* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download ~ IMPACT OF DENGUE/DENGUE HEMORRHAGIC FEVER ON THE
Survey
Document related concepts
Bioterrorism wikipedia , lookup
Poliomyelitis eradication wikipedia , lookup
Neglected tropical diseases wikipedia , lookup
Ebola virus disease wikipedia , lookup
Yellow fever wikipedia , lookup
West Nile fever wikipedia , lookup
2015–16 Zika virus epidemic wikipedia , lookup
Orthohantavirus wikipedia , lookup
1793 Philadelphia yellow fever epidemic wikipedia , lookup
Marburg virus disease wikipedia , lookup
Henipavirus wikipedia , lookup
Middle East respiratory syndrome wikipedia , lookup
Yellow fever in Buenos Aires wikipedia , lookup
Transcript
~ 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. I! ..~ 11 0) ai 0) 0) .-. 0) 0) ~ ] ~ O r0) .-. ~ , ro m ~ .t ;4 ~ o 0> r ~ ,s ., ~ 0 't: 0) ~ 0) :5 ,s '.:: ~t' ~ ~ Cj ~ ~ '0 § :g .!:1 't: ... ., i:S ~/! ,I;: .,~ ~(" 0 ('f) 0) ~ r t ~ " ~ ;;;;1 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 FI 60 iii" "0 " " " " O .0: '=" ., " " u '0 0 z 50 40 30 20 10 0 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. ~ <!;<I 4 ~ ~ ~p 1<: ~ ~ t£ ~ t ~~ at#? , ~ \- ! ..,;, .. ,~ , s ~ 1D """ .-a) ...u ~ ~ ~ ~ ~ a) =' b/) = a) "0 u .§ a) "0 .& "S ~ "0 2 ~ rn co a) ~ ~ ~ ~ ~ ~ ~ "0 § .'§, ~~ .S rn co a) ~ ~ ~ ~ a) C) C) ~ tj ~ .; ..." o ~ "'5 Q) > 0 "'"' .~ "' o 8 "; ~ .g .c ~ Q) ca -;S ] ... ~ ~ "C § :.:: ;j .c .c "'"' "' ;a "; .g 6 Lci " ~ 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~ ..Q "' 0 ~ "' ...0 .s .S;=(1!~~ Q "' .~ .~ (1!~Qo "'Q)oc Q) °0.Q",0. ~ .~ ., ~ 0 00 00 lOe ... "'<.'0Q) .qo .',...0.,,"0. ~ "' ~ 0 ° (1! .~ ..- v O 0 ""' "' 0 ,... .~ " "' u ..: 0 ", Q) (1! ~ .~ ., (1! Q) ~ .S C'JO .""' .,~ (1! (1! Q) ," bO c 0 00 (0 2?t-Q .~ c :::: 0. c ..."' .~ O "' ;g lQ (X)o~...too0").qo .c d Q)",v~o '1jOQ~~ "' "' .~010 (1! ;> ;::... 0 ~ 0)-5 0)0 I Q) ~... "'0 ..."" O)~ '1j~~.OS Q)~ Q)Q... ~"' >,~ Q) ...Q)0...~ Q) QQ)~ "' .~ v ~::::~ .~ j Q)Q)Qd '""' S~O> -:::: 0 '"' .~ .::::-~ ...Q) Q» ., Q) ""(1!.c0,... "';> >(1! 0 U ~ ~~~Sa '1j '1j Q 0 Q,...,", (1! 0 .~ ...Q) ~::::0.Q (1! .~ "" .Q c "' .""d 0.10 0(1!", ...Q) J5 ~~ ot-~O~ 0.C'J(1!Q)~ ~ .~.c~ Q U .c .s ]~~~[i gj .~ JJ] 5(1! "' (1! Q) d ~o ."'(1! ..."" >... Q)Q) .~0.QU9~ ~ '; ~ ~.."' ~ "' .~ .c Q) ., .~ " S .> 0", Q (1! '"' Q) ;a .~ " ~ ~ Qo Q) 0~>,0 ~ (1! """' 0 .~ 0", ~ 00 ~ (1!. S ;a ~ ~ ~ O lO "01'" (1!Q) Q).C ...E-o (1! .d .~ Q) ~ "' ;j >, ~ '1j ~O) ~ C;; .Q I ,... 0) d '1j (1!0) 0) Q);a Z:j --::-5., O...,.-'.1'1j~".s r:l "' >, ~ "' (1! ;g bO .~ ~ o~g~a:.?~", ~>,0)",(1! ~UQ)-.~ "' ~"'~.c..:~.."' "' ~ (1! ~ U OQ~S~ '1j~.C~0. ~o~- (1!~d(1! U ~ (1! ~.~0(1!~~ Q)'; ...Q) (1!bO", .d z ~'g '""' .~ .Q J5 .aU"'r:lo",(1!(1! ,., ., '-' Q)",o '"' -E(1! Q) > Q) .'"' ~ '1j Q) ~" ~ ,.. :::: ~ ~.C~O"' " 0 0 .."' (1!'"~0.~Q) d=(1!0.Q",S Q) ...OO.~Q~ > a '1j 5 .~ Z ~9Q)S:=~Q'1j ~ w.C...SQ 0 ~ O (1!r:lQ ~ .~ '1j ~ Q) ...(0 (O~ 0.0. " .-I" m "' U ...too too~~(X)~... ~lQ.,"",.0").I0.'""'