Download ~ IMPACT OF DENGUE/DENGUE HEMORRHAGIC FEVER ON THE

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ADVANCES IN VIRUS RESEARCH, VOL. 53
IMPACT OF DENGUE/DENGUE
HEMORRHAGIC
THE DEVELOPING WORLD
Duane J. Gubler*
FEVER ON
and Martin Meltzert
*Division of Vector-Borne Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Public Health Service
U.S. Department of Health and Human Services
Fort Collins, Colorado 80522
tOffice of Surveillance
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Public Health Service
U.S. Department of Health and Human Services
Atlanta, Georgia 30333
I.
II.
Introduction
Natural History
Transmission Cycles
III. Clinical Presentation
IV. Twentieth-Century Pandemic
V. Factors Responsible for Global Resurgence of Dengue
VI. Cases of Dengue Fever/Dengue Hemorrhagic Fever
A. Estimating Total Number of Cases
B. Assessing Global Economic Impact of Dengue Fever/Dengue
Hemorrhagic Fever
Appendix
References
I. INTRODUCTION
Epidemic dengue fever/dengue hemorrhagic fever (DEN/DHF) has
emerged as a global public health problem in the tropics in the past
20 years (1). This has been caused by the expanding geographic distribution of both the viruses and the principal mosquito vectors as a result
of global demographic and societal changes. During this period, most
tropical urban centers of the world have become hyperendemic (multiple dengue virus serotypes cocirculating), thus increasing the risk of
epidemic transmission and the emergence of DHF. Despite this dramatic emergence of an apparently new hemorrhagic disease, few estimates of the economic impact ofDEN/DHF have been attempted. There
have been some estimates of the dollar value of epidemics of dengue in
Puerto Rico (1977) (2), Cuba (1981) (3), and two outbreaks in Thailand
35
36
DUANE
GUBLER
AND
MARTIN
MELTZER
(1987-1988, 1994) (4,5), There are no readily available detailed dollar
estimates of the economic impact of endemic dengue, either for an
individual country or globally.
This report reviews the changing epidemiology of DEN/DHF, estimates the global growth in the number of casesofDEN/DHF from 1955
to 1996, and uses these incidence data to estimate the global economic
impact of this disease.
II. NATURAL HISTORY
There are four dengue virus serotypes: DEN-1, DEN-2, DEN-3, and
DEN-4 (1,6). They belong to the genus Flavivirus of the family Flaviviridae, which contains approximately 70 viruses (yellow fever is the type
species).There are several complexes within the Flaviviridae, including
those that are responsible for most human diseases,tick-borne encephalitis, Japanese encephalitis, yellow fever, and dengue. All flaviviruses
have common group epitopes on the envelope protein that result in
extensive cross-reactions in serologic tests, making unequivocal serologic diagnosis offlaviviruses difficult. This is especially true of the four
dengue viruses. Infection with one dengue serotype provides lifelong
immunity to that virus, but there is no cross-protective immunity to
the other serotypes (1,6). Thus persons living in a dengue-endemic area
can be infected with all four serotypes during their lifetime.
Transmission Cycles
The primitive enzootic transmission cycle of dengue viruses involves
canopy-dwelling Aedes species mosquitoes and lower primates in the
rain forests of Asia and Africa (6). Current evidence suggests that these
viruses do not regularly move out of the forest to urban areas and thus
are of little public health importance (7). An epidemic transmission
cycle may occur in rural villages or islands where the human population
is small. Introduced viruses quickly infect the majority of susceptible
individuals in these areas, and increasing herd immunity causes the
virus to disappear from the population. A number of Aedes (Stegomyia)
mosquito species may act as vectors in these situations, including Ae.
aegypti, Ae. albopictus, Ae. polynesiensis, and other members of the Ae.
scutellaris group. The most important transmission cycle from a public
health standpoint is the urban endemic/epidemic cycle, which now
occurs in most large urban centers of the tropics (1,4,6). The viruses are
maintained in an Ae. aegypti-human-Ae. aegypti cycle, with periodic
epidemics occurring at 3- to 5-year intervals. Often multiple virus sero-
types cocirculat
by different vir
Humans are
Aedes mosquito
black and whit
to lay its eggsin
found in and at
tires and parts
for water storal
some septic tan
toes in close pr,
Adult Ae. aE
indoors and to f
ally two peaks ,
after daybreak
However, these
on overcast da:
disrupting the f,
to the same or
Because of this
persons during
dengue virus to
only probe with
members of the
36-hour period,
infective mosqu
(1,9). It is this .
demic vector. II
of the presence
After a perso:
for 3 to 14 day
experience acut
signs and symp
as short as 2 da)
may circulate ir
the sick person
may become in
uninfected persl
Infection wit
spectrum of illn
~!
IMP ACT OF DENGUE
37
types cocirculate in the same city, with periodic epidemics being caused
by different viruses.
Humans are infected with dengue viruses by the bite of an infective
Aedes mosquito (6). Aedes aegypti, the principal urban vector, is a small,
black and white, highly domesticated, tropical mosquito that prefers
to lay its eggsin artificial containers that collect or hold water commonly
found in and around homes, for example, flower vases, old automobile
tires and parts, buckets, cans, and trash in general. Containers used
for water storage, such as 55-gallon drums, cement cisterns, and even
some septic tanks, produce large numbers of adult Ae. aegypti mosquitoes in close proximity to human dwellings.
Adult Ae. aegypti mosquitoes are unobtrusive, preferring to rest
indoors and to feed on humans during daylight hours. There are generally two peaks of biting activity: in the early morning for 2 to 3 hours
after daybreak and in the afternoon for several hours before dark.
