Dengue in the Americas by
Mary E Wilson# and Lin H Chen Division of Infectious Diseases, Mount Auburn Hospital, 330 Mount Auburn Street, Cambridge, MA 02238, USA Abstract Dengue has been present in the Americas for centuries, but the current situation is dynamic, and is worsening. The main vector, Aedes aegypti, infests most countries. Vector control efforts have been largely inadequate. Population growth, especially in urban, low latitude areas, has resulted in a greater risk for contact with a competent vector. An increasing number of cities have reached a size that can support ongoing circulation of dengue viruses. The mobility and increasing connectedness of human populations through rapid international air travel permit regular introductions of the dengue virus via viremic travellers. More geographic areas have concurrent or sequential circulation of more than one serotype, increasing the risk for severe and complicated dengue. Serological studies document that dengue infections frequently go unrecognized. Other infections, some treatable with specific antibiotics, are often misdiagnosed as dengue fever, and dengue fever is often presumptively diagnosed when other infections are the cause of illness. Rapid, reliable and inexpensive diagnostic tests are unavailable in most areas. Analyses of illness and death related to dengue show that the burden from dengue in tropical and subtropical America is substantial and is often underestimated. The health and economic impact from dengue is similar to that from other infections that have generated much more attention. Study of border areas that share similar geoclimatic conditions (for example, Mexico and the United States) can help identify risk factors and possible protective measures. Well-studied island epidemics (e.g. Cuba) have been valuable in defining the role of sequential infections, duration of relevant immunological memory, and potential impact of genotype in addition to serotype on the clinical course of the disease. Keywords: Dengue, Dengue haemorrhagic fever, epidemiology, vector control, Americas.
Introduction Dengue has long been present in the Americas. Historical records suggest that dengue outbreaks may have occurred in the French West Indies and Panama in the # For correspondence: mary_wilson@harvard.edu
1600s, in Peru, Mexico, Colombia, the United States (Philadelphia) and the Caribbean in the 1700s, and, in addition, in Brazil, Venezuela, and Argentina in the 1800s and the first half of the 1900s(1). Since the 1960s, dengue virus has spread to
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previously unaffected areas in the Americas and threatens a larger population than ever before in the Americas. Circulation of more than one serotype has been documented in more and more regions, increasing the risk of serious and complicated infections, i.e. dengue shock syndrome (DSS) and dengue haemorrhagic fever (DHF)(2,3). Trends in the region, including increasing urbanization, increasing travel and migration of humans, and expansion of the areas infested (and reinfested) by competent vectors, suggest that dengue will continue to be an important cause of morbidity and mortality in the region(4,5,6,7). This paper describes recent dengue activity in the Americas and discusses some of the features of its epidemiology and spread in the Western Hemisphere. A description of the 20012002 outbreak of dengue in Hawaii, transmitted by Aedes albopictus, is not included in this paper. Preliminary reports describing the outbreak in Hawaii are available from the publications of the Centers for Disease Control, Atlanta, and its website (www.cdc.gov/travel/other/denguehawaii.oct2001.htm).
dengue continues to occur in Asia, the situation in the Americas is dynamic, and is worsening. In 1998, the Americas reported >700,000 cases of DF and >12,000 cases of DHF. This year (2002) Brazil has experienced the worst epidemic in its history (see below). The number of dengue cases in the Americas should be considered in the context of the population size, which is small in comparision to Asia. The population of the Americas (not all of which is located in areas at risk for dengue infection) was estimated at 823 million in 1999, representing less than 14% of the world’s population. The population is distributed with about one-third residing in the US, one-third in Mexico and Brazil, and the remainder in the other 45 countries and territories(8). Aedes aegypti, the main vector for dengue in the Americas (note exception in Hawaii, 2001-2002) is believed to have been introduced into the Western Hemisphere on slave ships from West Africa in the fifteenth through the seventeenth centuries. The mosquito may also have reached the New World on European ships from Spain and Portugal. Aedes aegypti was well adapted to flourish in water storage containers on ships(9). Aedes aegypti became established widely in tropical and temperate areas of the Americas. An intensive campaign organized by the Pan American Health Organization (PAHO) starting in 1947 to control yellow fever transmission led to eradication of Ae. aegypti from all countries in the Americas except the U.S., Suriname, Venezuela and several Caribbean Islands by the late 1960s(1,4). Records show no evidence of epidemic dengue in the Americas from 1946 45
History of dengue in the Americas More than 2.5 billion people, or about 40% of the global population, live in dengueendemic regions, which encompass tropical and sub-tropical regions worldwide. An estimated 50 to 100 million cases of DF occur each year, including several hundred thousand cases of dengue haemorrhagic fever (DHF)(4,5). Most go unreported. Reports to WHO in 1998 recorded 1.2 million cases of dengue and DHF and 15,000 deaths. Although, globally, the greatest burden from Dengue Bulletin – Vol 26, 2002
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through 1963, presumably reflecting in part the benefits from the eradication programme. In areas where Aedes aegypti was eliminated, transmission of dengue virus was interrupted. Support for programmes waned and vector control activities declined allowing the mosquito to reinfest areas where it had been eliminated and to spread to areas where it had never previously been recorded. Aedes aegypti was repeatedly introduced from areas where the vector was not controlled. Dengue re-emerged in the 1960s and 1970s, initially affecting Jamaica, then Puerto Rico, other Caribbean islands, and Venezuela(10,11,12). Subsequently, dengue
was reported from at least 43 countries in the region(1,4,5,6,7,10). Outbreaks of classic dengue appeared, but these were followed by the appearance of DHF, initially in a massive epidemic in Cuba in 1981(10) and since then in other parts of the Caribbean and Central and South America (13). The second major DHF epidemic occurred in 1989-1990 in Venezuela, when 3,108 cases guruof DHF were identified(14). Table 1 provides a chronological listing of the country locations where different dengue serotypes have been documented, starting in 1953.
