Dengue fever as a classic case study of the impact of urbanization

Dengue fever is an old disease, and is the classic case study of the recent re-emergence of a globally significant disease that originated as a zoonosis. Its historical pattern of emergence provides many lessons for containing the global spread of other, more recently recognized, arboviral diseases with the potential for becoming major urban public health threats.

The first reports of illness clinically compatible with dengue date back to a Chinese medical encyclopedia first published in AD 265 and last edited during

Table 4.2 Urban emerging infectious diseases of public health importance

Family/virus

Vector

Vertebrate

Ecology

Disease in

Geographic

host

humans

distribution

Togaviridae

Chikungunya

Mosquitoes

Human,

U, S, R

SFI

Africa, Asia

primates

Ross River

Mosquitoes

Human,

R, S, U

SFI

Australia,

primates

South Pacific

Mayaro

Mosquitoes

Birds

R, S, U

SFI

South America

Flaviviridae

Dengue 1-4

Mosquitoes

Human,

U, S, R

SFI, HF

Worldwide

primates

in tropics

Yellow fever

Mosquitoes

Human,

R, S, U

SFI, HF

Africa,

primates

South America

Japanese

Mosquitoes

Birds,

R, S, U

SFI, ME

Asia, Pacific

encephalitis

pigs

St Louis

Mosquitoes

Birds

R, S, U

SFI, ME

Americas

encephalitis

West Nile

Mosquitoes

Birds

R, S, U

SFI, ME

Africa, Asia,

Virus

Europe, US

Bunyaviridae

Oropouche

Midges

?

R, S, U

SFI

Central and

South America

U, urban; S, suburban; R, rural; SFI, systemic febrile illness; ME, meningoencephalitis; HF, hemorrhagic fever Source: Gubler (2002).

U, urban; S, suburban; R, rural; SFI, systemic febrile illness; ME, meningoencephalitis; HF, hemorrhagic fever Source: Gubler (2002).

the Northern Sung Dynasty in AD 992. Epidemics of dengue-like illness were reported in 1635 in the Caribbean, and in 1699 in Panama. By the end of the eighteenth century the viruses and their vectors apparently had a worldwide distribution, with epidemics of dengue-like illness being reported in Batavia (Jakarta) in Indonesia (1779), Cairo in Egypt (1779), and Philadelphia in Pennsylvania, USA (1780) (Gubler, 1997). It should be noted that these were not confirmed dengue epidemics, because the viruses were not isolated until 1943-44. However, clinically and epidemiologically, the disease was compatible with dengue.

The historical evolution of dengue to become the most important arboviral disease of humans as we enter the twenty-first century is closely tied to the evolution of urbanization and commerce (globalized trade). The primitive cycle of dengue viruses involved canopy-dwelling mosquitoes and non-human primates in the rainforests of Asia, and possibly Africa. Humans who entered the forests to hunt, cut wood, or for other activities were exposed to the viruses through the bite of infected mosquitoes. With an incubation period of up to 14 days, people became ill (and infectious) after they returned to their village outside the forest, thus exposing peridomestic mosquitoes in the villages to the virus. These latter mosquitoes, such as A. albopictus, transmitted epidemics, but because of the small human populations in the villages the infections soon died out and transmission ceased until another virus was introduced. These epidemics were thus very infrequent and sporadic.

In the seventeenth, eighteenth, and nineteenth centuries, as global trade and the shipping industry developed, port cities sprouted on all continents, followed by the building of inland cities and larger port cities. The water barrels carried on sailing vessels were frequently infested with mosquitoes, and it was not uncommon for the ships to maintain active transmission of diseases like dengue and yellow fever among the mosquitoes and crew members (Gubler, 1997). When the ships docked at a port city, both the mosquitoes and the viruses went ashore with the crew. Thus were mosquitoes and viruses imported to and established in port cities around the world.

The history of the spread of A. aegypti provides a classic example. Although a feral mosquito in Africa, it was introduced to the villages and cities of West Africa, where it adapted to breeding in stored water containers. From there it was taken, along with yellow fever, to the Americas during the slave trade in the sixteenth and seventeenth centuries, infesting port and inland cities. Even the temperate United States was infested, with the mosquito being maintained in the port cities of the Gulf Coast during the winter and expanding up the rivers and waterways to inland cities during the summer months (Gubler, 1997). The epidemics of dengue and yellow fever in cities like Philadelphia were the direct result of this kind of commerce. From the Americas, A. aegypti spread to the Pacific and Asia by the same means. This mosquito ultimately became highly adapted to humans and the urban environment, infesting most tropical cities of the world, and became the most efficient epidemic vector of urban dengue and yellow fever (Gubler, 1989, 1998b).