However, these mosquitoes will feed all day indoors, in the shade, and
on overcast days. The female mosquitoes are very nervous feeders,
disrupting the feeding process at the slightest movement, only to return
to the same or a different person to continue feeding moments later .
Because of this behavior, Ae. aegypti females will often feed on several
persons during a single blood meal and, if infective, may transmit
dengue virus to multiple persons in a short period of time, even if they
only probe without taking blood (8). It is not uncommon to see several
members of the same household contract dengue fever within a 24- to
36-hour period, suggesting transmission to all of them by a single
infective mosquito (D. J. Gubler, 1977, 1984, 1986, unpublished data)
(1,9). It is this behavior that makes Ae. aegypti such an efficient epidemic vector. Inhabitants of dwellings in the tropics are rarely aware
of the presence of this mosquito, making its control difficult.
After a person is bitten by an infective mosquito, the virus incubates
for 3 to 14 days (average, 4 to 7 days), after which the person may
experience acute onset of fever accompanied by a variety of nonspecific
signs and symptoms. During this acute febrile period, which may be
as short as 2 days or as long as 10 days (average, 5 days), dengue viruses
may circulate in the peripheral blood (6). Ifuninfected mosquitoes bite
the sick person during this febrile viremic stage, these mosquitoes
may become infected and subsequently transmit the virus to other,
uninfected persons after an extrinsic incubation period of 8 to 12 days.
III.
CLINICAL PRESENTATION
Infection with dengue viruses of all four serotypes may cause a
spectrum of illness ranging from inapparent infection, to a mild, non-
38
DUANE J. GUBLER AND MARTIN MELTZER
specific viral syndrome, to classical DEN, to severe and fatal DHF. In
dengue-endemic areas, the viruses may cycle silently during interepidemic periods, causing primarily a mild viral syndrome in children (1).
Classical DEN is primarily a disease of older children and adults. It
is characterized by fever, frontal headache, retroorbital pain, myalgia,
malaise, nausea and vomiting, altered taste sensation, rash, and, on
occasion, bone and joint pain (10). Hemorrhagic manifestations are not
uncommon. Leukopenia with a left shift occurs in most patients, and
there may be thrombocytopenia and elevated liver enzymes. The disease may last for 2 to 10 days. It is rarely fatal, and recovery is complete (10).
DHF is most commonly a disease of children in Asia, where most
adults are immune (11). In the Americas, however, DHF occurs in both
children and adults (12,13). The acute stage of DHF is difficult to
differentiate from that of viral syndrome or classical DEN. The critical
stage occurs when the temperature falls to or below normal. At that
time, the patient may present with hemorrhagic manifestations and/
or signs of circulatory failure, go into shock, and die if DHF is not
recognized and treated (11). The principal pathophysiologic change in
DHF is vascular leakage. All patients have hemoconcentration or other
objective evidence of plasma leakage such as pleural effusions and
hypoproteinemia. The vascular leak may be mild and transient or severe, causing hypovolemia, shock, and death. All DHF patients have
thrombocytopenia, and most have elevated levels of liver enzymes. If
DHF is properly managed, recovery is generally rapid and uneventful
(11). Case fatality rates in countries with good case management are
generally below 1%.
IV.
TwENTIETH-CENTURY
PANDEMIC
The disease pattern associated with dengue-like illness from 1780
to 1940 was characterized by relatively infrequent but often large epidemics (1,6,14). The epidemiology of dengue viruses changed with the
ecologic disruption in Southeast Asia during World War .II, with a
greatly expanded geographic distribution and increased population
densities of Ae. aegypti and increased movement of viruses between
cities, countries, and other regions, primarily in soldiers (1,6,14). The
war years were thus responsible for creating the conditions (hyperendemicity and high densities of Ae. aegypti) for the emergence of DHF
in Southeast Asia.
In the years following World War II, unprecedented economic growth
and urbanization of Southeast Asia began, with millions of people mov-
ing to the citi
expanded rapi.
was inadequa1
deteriorated. 1
in this new e(
quency of denl
of children. Th
today, leading
people (and, w
(1). Those COUJ
virus serotype
four serotypes,
in most urban
was dramatica
gence of DHF .
public health I
as sporadic caE
nating in a m~
epidemic activ
5 years. Chara
larger as a res
The first Dl
the Philippine
gests that earl
known (1,15).
recognized, it ,
it had become
dren by the mi
geographic ex]
India, Pakista:
People's Repul
in Singapore, v
in 1996 (16).
SurveillancE
cases are repo
Thus, only the
the most undeI
Even so, appr(
to WHO durin!
30 years (Fig.
and death am(
IMP ACT OF DENGUE
39
ing to the cities of the region (1). Urban centers in most countries
expanded rapidly in an uncontrolled and unplanned fashion. Housing
was inadequate, and water, sewer, and waste management systems
deteriorated. The Ae. aegypti populations and dengue viruses thrived
in this new ecologic setting: transmission increased, as did the frequency of dengue epidemics occurring in the indigenous populations
of children. The economic expansion that began in the region continues
today, leading to continued urbanization and increased movement of
people (and, with them, dengue viruses) between cities and countries
(1). Those countries that did not already have multiple cocirculating
virus serotypes quickly became hyperendemic. The viruses, often all
four serotypes, were maintained in a human-Ae. aegypti-human cycle
in most urban centers of Southeast Asia. The result of these changes
was dramatically increased dengue virus transmission and the emergence of DHF. In every country where the disease emerged as a major
public health problem, it evolved in a similar manner, :first appearing
as sporadic casesofDHF occurring for several years, ultimately culminating in a major epidemic. Following the :first epidemic, a pattern of
epidemic activity was established, with epidemics occurring every 3 to
5 years. Characteristically, succeeding epidemics became progressively
larger as a result of geographic expansion of DHF within the country .
