Vol. 18, No. 2	July 1997

Re-emergence of Dengue in the Americas

	Introduction
	Present Situation
	Historical Overview
	Re-emergence of Dengue
	The Emergence of DHF
	Causes of the emergence/re-emergence
	Prevention and control
	References

Clinically dengue fever has been recognized for more than 200 years and a disease similar to dengue hemorrhagic fever (DHF) was first described in northern Australia at the end of the past century (1). Although several dengue epidemics or pandemics have been described in previous centuries and in the first half of this century, a remarkable increase of their incidence has been noted since the 1950s. A main concern was the appearance of epidemic DHF in the Philippines in 1954, which rapidly spread to Thailand, Vietnam, Indonesia and to other Asian and Pacific countries, becoming endemic and epidemic in several of them (1). The first DHF epidemic in the Americas occurred in Cuba in 1981 (2) and subsequently 24 other countries in the Region have reported DHF. Also of great concern has been the occurrence of several pandemics and countless epidemics of dengue fever over the past 40 years causing considerable health, social and economic impact.

About two-thirds of the world’s population live in areas infested with dengue vectors, mainly Aedes aegypti. All four dengue viruses are circulating, sometimes simultaneously, in most of these areas. It is estimated that up to 80 million persons become infected annually although marked underreporting results in the notification of much smaller figures.

Currently dengue is endemic in all continents except Europe and epidemic DHF occurs in Asia and in the Americas. The incidence of DHF is greater by far in the Asian countries than in the Americas. In the Americas, the emergence of epidemic DHF occurred in 1981 almost 30 years after its appearance in Asia and its incidence is showing a marked upward trend.

Historical overview.

The first description of a dengue-like disease in the Americas relates to an outbreak that occurred in Philadelphia, United Sates, in 1780 (1). In the following century four large epidemics affected Caribbean countries and the southern United States which occurred during the periods 1827-28, 1850-51, 1879-1880 and 1897-1899 (5). Interestingly, small-joint arthritis including swelling, which are commonly found in infections associated with the arboviruses Chikungunya and Mayaro, were among the clinical manifestations observed during the dengue outbreaks between 1827-1880 but not since this period. In the first half of this century four epidemics were reported in the same countries the last one being during the period 1941-1946 which affected cities in the Texas Gulf, several Caribbean islands including Cuba, Puerto Rico and Bermuda, Mexico, Panama and Venezuela. (5). In Brazil epidemics of dengue were recorded during 1846-1848 and 1851-1853. From then until 1982 only two outbreaks were reported, in 1916 and 1923 (6,7). Peru reported cases of dengue during the 1950s but not in the following three decades (8). In 1953 dengue virus which was identified as serotype 2 was isolated for the first time in the Americas in the island of Trinidad. Several isolates of dengue-2 were obtained from persons in the same island during 1953-1954 but interestingly no outbreaks were reported in this period in Trinidad nor in any other Caribbean islands .

During the 1960s two extensive pandemics of dengue affected the Caribbean and Venezuela. The first one which broke out in 1963 was due to dengue-3 and swept the Caribbean after almost 20 years of silence. Jamaica, Puerto Rico, islands of the Lesser Antilles and Venezuela were among the countries affected but interestingly Cuba, Hispañiola and Trinidad were spared in this outbreak. The second epidemic occurred in the Caribbean and Venezuela during 1968-1969 and although dengue-2 was predominantly isolated, dengue-3 was also recovered from persons in some islands (5). During the 1970s these two serotypes caused extensive epidemics in Colombia where dengue had not been recognized since 1952 (10). The first epidemic occurred during 1971-1972 and was due to dengue-2 whereas the 1975-1977 epidemic was associated with dengue-3. It was estimated that more than half a million persons became infected however both outbreaks occurred "silently" for the most part or were confused with other illnesses and did not draw much attention of the health authorities.