..qo " . . .3'1j'-' ~.- < s. 0 ~ ~ (1!",.a~QQ)C'Jo ~.~'1j~ c~ .c .~~ r "' (1! Q) '""' Q) 0 QbO " .~ O ~'1j Co1 °.qo(O.qo~ o ~ot ~ ~ ot- "'C'jO OC'jC'j C':!~C'j ~O~ "' ~ ~~ ~ .~ ~ ~ ~ .~ 0. s ~ ~O) 0) ~ ~0)~ "' 0 > ~-.(0 :, -0~ ;:v(O ; 1O Oo ~. "' .E Q -0 .~ j! C'I" r:.: " .~ ..- "' Q) .~" ~ " "' ~ ", ., "0... "" .(1!~.~Q)~ U (1! U Q) "' .~(1! "' .,.!t.'""' .U-~ w -;j .~ (1! < ..." ~ ~" ICCX>~IOIO ~0) ~" ~ "' .~ ~ '£ 1.. .~ 0 "' .& ~ "!j ~ "' .~ ~ 35 :j ~ ~ ""-0) "' Q S ~ ~"!j-", w 0 8 "' 0 ..." IOr--(j) " 0'0~~00~t-~00~0'0t-t00" 00 0'0 ot-~0~ .,; o~~0'0o~t-~~ ~" ~" ~ ro ~~ ~~tO~t-"oi!"oi!t-~ "'" '01!' o.co.c~~~oCX>o~ 1:I:-~O.Co) o.c """ to' m~~<x><x>~~~<x>tOom ~m"ol!t-<x>tOt <x>~ t-" m -, > :r: bi) ~ ;e :j ""i3 ~ -;;; 0) "' ~ 0) :a 0) -,~ >, ..."5 ~ ~ "' 'S. 0) ~ ~:$ ~ ~ >, = .~ 0. .& ~ ~ 0 0. ~ Q) -'" ~~...:$..:Q'6' t: ~ .& -0) Q 0. ~ 0 ~ ~ "" -'" :j >< ;;;. ~ ,~ 0) ~ .~ ~ ~ ~ 0) ~C)""C)C)LOCDoC)C)C)O00""CD CDtooLOtootootooC)""LOOtoo~CDCDC) O)C)O0000 .r) 000~LOtooOO too" 0" " " C)" ~ U 0) a :j ~ (1!.-.(1!~Q)" "' 0. t.oOC'lt.oOCI) ~0')-.j!t.o ...t.oOt.o-.j! ..." r C'ltOlCr--lOCX> to C')IOCX>C'I t'-O)CX>oooooo ~CX>o~~t'- ~. '""'" LO 'Ii, "' ., C! ~ .-"' ~ ~ .-~ ~ ~ '... ° ""' "' QI .,., ~ ~ '""'" "..00 ~~ ~. ~.,;.a. oo~oo -0;0"..,"",".. "..(0 ~..,."'C) ~~oot-~oo ~a.,:? ..,. 00 I!'~..' I!' OOCQIDIDIDOO --;0 00 ., ..~-..9 -~ ~ o ~ .:E ..s tj "' ~ ~ "'~ '>, 'fiJ .b -+"-+" ~~ .,., ., ~~ ~ =~~...~ "" .0 ;:: ~ ~ .Q) ~ 0""",-, ...'1jQ)0~(1!;>,.,?; 0 ~ .. ~ ~ (\1 (\1 ~ (\1 :E .~ o .::.? ~ ;j -+" "' "' :.s ~ ,~ ~~ ~., uu 'C ~~~~W~~0~~~~~~~ 0.:-: ~ ;j ~ I tIj bD ~ < ...§ ;j .~ o bD ~ ~ "g "Q ~ 0) .;1 ~ " "~ ~ 0 ~ ~ "3 1:1. o 1:1. d ~ u "0 .Q ~ ~ > ~ ~ u s a Q ::J as ;a Q ~ .bD (1) 0. ;3 ~ ""' - "., .s ..Q u 0) ...Q ~ j ~ rn >- .Q Q) 1:1. ..., "' .§ .. ~ ~ ~ ~ 5 z ~ ~ Q ~ ~ 5 z ~ ~ ;j ~ ~ ~ E-- ~ ! ~ r.. ~ ~ 1 Q ~ :; ~ ~ "" :Q ~ Q ~ (1) 00 Q ---+" = '"' ,u u ,~.,., .'~-+".'-+"-+" =~.,0.~o.o. =~0.~;a~~ ~ Z ~-+"lO~lOlO ~""lO~""t-m ~ 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( 230, 244-251. 32. Porter, K R., EwiJJ (1997). Genotype a River Basin of Pen No.567). 33. Centers for Disease 1993-1994. Morbid, 34. Pan American Heal Epidemial. Bull. lE 35. Pinheiro, F. P ., an haemorrhagic feve' 50, 161-169. 36. Carey, D. E., Cause febrile patients in ] 37. Gubler,D.J.,andT rhagic fever as a pul 38. Newton, E. A. C., a with an evaluation on dengue epidemi. 39. World Health Orga of Dengue/Dengue . India (in press). 40. Murray, C. J. L., a Burden ofDisease a 41. Meltzer, M. I., Rigf Using DALYs to a~ Am. J. Trap. Med. 42. United Nations (19 43. United Nations (19 44. United Nations (19 45. Bruning, J. L., and ed. Scott, ForesmaJ 46. Murray, C. J. L., ar and global and reg Global Burden ofD Vol. 1, pp. 118-20( 47. The World Bank (: Oxford University 48. Murray, C. J. L. (1 disability-adjusted 49. Murray, C. J. L., aJ of Disease and Injt 50. Shepard, D. S., an( Japanese encephaJ (D. T. Jamison, ed.) 51. Critchfield, G. C., f using Monte Carlo 70 DUANE GUBLER AND MARTIN MELTZER 52. Dobilet, P., Begg, C. B., Weinstein, M. C., Braun, P., and McNeil, B. j. (1985). Probabilistic sensitivity analysis using Monte Carlo simulation: A practical approach. Med. Decis. Making 5, 157-177. 