The :first DHF epidemic ever recorded as such occurred in Manila,
the Philippines, in 1953-1954, although retrospective analysis suggests that earlier outbreaks occurred before the etiology of dengue was
known (1,15). During the :first 20 years in which epidemic DHF was
recognized, it was localized in several Southeast Asia countries, where
it had become a major cause of hospitalization and death among children by the mid-1970s (11). The 1980s and early 1990s saw a dramatic
geographic expansion of epidemic DHF in Asia; it moved west into
India, Pakistan, Sri Lanka, and the Maldive Islands and east into the
People's Republic of China (1). There was also a resurgence of disease
in Singapore,whichled to the highest incidence in that country's history
in 1996 (16).
Surveillance for DHF is passive in most Asian countries; only severe
cases are reported to the World Health Organization (WHO) (1,11).
Thus, only the tip of the iceberg is known, making DENJDHF one of
the most underreported tropical infectious diseasesin the past 20 years.
Even so, approximately four times as many DHF cases were reported
to WHO during the 15-year period from 1981 to 1995 as in the previous
30 years (Fig. 1). In 1998, DHF was a leading cause of hospitalization
and death among children in many countries of Asia (11,17).
40
DUANE J. GUBLER AND MARTIN MELTZER
5
4
«
(/)
0>
(/)
cu
()
"6
O
z
3
2
0
1950-1980
1981-1998
.Reports to WHO; Millions of Cases
FIG 1. Number ofDHF casesreported to WHO, 1950-1980 and 1981-1998. *Millions
of cases.
Activities related to World War II also resulted in expanded geographic distribution and increased densities of Ae. aegypti in the south
and central Pacific Islands. A major regional pandemic ofDEN-l occurred on most islands from 1942 to 1945, affecting both indigenous
and military populations (18). Following the war, the isolation of the
Pacific Islands and their small human populations resulted in the disappearance of dengue viruses from the area until the mid-1960s, when
a small outbreak ofDEN-3 occurred in Tahiti (19). In late 1971, DEN2 was introduced into the Pacific, followed in 1975 by a new strain of
DEN-l, in 1979 by DEN-4, and in the early 1980s by a new strain of
DEN-3 (1,20). All virus serotypes caused major epidemics ofDEN, and
some islands experienced severe hemorrhagic disease compatible with
DHF. The events in the Pacific have been reviewed in detail (1).
Epidemic dengue occurred rarely in Caribbean Basin countries after
the 1930s, and from 1946 to 1963 there was no recorded epidemic
transmission, despite evidence that at least one serotype (DEN-2) was
endemic in the region (1,21,22). Epidemic dengue did not reemerge as
a public health problem in the Americas until the late 1970s (23,24).
This 40-year period of quiescence was probably due to several factors,
the most important of which was the Ae. aegypti eradication program
initiated by the Pan American Health Organization (PAHO) in 1946
to prevent urban epidemics of yellow fever (25). The program was
successful, and
(Fig. 2). Unfor1
1970s, and faiv
suIted in repea
that had achie'
Ae. aegypti sur
merged with m.
of the decade, J
The reinfestati<
(1,17,24). In 19!
1940s before er
The expandi:
and 1980s coin<
into and withiI
DEN-2 and DE:
although DEN.
caused the firs1
Rico in 1963, an
again in the Ca
been achieved. :
distinct genetic
in Colombia an<
pearing from th,
of the Americas
mi city (no viru!
present) (22-24
DEN-1 was I
demics in Jam~
1978 (23). In th
the Caribbean 1.
South America,
of these epidem
into the eastern
spread rapidly t
America, and n<
ics, many of th
epidemics. Som
Puerto Rico, 19
gence of DHF f
the most part (
isolated in each
also present.
~
IMPACT OF DENGUE
41
successful, and eradication was achieved in most countries of the region
(Fig. 2). Unfortunately, the program was discontinued in the early
1970s, and failure to eradicate Ae. aegypti from the whole region resulted in repeated reinfestations by this mosquito of those countries
that had achieved eradication (24,26). During the 1970s, support for
Ae. aegypti surveillance and control programs waned, as they were
merged with malaria control programs in many countries. By the end
of the decade, many countries had been reinfested with Ae. aegypti.
The reinfestation of the region continued during the 1980s and 1990s
(1,17,24). In 1999, Ae. aegypti had a distribution similar to that in the
1940s before eradication was initiated (Fig. 2).
The expanding geographic distribution of Ae. aegypti in the 1970s
and 1980s coincided with increased movement of dengue viruses both
into and within the American region (24,26,27). Prior to 1977, only
DEN-2 and DEN-3 viruses were known to be present in the Americas,
although DEN-l was probably present in the early 1940s. DEN-3
caused the first epidemics in nearly 20 years in Jamaica and Puerto
Rico in 1963, and DEN-2 caused epidemics in 1969 and the early 1970s,
again in the Caribbean Islands, where Ae. aegypti eradication had not
been achieved. Both of these viruses were maintained in the region as
distinct genetic genotypes, and DEN-3: caused subsequent epidemics
in Colombia and Puerto Rico in the mid-1970s before apparently disappearing from the region (1). A characteristic of dengue in most countries
of the Americas from the 1950s through the early 1980s was nonendemicity (no viruses present) or hypo endemicity (only a single serotype
present) (22-24,27).
