A domestic, day-biting mosquito that prefers to feed on humans, is the most common Aedes species
Dengue Fever
Dengue fever and dengue hemorrhagic fever (DHF) are viral diseases transmitted by Aedes mosquitoes, usually Aedes aegypti. The four dengue viruses (DEN-1 through DEN-4) are immunologically related, but do not provide cross-protective immunity against each other.
Dengue, a disease found in most tropical and subtropical areas of the world, has become the most common arboviral disease of humans. More than 2.5 billion persons now live in areas where dengue infections can be locally acquired (1). Reported attack rates for disease during epidemics range from 1 per hundred to 1 per thousand of the population (2). However, because persons with milder illness may not seek medical attention and subsequently be reported, the actual number of infections in a population may be 5 to 10 times greater than the number reported. Epidemics caused by all four virus serotypes have become progressively more frequent and larger in the past 25 years. As of 2005, dengue fever is endemic in most tropical countries of the South Pacific, Asia, the Caribbean, the Americas, and Africa (see Maps 4-1, 4-2). Additionally, most tropical urban centers in these regions have multiple dengue virus serotypes co-circulating (hyperendemicity), which is associated with increased dengue transmission and the appearance of DHF. Future dengue incidence in specific locales cannot be predicted accurately, but a high level of dengue transmission is anticipated in all tropical areas of the world for the indefinite future. The incidence of the severe disease, DHF, has increased dramatically in Southeast Asia, the South Pacific, and the American tropics in the past 25 years, with major epidemics occurring in many countries every 3-5 years. The first major epidemic in the Americas occurred in Cuba in 1981, and a second occurred in Venezuela in 1989-1990 (3,4). Since then, outbreaks and rates of endemic, confirmed DHF have occurred in most tropical American countries. After an absence of 35 years, several locally acquired cases of dengue fever occurred in southern Texas in 1980 associated with epidemic dengue in adjacent states in Mexico (5). In the last decade, such dengue cases have been identified in Texas every 1 to 5 years. The most recent cases in 2005 included the first locally acquired DHF case in the continental United States (6). After an absence of 56 years, a limited outbreak of dengue fever occurred in Hawaii in 2001, associated with imported cases arriving from areas with epidemic dengue in the South Pacific (7).

Risk for Travelers
The principal mosquito vector, Ae. aegypti, is most frequently found in or near human habitations and prefers to feed on humans during the daytime. It has two peak periods of biting activity: in the morning for several hours after daybreak and in the late afternoon for several hours before dark. Nevertheless, the mosquito may feed at any time during the day, especially indoors, in shady areas, or when it is overcast. Mosquito breeding sites include artificial water containers such as discarded tires, uncovered water storage barrels, buckets, flower vases or pots, cans, and cisterns.
Cases of dengue fever and DHF are confirmed every year in travelers returning to the United States after visits to tropical and subtropical areas (8). Studies of military and relief workers placed the estimated risk for travelers returning from dengue-endemic areas near one illness per thousand travelers (9, 10). This estimate may overstate the danger for tourists who may have less contact with the vector when they stay only a few days in air-conditioned hotels with well-kept grounds, or when they participate in outdoor recreational activities where the vector mosquito may be absent (such as sunbathing or playing golf in the middle of the day). A recent study of tourists visiting Hawaii during a dengue outbreak in 2001 failed to identify serologic evidence of dengue infection among over 3,000 travelers; however, this study was limited by the fact that only persons sick enough to seek medical attention received dengue testing (11). As a result, milder dengue infections that did not require medical attention might have been missed. Moreover, travelers who stay in the homes of friends and relatives in locations with intense disease transmission may have a higher risk of illness. Therefore, travelers to endemic and epidemic areas should take precautions to avoid mosquito bites (see Chapter 2).
Current data suggest that co-circulation of all four dengue strains in the same geographic region, virus genotype, and host factors such as immune status (i.e., having had a previous dengue infection), age, and genetic background are the most important risk factors for developing DHF (12). In Asia, where a high proportion of the population has experienced a dengue infection early in life, DHF is observed most commonly in infants and children younger than 15 years of age who are experiencing a second dengue infection. In the Americas and the Pacific, where primary infection at a young age is less common, DHF is typically observed in older children and adults. Therefore, international travelers from nonendemic areas (such as the United States) are generally at low risk for DHF.
