Dengue virus infection: Epidemiology

INTRODUCTION — Records of dengue-like illness date back more than 200 years and the viral etiology of dengue virus (DENV) was established in the 1940s [1,2]. Major changes in the epidemiology of dengue virus infections began after World War II, and geographic expansion of transmission has continued to date. Given estimates of 390 million infections worldwide each year and over 2.5 billion individuals at daily risk for infection [3], the DENVs remain important arthropod-borne viruses from a medical and public health perspective.

The cardinal features of the DENV transmission cycle, the characteristics of the mosquito vectors, and the factors that contribute to DENV transmission in the major affected regions will be reviewed here. The pathogenesis, clinical manifestations, diagnosis, treatment, and prevention of DENV infection are discussed separately. (See "Dengue virus infection: Pathogenesis" and "Dengue virus infection: Clinical manifestations and diagnosis" and "Dengue virus infection: Prevention and treatment".)

CLASSIFICATION — Dengue viruses are members of the family Flaviviridae, genus Flavivirus [4,5]. The DENV complex comprises at least four antigenically related but distinct viruses, designated DENV types 1 through 4. All DENVs are mosquito-borne human pathogens that exclusively cause acute infection.

TRANSMISSION CYCLE — Both epidemic and endemic transmissions of the DENVs are maintained through a human-mosquito-human cycle involving mosquitoes of the genus Aedes (Stegomyia) [6]. Transmission of DENVs between mosquitoes and nonhuman primates has been demonstrated in Asia and Africa, but spillover from sylvatic transmission does not appear to be an important driver of viral transmission to humans [6,7].

Susceptible humans become infected after an infected female Aedes mosquito takes a human blood meal. Viremia in humans begins toward the end of a four- to six-day incubation period and persists until around the time fever abates, which is typically three to seven days [8,9]. An uninfected Aedes mosquito may acquire the virus from an infected human if they feed during this time and the human viremia is of sufficient titer to support mosquito infection. The incubation period within the mosquito is 8 to 12 days; after this period, it can transmit the virus to humans. Once infected, mosquitoes may carry the virus for their lifespan and remain infective.

MOSQUITO VECTORS — Aedes (Stegomyia) aegypti mosquitoes, the principal vector for the transmission of the DENVs, have many characteristics that make them ideal for dissemination of the virus [6,10]. Ae. aegypti typically breed in or close to houses, laying eggs in both man-made and natural water containers. The typical flight distance is relatively short [11]. Ae. aegypti are preferentially daytime feeders, and their feeding episodes often go unnoticed. They are easily interrupted in their feeding and often move on to another host, frequently taking multiple blood meals in a single breeding cycle [12]. Thus, an infected Ae. aegypti mosquito may transmit a DENV to several individuals within the household. For these reasons, family members who are at home during the daytime, typically women and young children, are at particularly high risk for exposure and infection.

Ae. aegypti are widely distributed in tropical and subtropical areas from latitude 45ºNorth to 35ºSouth. Yellow fever is also principally transmitted by Ae. aegypti; efforts to control urban yellow fever in the Americas in the 1940s greatly restricted the distribution of the mosquitoes in the Western hemisphere, but the mosquitoes have since reinfested nearly all of their former habitats [8].

Ae. albopictus mosquitoes are also a competent vector for the transmission of the DENVs under both experimental and natural conditions [6,13]. Ae. albopictus species are more tolerant of the cold and have a wider geographic distribution than Ae. aegypti [13,14]. However, they are less likely to transmit virus since they do not feed on humans as frequently as Ae. aegypti and appear to be less efficient natural vectors for the DENVs. Endemic transmission or large outbreaks in regions that have Ae. albopictus but not Ae. aegypti mosquitoes are rare. Both Ae. albopictus and Ae. aegypti are also competent vectors for transmission of zika and chikungunya viruses; their ability to transmit both the dengue and chikungunya viruses has led to simultaneous outbreaks of both diseases in some areas [15]. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)

Other Aedes mosquitoes have been suspected of DENV transmission in isolated outbreaks in certain Pacific islands [16]. However, these species appear to play an insignificant role in the global transmission of dengue.