Table 1. The introduction of dengue serotypes (DEN-1, 2, 3, 4) in the Americas: predominant serotypes, arrival of new strains, countries in which they were identified and associated Year 1953 1963-64 DEN-1 DEN-2 Trinidad Jamaica Puerto Rico Lesser Antilles Venezuela Caribbean Venezuela Colombia Colombia Jamaica Cuba 1978 Venezuela Colombia Guyana Suriname French Guiana Honduras El Salvador Guatemala Belize Mexico Caribbean Venezuela DEN-3 DEN-4 Comments and References(i,ii) First-ever isolation of DEN-2 in the Americas; no outbreak was reported(iii). A Caribbean pandemic occurred(iv). > 27,000 cases occurred in Puerto Rico(v).
1968-69
DEN-2 and DEN-3 were found in Jamaica(vi). Aedes aegypti reinfestated the country, followed by a dengue epidemic(vii). A second dengue epidemic occurred in Colombia(vii). DEN-1 was introduced, and spread in Caribbean, South America, Central America, and led to a pandemic(viii). From 1977-80, 702,000 cases were reported to PAHO from the Americas, but estimates from Colombia, Cuba, and Venezuela suggested >5 million cases(ix). Epidemic in Central America affected Honduras(x), followed by El Salvador, Guatemala, Belize, and spread to Mexico.
1971-72 1975-77 1977
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Dengue in the Americas Year 1980 1981 DEN-1 Texas, USA Cuba Caribbean S. America C. America Mexico Puerto Rico 1982 Colombia Brazil Colombia Brazil El Salvador Puerto Rico Colombia El Salvador Jamaica Trinidad DEN-2 DEN-3 DEN-4 Comments and References(i,ii) Most cases occurred near the TexasMexico border(xi). New DEN-2 strain was introduced in Cuba; 1st major DHF epidemic, total of 344,203 cases, 10,312 severe, 158 fatal(xii). DEN-4 was introduced(xiii), affecting the Caribbean, northern South America, Central America, and Mexico. 8350 cases(i) 6776 cases(i) >12,000 cases(i) 5166 cases(i) 9536(1) 4977 cases(xiv) 3814 cases(i) DEN-2 predominated(xiv) DEN-4 predominated(xiv) 19,028 cases(i) DEN-1,2,4 continued to circulate, causing 43,435 cases in the region(xv). Nicaragua Aruba Honduras El Salvador Venezuela Colombia Puerto Rico Brazil Puerto Rico Puerto Rico Puerto Rico Nicaragua 17,483 cases(xv,xvi) 24,000 cases(i) Venezuela
1983
Colombia Jamaica Trinidad Mexico
Mexico 1984 1985
Venezuela Colombia Puerto Rico
7797 cases(xv) 47,370 cases; major outbreak occurred in Rio de Janeiro(xvii,xviii). 10,659 cases, predominantly DEN-4(xix), followed by continued outbreaks ever since. 1994 cases and 4847 cases the following year(i). 405 cases followed by 41,800 cases the following year(i). Epidemic occurred in Guayaquil, following Aedes aegypti reinfestation (detected in 1985)(xx).
1986
1987 1988
Bolivia Paraguay Ecuador
1989-90
Venezuela
Venezuela
Venezuela
2nd DHF epidemic in the Americas – 3108 cases of DHF, 73 deaths, with annual epidemics ever since; DEN-2 was predominant(xxi). 7858 cases, followed by continued transmission(i,xxii). Epidemic occurred in the state Rio de Janeiro(xiii).