A milestone in the re-emergence of dengue in the Americas was the introduction of dengue-1 in 1977. This was followed by a devastating pandemic that lasted until 1980 (11). The virus was initially detected in Jamaica, possibly having been imported from Africa, and from there the epidemic spread to virtually every island of the Caribbean. The epidemic in South America began in 1978, affecting Venezuela, Colombia, Guyana, Surinam and French Guiana. The epidemic in Central America was also detected in 1978 affecting Honduras initially and subsequently El Salvador, Guatemala and Belize. Spreading to the north the epidemic reached Mexico at the end of 1978 and during 1979-1980 continued to affect other Mexican states, and arrived in the state of Texas in the second half of 1980. About 702,000 cases were reported to the Pan American Health Organization (PAHO) for the period 1977-1980, but the incidence was much higher since estimates from Colombia, Cuba and Venezuela alone indicated that over 5 million persons became infected. In 1981 dengue-4 strain probably imported from Pacific islands emerged in the Americas causing a series of outbreaks in the Caribbean, northern South America, Central America and Mexico; with some exceptions dengue-4 infection has generally been associated with mild disease (11)).

During the 1980s five countries in South America namely Brazil, Bolivia, Paraguay, Ecuador and Peru, that had not experienced dengue before or had been free of the disease for several decades were affected by explosive epidemics caused by serotype 1 (11); in the epidemic in Peru serotype 4 was also isolated (12). The first epidemic which occurred in northern Brazil in 1982 was associated with serotypes 1 and 4 (13); vector control measures were implemented and since then no dengue activity has been reported in this area. In 1986 dengue 1 was introduced in Rio de Janeiro, Brazil, causing major outbreaks (14). It was subsequently disseminated to most states in Brazil. Following its introduction in those countries, dengue-1 virus has continued to cause major epidemics in Brazil, Ecuador and Peru in subsequent years.

During 1993 the last two tropical Latin American countries which had been free of dengue for several decades, namely Costa Rica and Panama, reported indigenous transmission of dengue; the serotype was dengue-1 and its introduction in Costa Rica was associated with severe outbreaks in this year and in subsequent years (15). In 1994 dengue-3 was reintroduced in the Americas after an absence since 1978 when was last isolated in Puerto Rico (16). This serotype was initially detected in Panama and Nicaragua and in the following year it spread to other Central American countries and to Mexico, causing numerous epidemics of dengue. In Nicaragua, in 1994, the introduction of dengue 3 was associated with a countrywide epidemic of dengue/DHF but dengue-1 was also present. The introduction of dengue-3 in Mexico in 1995 coincided with an increased number of DHF cases, however only dengue-1 and particularly dengue-2 were associated with DHF (17). It should be noted that this dengue-3 virus belongs to the a genotype that has caused major epidemics of DHF in Sri Lanka and India (16). As of June 1997 dengue-3 has not been isolated outside Central America and Mexico. Over 250,000 cases of dengue were reported in the Region in each of 1995 and 1996.

In 1981 Cuba reported the first major outbreak of DHF in the Americas (2). Prior to this event suspected cases of DHF or fatal dengue cases had been reported by five countries or territories namely Venezuela, Jamaica, Honduras, Curacao and Puerto Rico, but only a few of them fulfilled the WHO criteria for diagnosis of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) and most were not laboratory confirmed (11). During the Cuban epidemic a total of 344, 203 cases of dengue were notified, of which 10,312 were classified as severe cases (WHO grades II-IV) and 158 were fatal; a total of 116,143 patients were hospitalized, the majority of them during a three-month period (2). The DHF Cuban epidemic was associated with a strain of dengue-2 virus and it occurred four years after dengue-1 had been introduced in the island causing epidemics of dengue fever and infecting almost half of the country’s population.