DEN-l was reintroduced to the American region in 1977, with epidemics in Jamaica and Cuba, and in Puerto Rico and Venezuela in
1978 (23). In the succeeding 4 years, this serotype spread throughout
the Caribbean Islands, Mexico to Texas, Central America, and northern
South America, causing major or minor epidemics. The illness in all
of these epidemics was classical DEN. In 1981, DEN-4 was introduced
into the eastern Caribbean islands (24). Like DEN-l, this serotype also
spread rapidly to other islands in the Caribbean and to Mexico, Central
America, and northern South America, causing major or minor epidemics, many of them in countries that had experienced recent DEN-l
epidemics. Some of these outbreaks (Suriname, 1982; Mexico, 1984;
Puerto Rico, 1986; El Salvador, 1987) were associated with the emergence of DHF for the first time in history, occurring sporadically for
the most part (24,27). Although DEN-4 was the predominant virus
isolated in each of these epidemics, other dengue virus serotypes were
also present.
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Also in 1981, E
into Cuba from S(
ics, the 1981 Cul
of cases of severe
epidemic in the ,
10,312 cases ofD
likely because of
persons suspecte<
116,343 persons v
apy (28). Althoug
for study, DEN-2
the Cuban epideJ
quenced. The dat
new strain introd
several thousanc
(D. J. Gubler, un"
The second m;
Venezuela in 19t
The virus serotYI
1,DEN-2, and DE
DEN-2 appeared
Pinheiro, PAHO,
same genotype as
in 1981 (30,31). J
genotype of DEN.
Rico, and Mexico
as the Cuban epic
2 occurred in Per
studies of this rn
to the same geno"
In 1994, a ne\\
region, causing a
small outbreak a
virus was shown
viouslyoccurred
the virus that ca
Sri Lanka and II
Gubler, unpublisJ
ently was also a
throughout CentJ
demics (34). In J;
IMP ACT OF DENGUE
43
Also in 1981, a strain of DEN-2 new to the region was introduced
into Cuba from Southeast Asia. Unlike the DEN-1 and DEN-4 epidemics, the 1981 Cuban DEN-2 epidemic was associated with thousands
of cases of severe hemorrhagic disease; this was the first major DHF
epidemic in the Americas (3,28). Although there were an estimated
10,312 cases of DHF, the case fatality rate was low (158 deaths), most
likely because of rapid hospitalization and effective management of
persons suspected to have DHF; in the 3-month period of the epidemic,
116,343 persons were hospitalized and received fluid replacement therapy (28). Although the viruses isolated in Cuba have been unavailable
for study, DEN-2 viruses isolated in Jamaica during and shortly after
the Cuban epidemic (D. J. Gubler, unpublished data, 1982) were sequenced. The data suggest that the virus causing the epidemic was a
new strain introduced from Asia, most likely from Vietnam (7), where
several thousand Cuban aid personnel were working at the time
(D. J. Gubler, unpublished data, 1989).
The secopd major epidemic of DHF in the Americas occurred in
Venezuela in 1989-1990, with over 6000 cases and 73 deaths (29).
The virus serotype responsible is not definitely known because DEN1, DEN-2, and DEN-4 viruses were all isolated from patients. However,
DEN-2 appeared to b~ most frequently associated with fatal cases (F.
Pinheiro, PAHO, personal communication, 1991); this virus was the
same genotype as the virus thought to have caused the Cuban epidemic
in 1981 (30,31). DHF epidemics of variable intensity caused by this
genotype of DEN-2 subsequently occurred in Colombia, Brazil, Puerto
Rico, and Mexico, but none was of the same magnitude and severity
as the Cuban epidemic of 1981. Ofinterest is that an epidemic ofDEN2 occurred in Peru in 1995, with no DHF cases reported (32). Genetic
studies of this DEN-2 virus strain, however, showed that it belonged
to the same genotype as the strain that was present prior to 1981.
In 1994, a new strain of DEN-3 was introduced into the American
region, causing a major epidemic of DEN/DHF in Nicaragua and a
small outbreak associated with classical DEN in Panama (33). This
virus was shown to be genetically distinct from the DEN-3 that previously occurred in the Americas. It belongs to the same genotype as
the virus that caused the DHF epidemics of the 1980s and 1990s in
Sri Lanka and India (R. Lanciotti, I. Quiros, G. G. Clark, and D. J.
Gubler, unpublished data, 1994). This strain of DEN-3, which apparently was also a recent introduction from Asia, subsequently spread
throughout Central America and Mexico in 1995, causing major epidemics (34). In January 1998 it was detected in Puerto Rico and will
.
44
DUANE J. GUBLER AND MARTIN MELTZER
likely spread quickly to other Caribbean islands and South America
(CDC, unpublished data, 1998).
The sequence of events associated with the changing epidemiology
ofDENIDHF in the Americas in the 1970s, 1980s, and 1990s was nearly
identical to that which occurred in Southeast Asia in the 1950s, 1960s,
and 1970s (24,27). Thus, reinvasion of Central and South America by
Ae. aegypti in the 1970s and 1980s, combined with increased urbanization, increased movement of people, and, with them, dengue viruses,
resulted in most countries evolving from nonendemicity or hypoendemicity to hyperendemicity. This resulted in an increased frequency of
epidemic activity and the emergence ofDHF. Several countries (Cuba,
Venezuela, Brazil, Colombia, and Nicaragua) had major epidemics
of DHF in the 1980s and 1990s. Moreover, outbreaks with sporadic
or small numbers of cases of DHF have occurred in Panama, Costa
Rica, Nicaragua, Honduras, El Salvador, Guatemala, Mexico, Colombia, French Guiana, Suriname, Aruba, Trinidad, Barbados, St. Lucia,
Puerto Rico, Jamaica, the Dominican Republic, the U .S. Virgin Islands,
Martinique, and Cura~ao. In 1980, DHF was not considered endemic
in any American country. Between 1981 and 1998, however, there was
a dramatic emergence of DHF, with 24 countries reporting laboratoryconfirmed DHF that met the WHO case definition (Fig. 3) (35). This
disease is now endemic in most of the countries where multiple dengue
virus serotypes cocirculate, and the number of cases reported to PAHO
has increased dramatically (Fig. 4). If the disease pattern continues to
evolve in the Americas as it did in Southeast Asia, the initial years of
the twenty-first century will bring more frequent and larger epidemics
of DHF .