There is little information in published reports about the consequences of dengue infection for pregnant women. No convincing evidence demonstrating an association between dengue infection during pregnancy and congenital malformations has been reported. However, if the mother is ill with dengue at the time of delivery, the child can be born with dengue infection or can acquire dengue through the delivery process itself, and then develop the manifestations of dengue fever or DHF (13). Passive transplacental transfer of maternal anti-dengue antibodies acquired from a previous maternal infection can also place infants at greater risk of DHF with their first dengue infection, but these maternal antibodies are cleared by 9-12 months of age (14,15). Transfusion-related dengue infection is a theoretical possibility (16).

Clinical Presentation
Dengue fever is characterized by sudden onset after an incubation period of 3-14 days (most commonly 4-7 days) of high fevers, severe frontal headache, and joint and muscle pain. Many patients have nausea, vomiting, and a maculopapular rash, which appears 3-5 days after onset of fever and can spread from the torso to the arms, legs, and face. The disease is usually self-limited, although convalescence can be prolonged. Most patients report a nonspecific viral syndrome or a flu-like illness. Asymptomatic infections are also common. Although these patients do not experience symptoms at the time of the acute infection, the immunity that results increases the risk for DHF during a subsequent infection. Approximately 1% of patients with dengue infection progress to DHF. As the patient’s fever resolves, usually 3-5 days following the onset of fever, patients may develop leaky capillaries, which allow serum proteins and fluid to accumulate in the pleural and abdominal cavities. Thrombocytopenia and hemorrhagic manifestations, which can range from microscopic hematuria or increased menstrual flow to hemetemesis, are part of the syndrome. Neutropenia, elevated liver enzymes, and disseminated intravascular coagulation are also common. The case-fatality ratio for DHF averages about 5% worldwide, but can be kept below 1% with proper clinical management. Dengue shock syndrome is the progression of DHF to a hypotensive state. Despite the name, the progression of DHF to DSS is primarily due to capillary leakage rather the hemorrhaging (12).
Physicians should consider dengue in the differential diagnosis of all patients who have fever and a history of travel to a tropical area within 2 weeks of onset of symptoms. Commercial tests are available for serologic diagnosis, but their results must be interpreted with care. Sensitivity and specificity of kits may vary among manufacturers, laboratories, and over time. In combination with a compatible travel history and symptom profile, anti-dengue IgM positivity suggests a recent dengue infection, but IgG positivity may only indicate infection at an indeterminate time in the past. Both anti-dengue IgM and IgG antibodies cross-react with anti-West Nile, -yellow fever, -Japanese encephalitis, and -other flavivirus anti-bodies; therefore, prior infection or vaccination with another flavivirus may also result in positive anti-dengue antibody results. If testing at CDC is requested, acute- and convalescent-phase serum samples (collected 0-5 days and 6-30 days from fever onset, respectively) should be obtained and sent through state or territorial health department laboratories to CDC’s Dengue Branch, Division of Vector-Borne Infectious Diseases (DVBID), National Center for Infectious Diseases, 1324 Calle Cañada, San Juan, Puerto Rico 00920-3860. Serum samples should be accompanied by clinical and epidemiologic information, including the date of disease onset, the date of collection of the sample, and a detailed recent travel history.
No vaccine is available. Travelers should be advised that they can reduce their risk of acquiring dengue by remaining in well-screened or air-conditioned areas when possible, wearing clothing that adequately covers the arms and legs, and applying insect repellent to both skin and clothing. The most effective repellents are those containing N,N-diethylmetatoluamide (DEET) (see Chapter 2).

Acetaminophen products are recommended for managing fever. Acetylsalicyclic acid (aspirin) and nonsteroidal anti-inflammatory agents (such as ibuprofen) should be avoided because of their anticoagulant properties. Salicylates (e.g., aspirin) should be especially avoided in children due to the association with Reye syndrome. Patients should be encouraged to rest and take fluids. Warning signs of progression to severe disease include abrupt change from fever to hypothermia, severe abdominal pain, prolonged vomiting, and altered mental status (e.g., irritability, confusion, lethargy). Prompt treatment of DHF with intravenous fluid can improve patient outcomes. In such cases, hospitalization with close monitoring of vital signs, fluid balance, and hematologic parameters is indicated, as well as additional supportive measures (12).