As noted above, by the late eighteenth century dengue viruses had a worldwide distribution in the tropics. Because the viruses were dependent on sailing vessels for geographic spread, however, epidemics were infrequent, often with periods of 10-40 years with no epidemic activity. Once a virus was introduced to a new region, however, it would move from country to country within that region at a much faster pace. This was the status of the disease at the beginning of World War II.

The war in the Pacific and Asian Theaters initiated the twentieth-century pandemic of dengue (Gubler, 1998b). Both the Allied and Japanese armies put hundreds of thousands of susceptible troops into the area. The movement of those troops, along with war materials, was responsible for all four dengue virus serotypes and A. aegypti mosquitoes being spread throughout the region. By the end of the war, dengue was hyperendemic (the co-circulation of multiple virus serotypes) in most countries of Asia.

In the years following World War II, an economic boom began in Asia that is continuing today. It was this dramatic economic development, combined with unprecedented population growth, that was the primary driving force of uncontrolled urbanization that has occurred in most Asian cities in the past 50 years. The influx of people, primarily from rural areas, led to rapid and uncontrolled urban growth. Forced to live in inadequate housing in areas where there was no water, sewage, electricity, or waste management, people had to store water in containers, which made ideal larval habitats for A. aegypti mosquitoes. The large mosquito populations living in intimate association with crowded human populations similarly provided ideal conditions for epidemic transmission of the dengue virus. It was in this setting in the 1950s and 1960s that the much more serious and sometimes fatal form of dengue, dengue hemorrhagic fever (DHF), emerged in epidemic form. By 1970, DHF was a leading cause of hospitalization and death among children in Southeast Asia. In the latter two decades of the twentieth century, epidemic DHF spread throughout Asia, east to China and Taiwan, and west to the Indian subcontinent.

Urbanization was occurring in other parts of the world as well, especially in the Americas. Fortunately, however, dengue and yellow fever had been effectively controlled in the 1950s and 1960s in the Americas by the A. aegypti eradication program initiated in 1946, which focused on larval mosquito control using a combination of environmental management and DDT. Because there were no epidemics of dengue and yellow fever, however, this program was disbanded in the early 1970s (Gubler, 1989; Gubler and Trent, 1994). Thus began the reinvasion of tropical American countries by A. Aegypti - but this time there were much larger cities to host them. By the beginning of the twenty-first century, Mexico and most of the Caribbean, South and Central American countries had been re-colonized by this mosquito.

The era of jet travel and modern transportation began in the 1960s, but accelerated in the 1970s and 1980s. This provided the ideal mechanism for the hyper-endemic dengue melting pot of Southeast Asia to seed the rest of the world with dengue viruses. The viruses first moved into the Pacific Islands in the early 1970s, and into the Americas in the late 1970s. The 1980s and 1990s saw the whole of the tropical world become hyperendemic, resulting in greatly increased frequency of epidemic dengue fever and the emergence of DHF in the Pacific and Americas (Gubler, 1997). As shown by the maps in Figure 4.3, in 1970 dengue was either hypoendemic with only one virus serotype circulating, or non-endemic in most countries of South and Central America, the Caribbean and West Africa; only Southeast Asia was hyperendemic with all four serotypes co-circulating. Today, the whole of the tropical world is hyperendemic, with all four virus sero-types co-circulating throughout the Americas, across tropical Africa, South Asia, Southeast Asia, Australasia, and Oceania. As a result, the epidemics have became more frequent, and larger, on a global level. In 2006, approximately 2.5-3 billion people live in areas at risk for dengue, which infects an estimated 50-100 million

1970

1970

Denv Who Country Area Risk
Figure 4.3 Global distribution of dengue virus serotypes in 1970 and 2006. Source: Gubler (1998b).

persons per year, with 500,000 cases of DHF and 20,000-25,000 deaths (Gubler, 1998b; World Health Organization, 1999).

As can be seen in Figure 4.4, the increased incidence of DF/DHF in the past 50 years closely tracks global population growth, most of which is urban population growth. In Thailand, the annual number and frequency of dengue cases closely tracks the historic population increase across the country and in Bangkok.