Surveillance for DENIDHF in Africa was poor during the twentieth
century (1). Prior to the 1980s, confirmed DEN epidemics were rare.
Endemic transmission of DEN-l and DEN-2 was documented in
Nigeria, but outbreaks were not reported (36). Although surveillance
did not improve, reports of epidemic dengue fever increased dramatically after 1980 (1). Limited outbreaks occurred in West Africa (Angola,
1986; Senegal, 1990), but most of the epidemic activity occurred in East
Africa and the Middle East, including the Seychelles (1977), Kenya
(1982), Mozambique (1985), Sudan (1985), Djibouti (1991), Somalia
(1982, 1993), Comoros (1993), Saudi Arabia (1994), and Eritrea (1997).
All four dengue virus serotypes were involved, but to date, epidemic
DHF has not been reported in Africa or the Middle East. However,
sporadic cases of disease clinically compatible with DHF have been
reported from Mozambique, Djibouti, and Saudi Arabia (1).
Prior to
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46
DUANE J. GUBLER AND MARTIN MELTZER
v.
FACTORS
RESPONSIBLE
FOR
GLOBAL
RESURGENCE
OF DENGUE
The reasons for the dramatic resurgence of epidemic DEN/DHF in
the waning years of the twentieth century are complex and not fully
understood, but are most likely associated with demographic and societal changes that have occurred over the past 50 years. These changes
have been reviewed (1,17,37). Briefly, unprecedented population
growth, primarily in tropical developing countries, with coincident uncontrolled and unplanned urbanization, has resulted in large, crowded
human populations living in urban centers in substandard housing
with inadequate water, sewer, and waste management systems. Lack
of effective mosquito control plus increased types and numbers oflarval
habitats (such as automobile tires, buckets, tins, used appliances/machinery, and flower pots in the urban environment) have resulted in the
expanded geographic distribution and increased population densities of
the principal mosquito vector, Ae. aegypti (26,38). Thus, hundreds of
millions of people in urban centers of the tropics are living in intimate
association with large populations of an efficient epidemic mosquito
vector of dengue viruses. Increased air travel by humans who are incubating the virus is an ideal mechanism for transporting dengue viruses
between population centers of the tropics, resulting in increased movement and a constant exchange of dengue viruses among cities and
countries in different regions (1,17,37).
Finally, the public health infrastructure required to deal with epidemic vector-borne infectious diseaseshas deteriorated during the past
30 years in most countries of the world (1,37). Limited financial and
human resources, as well as competing priorities for those resources,
have resulted in a crisis mentality among public health officials (26).
The emphasis has thus been on implementing emergency mosquito
control programs in response to epidemic transmission rather than on
developing effective strategies to prevent epidemics. The emergency
response approach has been particularly detrimental to dengue prevention and control because in most countries surveillance is insensitive;
the passive surveillance systems relied on to detect increased transmission are dependent on reports by local physicians, who often have a
low index of suspicion and do not consider dengue in their differential
diagnosis of dengue-like illness (6,26). As a result, the epidemic often
reaches or passes peak transmission before it is detected, and emergency control measures are almost always implemented too late to have
any impact on the course of the epidemic.
VI.
ESTIMATED CA1
In 1999, DEN!D
tropical infectious (
billion) living in aI
has been estimated
DEN, 500,000 hosp:
estimates are base
there are many caE
case report data tc
accurately, the tot
calculations, we ha'
below are still prot
A
1. Database
The WHO has a
occasionally DEN)
WHO-defined regia
America, and the (
Switzerland). SomE
the economic impa.
of other infectious I
subtracted the nun
Southeast Asia aru
combined the rema:
Southeast Asia (Ta
2. Asia
Since the numb.
iceberg (27), the fi]
DHF is to estimatl
data from the WHC
Pacific, and excludj
to estimate actual
*Countries in WHO-c
Bhutan, Korea (DPR), .
Lanka, Thailand. West.
Kong (now reintegrated
Papua New Guinea, the
I
47
IMPACT OF DENGUE
VI.
ESTIMATED CASES OF DENGUE FEVER/DENGUE HEMORRHAGIC FEVER
In 1999, DEN/DHF was the second (after malaria) most important
tropical infectious disease, with over half of the world's population (2.5
billion) living in areas of risk for dengue transmission (1) (Fig. 5). It
has been estimated that each year there are 50 to 100 million cases of
DEN, 500,000 hospitalized DHF patients, and 25,000 deaths (39). These
estimates are based on the fact that for every case of DHF reported,
there are many cases of DEN that go unreported. Here we use WHO
case report data to estimate, more systematically and perhaps more
accurately, the total number of cases of DEN/DHF. In all of these
calculations, we have used conservative estimates, so the numbers used
below are still probably underestimates.
A.
Estimating
Total
Number
of Cases
1. Database
The WHO has assembled a database on the number of DHF (and
occasionally DEN) cases reported during the years 1955-1996 in the
WHO-defined regions of Southeast Asia,* the Western Pacific,* Latin
America, and the Caribbean (courtesy of R. Aurthur, WHO, Geneva,
Switzerland). Some of these data have been published (35). To compare
the economic impact of dengue estimated in this study to the impact
of other infectious diseases estimated by a World Bank study (40), we
subtracted the number of reported cases for India and China from the
Southeast Asia and Western Pacific data sets, respectively. We then
combined the remaining data from Asia to form a data set representing
Southeast Asia (Table I).