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Kouri GP, Guzman MG, Bravo JR, Triana C. Dengue haemorrhagic fever/dengue shock syndrome: lessons from the Cuban epidemic, 1981. Bull World Health Organ. 1989;67:375-80.
Pan American Health Organization. Dengue hemorrhagic fever in Venezuela. Epidemiol Bull. 1990;11:7-9.
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Lacayo M, Taylor R, Duran H, Abell A, et al. Outbreak investigation of dengue—Texas, 2005 (Late-breaker). Presented at 54th Annual Meeting: American Society of Tropical Medicine and Hygiene. Washington, DC, December 11-15, 2005.
Effler PV, Pang L, Kitsutani P, Vorndam V, Nakata M, Ayers T, et al., and Hawaii Dengue Outbreak Investigation Team. Dengue Fever, Hawaii, 2001–2002. Emerg Infect Dis. 2005;11:5:742-749.
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Trofa AF, DeFraites RF, Smoak BL, Kanesathasan N, King AD, Burrous JM, et al. Dengue fever in US military per-sonnel in Haiti. JAMA. 1997;277:1546-8.
O’Leary DR, Rigau-Pérez JG, Hayes EB, Vorndam AV, Clark GG, Gubler DJ. Assessment of Dengue risk in relief workers in Puerto Rico after Hurricane Georges. Am J Trop Med Hyg. 2002;66:35-39.
Smith CE, Tom Tammy, Sasaki J, Ayers T, Effler PV. Dengue risk among visitors to Hawaii during an outbreak. Emerg Infect Dis. 2005;11:750-66.
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Beatty ME, Biggerstaff B, Rigau J, Petersen L. Estimated risk of transmission of dengue virus through blood transfusion in Puerto Rico (#126). At 5th International Conference on Emerging Infectious Diseases. Atlanta, GA. March 19-22, 2006.
Dengue (DF) and dengue hemorrhagic fever (DHF) are caused by one of four closely related, but antigenically distinct, virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4), of the genus Flavivirus. Infection with one of these serotypes provides immunity to only that serotype for life, so persons living in a dengue-endemic area can have more than one dengue infection during their lifetime. DF and DHF are primarily diseases of tropical and sub tropical areas, and the four different dengue serotypes are maintained in a cycle that involves humans and the Aedes mosquito. However, Aedes aegypti, a domestic, day-biting mosquito that prefers to feed on humans, is the most common Aedes species. Infections produce a spectrum of clinical illness ranging from a nonspecific viral syndrome to severe and fatal hemorrhagic disease. Important risk factors for DHF include the strain of the infecting virus, as well as the age, and especially the prior dengue infection history of the patient.
History of Dengue
The first reported epidemics of DF occurred in 1779-1780 in Asia, Africa, and North America. The near simultaneous occurrence of outbreaks on three continents indicates that these viruses and their mosquito vector have had a worldwide distribution in the tropics for more than 200 years. During most of this time, DF was considered a mild, nonfatal disease of visitors to the tropics. Generally, there were long intervals (10-40 years) between major epidemics, mainly because the introduction of a new serotype in a susceptible population occurred only if viruses and their mosquito vector could survive the slow transport between population centers by sailing vessels.
A pandemic of dengue began in Southeast Asia after World War II and has spread around the globe since then. Epidemics caused by multiple serotypes (hyperendemicity) are more frequent, the geographic distribution of dengue viruses and their mosquito vectors has expanded, and DHF has emerged in the Pacific region and the Americas. In Southeast Asia, epidemic DHF first appeared in the 1950s, but by 1975 it had become a frequent cause of hospitalization and death among children in many countries in that region.
Current Trends
In the 1980s, DHF began a second expansion into Asia when Sri Lanka, India, and the Maldive Islands had their first major DHF epidemics; Pakistan first reported an epidemic of dengue fever in 1994. The epidemics in Sri Lanka and India were associated with multiple dengue virus serotypes, but DEN-3 was predominant and was genetically distinct from DEN-3 viruses previously isolated from infected persons in those countries. After an absence of 35 years, epidemic dengue fever reemerged in both Taiwan and the People's Republic of China in the 1980s. The People's Republic of China had a series of epidemics caused by all four serotypes, and its first major epidemic of DHF, caused by DEN-2, was reported on Hainan Island in 1985. Singapore also had a resurgence of dengue/DHF from 1990 to 1994 after a successful control program had prevented significant transmission for over 20 years. In other countries of Asia where DHF is endemic, the epidemics have become progressively larger in the last 15 years.