Figure 4.5 shows that the increase in dengue cases in Bangkok closely tracks population growth, and can therefore be projected to increase for at least several decades under current conditions. Moreover, dengue frequency in terms of

(Correlation of population to mean number of cases: R = 0.96)

(Correlation of population to mean number of cases: R = 0.96)

Years

Figure 4.4 Estimated total cases of dengue hemorrhagic fever for Southeast Asia, India, China, Latin America, and the Caribbean. Source: Gubler and Meltzer (1999).

Years

Figure 4.4 Estimated total cases of dengue hemorrhagic fever for Southeast Asia, India, China, Latin America, and the Caribbean. Source: Gubler and Meltzer (1999).

the proportion of months with reported cases tends to increase sharply for provinces exceeding about 500,000 in population size (Wearing and Rohani, 2006). Population growth is a surrogate measure of urbanization and all its attendant social-ecological factors that facilitate disease emergence.

One recent study documented how dengue epidemics travel in a wave out from Bangkok at an average rate of 148 km per month (Cummings etal., 2004). Bangkok serves as a regional "epicenter" for major epidemics in Thailand on a 3- to 5-year cycle (Nisalak et al., 2003). These patterns, being uncovered through the accumulation of increasingly detailed data and more sophisticated molecular and statistical research tools, are probably representative of what is occurring in all the cities of tropical developing countries. These tropical urban centers are the spawning grounds for epidemic dengue (Gubler, 2004a).

The key to understanding the recent major resurgence of dengue, along with most of the other 177 or more emerging infectious diseases, requires an appreciation of dynamics of a "coupled human-natural system" mentioned earlier, seen as

Urban growth and dengue emergence in Bangkok (population and no. of cases as surrogates)

2500

Urban growth and dengue emergence in Bangkok (population and no. of cases as surrogates)

-1000 J

1960 1970 1980 1990 2000 2010 2020 Year

Figure 4.5 Historical and projected growth in dengue cases and urban population in Bangkok. Population growth serves as a surrogate or indicator of a wide range of social-ecological factors accompanying urbanization. Dashed line represents projected dengue cases assuming current circumstances, such as per capita levels of vector-control efforts, remain constant. Source: Wilcox (unpublished); based on historic and projected population size of greater Bangkok and dengue case data for the Queen Sirikit National Institute of Child Health in Bangkok, published in Nisalak et al. (2003). Projected future cases, year 2000 on, were estimated by linear extrapolation from least-squares fitted regression for peak years and trough years as a function of population size.

-2000 i

-1000 J

1960 1970 1980 1990 2000 2010 2020 Year

Figure 4.5 Historical and projected growth in dengue cases and urban population in Bangkok. Population growth serves as a surrogate or indicator of a wide range of social-ecological factors accompanying urbanization. Dashed line represents projected dengue cases assuming current circumstances, such as per capita levels of vector-control efforts, remain constant. Source: Wilcox (unpublished); based on historic and projected population size of greater Bangkok and dengue case data for the Queen Sirikit National Institute of Child Health in Bangkok, published in Nisalak et al. (2003). Projected future cases, year 2000 on, were estimated by linear extrapolation from least-squares fitted regression for peak years and trough years as a function of population size.

an inherent characteristic of urban ecosystems when viewed from a social ecological perspective (Wilcox and Colwell, 2005). Thus, this complex situation can be simplified somewhat by considering it from the standpoint of how human society -in this case in the form of poorly or ill-guided public policy with regard to public health, urbanization, and globalization - and nature interact. "Nature" here refers to the ecological and associated evolutionary processes represented by viral (and vector) dispersal, genetic change, inter-serotype and serotype-host interaction occurring across spatial scales involving virus-mosquito-human interactions in a single village or urban neighborhood to the regional and global level, with urban expansion and global transport as the dominant influences. Based on this perspective, the re-emergence of dengue and similar diseases can be described as follows.