The outbreak of DHF/DSS in Cuba is the most important event in the history of dengue in the Americas. Subsequent to it, in every year except 1983, confirmed or suspected cases of DHF have been reported in the Americas. A marked increase in the annual incidence occurred in 1989 which was due to a countrywide epidemic in Venezuela. This was the second major DHF epidemic in the Americas with 3,108 DHF cases and 73 deaths being reported between December 1989 and April 1990 when it was declared over. Dengue-2 was the predominant serotype isolated from cases but serotypes 1 and 4 were also recovered from patients; although no isolate were obtained from fatal cases, immunohistochemical analysis performed with formalin-fixed paraffin-embedded tissues of fatal cases revealed the presence of dengue-2 antigen in the liver of four of them (18). The epidemic recurred in the second half of 1990 and since then Venezuela has suffered epidemics of DHF every year.

Between 1981 and 1996 a total of 41,977 cases of DHF and 570 deaths were reported by 25 countries in the Americas. The distribution of cases by country where it can be observed that 22,170 (53%) of the reports originated from Venezuela. It can also be seen that excluding Cuba and Venezuela, the number of cases by country varies from 1 to 3,740 cases. Colombia, Nicaragua and Mexico have each reported over 1,000 cases, most of which during the period 1992-1996. About 74% of the Colombian cases were notified during 1995-1996 whereas 97% of the Mexican cases were reported during 1995-1996. In Brazil four fatal cases which exhibited fever, hemorrhages and shock occurred during 1986-1987 and were associated with dengue-1 virus; confirmation was obtained by virus isolation or by antigen detection (11). In 1990-1991 an outbreak of DHF was recorded in Rio de Janeiro, Brazil (19) and 24 cases with 11 deaths occurred in the Brazilian State of Ceara (20).

Studies of DHF cases in the Americas (21, 18, 22, 23) revealed similarities to the clinical manifestations exhibited by DHF patients in Asia. However, the incidence of gastrointestinal hemorrhages observed in Cuba and Puerto Rico seem to be higher than that seen in Thai children (24). Liver necrosis, was described in 70% of 72 children who died of DHF in Cuba in 1981 (24). Severe neurological manifestations, renal failure and myocarditis have been occasionally reported in the Americas (20, 25, 26).

The age distribution of DHF cases in the Americas is different from that observed in Asia. In the outbreaks in Cuba and Venezuela the disease has occurred in all age groups, although children under 15 years of age have comprised about two-thirds of the fatalities. Studies of DHF cases that fulfilled WHO’s criteria done in Brazil (24) showed a modal age range of 31-45 years. Observations made in Puerto Rico showed distinct age distribution patterns of cases that fulfilled WHO’s criteria: in 1986 two-thirds of the cases were under 15 years of age but during 1990-91 the mean age of patients was 38 years (26, 22). This age distribution pattern is different from that found in South-East Asia where young children are affected predominantly. It should be noted, however, that a marked increase in the number of DHF cases in people over 15 years old has been observed in the Philippines and Malaysia during recent years (27). Regarding the sex distribution, Cuba reported no significant female predominance a finding that is in contrast with observations from Asia.

The epidemics in Cuba and Brazil were clearly associated with dengue-2 virus. In both countries dengue-1 had been introduced four years earlier, after a period of several decades of absence of dengue virus circulation. However, Cuba suffered a major epidemic while only relatively small outbreaks have been observed in Brazil. Other countries such as Peru and Ecuador have experienced a similar sequence of dengue infections with these serotypes, but no DHF epidemics were recorded. A distinct epidemiological pattern was observed in Venezuela and in French Guiana where dengue was endemic for over 20 years before the emergence of their first epidemics of DHF in 1989-1990 and 1990-1991 respectively: Dengue-2 was predominant in Venezuela (18) and in French Guiana (28) and the only serotype found in the tissues of fatal cases in Venezuela (18). Interestingly in French Guiana the dengue-2 strains isolated during the DHF outbreak and during an outbreak of dengue fever that occurred in 1986 were genetically similar and belonged to the Jamaican genotype which in turn has a genome sequence very close to dengue-2 strains from Vietnam where DHF is highly endemic (28). These findings illustrate the complexity of the factors responsible for triggering DHF. Studies in Cuba suggested that individual risk factors for DHF include chronic diseases such as bronchial asthma, diabetes mellitus and sickle cell anemia, and that race seems also to be important, since DHF/DSS was more prevalent in white than in black persons (29).