In the Pacific, dengue viruses were reintroduced in the early 1970s after an absence of more than 25 years. Epidemic activity caused by all four serotypes has intensified in recent years with major epidemics of DHF on several islands.
Despite poor surveillance for dengue in Africa, epidemic dengue fever caused by all four serotypes has increased dramatically since 1980. Most activity has occurred in East Africa, and major epidemics were reported for the first time in the Seychelles (1977), Kenya (1982, DEN-2), Mozambique (1985, DEN-3), Djibouti (1991-92, DEN-2), Somalia (1982, 1993, DEN-2), and Saudi Arabia (1994, DEN-2). Epidemic DHF has not been reported in Africa or the Middle East, but sporadic cases clinically compatible with DHF have been reported from Mozambique, Djibouti, and Saudi Arabia.
The emergence of dengue/DHF as a major public health problem has been most dramatic in the American region. In an effort to prevent urban yellow fever, which is also transmitted by Ae. aegypti, the Pan American Health Organization started a campaign that eradicated Ae. aegypti from most Central and South American countries in the 1950s and 1960s. As a result, epidemic dengue occurred only sporadically in some Caribbean islands during this period. The Ae. aegypti eradication program, which was officially discontinued in the United States in 1970, gradually weakened elsewhere, and the mosquito began to reinfest countries from which it had been eradicated. As a result, the geographic distribution of Ae. aegypti in 2002 was much wider than that before the eradication program (Figure 1).
Figure 1. Distribution of Aedes aegypti (red shaded areas) in the Americas in 1970, at the end of the mosquito eradication program, and in 2002.
In 1970, only DEN-2 virus was present in the Americas, although DEN-3 may have had a focal distribution in Colombia and Puerto Rico. In 1977, DEN-1 was introduced and caused major epidemics throughout the region over a 16-year period. DEN-4 was introduced in 1981 and caused similar widespread epidemics. Also in 1981, a new strain of DEN-2 from Southeast Asia caused the first major DHF epidemic in the Americas (Cuba). This strain has spread rapidly throughout the region and has caused outbreaks of DHF in Venezuela, Colombia, Brazil, French Guiana, Suriname, and Puerto Rico. By 2003, 24 countries in the American region had reported confirmed DHF cases (Figure 2), and DHF is now endemic in many of these countries.
DEN-3 virus reappeared in the Americas after an absence of 16 years. This serotype was first detected in association with a 1994 dengue/DHF epidemic in Nicaragua. Almost simultaneously, DEN-3 was confirmed in Panama and, in early 1995, in Costa Rica.
Viral envelope gene sequence data from the DEN-3 strains isolated from Panama and Nicaragua have shown that this new American DEN-3 virus strain was likely a recent introduction from Asia since it is genetically distinct from the DEN-3 strain found previously in the Americas, but is identical to the DEN-3 virus serotype that caused major DHF epidemics in Sri Lanka and India in the 1980s. As suggested by the finding of a new DEN-3 strain, and the susceptibility of the population in the American tropics to it DEN-3 spread rapidly throughout the region causing major epidemics of dengue/DHF in Central America in 1995.
In 2005, dengue is the most important mosquito-borne viral disease affecting humans; its global distribution is comparable to that of malaria, and an estimated 2.5 billion people live in areas at risk for epidemic transmission (Figure 4). Each year, tens of millions of cases of DF occur and, depending on the year, up to hundreds of thousands of cases of DHF. The case-fatality rate of DHF in most countries is about 5%, but this can be reduced to less than 1% with proper treatment. Most fatal cases are among children and young adults.
Figure 4. World distribution of dengue viruses and their mosquito vector, Aedes aegypti, in 2005.