1990
Peru Brazil Brazil
Peru
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Dengue in the Americas Year 19911992 1993 1994 Costa Rica DEN-1 DEN-2 French Guiana Panama Brazil Puerto Rico Nicaragua Panama Panama DEN-3 DEN-4 Comments and References(i,ii) DEN-2 predominated although DEN-1 was also present(xiv). 1st outbreak since 1942(xv) 4612 cases(xvi). 54,453 cases, reaching 530,578 cases by 1998(i,xvii). 22,000 cases(i). Reappearance of DEN-3; total 20,469 cases; 1247 cases DHF; incidence 4.8/1000(xv). DEN-3 was of the Sri Lanka/India genotype, DEN-1 was predominant(xv). Costa Rica 1995 Costa Rica Costa Rica Mexico Guatemala 19961997 1997 Brazil Brazil Cuba Costa Rica 13,929 cases(i) DEN-3 identified in Mexico(xviii). Total of 316,411 cases occurred in the Americas(i). DEN-3 predominated for next 3 years(xix). Epidemic in Belem, Para State(xxx). DEN-2 re-emerged in Cuba; 2946 laboratory-confirmed cases; 205 DHF/DSS(xxxi). 1st cases since 1916 were identified(xxxii). Nicaragua DEN-3 predominated(xxxiii). All serotypes are present in the 1990s(xxxiv). 16,355 cases 5963 cases 8715 cases 5233 cases 2113 cases DEN-3 appeared in Brazil in 2000(xxxv). Huge epidemic; 711,919 cases reported, 2229 DHF, 130 deaths as of September 15(xxxvi,xxxvii). Colombia El Salvador
Argentina 1998 2000 El Salvador Guatemala Honduras Nicaragua Costa Rica Nicaragua
Nicaragua Costa Rica Brazil Brazil
2002
(i) (ii) (iii)
DEN-1, 2, 3, 4 are reported to be circulating in Colombia and El Salvador(xxxvii). Epidemics have also been reported from Honduras, Nicaragua, Venezuela(xxxvii). WHO. Chapter 6 – Dengue and dengue haemorrhagic fever. In WHO Report on Global Surveillance of Epidemic-Prone Infectious Diseases. Available at www.who.int/emcdocuments/surveillance/docs/ whocdscsrisr2001.pdf/dengue.pdf. Pinheiro FP and Corber SJ. Global situation of dengue and dengue haemorrhagic fever, and its emergence in the Americas. World Health Statist Quart, 1997, 50: 161-168. Anderson CR, Downs WG and Hill AE. Isolation of dengue virus from a human being in Trinidad. Science, 1956, 124: 224-225.
Colombia El Salvador
Colombia El Salvador
Colombia El Salvador
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Dengue in the Americas (iv) (v) (vi) (vii) (viii) Ehrenkranz NJ, Ventura AK, Cuadrado RR, et al. Pandemic dengue in Caribbean countries and the southern United States – Past, present and potential problems. N Eng J Med, 1971, 285: 1460-1469. Neff JM, Morris L, Gonzalez-Alcover R, et al. Dengue fever in a Puerto Rican community. Am J Epidemiol, 1967, 86: 162-184. Ventura AK and Hewitt CM. Recovery of dengue-2 and dengue-3 viruses from man in Jamaica. Am J Trop Med Hyg, 1970, 19: 712-715. Groot H. The reinvasion of Columbia by Aedes aegypti: aspects to remember. Am J Trop Med Hyg, 1980, 29: 330-339. Bres P. Historical review of dengue 1: Implication of its introduction in the western hemisphere in 1977. Working Group on Dengue in the Caribbean, ed. Dengue in the Caribbean. Washington, DC: Pan American Health Organization Scientific Publication 1979 no. 375, 410. PAHO. Dengue and dengue haemorrhagic fever in the Americas: guidelines for prevention and control. Pan American Health Organization Scientific Publication 1994 N. 548. Figueroa M, Pereira R, Gutierrez H, et al. Dengue epidemic in Honduras, 1978-1980. Bull Pan Am Health Organ, 1982, 16(2): 130-137. Hafkin B, Kaplan JE, Reed C, et al. Reintroduction of dengue fever into the continental United States. I. Dengue surveillance in Texas, 1980. Am J Trop Med Hyg, 1982; 31: 1222-1228. Kouri G, Guzman MG and Bravo J. Haemorrhagic dengue in Cuba; History of an epidemic. Bull Pan Am Health Organ, 1986, 20: 24-30. CDC. Dengue type 4 infections in US travelers to the Caribbean. MMWR, 1981, 30: 249-250. CDC. International notes dengue – Americas, 1983. MMWR, 1984, 33: 327-328, 333-335. CDC. Dengue in the Americas, 1985. MMWR, 1986, 35: 732-733. Kouri G, Valdez M, Arguello L, et al. Dengue epidemic in Nicaragua, 1985. Rev Inst Med Trop Sao Paulo, 1991, 33: 365-371. Schatzmayr HG, Nogueira RM, Travassos Da Rosa APA. An outbreak of dengue virus at Rio de Janeiro. Memorias do Instituto Oswaldo Cruz, 1986, 81: 245-246. Isturiz RE, Gubler DJ and del Castillo JB. Emerging and re-emerging diseases in Latin America: dengue and dengue haemorrhagic fever in Latin America and the Caribbean. Infect Dis Clin N Am, 2000, 14: 121-140. Dietz V, Gubler DJ, Ortiz S, et al. The 1986 dengue and dengue haemorrhagic fever epidemic in Puerto Rico: epidemiologic and clinical observations. Puerto Rico Health Sciences Journal, 1996,; 15: 201-210. CDC. International notes dengue epidemic – Ecuador, 1988. MMWR, 1989, 38: 419-421. PAHO. Dengue haemorrhagic fever in Venezuela. Epidemiol Bull, 1990, 11(2): 7-9. Phillips I, Need J, Escamilla J, et al. First documented outbreak of dengue in the Peruvian Amazon Region. Bulletin of the Pan American Health Organization, 1992, 26: 201-207. Nogueira RM, Miagostovich MP, Lampe E, et al. Dengue epidemic in the state of Rio de Janeiro, Brazil, 1990-1: Co-circulation of dengue 1 and dengue 2 serotypes. Epidemiol Infect, 1993, 111: 163-170. Reynes JM, Laurent A, Deubel V, et al. The first epidemic of dengue haemorrhagic fever in French Guiana. Am J Trop Med Hyg, 1994, 51: 545-553. CDC. Dengue type 3 infection – Nicaragua and Panama, October-November 1994. MMWR, 1995, 44: 21-24. PAHO. Dengue fever in Costa Rica and Panama. Epidemiol Bull, 1994, 15: 9-10. Vasconcelos PFC, Menezes DB, Melo LP, et al. A large epidemic of dengue fever with dengue haemorrhagic cases in Ceara State, Brazil, 1994. Rev inst med Trop Sao Paulo, 1995, 37(3): 253-255. Briseno-Garcia B, Gomez-Dantes H, Argott-Ramirez E, et al. Potential risk for dengue haemorrhagic fever: the isolation of serotype dengue-3 in Mexico. Emerg Infect Dis, 1996, 2. Usuku S, Castillo L, Sugimoto C, et al. Phylogenetic analysis of dengue-3 viruses prevalent in Guatemala during 1996-1998. Arch Virol, 2001, 146: 1381-1390.