53. Dittus, R. S., Roberts, S. D., arid Wilson, J. R. (1989). Quantifying uncertainty in medical decisions. J. Am. Coll. Cardiol. 14, 23A-28A. 54. Palisade Corp. (1995). "@Risk," User's Manual. Palisade Corp., Newfield, NY. 55. United Nations (1995). "Demographic Yearbook: 1993." United Nations, New York. 56. Poston, D. L., and Yaukey, D. (1992). "The Population of Modern China." Plenum, New York. 57. Banister, J. (1987). "China's Changing Population." Stanford University Press, Stanford, CA. 58. Patz, J. A., Epstein, P. R., Burke, T. A., and Balbus, J. M. (1996). Global climate change and emerging infectious diseases. JAMA, J. Am. Med. Assoc. 275, 217-223. 59. Lindsey, S. W., and Birley, M. H. (1996). Climate change and malaria transmission. Ann. Trop. Med. Parasitol. 90, 573-588. 60. McMichael, A. J., and Haines, A. (1997). Global climate change: The potential effects on health. Br. Med. J. 315, 805-809. 61. Haines, A., and McMichael, A. J. (1997). Climate change and health: Implications for research, monitoring, and policy. Br. Med. J. 315, 870-874. 62. Jet ten, T. H., and Focks, D. A. (1997). Potential changes in the distribution of dengue transmission under climate warming. Am. J. Trop. Med. Hyg. 57, 285-287. 63. Jauregui, E. (1997). Heat island development in Mexico City. Atmos. Environ. 31, 3821-3831. 64. Jauregui, E., Cervantes, J., and Tejeda, A. (1997). Bioclimatic conditions in Mexico City. Int. J. Biometeorol. 40, 166-177. 65. Anderson, J., MacLean, M., and Davies, C. (1996). "Malaria Research: An Audit of International Activity," PRISM Rep. No.7. Unit for Policy Research in Science and Medicine, The Wellcome Trust, London. 66. Centers for Disease Control and Prevention (1998). One thousand days until the target date for global poliomyelitis eradication. Morbid. Mortal. Wkly. Rep. 47, 234. 67. Centers for Disease Control and Prevention (1997). Measles eradication: Recommendations from a meeting cosponsored by the World Health Organization, the Pan American Health Organization and CDC. Morbid. Mortal. Wkly. Rep. 46 (Recomm. Rep. No.11), 1-32. 68. Halstead, S. B. (1980). Dengue hemorrhagic fever-a public health problem and a field for research. Bull. W.H.O. 58, 1-21. 69. Burke, D. S., Nisalak, A., Johnson, D. E., and Scott, R. M. (1988). A prospective study of dengue infections in Bangkok. Am. J. Trop. Med. Hyg. 38, 172-180. 70. United Nations (1982). "Demographic Yearbook: 1980." United Nations, New York. 71. United Nations (1978). "Demographic Yearbook: 1977." United Nations, New York. 72. U.S. Bureau of the Census (1997). "Statistical Abstract of the United States," 117th ed. U .8. Department of Commerce, Washington, DC. 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,