There is a small risk for dengue outbreaks in the continental United States. Two competent mosquito vectors, Ae. aegypti and Aedes albopictus, are present and, under certain circumstances, each could transmit dengue viruses. This type of transmission has been detected six times in the last 25 years in south Texas (1980 -2004) and has been associated with dengue epidemics in northern Mexico by Aedes aegypti and in Hawaii (2001-02) due to Ae. albopictus. Moreover, numerous viruses are introduced annually by travelers returning from tropical areas where dengue viruses are endemic. From 1977 to 2004, a total of 3,806 suspected cases of imported dengue were reported in the United States. Although some specimens collected were not adequate for laboratory diagnosis, 864 (23%) cases were confirmed as dengue. Many more cases probably go unreported each year because surveillance in the United States is passive and relies on physicians to recognize the disease, inquire about the patient's travel history, obtain proper diagnostic samples, and report the case. These data suggest that states in southern and southeastern United States, where Ae. aegypti is found, are at risk for dengue transmission and sporadic outbreaks.
Although travel-associated dengue and limited outbreaks do occur in the continental United States, most dengue cases in US citizens occur as endemic transmission among residents in some of the US territories. CDC conducts laboratory-based passive surveillance in Puerto Rico in collaboration with the Puerto Rico Department of Health. The weekly surveillance report from this collaboration.
Dengue Surveillance Report
The reasons for the dramatic global emergence of DF/DHF as a major public health problem are complex and not well understood. However, several important factors can be identified.
First, major global demographic changes have occurred, the most important of which have been uncontrolled urbanization and concurrent population growth. These demographic changes have resulted in substandard housing and inadequate water, sewer, and waste management systems, all of which increase Ae. aegypti population densities and facilitate transmission of Ae. aegypti-borne disease.
In most countries the public health infrastructure has deteriorated. Limited financial and human resources and competing priorities have resulted in a "crisis mentality" with emphasis on implementing so-called emergency control methods in response to epidemics rather than on developing programs to prevent epidemic transmission. This approach has been particularly detrimental to dengue control because, in most countries, surveillance is (just as in the U.S.) passive; the system to detect increased transmission normally relies on reports by local physicians who often do not consider dengue in their differential diagnoses. As a result, an epidemic has often reached or passed its peak before it is recognized.
Increased travel by airplane provides the ideal mechanism for infected human transport of dengue viruses between population centers of the tropics, resulting in a frequent exchange of dengue viruses and other pathogens.
Lastly, effective mosquito control is virtually nonexistent in most dengue-endemic countries. Considerable emphasis in the past has been placed on ultra-low-volume insecticide space sprays for adult mosquito control, a relatively ineffective approach for controlling Ae. aegypti.
Future Outlook
No dengue vaccine is available. Recently, however, attenuated candidate vaccine viruses have been developed. Efficacy trials in human volunteers have yet to be initiated. Research is also being conducted to develop second-generation recombinant vaccine viruses. Therefore, an effective dengue vaccine for public use will not be available for 5 to 10 years.
Prospects for reversing the recent trend of increased epidemic activity and geographic expansion of dengue are not promising. New dengue virus strains and serotypes will likely continue to be introduced into many areas where the population densities of Ae. aegypti are at high levels. With no new mosquito control technology available, in recent years public health authorities have emphasized disease prevention and mosquito control through community efforts to reduce larval breeding sources. Although this approach will probably be effective in the long run, it is unlikely to impact disease transmission in the near future. We must, therefore, develop improved, proactive, laboratory-based surveillance systems that can provide early warning of an impending dengue epidemic. At the very least, surveillance results can alert the public to take action and physicians to diagnose and properly treat DF/DHF cases.

Glossary of terms
Endemic - means a disease occurs continuously and with predictable regularity in a specific area or population .
Epidemic - a widespread outbreak of an infectious disease where many people are infected at the same time.
Igm - a protein that recognizes a particular epitope on an antigen and facilitates clearance of that antigen and is the primary antibody response to a viral infection
Outbreak - an epidemic limited to localized increase in the incidence of a disease, e.g., in a village, town, or closed institution
Pandemic - an epidemic occurring worldwide, or over a very wide area, crossing international boundaries, and usually affecting a large number of people.
Recombinant vaccine - using the technique of recombination to create an attenuated virus which elicits an immune response against the viral strain of interest in order to use as a vaccine in humans.
Seroytpe - a closely related set of viruses that can be differiented by the immune response they produce.
Viral envelope gene sequence - the nucleic acid composition in the envelope gene