(ix) (x) (xi) (xii) (xiii) (xiv) (xv) (xvi) (xvii) (xviii) (xix) (xx) (xxi) (xxii) (xxiii) (xxiv) (xxv) (xxvi) (xxvii) (xxviii) (xxix)
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Dengue in the Americas (xxx) (xxxi) (xxxii) (xxxiii) (xxxiv) (xxxv) (xxxvi) (xxxvii) Travassos da Rosa APA, Vasconcelos PFC, Travassos da Rosa ES, et al. Dengue epidemic in Belem, Para, Brazil, 1996-97. Emerg Infect Dis, 2000, 6: 298-301. Kouri G, Guzman MG, Valdes L, et al. Reemergence of dengue in Cuba: a 1997 epidemic in Santiago de Cuba. Emerg Infect Dis, 1998, 4(1): 89-92. Aviles G, Rangeon G, Vorndam V, et al. Dengue reemergence in Argentina. Emerg Infect Dis, 1999, 5(4): 575-578. Harris E, Videa E, Perez L, et al. Clinical, epidemiological, and virological features of dengue in the 1998 epidemic in Nicaragua. Am J Trop Med Hyg, 2000, 63: 5-11. PAHO. Dengue in the Americas: the epidemics of 2000. Epidemiol Bull, 2000, 21(4). Nogueira RMR, Miagostovich MP, Filippis AMB, et al. Dengue virus type 3 in Rio de Janeiro, Brazil. Memorias do instituto oswaldo Cruz, 2001, 96: 925-926. Barbosa de Silva J jr, Sigueira JB jr, Coelho GE, et al. Dengue in Brazil; current situation and prevention and control activities. Epidemiol Bull, 2002, 23(1): 3-6. PAHO. 2002: number of reported cases, dengue & dengue haemorrhagic fever. Available at www.paho.org/English/HCP/HCT/VBD/dengue-cases-2002.htm.
Programmes to control vectors face new challenges. Resistance of vectors to insecticides is increasing, limiting the available options. Resistance of Aedes aegypti to pyrethroids is now widespread(15). Other factors have also contributed to increased vector abundance, among them expansion of water storage locations and a plethora of vector breeding sites in used tyres, flower pots, and discarded plastic cups and other non-biodegradable containers. Inadequate piped water supplies lead people to store water in and around homes.
crowded living conditions, inadequate waste disposal and lack of clean water. This contemporary landscape provides an ideal environment for breeding of Aedes aegypti, a mosquito that is well adapted to the urban habitat. Poor housing and absence of screens increase the potential contact between mosquitoes and humans. More urban centres have reached a population size that it takes to sustain the ongoing circulation of a dengue virus in a population, which increases the risk of severe forms of dengue. Recent studies also point to another reason to be concerned about population size. Over the past two centuries the number of dengue lineages has been increasing roughly in parallel with the size of the human population(16). Scientists have suggested that a larger human population in which the virus replicates allows increased opportunities for viral evolution and enhances the potential for the appearance of more virulent strains. Intra-serotype recombination events may also play an important role in genetic diversity of the dengue virus(17). More opportunities for such genetic exchange exist in populations with hyperendemic dengue.