2. Asia
Since the number of reported cases represents only the tip of the
iceberg (27), the first step in assessing the economic impact of DEN/
DHF is to estimate the number of actual cases. With the use of the
data from the WHO-defined regions of Southeast Asia and the Western
Pacific, and excluding India and China, two methodologies were used
to estimate actual number of cases. Method A estimates the number
*Countries in WHO-defined regions are as follows. Southeast Asia region: Bangladesh,
Bhutan, Korea) (DPR), India, Indonesia, the Maldives, Myanmar (Burma), Nepal, Sri
Lanka, Thailand. Western Pacific region: Australia, Brunei, Cambodia, China, Hong
Kong (now reintegrated into China), Japan, Laos, Malaysia, Mongolia, New Zealand,
Papua New Guinea, the Philippines, Korea (Rep.), Singapore, Vietnam, Pacific Islands.
~
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AND OF DENGU:
NUMBER OF CASES OF
Asia
Southej
89
1,123
141
2,793
266
2,456
1,957
6,335
2,777
8,989
4,861
15,191
4,132
8,322
10,256
5,823
15,769
28,851
35,405
23,016
45,536
38,387
94,984
41,414
101,675
97,077
71,406
74,182
198,126
119,268
150,155
98,873
579,188
169,231
146,481
194,252
198,960
131,846
158,656
.
I
TABLE
NUMBER OF CASES OF DENGUE HEMORRHAGiC
I
FEVER IN SOUTHEAST AsiA,
AND OF DENGUE FEVER AND DENGUE HEMORRHAGiC
INDIA, AND CHINA
FEVER IN LATIN AMERICA,
THE CARIBBEAN, AND SINGAPORE."
Reported
cases of dengue
Latin
America and
Southeast
rear
1955
1956
1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
Asia
89
1,123
141
2,793
266
2,456
1,957
6,335
2,777
8,989
4,861
15,191
4,132
8,322
10,256
5,823
15,769
28,851
35,405
23,016
45,536
38,387
94,984
41,414
101,675
97,077
71,406
74,182
198,126
119,268
150,155
98,873
579,188
169,231
146,481
194,252
198,960
131,846
158,656
India
China
7
84
11
7
9
46
105
29
42
92
58
705
154
137
107
70
246
199
1,249
587
1,239
1,586
3,238
1,494
6,179
3,512
85,293
51,510
37 ,886
376
6,291
2,683
11,125
902
46,095
359
Caribbean
550
821
822
27 ,667
22,367
4 ,703
7 ,758
1,337
970
21,224
587
65
119
821
524
1,244
0
478,442
291,498
1,497
66,018
388,729
68,930
40,716
39,311
66,993
88,708
134,397
47,783
89,138
116,389
158,110
104,291
63 ,531
Singapore
848
189
71
116
64
1,187
229
59
30
92
384
156
244
133
216
205
86
126
354
436
245
944
1,733
2,179
2,878
837
{continues)
49
50
DUANE J. GUBLER AND MARTIN MELTZER
TABLE I (Continued
1998 Puerto Rico
groups and the D
for Asia (see Tab.
Reported cases of dengue
Latin
Asia
1994
1995
1996
141,958
216,133
217,447
4. Comparison 01
America and
Southeast
India
7,494
7,847
16,517
China
2
6,114
7
Caribbean
150,860
284,483
250,707
Singapore
1,216
2,008
3,128
a Reported to WHO. The countries included here in Southeast Asia are the sum of
two WHO-defined regions. The Southeast Asia region includes Bangladesh, Bhutan,
Korea (DPR), Indonesia, the Maldives, Myanmar (Burma), Nepal, Sri Lanka, and Thailand. The Western Pacific region includes Australia, Brunei, Cambodia, Japan, Laos,
Malaysia, Mongolia, New Zealand, Papua New Guinea, the Philippines, Korea (Rep.),
Singapore, Vietnam, and the Pacific Islands.
When 5-year i
cases for Southea
to the growth in
cases for Southel
Caribbean were c.
were plotted on t
Pearson producttween the estim,
t-test was then UE
coefficient (45).
5. Number of Del
of annual cases by multiplying the number of reported cases by a
factor of 165 to 112, depending on the actual year (see Appendix for
further details).
Method B is an incidence-based approach. First, we calculated the
incidence of all cases per million population in a specific country in
Asia (an "indicator" country). This estimated incidence per million population was then multiplied by the total population in the United
N ations-defined region of Southeast Asia t to provide an estimate of all
cases ofDEN and DHF in Asia (excluding India and China). Based on
the availability of data, Malaysia and Singapore were chosen as indicator countries. The Appendix contains a more detailed explanation, as
well as the values used with this method.
3. Latin America and the Caribbean
The total number of cases in the Latin American and Caribbean
region was calculated by proportioning the DEN and DHF case reports
for Latin America and the Caribbean into two age groups (:515 years
and > 15 years) using age distribution data (41-44) and multiplying
the number in each by the same age-dependent multipliers used in a
tThe countries defined by the United Nations as being in Southeast Asia are Brunei
Cambodia, Indonesia, Laos, Malaysia, Myanmar (Burma), the Philippines, Singapore
Thailand, and Vietnam (41), ,
Murray and I
numbers of deat
researchers prese
studied here. Ho,
estimates. For eJi
and the Caribbe.
had 7000 deaths,
from DEN and I
and the Caribbe
and 0, respectivel
numbers of deatl
deaths may be u
reported number
suggest that the
reported. Thus,
deaths probably:
DEN and DHF c
6. Results: Numb
As determined
cases in Southea
dramatically over
1956, the estimaj
119,000, respectiv
approximately 14
52
DUANE J. GUBLER AND MARTIN MELTZER
70
500
[Correlation
of population
to Method
A: R = 0.93]
"ii)' 60
c:
450
...