DISTRIBUTION OF DENGUE VIRUSES AND THEIR VECTORS — Ae. aegypti and the DENVs are endemic in many countries, as shown on the online map maintained by the United States Centers for Disease Control and Prevention (CDC) [5,17-19]. The risk for exposure to Ae. aegypti is often increased in urban areas. Many tourist residencies present a lower risk of mosquito exposure than local residential areas because of air conditioning, less standing water, grounds keeping, elevation, or combinations of these factors. The effect of climate change on Ae. mosquito habitats and associated arboviral disease epidemiology in human populations is under investigation [20].

The number of cases of dengue fever (DF) and DHF varies, on a global scale from year to year, although the overall trend is one of increasing incidence. Periodic shifts in the ratio of clinically symptomatic to asymptomatic infections occur at varying intervals of several years [21,22].

The reported dengue activity in specific regions is described further below. Most available information is gathered through passive surveillance activities and must be interpreted cautiously in light of underreporting of cases [23,24] and lack of laboratory confirmation. The United States CDC maintains a listing of global dengue activity (https://www.cdc.gov/dengue/areaswithrisk/around-the-world.html).

Asia and Pacific

Southeast Asia — Ae. aegypti mosquitoes are present throughout the region, extending to southern China and the south of the island of Taiwan, and all countries in the region are affected by DENV infection [25]. Hyperendemic transmission of all four DENV types (with cases of DHF) has occurred in Thailand, Vietnam, and Indonesia for over 40 years. Epidemic dengue reemerged in China during the 1980s and 1990s after an absence of several decades and was associated with the first occurrence of DHF in that country [26]. A review of epidemiologic trends between 1980 and 2010 indicated increasing incidence of DENV infection, with annual average percentage change of 6 percent in Thailand, 10 percent in Vietnam, 12 percent in Indonesia, 18 percent in Malaysia, and 24 percent in the Philippines [27].

Over 140 locally acquired cases of dengue were detected in Japan in 2014, representing the first occurrence of transmission in that nation since World War II [28,29]. More than 80 percent of cases were associated with visiting a single location in Tokyo, and Ae. albopictus was the apparent vector in this outbreak.

Dengue virus transmission occurs year round but typically reaches a seasonal peak that varies in timing between countries (for example, between June and November in Thailand, between January and February in Indonesia). More than 200,000 cases of DHF were reported from the region each year since 2010, with the exception of 2011 (177,500 cases); Indonesia and Thailand accounted for the majority of cases in each of these years. A completed dengue vaccine trial in Thailand, Indonesia, Philippines, Malaysia, and Vietnam demonstrated significant reporting differences between national surveillance systems and the trial's active case finding [30].

South Asia — Ae. aegypti are widely distributed in India, Pakistan, and Sri Lanka. Dengue virus transmission, particularly in India and Sri Lanka, increased substantially over the past several decades [25]. Hyperendemic circulation of all four DENV types appears to be established, and outbreaks of DHF have become more frequent. Over 180,000 cases were reported from India in 2017, more than twice the average over the previous decade. A seroprevalence study among children living in India conducted between January 2011 and October 2012 noted rates of seropositivity between 60 and 80 percent [30,31].

Western Pacific islands — Ae. aegypti mosquitoes are present in most of the region. High incidence rates of dengue have been reported from several island nations, including American Samoa, Cook Islands, French Polynesia, New Caledonia, and Tonga [32,33]. (See "Potential health hazards in travelers to Australia, New Zealand, and the southwestern Pacific (Oceania)".)

Australia — Ae. aegypti mosquitoes are present in the northeastern corner of Australia. Dengue viruses are not endemic to the continent, but periodic introduction of dengue viruses from neighboring islands has led to epidemics in urban areas of north Queensland [34,35]. In Australia in 2013 to 2014, 212 dengue virus infections were acquired in Australia and 1795 cases were acquired overseas [36]. (See "Potential health hazards in travelers to Australia, New Zealand, and the southwestern Pacific (Oceania)".)

Africa and Eastern Mediterranean — Ae. aegypti mosquitoes are present in much of sub-Saharan Africa and the Middle East. Data are scant on DENV transmission [24,37,38]. However, documented infections in visitors to the area indicate that there is ongoing dengue virus transmission [39,40]. Several outbreaks were reported from Central Africa, East Africa, and the Middle East during the 1990s and 2000s [15,17].

A systematic review of records from Middle East and North African countries identified 81 outbreaks reported from 9 countries between 1941 and 2015; Ae. aegypti and/or Ae. albopictus are present in 15 countries [41].