Human population The human population has also grown but more relevant is the location of the population expansion. Most of the population growth has occurred in urban areas. Globally, more people now live in urban areas than ever before. In South America, 78% of the population lived in urban areas in 1995; this is projected to increase to 88% by 2025. (The comparable figures for the world are 45% in 1995 and 60% by 2025.) Much of the growth of cities is unplanned and unregulated, and huge slums surround some cities. Many of these areas are characterized by poor housing, 50
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This large and growing urban population in low latitude areas is increasingly linked by air travel to other areas of the world. Global travel continues to increase. In 1996, 2.5 billion persons passed through airports and more than 500 million persons crossed international borders on commercial airplane flights. Air traffic volume has increased about 7% per year for the past 20 years. As of the mid-1990s, about 5000 airports had scheduled worldwide service. This massive movement of the human population links all major urban areas of the world. Speed of travel means that a person bitten by an infective mosquito (carrying dengue) in Thailand can reach home in Brazil before the symptoms of the infection begin to show. Viremia, which may persist for as long as 7-8 days, typically begins 2 days before the onset of the symptoms, during which the viremic human may continue his usual activities and may encounter competent vectors at work, home and elsewhere. Levels of virus in blood may be high. In a study of plasma viral RNA levels in children in Thailand, levels ranged as high as 109 RNA copies/ml, peaked an average of 2 days before defervescence, and dropped rapidly during the last several days of fever(18). Table 2a contains the tourist arrivals to a number of the countries in the Americas that have had the highest volumes of visits, as well as the recent incidence of dengue in the local population as reported to the Pan American Health Organization (PAHO). Costa Rica reported the population at risk, and the incidence was calculated based on that figure. Bolivia reported the population at risk for 2001 also. The other countries in the table reported projected populations. Table 2b lists international arrivals in each
sub-region. These figures indicate that dengue-endemic countries in the Americas receive over 50 million international arrivals each year. Table 2a: International arrivals in some dengue-endemic countries in the Americas International arrivals in 2000a 2,949,000 1,577,000 5,313,000 1,088,000 1,741,000 Incidence of dengue in local population (per 100,000)b 2000 4.59 0 136.07 434.63 c
Country
2001 0.03
Argentina Bahamas Brazil Costa Rica Cuba (air arrivals only) Dominican Republic (air arrivals only) Jamaica (air arrivals only) Mexico Peru Puerto Rico (air arrivals only) a
239.38 818.163c 101.58
1.23
2,972,000
40.75
42.28
1,323,000
0.97
1.50
20,641,000 1,027,000 3,341,000
21.96 21.38 62.88
6.19 89.41 132.41
From World Tourism Organization News Release, www.world-tourism.org/newsroom/releases/more_ releases/january2002/numbers_2001.htm b
PAHO. www.paho.org/English/HCP/HCT/VBD/ dengue-cases-2000.htm and www.paho.org/English/HCP/HCT/VBD/dengue-cases2001.htm. c
Based on population at risk.
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Table 2b: International arrivals in sub-regions in the Americas in 2000 Sub-Region North America Caribbean Central America South America Total for Americas a
epidemics of dengue fever and dengue haemorrhagic fever in this region.
Arrivals in 2000 (millions)a 91.2 (Canada 19.7; USA 50.9) 17.3 4.4 15.5 (Chile 1.7; Uruguay 2.0) 128.3
Recent dengue outbreaks in specific countries All four serotypes have circulated widely and continue to cause dengue outbreaks in the Americas(22). All four serotypes have been associated with epidemics in the 1990s in Costa Rica, El Salvador, Guatemala, Honduras and Nicaragua. As of early 1999 all four serotypes had also been documented in Mexico and Puerto Rico(23,24). As of September 15, 2002, numerous countries have reported dengue and DHF to PAHO, including Brazil, Colombia, Costa Rica, Cuba, El Salvador, Honduras, Peru, Venezuela, Barbados, and Trinidad & Tobago(25) (See Table 3). In Brazil, more than 500,000 dengue cases were reported in 1998 and Aedes aegypti infested all important urban centres of the country. DEN-1 has been present since 1986 and DEN-2 since 1990(26,27), setting the stage for widespread DHF/DSS if new serotypes of dengue are introduced. As of September 2002, more than 711,919 cases of dengue (predominantly DEN-3, although DEN-1 and DEN-2 are also present) as well as 2,229 cases of DHF and 130 deaths had been reported in the country(25). The dengue epidemic affected Rio de Janeiro state most severely(28). Aedes aegypti reinfested Argentina as far south as Buenos Aires after the vector had been eradicated in 1963. In 1996 and 1997, high levels of infestation were noted in Buenos Aires province and the Federal District. In 1997, viremic travellers brought dengue virus to Argentina and local transmission occurred in
From World Tourism Organization News Release, www.world-tourism.org/newsroom releases/ more_releases/january2002/numbers_2001.htm
Vector populations Shipping and trade have allowed the introduction of Aedes albopictus, also a competent vector for dengue, into previously uninfested countries. In 1985, Aedes albopictus was introduced into North America, probably via used tyres shipped from north Asia. It was first found in Texas and within 12 years had spread to 678 counties in 25 states(19,20). Its dispersal followed inter-state highways, and presumably was carried with human traffic and trade. As of the late 1990s, Aedes albopictus had been introduced into Brazil, the Dominican Republic, Guatemala, Mexico, Cuba, Bolivia, El Salvador and Colombia, and was continuing to spread(21). Modern ships, especially those with container vessels, are effective in dispersing the immature stages of mosquitoes. Most successful mosquito invasions have resulted from ship transport. Desiccation-resistant Aedes eggs are effectively transported in tyres. The reinfestation of Aedes aegypti and the establishment of Aedes albopictus in the Americas provide the vehicles for major
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Salta province in northern Argentina. This was the southern most extension of dengue noted to that point(29). Similarly, Easter Island, Chile and Hawaii (USA) recently suffered outbreaks of dengue. Both outbreaks were caused by DEN-1, and probably had been spread by travellers from Tahiti, the American Samoa or Western Samoa. More than 100 cases of dengue have been reported from Hawaii since 2001(30) and more than 130 cases have been reported from Easter Island in 2002(25). Although small in comparison to the outbreaks elsewhere in the Americas, these
mark new territories of dengue invasion in 2001-2002. Table 3 lists dengue cases by country from 1997 to 2002. Note that Brazil, Colombia, Costa Rica, Cuba, Ecuador, Guatemala, Honduras, Mexico, Nicaragua, Peru, Puerto Rico and Venezuela have had major dengue outbreaks or epidemics during this period. Over 320,000 cases of dengue fever were reported annually from the region since 1997. In the first quarter of 2002, there were already more than 400,000 cases reported.