~
Population of Southeast Asia
(right-hand scale)
-
I
50
LL
I
O
"U 40
c:
ro
Z
UJ 30
O
<Ii
0)
In
(/)
c:
.
350
~
I
Method
c:
O
A
300 :i:j
tU
5-year moving
average: Method
20
~
A
..
v
../
Metho.l!B
,
...\
I
-1/)c:
\ ...
150
1960
1965
1970
1975
1980
1985
140
200
I
0
1955
[Corrclati
\/\J
f~
.'
160
"5
0.
O
250 D-
A
~
ro
"0 10
1--
400
-.,.
2.5 million in 196~
million, and 9.8 In
Similar results WE
generate rates ofj
When Method .
global total numbt
from 10,000-300,(
(Fig. 7). In the tim
1990
1995
Year
FIG 6. Comparing two methods for estimating the total number of clinical cases of
DEN and DHF in Southeast Asia. Notes: (a) With the use of a two-tailed t-test, the
calculated correlation coefficient is significant at 0.001. (b) Number of casesin Southeast
Asia usingWHO-defined regions of Southeast Asia and the Western Pacific but excluding
India and China (see text for a list of countries in these two regions). (c) Method A
assumes that each reported case represents approximately 105-112 additional cases of
DEN (seeAppendix for details). (d) Five-year moving average: For a given year, the data
point is calculated as an average of the given year, 2 years earlier, and 2 years later.
(e) Method B calculated the incidence of dengue in Singapore and then applied this
incidence to the entire population in Southeast Asia (see text and Appendix for details).
(f) Countries included in population estimates of Southeast Asia: Brunei, Myanmar
(Burma), Cambodia, Indonesia, Laos; Malaysia, the Philippines, Singapore, Thailand,
Vietnam (defined by United Nations; see references 42-44, 55, 70, and 71).
120
~
I
QJ
:J
0>
c:
QJ
-0
O
1/)
QJ
1/)
(1]
u
ro
a
f-
100
80
60
40
20
0
J
II
1955
numbers of c~ses were 16.1 million, 24.5 million, and 24.7 million,
respectively. The 5-year moving average centered on 1994 was 19.7
million cases. The calculated Pearson product-moment correlation coefficient between the population of Southeast Asia and the number of
cases estimated by using Method A was 0.93 CP:5 0.001).
Figure 6 also contains a plot of the estimated number of cases when
Method B was ~$ed, with data from Singapore used as the indicator
country. The estimated number of casesin Southeast Asia ranged from
"
I I.:
1960
FIG 7. Estimated to
Asia, India, China, Lati
mated for Southeast At
reported case by a factc
for more details). Numb
the same methodology t
calculated correlation co
tiles represent estimate
Latin America and the
included in the calculatj
56
DUANE
J. GUBLER
AND
MARTIN
MELTZER
of magnitude. T
two diseases or
estimated losses
in only three pro'
lost to other dise:
population (see j
For India, Lat
ofDEN and DHF
groups, is much
In India, the est
is of the same <
country from HJ
encephalitis, an<
and the Caribbe:
and DHF is sim
trachoma, the tr
helminths (Table
When the avel
the world averag,
and 95th percent
incsize to individl
and C, the tropic
and intestinal he:
or disease grOUpE
of magnitude as t
DHF in the four
Southeast Asia a
diarrheal disease
percentile of the ,
4. Accuracy and .
Investigators s
methodologies th
cases. The very la
bers of actual case
methodologies. TJ
multiplier-based :
estimates of actua
produced by using
Both methods hay
the method of re]
thus that the de~
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60
DUANE J. GUBLER AND MARTIN MELTZER
Changes in, technology and organization are examples of factors that
may affect the reporting rate. Epidemics might also cause health-care
workers to overreport, whereas underreporting may occur during interepidemic periods (26). The incidence-based methodology (Method B) is
also sensitive to factors that change the reporting rate, and it further
assumes that the incidence in one or more indicator countries is representative of the incidence across regions. This is definitely not the case
for Singapore, which had a highly successful prevention and control
program from 1968 to 1986, and which has consistently had a much
lower incidence than other countries in the region.
It is important to note that none of the estimates presented here
included estimates of the DEN/DHF cases from Africa. Although cases
of DEN have been recorded in Africa (see earlier), there are no data
sets of reported cases over time that would allow the use of either
Method A or Method B (Fig. 6) to estimate actual cases. Thus, the
results presented in this article are likely to be underestimates of the
global number of cases.
Methodological problems aside, the estimates of cases in Southeast
Asia (Fig. 6) and in the four regions studied (Fig. 7) are among the few
whose methodology has been described. A logical question is: What can
be done to improve the accuracy of the estimates? Given the paucity
of data (Table I), increasing the complexity of mathematical methods
of extrapolation is unlikely to be of much benefit. What is required is
improved surveillance for DEN/DHF in selected countries and regions
to capture a large proportion of all cases that occur. The data so gathered can then be compared to the cases reported through the existing
system, and an empirically based multiplier can be readily calculated.