Europe — Ae. albopictus is present across much of southern Europe [42]. Most dengue cases reported from the region have been acquired during travel to endemic countries. However, local transmission of dengue virus was documented in both southern France and Croatia in 2010 [43]. In 2012, an outbreak of dengue was reported on Madeira Island (Portugal), associated with the presence of Ae. aegypti [43]. Five locally acquired cases were confirmed in Spain in 2018 [44] and another five in northeast Italy in 2020, the first locally acquired cases in that country [45].

Americas — Dengue cases declined by over 50 percent in 2017 and 2018, following the epidemic transmission of zika virus. Dengue cases rebounded in 2019, however, and the region experienced the highest number of dengue cases ever recorded.

North America — Ae. aegypti mosquitoes are present in most areas of Mexico and in the southern United States. Ae. albopictus is also present in Mexico and the southern United States; however, its range extends farther north, nearly to the Great Lakes.

In Mexico, hyperendemic transmission of all four DENV serotypes is present throughout the range of Ae. aegypti. Dengue virus transmission is seasonal, with peak activity in late summer and fall. In 2019, over 268,000 cases of dengue infection were reported from Mexico, including more than 3,500 cases of severe dengue and 421 deaths [21].

The southern United States is an ideal setting for the introduction and spread of dengue virus, given the widespread presence of Ae. aegypti mosquitoes, the appropriate environmental conditions for transmission, and the large volume of travelers arriving from Latin America and the Caribbean, where dengue is endemic [46].

In 2022, the CDC reported 1188 cases in the United States (50 states and the District of Columbia), with 67 being locally acquired (65 in Florida and 2 in Arizona) [47]. Between 2010 and 2017, 5387 dengue cases were reported from the United States; 93 percent were travel associated [48]. Locally acquired cases were reported from Hawaii, Florida, Texas, and New York (case counts were 250, 103, 24, and 1, respectively). In 2010, DF was reported in 28 residents of Key West, Florida, who had not traveled abroad [49], and a serosurvey of 240 participants living in Key West found that 5 percent had evidence of recent dengue infection. Local transmission of dengue virus continues to occur in south Florida.

There was an outbreak of dengue in Hawaii between 2015 and 2016 [50]. The Hawaii Department of Health reported a total of 264 cases were confirmed, with 26 being in travelers and the remainder Hawaiian residents. These were the first cases in Hawaii since 2011 [51].

Central America — Ae. aegypti mosquitoes and hyperendemic transmission of all four DENV types are present throughout the region. The region experienced a major outbreak in 2019; Nicaragua and Honduras reported among the highest numbers of cases of dengue (186,000 and 132,000, respectively) and incidence rates (over 1000 cases per 100,000 population) that year [21]. However, all of these countries have had one or more years of heavy dengue activity during the past decade. The Pan American Health Organization (PAHO) reported over 63,000 laboratory-confirmed cases in Central America and Mexico during 2019; underreporting is suspected to be considerable.

Caribbean — Ae. aegypti mosquitoes are present throughout the region. Hyperendemic circulation of DENV types 1, 2, and 4 has been present on the larger islands (other than Cuba) for several decades, and DENV type 3 has been present since 1998. In Puerto Rico, peak DENV transmission usually occurs between October and December; over 21,000 cases of DENV infection were reported there in 2010, representing the largest outbreak ever recorded [33]. The Dominican Republic (20,000 cases), Jamaica (7500 cases), Guadeloupe (3000 cases), Cuba (3000 cases), and Martinique (1500 cases) all reported major outbreaks in 2019 [21]. Other islands have experienced periodic dengue epidemics.

South America — Ae. aegypti mosquitoes are present in every South American country except Chile [17]. Hyperendemic circulation of all four DENV types has been present in the north of the continent since the reintroduction of DENV serotype 3 was detected in Brazil and Venezuela during 2000. According to PAHO, Brazil and Colombia reported the largest number of confirmed dengue cases in 2019. Low-level year-round transmission has been observed, but most cases follow an epidemic pattern; in Brazil, peak dengue transmission occurs between February and May [52].

Brazil experienced major outbreaks in 2019 and 2022, with over 2 million cases nationwide in each year, including over 1400 cases of severe dengue [21]. Colombia (127,000 cases) also reported a major dengue outbreak in 2019. According to PAHO, the Andean and Southern cone of South America reported over 1.2 million laboratory-confirmed cases in 2022, of which more than 95 percent occurred in Brazil.