Table 3: Countries in the Americas and reported dengue cases (1997-2002) Country or Region Anguilla Antigua& Barbuda Argentina Aruba Bahamas Barbados Belize Bermuda Bolivia Bonaire Brazil British Virgin Islands Cayman Islands Chile (Easter Island) Colombia Costa Rica Cuba Curacao Dominica Dominican Republic Ecuador Dengue Bulletin – Vol 26, 2002 0 199 141 0 539 − 254,109 0 0 − 24,290 14,267 3,012 − 0 608 3,871 336 852 8 0 49 − 535,388 1 2 − 63,182 2,628 − 7 1 3,049 4,606 19971 0 7 19982 0 4 822 19993 12 2 3 130 0 696 3 3 43 − 204,201 0 1 − 20,336 6,040 0 5 1 1,088 2,901 20004 3 8 1,700 76 0 744 4 0 73 − 231,471 3 0 − 22,775 4,907 138 10 15 3,462 22,937 20015 25 20 11 0 0 1,043 3 0 176 − 413,067 23 0 − 55,437 9,237 11,432 0 5 3,592 10,919 2002 (as of September 15)6 10 14 234 28 0 488 19 0 661 − 711,919 7 1 636 34,559 5,509 3,011 − 0 736 5,833 53
Dengue in the Americas 2002 (as of September 15)6 17,123 221 3,986 9,180 − 27,113 27 3005 4 − 4,258 405 1,795 7,196 1,662 18 44 − 124 220 2,625 0 26,413 3 869,087
Country or Region El Salvador French Guiana Grenada Guadaloupe Guatemala Guyana Haiti Honduras Jamaica Martinique Mexico Montserrat Netherland Antilles Nicaragua Panama Paraguay Peru Puerto Rico St. Kitts/Nevis St. Lucia St. Martin St. Vincent & Grenadines Suriname Trinidad & Tobago Turks & Caicos Islands Venezuela USA (Hawaii) Total
19971 423 851 22 0 5,385 0 − 11,873 16 235 53,541 − − 3,126 2,628 1,357 6,955 0 12 − 3 90 784 0 33,654 − 421,998
19982 1688 534 4 4,655 42 − 22,218 1,551 44 23,639 0 − 13,592 2,717 988 17,241 1 − 88 1,151 3,120 − 37,586 − 741,794
19993 626 88 85 41 3,617 0 − 17,835 24 268 14,875 0 − 11,150 2,783 1,164 554 4,993 1 3 − 8 695 1,265 0 26,716 − 322,256
20004 3248 186 27 60 9,006 19 − 13,642 25 171 21,715 9 − 7,317 317 24,282 5,486 2,433 5 0 − 5 1,073 2,066 0 21,101 − 400,519
20015 1093 2830 12 0 4,516 60 − 9,077 39 4,471 6210 1 − 2,104 1,545 38 23,329 5,233 89 292 − 3 760 2,244 0 83,180 96 652,212
1 PAHO. www.paho.org/english/hcp/hct/dengue_1997.htm 2 PAHO. www.paho.org/english/hcp/hct/dengue_1998.htm. 3 PAHO. www.paho.org/english/hcp/hct/dengue_1999.htm. 4 PAHO. www.paho.org/english/hcp/hct/vbd/dengue-cases-2000.htm 5 PAHO. www.paho.org/english/hcp/hct/vbd/dengue-cases-2001.htm 6 PAHO. www.paho.org/english/hcp/hct/vbd/dengue-cases-2002.htm –=Data not available.
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Burden from dengue The health and economic burden posed by dengue in the Americas has probably been underestimated because the number of deaths has been relatively low and the infection is often not diagnosed. A recent analysis showed that the impact of dengue in Latin America and the Caribbean as calculated by disability-adjusted life years (DALYs) was considerable. Meltzer et al. assessed DALYs lost to dengue in Puerto Rico for the period 1984 to 1994, using DALYs as a non-monetary measure of the economic impact(31). They found that in Latin America and the Caribbean, the loss of DALYs per million persons from dengue fever was similar to that from malaria and from a cluster of childhood diseases (polio, measles, pertussis, diphtheria, tetanus). Cuba provides an especially good case study because of sequential outbreaks caused by different dengue serotypes and good surveillance of clinical disease. In 1977, Cuba experienced an epidemic of DEN-1, with an estimated 4.5 million cases but no DHF or DSS. A subsequent epidemic of DEN-2 followed in 1981, causing more than 10,000 cases of DHF/DSS and 158 deaths(13); 95% of the cases of DHF/DSS occurred in persons with secondary dengue infections. In 1997, another outbreak of DEN-2 occurred in Santiago de Cuba, causing more than 5000 cases of laboratoryconfirmed DEN-2 infections, including 205 cases of DHF and 12 deaths(32,33). In this outbreak more than 98% of those with dengue fever and DHF had secondary dengue infections. Severe dengue did not occur in anyone 18 years and younger. This Dengue Bulletin – Vol 26, 2002
observation suggested that previous infection was the major risk factor, and also that increased risk for DHF was still present 1620 years after the primary infection, in this case DEN-1(34). Also notable in this epidemic was that almost all (97%) primary DEN-2 infections were mild or inapparent and were identified only by serological testing(33). Dengue in the United States is largely an imported infection. As suggested by the studies noted above, the infection is probably under-recognized and underreported. In 1997 and 1998, 143 persons with laboratory-diagnosed dengue were reported. Among the 122 patients for whom a travel history was available, 61 infections were probably acquired in the Caribbean islands, 30 in Asia, 23 in Central America, 4 in South America and 3 in Africa(35). The distribution reflects the travel patterns of US travellers and not the relative intensity of transmission in different geographical regions. One patient died; DEN-2 was documented on immunohistochemistry on autopsy tissue. The number of cases reported in 1998 was more than double the number reported in 1997. In 1999 and 2000, the number of documented cases in US travellers dropped to 41 cases(36).