Overall, the case-fatality rate (CFR) of DHF in the Americas is 1.4%. However, a marked variation has been observed among countries. In 1995 the CFR ranged from 8.3% in Puerto Rico to 0.8% in Venezuela. This variation could be due to several factors such as reporting criteria, viral strain, case management, host genetic factors and possibly other causes.

In 1947 PAHO was entrusted by its Directing Council to organize a hemispheric campaign to eradicate the mosquito Aedes aegypti. By 1962, 18 continental countries and several Caribbean island countries had successfully achieved eradication. Unfortunately after 1962 only three new countries eliminated the vector. Even more serious, however, was that the countries that had achieved eradication, became re-infested with the vector in the 1960s and in subsequent decades. Countries still infested (the United States, Cuba and some other Caribbean islands, Venezuela) became sources of reinfestation for those that had eradicated the vector. Other reasons for the program failure include reduced political support for the programs, resulting in inadequate management and scarcity of trained technical personnel; resistance of A. Aegypti to chlorinated insecticides and high cost of materials, equipment and wages. There was progressive dissemination of the vector so that by 1997 with the exception of Canada, Chile and Bermuda, all countries in the Americas are infested. The practice of water storage in domestic settings due to the problems of water supply and the exponential growth of containers than can hold water (tires, disposable containers) greatly contribute to the increase of vector densities favoring virus transmission. Other factors contributing to the emergence/re-emergence of dengue/DHF include the rapid growth and urbanization of populations in Latin America and the Caribbean, and increased travel of persons which facilitates dissemination of dengue viruses. Presently all four dengue serotypes are circulating in the Americas, thus increasing the risk for DHF in this Region.

The high number of dengue and DHF cases, the presence of all 4 dengue virus serotypes in the Region, and the extensive range of the vector make it necessary to intensify disease prevention and control activities.

Unfortunately a vaccine against dengue is presently not available. A live attenuated tetravalent vaccine developed in Thailand looks promising but field efficacy trials have not yet been undertaken. In parallel, efforts are being made to develop a genetically engineered dengue vaccine. Different approaches are being explored such us chimeric infectious clone using dengue-2 attenuated or 17D yellow fever strains as backbones, and a DNA naked vaccine. Despite these efforts it may take 5 to 10 years to have a vaccine safe and efficacious for the immunization of children available.

Therefore vector control is at present the only approach to combat dengue/DHF. Recent discussions concerning a new effort to eradicate the vector from the Americas have not been universally well received by countries due to its high cost, and the need for hemispheric commitment and implementation and several operational obstacles, such as difficulties in establishing a vertical program and problems of access to certain slum areas due to safety reasons. At a meeting in Caracas, Venezuela, in April 1997, experts recommended a 5-step approach beginning with control programs and leading to eventual eradication.

PAHO has developed guidelines (24) for the prevention and control of dengue/DHF and A. aegypti which includes several components that should be implemented together. These components are as follows: 1-Epidemiologic surveillance (active, with laboratory support); 2-Education of the medical community to recognize and properly treat dengue/DHF cases; 3-Entomological surveillance; 4-Vector control with emphasis on source reduction utilizing environmental management (improvement of water supply, adequate solid waste management, naturalistic methods), chemical methods and biologic control; 5-Community participation with efforts oriented towards the elimination or proper handling of potential breeding sites, physical protection of water storage areas and clean up campaigns; and 6-Emergency plans to cope with epidemics of dengue/DHF.

There is a lack of well organized and effective control programs at present as evidenced by the frequent outbreaks epidemics of dengue fever and the increase of DHF in several countries. Emergency measures to combat the epidemics have had limited impact. A reliance on emergency as the basis for response to this disease cannot be successful. Rather, countries must dedicate themselves to coordinated prevention and control programs in order to be effective.

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