Compared to Asia and China, the impact ofDEN and DHF in DAL Y s
per million population is greatly reduced in Latin America and the
Caribbean (Table II). This is not necessarily true for the entire Latin
American and Caribbean region. Meltzer et al. (41) calculated that in
Puerto Rico, for the period 1984-1994, DEN and DHF caused an impact
similar to the 5-year average calculated in this article for China and
Asia (Table 11). The most obvious reason why the estimates for the
entire American region are noticeably smaller than those for Puerto
Rico, China, and Asia is that DEN and DHF began to reemerge as a
large-scale public health problem in the Americas only after the late
1970s (24,27). Thus, the difference in impact between Latin America
and the Caribbean and other regions may be due to time. It could well be
that, without successful interventions, the number of casesand DAL Y s
lost per million in Latin America and the Caribbean will soon approach
that seen in Asia and China. A similar argument can be made for India.
Although correit is clear from F
total number of I
rate of the human
the growth in case
as malaria (reporl
that some attribu1
of carbon-based f
between populati(
that factors such f
warming, may be
creased urbanizat
facilitate mosquit
casesofDEN/DHI
in Mexico City weJ
tures were found
up to 5°C higher a
data-collecting sit
maximum heat if
whereas human 1=
these heat island
human population
climatic effects. T
variable that coul(
in DEN/DHF case
If there is a Cf
casesof DEN/DHI
cies aimed at alteJ
have little impact
such as urban hea
number of DEN/I
programs will hav
Thus, the developr
such as vaccines
number of DENID
Developing effe
quires resources. ,
as a guide (Table :
resources for rese;
to many other infe
that, in 1993, the
approximately UE
~
IMP ACT OF DENGUE
Although correlation is not proof of a cause-and-effect relationship,
it is clear from Figs. 6 and 7 that the growth rate in the estimated
total number of DENIDHF cases over time is similar to the growth
rate of the human population. Several authors have attempted to link
the growth in cases ofDENIDHF and other vector-borne diseases such
as malaria (reported or estimated) to global warming, a phenomenon
that some attribute to increased human activities such as the burning
of carbon-based fossil fuels (58-62). However, the close correlation
between population growth and growth in DENIDHF cases suggests
that factors such as urbanization, which are more localized than global
warming, may be driving the increase in DENIDHF cases (1,17). Increased urbanization causes localized urban heat islands, which may
facilitate mosquito breeding and ultimately increase the number of
casesof DENIDHF. For example, when the near-surface temperatures
in Mexico City were compared to those in a rural site, the city temperatures were found to be 1-3°C higher at noon in the wet months and
up to 5°C higher at daybreak in the dry months (63,64). Data from one
data-collecting site in Mexico City show that, from 1920 to 1985, the
maximum heat island intensity increased by a factor of almost 3,
whereas human population increased by a factor of 12 (64). Because
these heat island effects are primarily dependent on the density of
human populations, they are probably largely independent of any global
climatic effects. Thus, urban heat islands are examples of a localized
variable that could link the growth in human population to the growth
in D!ENIDHF cases.
If there is a cause-and-effect relationship between the growth in
casesof DENIDHF and the growth in human population, pursing policies aimed at altering variables such as global warming will probably
have little impact on the number of cases(58,61). In fact, if local effects
such as urban heat islands are found to be significant predictors of the
number of DENIDHF cases, it may well be that local vector control
programs will have to be even more effective to prevent transmission.
Thus, the development of effective therapy and prevention technologies
such as vaccines could be the best hope for effectively reducing the
number of DENIDHF cases.
Developing effective treatments and prevention technologies requires resources. With the use of the DAL Y s lost to infectious diseases
as a guide (Table II), it can be argued that DENIDHF should be given
resources for research, control, and prevention similar to those given
to many other infectious and parasitic diseas~s. It has been estimated
that, in 1993, the total global expenditure o~ malaria research was
approximately US$84 million (65). Unfortunately, there are no pub-
where D is the (
perfect health); C
a is the age of or
in Table A.m); 1
lost due to prema
lost is a measurl
engagefully in hi
ation, and occup;
The disability we
lower the weight
of a person to con
tion that defines
years at onset (4
Table A.m. To a]
be lost to other d
as those used in
eachage-specific,
multiplied by the
give annual total
populations to gj
allows compariso:
1. Gubler, D. J. (199
gence as a global p
(D. J. Gubler and
2. Von Allmen, S. D
J., and Casta-Veh
analysis. Am. J. 7
3. Kouri, G. P., GUZI
4.
5.
6.
7.
8.
9.
rhagic fever/dengt
W.H.O. 67, 375-3
Halstead, S. B. (19
in the developing
Sornmani, S., Oka
of Dengue Haemo
Gubler, D. J. (19:
(T. P. Monath ed.:
Rico-Hesse, R. (19
1 and 2 in nature.
Gubler, D. J., and
sion of dengue vin
Med. Hyg. 25, 146
Putman, J. L., an.
infected Aedes aeg
31. Rico-Hesse, R., HaJ
J., de Mesa, M., Nc
type 2 viruses ass(
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(1997). Genotype a
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50, 161-169.
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of Dengue/Dengue .
India (in press).
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Burden ofDisease a
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Using DALYs to a~
Am. J. Trap. Med.
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Oxford University
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(D. T. Jamison, ed.)
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using Monte Carlo
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I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
Introducti!
Human In
Virus Stt:U
Epidemiol!
Pathogene
Transmiss
A. Heter!
B. Mothe
RecombinE
Treatment
Summary
ReferenceE
The first rE
(AIDS) emerg
of unusual dis
recognized AIJ
monia, were o
others, such a
population sul
origin. Within
ciency were ob
afterward, in
referred for dj
Among the
rus that migh
(2-4) because
Further studi
distantly rela
primate lenti,