Border areas A study of the populations along the USMexico border has been instructive in trying to understand the risk factors for infection and the dynamics of its spread. In 1986, at least 9 cases of laboratory-diagnosed dengue in Texas were acquired locally. In 1995, during another period of intense transmission in Mexico (and with the 55
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circulation of all 4 dengue serotypes in Mexico), of the 23 cases of laboratoryconfirmed dengue in Texas between September and mid-November, at least 7 had been acquired in Texas. Both Aedes aegypti and Aedes albopictus were abundant in south Texas(37). From January to July 1999, at a time when an outbreak of more than 300 cases had been reported in Nuevo Laredo, Tamaulipas, Mexico, no cases of dengue fever were reported across the border in Laredo, Texas, USA. Each month, an estimated 2 million border crossings occur between Laredo and Nuevo Laredo. Aedes aegypti infests both cities. The Texas Health Department undertook a review of medical records to assess whether dengue fever was absent in Texas or whether it was unrecognized or unreported(38). They reviewed the medical records from patients who presented themselves to five medical facilities with febrile illness (with arthralgia, myalgia, rash or headache) during a 4-week period. When they collected blood samples and tested for dengue, they found that almost 50% of those tested had serological evidence of recent dengue infection. Most, but not all, reported recent travel to Mexico within the 2 weeks prior to the onset of symptoms. Diagnoses that had been recorded for the patients at the time they were evaluated included viral syndrome and flu-like illness. After the Texas Department of Health issued an alert about dengue, 161 cases of suspected dengue were reported from mid-August through December 1999, and 18 were documented to be of dengue fever.
Underdiagnosis and misdiagnosis Although 4 serotypes of dengue virus exist, there are also multiple genotypes(39,40), and these may differ in clinical manifestations and potential for enhancement with subsequent dengue infections. Furthermore, the consequences of previous infection with non-dengue flaviviruses on susceptibility to dengue and clinical expression of dengue, and vice versa, are unclear. Studies looking at these interactions are limited and are complicated by difficulties in the serological diagnosis of dengue and related flavivirus infections. Active surveillance programmes document that dengue infections may be more common than recognized. A laboratory-based active surveillance programme for dengue in Florida in 19971998 detected 18 cases of dengue, all in persons who had recently travelled to dengue endemic areas(41). Infections involved all four serotypes. In the preceding 10 years an average of 1.3 cases per year had been detected with a passive surveillance system. This is relevant because this area of Florida is inhabited by two competent vectors, Aedes aegypti and Aedes albopictus(42). Many cases of dengue infection are not identified because they are asymptomatic or mild or resemble many other febrile illnesses. Silent transmission of dengue viruses is more likely in populations without previous dengue, especially if caused by “low virulence” strains. For example, primary DEN-2 tends to cause mild disease, in contrast to DEN-1, which has caused highly visible epidemics in virgin
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populations. Primary infections with some strains of DEN-2 and DEN-4 are largely subclinical in some settings. In Cuba, for example, 97% of the primary DEN-2 infections were clinically inapparent. In Haiti where the annual infection rate is about 30% and 85% of the residents have antibodies to two or more dengue serotypes, there have been no major outbreaks of DHF(43). In Iquitos, Peru, DEN-1 was introduced in 1990, followed by the circulation of DEN-2 in 1995. Among the 129 students for whom serum samples were available before and after the 1995 epidemic, 60.5% were found to have secondary DEN-2 infections, caused by the American DEN-2 genotype. No cases of DHF or DSS were found, suggesting that even secondary infections with some genotypes were unlikely to cause (44) complicated dengue . Dengue infections and even outbreaks can be missed if they are occurring in the setting of other febrile illnesses with overlapping clinical features. Several studies confirm this observation. In a serological study of diseases causing rash in Rio de Janeiro between 1994 and 1998 (set up to assess measles status in the population), investigators found that dengue was the most common diagnosis causing fever and rash(45). Among the 71.3% patients with a confirmed diagnosis (out of 327 patients with rash diseases) 33% had dengue fever, 20.2% had rubella, 9.2% had parvovirus, 6.7% had measles and 4.2% had serological evidence of infection with HHV-6. At the time of the study, 67.6% of the cases of dengue in the area occurred in persons 15 years or older. Other studies also confirm confusion between dengue and rubella(46) and rickettsial infections(47). Dengue Bulletin – Vol 26, 2002
