak before it is recognized.
- Increased
travel by airplane provides the ideal mechanism for infected human transport
of dengue viruses between population centers of the tropics, resulting
in a frequent exchange of dengue viruses and other pathogens.
- Lastly, effective
mosquito control is virtually nonexistent in most dengue-endemic countries.
Considerable emphasis in the past has been placed on ultra-low-volume
insecticide space sprays for adult mosquito control, a relatively ineffective
approach for controlling Ae. aegypti.
No dengue vaccine is available. Recently, however, attenuated candidate
vaccine viruses have been developed. Efficacy trials in human volunteers
have yet to be initiated. Research is also being conducted to develop
second-generation recombinant vaccine viruses. Therefore, 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 DF/DHF cases.
Glossary
of terms
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Endemic - means a disease occurs continuously and with predictable regularity
in a specific area or population .
Epidemic - a widespread outbreak of an infectious disease where many people are
infected at the same time.
Igm - a protein
that recognizes a particular epitope on an antigen and facilitates clearance
of that antigen and is the primary antibody response to a viral infection
Outbreak - an epidemic limited to localized
increase in the incidence of a disease, e.g., in a village, town, or closed
institution
Pandemic - an epidemic occurring worldwide,
or over a very wide area, crossing international boundaries, and usually
affecting a large number of people.
Recombinant
vaccine -
using
the technique of recombination to create an attenuated virus which elicits
an immune response against the viral strain of interest in order to use
as a vaccine in humans.
Seroytpe
- a closely
related set of viruses that can be differiented by the immune response
they produce.
Viral
envelope gene sequence - the nucleic acid composition
in the envelope gene
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