PATTERNS OF TRANSMISSION — Dengue virus transmission follows two general (but not mutually exclusive) patterns, with different implications for disease risk in both the local population and travelers.

Sporadic/Epidemic dengue — Sporadic DENV transmission occurs when the introduction of DENV into a region is an isolated event involving a single virus strain. If sufficiently large populations of susceptible hosts and mosquitoes are present, transmission of DENVs is explosive, leading to a recognizable epidemic. The incidence of infection among susceptible individuals often reaches 25 to 50 percent [53] and can be considerably higher. Herd immunity, changes in weather, and mosquito control efforts can all contribute to the termination of the epidemic [6].

Prior to World War II, transmission of DENVs almost exclusively followed this pattern [54]. Seaports frequently were the point of initial introduction of DENVs, and these port cities then acted as distribution points to nearby inland areas.

In smaller island nations, certain areas of South America and Africa, and in the areas of Asia where DENV transmission has reemerged, epidemic activity is the predominant pattern of DENV transmission. The incidence of DENV infections in these locations varies considerably from year to year. Intervals of several years or more usually pass between epidemics, allowing the number of susceptible individuals to accumulate so that the next epidemic can be perpetuated.

In the setting of epidemic transmission, adults and children in the local population are affected. Among travelers, the risk for DENV acquisition is high during an epidemic but low at other times. The frequency of dengue hemorrhagic fever (DHF) is usually low, with some exceptions [55]. The DENV type and strain and the interval since the previous epidemic seem to influence the risk for DHF. (See "Dengue virus infection: Pathogenesis".)

Hyperendemic dengue — "Hyperendemic" transmission refers to the continuous circulation of multiple DENV types in the same area. This requires the year-round presence of competent vector mosquitoes and either a large population or steady movement of individuals into the area to maintain a pool of susceptible individuals. Hyperendemic circulation involves the occurrence of multiple epidemics in a smaller geographic scale (eg, village or school) [56].

Seasonal variation in virus transmission is common. The incidence of infection also varies from year to year, with increased DENV transmission at intervals of three to four years, but this variation is not as dramatic as in areas where transmission predominantly follows the epidemic pattern. A mathematical analysis of data from Thailand suggested that these surges in DENV transmission originate in waves from major urban centers [57].

Areas with hyperendemic DENV transmission contribute to the majority of cases of DENV infection globally. In some regions, 5 to 10 percent of the susceptible population experiences DENV infection annually [58-60]. Urban areas are particularly affected.

In the setting of hyperendemic transmission, the prevalence of antibody against the DENVs rises with age. Children are more likely than adults to experience disease, and most adults in the local population are immune to infection. Among travelers, the risk for acquisition is higher than in areas that experience epidemic transmission, but the seasonal variation in risk is somewhat predictable. Hyperendemicity is a major factor contributing to the occurrence of DHF.

FACTORS INFLUENCING TRANSMISSION — The worldwide incidence of dengue and dengue hemorrhagic fever (DHF) has been increasing in the past several decades, and the geographic distribution of these diseases has expanded. The emergence of DHF as a public health problem has largely been a result of human behaviors including population growth; poor urban planning with overcrowding and poor sanitation; modern transportation, which allows increased movement and colocation of humans; mosquitoes; viruses; and lack of effective and sustained mosquito control [8].

The potential effects of global climate change are a major source of concern for the future. Increased DENV transmission has been associated with El Niño/Southern Oscillation events [61,62]. Mathematical models predict that increased global temperatures will further expand the range of Ae. aegypti and the DENVs [63,64].

The transmission cycle for DENVs is dependent upon the interaction between infective mosquitoes and susceptible humans and between susceptible mosquitoes and viremic humans. Changes in social practices and human movement behavior have the potential to alter patterns of DENV transmission. Statistical modeling estimated that there was a significant reduction in the incidence of dengue in many countries during 2020 due to such measures implemented in response to the COVID pandemic [65]. Dengue virus transmission is boosted by the following factors [6]:

●Increased vector density – One study of naturally infected humans estimated that viremia levels of approximately 6 to 8 log10 RNA copies/mL led to infection of half of Ae. aegypti mosquitoes that took a blood meal under laboratory conditions [66]. In many tropical countries, seasonal increases in rainfall contribute to an increased density of mosquitoes. One factor that can be modified is the presence of open water storage containers in or near the home.