In distinguishing dengue from other febrile illnesses, it is important to know what other infections dengue can resemble. Several studies and observations illustrate how dengue fever can be missed or misdiagnosed. In Barbados, the peak of leptospirosis coincides with the increase in rainfall. This island also experienced dengue epidemics in 1995 and 1997. In 1995 and 1997, among the patients investigated for leptospirosis, more were found to have dengue than leptospirosis(48). On the other hand, in a large urban outbreak of leptospirosis in Salvador, Brazil, in 1994, 43% of the patients with confirmed or probable leptospirosis were initially diagnosed as having dengue fever(49). In late 1994 hundreds of people in a rural area north of Lake Managua, Nicaragua developed acute illness with fever, headaches and muscle aches, and fatalities resulted from respiratory distress and pulmonary haemorrhage. Again, the initial focus was on dengue haemorrhagic fever, but the dengue studies were negative. Additional studies revealed leptospirosis as the cause. Heavy rains and flooding had preceded the outbreak(50). Another outbreak of haemorrhagic fever, which occurred in Guanarito, Portuguesa State, Venezuela, in 1989, was initially thought to be dengue haemorrhagic fever – but studies for dengue were negative. Subsequent studies identified a previously unrecognized virus, an arenavirus designated as Guanarito virus, as the cause of the disease, later called Venezuelan haemorrhagic fever(51). The source of the virus was the cotton rat. Development of new agricultural lands and migration of large
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numbers of workers into the area had increased the likelihood of human-rodent contact. When military troops were deployed in Haiti starting in 1994, routine medical surveillance was carried out at 22 military clinics(52). Among the 406 combat support hospital admissions during the first 6 months of deployment, 25% were due to febrile illnesses. More detailed diagnostic studies showed that dengue fever accounted for at least 30% of febrile illnesses leading to hospitalization. DEN-1, DEN-2 and DEN-4 were isolated from the troops. The clinicians observed that they were unable to diagnose dengue based on clinical grounds alone(53).
New approaches to surveillance In Puerto Rico dengue is a well-known and common infection, and surveillance systems are in place. In contrast, leptospirosis is rarely reported, though a seroprevalence study found antibodies in 14% of the population. After Hurricane Hortense hit the island in 1996, resulting in heavy rains and flooding, leptospirosis was diagnosed in patients initially suspected to have dengue fever. This led investigators to do a study using an island-wide dengue laboratorybased surveillance system. Serum samples from patients with suspected dengue that tested negative for dengue were subsequently tested for the evidence of leptospirosis. They found that before the hurricane, 6% of the dengue-negative patients have had leptospirosis. This increased to 24% (17/70) during the post hurricane period(62). In French Guiana investigators tested a laboratory surveillance system to try to find a way to identify a dengue epidemic early in its course(63). Because the area is endemic for malaria and malaria smears are typically included as part of the work up of a febrile patient, they monitored the number of studies for malaria that were negative for malaria as a way to capture non-specific febrile illnesses. In that setting, the number of negative malaria studies was found to be a good predictor of dengue fever in some towns. This underscores the need to have baseline information about diseases present in an area and to base surveillance systems on local or regional characteristics relevant to the population.
Clinical highlights The clinical presentations of dengue in the Americas are generally similar to the cases in south-east Asia. However, the age distribution of DHF cases in the Americas differed somewhat from Asia. In Puerto Rico in 1990-1991 the mean age of patients who developed DHF was 38, whereas in southeast Asia primarily young children become ill with DHF(54). In the 1994 epidemic of dengue fever and dengue haemorrhagic fever in Ceara State, Brazil, the mean age of DHF cases was 42(55). In the 1990-91 study of 56 confirmed cases of DHF in Rio de Janeiro, Brazil, the modal age range was 3145(56). Likewise, in the 1997 outbreak in Cuba, DHF primarily affected young adults(33). The overall case-fatality rate of DHF in the Americas from 1997-2002 ranges from 0.9% to 1.6%(24,57,58,59,60,61).
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Conclusions and recommendations Dengue is spreading geographically in the Americas, reaching larger populations and causing a more severe disease in areas that have concurrent or sequential circulation of multiple serotypes. Sustained control of the vector is difficult to achieve. Programmes to date have had limited sustained success, except perhaps in focal areas. Better rapid diagnostic tests are needed. Also needed are more complete epidemiological studies by geographical area which would provide a profile of common infections in each area that can resemble dengue fever. Experience gained from outbreak investigations and surveillance studies, as described above, has shown that diseases as diverse as leptospirosis,
Venezuelan haemorrhagic fever, influenza, rubella, measles, and rickettsial infections have been misdiagnosed as dengue fever, or vice versa. Mechanisms of transmission, approaches to treatment, and control measures vary substantially among these infections, making accurate and timely diagnoses essential to provide informed interventions. Perhaps because dengue fever is often not diagnosed or reported, the impact of the disease has been underestimated. Given the current circumstances in the Americas (population location, density, mobility, living conditions and current status of vector distribution and density) and what is known about the complexity of dengue viruses and the immune response they induce, it is likely that dengue fever will grow in importance in the Americas in the coming decades.
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