●Shorter mosquito incubation – The length of the incubation time in the mosquito (known as the extrinsic incubation period) is inversely associated with the ambient temperature. Warmer temperatures increase the length of time that a mosquito remains infective.

●Increased movement of mosquito vectors and DENVs – Air, land, and water transportation of mosquitoes or viremic humans facilitate the dissemination of DENVs.

●Increased density of susceptible hosts – Crowded conditions probably increase the potential for virus transmission. However, as the prevalence of prior infection increases, the fraction of the population that remains susceptible is reduced.

●Increased duration and magnitude of viremia in humans – Attenuated virus strains produced in the laboratory have been shown to produce low titers of virus in the blood, which are not efficiently transmitted to mosquitoes [67,68]. It is unclear whether natural strains of DENV differ in the viremia titers they produce [69].

OTHER ROUTES OF TRANSMISSION — Given the high titers of infectious DENVs found in blood and tissues during acute infection, the potential exists for virus transmission by routes other than mosquito vectors.

Nosocomial transmission — Dengue virus may be transmitted via blood products, needlestick injury, and mucocutaneous exposure [70-72]. Blood donors may be asymptomatic even in the setting of viremia [71]. One report estimated a DENV transmissibility rate of 37 percent via blood products [72].

Vertical transmission — Vertical DENV transmission has been reported in a few small case series [73]; based on these cases and the known pattern of viremia, this possibility should be considered in cases where illness in the mother occurs within the 10 days before delivery (including onset on the day of delivery). Illness presents in these newborns up to 11 days (median 4 days) after birth.

Pregnancy does not appear to increase the incidence or severity of dengue [74]. In a prospective study conducted in Kuala Lumpur of 2958 parturients, 2531 paired maternal-umbilical cord blood samples were tested for dengue-specific immunoglobulin (Ig)M to determine the prevalence of infection and the vertical transmission rate [75]. Sixty-three women (2.5 percent) had a positive IgM serology. Only one (1.6 percent, 95% CI 0-9.5 percent) of the paired umbilical cord samples was seropositive for dengue. None of the maternal and fetal blood samples had evidence of viral RNA by polymerase chain reaction.

Breastfeeding has been proposed as a route of vertical DENV transmission [76].

Sexual transmission of the DENVs appears to be an infrequent event, if it occurs at all [77].

SUMMARY

●Virology – Dengue viruses (DENVs) are members of the family Flaviviridae, genus Flavivirus. The DENV complex comprises four antigenically related but distinct viruses, which are mosquito-borne human pathogens. (See 'Classification' above.)

●Transmission cycle – Susceptible humans can become infected after an infected female Aedes mosquito takes a blood meal. Viremia in humans begins toward the end of a four- to six-day incubation period and persists until fever abates. An uninfected Aedes mosquito may acquire the virus after feeding on an infected individual during this viremic period. Once infected, mosquitoes carry the virus for their lifespan and remain infective for humans. (See 'Transmission cycle' above.)

●Mosquito vectors – Aedes aegypti mosquitoes are daytime feeders that prefer to bite humans and are frequently unnoticed. They are easily interrupted in their feeding and move on to another host, frequently taking multiple blood meals in a single breeding cycle. Thus, an infected Ae. Aegypti mosquito may transmit a DENV to several individuals within a small geographic area. (See 'Mosquito vectors' above.)

●Dengue epidemics – Epidemic DENV transmission occurs when the introduction of a DENV into a region is an isolated event involving a single DENV type. If sufficiently large populations of susceptible hosts and mosquitoes are present, transmission of dengue is explosive, leading to a recognizable epidemic. Herd immunity, changes in weather, and mosquito control efforts can all contribute to the termination of the epidemic. (See 'Sporadic/Epidemic dengue' above.)

●Endemicity – "Hyperendemic" transmission refers to the continuous circulation of multiple DENV types in the same area. This requires the year-round presence of competent vector mosquitoes and an ongoing presence of susceptible individuals. (See 'Hyperendemic dengue' above.)

●Environmental factors – Dengue virus transmission is enhanced by multiple factors, including higher vector density, greater movement of mosquito vectors, and increased density of susceptible humans. The effect of climate change on dengue prevalence is currently unknown. (See 'Factors influencing transmission' above.)

●Geographic distribution – Ae. aegypti and DENVs are endemic in every continent except Europe and Antarctica, although epidemic dengue hemorrhagic fever occurs predominantly in Asia and the Americas. (See 'Distribution of dengue viruses and their vectors' above.)