In the first half of the twentieth century public health measures focused on vector control, and were very effective in controlling dengue and other A. aegypti-borne diseases such as yellow fever. Beginning in the second half of the twentieth century, and especially during the latter 30 years, rapid, uncontrolled urbanization in tropical regions of the developing world combined with exponentially increasing global transport of people, animals, and commodities developed o </>

200,000 180,000160,000140,000120,000100,000-s0,000 60,000 40,000 20,000 0

Thailand

I..I111II1

300,000 250,000

50,000

Mill

Vietnam

Figure 4.6 The dynamics of dengue. Dengue outbreaks in Thailand and Vietnam now occur on a 3- to 5-year cycle instead of the 10- to 40-year prior historical pattern. Source: Gubler (2004a).

into dominant social-ecological forces, as already noted above. A growing lack of effective mosquito control in crowded urban centers and the increasing movement of viruses via modern transportation facilitated increasing hyperendemicity in large urban centers in the tropics. The result has been epidemic cycles shortened from a 10- to 40-year to a 3- to 5-year cycle, as the case data for Vietnam and Thailand show in Figure 4.6.

Finally, dengue provides the classic model of how the geographic spread of an infectious disease, a principal characteristic by which many viral diseases are classified as emerging, can be revealed by the tracking of a specific viral genetic strain on a map. Before 1989 DHF was common in Southeast Asia, but rare on the Indian subcontinent, despite the circulation of all four serotypes. After 1989, regular epidemics of DHF were reported on the Indian subcontinent and Sri Lanka.

The change did not appear to be due to a general increase in viral transmission, but to a change in virus subtype (Lanciotti et al., 1994; Messer et al., 2003). The majority of people with severe disease were infected with a new subtype of DENV-3, which was clearly derived from the pre-DHF epidemic DENV-3 strain, most likely via genetic drift and selection (Bennett et al., 2003). While the exact processes by which epidemic DHF arose in Sri Lanka are not fully understood, it is clear that the DENV-3 strain associated with DHF in Sri Lanka was derived from the strain previously circulating in Sri Lanka, and was not the same as the DENV-3 circulating in the Southeast Asia region. It appears this Indian subcontinent subtype then spread from South Asia to East Africa (Gubler et al., 1986; Messer et al., 2003). Genetic studies show the DENV-3 subtype III viruses currently found in Latin America are also closely related to isolates found in East Africa and South Asia. Figure 4.7 illustrates the most likely route of the global spread of DENV-3, subtype III from South Asia to East Africa and Central and South America, and, although based on global population movement data, it is likely that the American DENV-3 was introduced from Asia.

Two other arboviral diseases, yellow fever and Chikungunya fever, whose emergence appears to be following a pattern disturbingly similar to the early re-emergence of dengue, also have a transmission cycle in urban areas similar to dengue, being transmitted by A. aegypti and A. albopictus. Changes in the transmission dynamics of both are also associated with social ecological changes accompanying urbanization, along with regional environmental change and globalization.

Chikungunya is Swahili for "that which bends up," and the name comes from the muscle and joint symptoms of the diseases, which can be debilitating and last for weeks or months. People with Chikungunya experience a range of other symptoms, such as fever, headache, fatigue, nausea, vomiting, and skin rash. Like dengue and yellow fever, the Chikungunya virus exists in a natural cycle involving mosquitoes and monkeys in the rain forests of Africa. It was first isolated in Tanzania in 1953, and has since been identified in epidemics in western, central and southern Africa, and in a number of Asian countries, such as Indonesia, the Philippines, Thailand, Myanmar, and India. In 2005 and 2006 there were numerous epidemics in India and the islands off the east coast of Africa. A large epidemic in the heavily populated Indian state of Andhra Pradesh spread to neighboring states with fatalities in a number of cities, including Udaipur, Chittorgarh, and Bhilwara. By the time this chapter was going to press 1.39 million cases had been reported across 13 Indian states (NVBDCP, 2006). Currently, Chikungunya fever is most likely spread by infected travelers, but it has been endemic in Asia for decades, and has the potential to become an urban disease globally.

Yellow fever was the most important urban infectious disease in the Americas until the twentieth century. The A. aegypti eradication program noted above eliminated the mosquito and the disease throughout most of the Americas (Gubler, 2004b). Endemic in Africa and South America, the first recorded outbreak of

Denv Subtype

Countries without endemic dengue transmission

Countries with endemic DENV-3, subtype III transmission

Figure 4.7 Global spread of dengue virus 3 (DENV-3). Subtyping studies show the likely spread of a single subtype of dengue virus 3 from its origin on the Indian subcontinent to East Africa and Latin America. Source: Messer etal. (2003).

Countries without endemic dengue transmission

Countries with endemic dengue transmission

Countries with endemic DENV-3, subtype III transmission

Figure 4.7 Global spread of dengue virus 3 (DENV-3). Subtyping studies show the likely spread of a single subtype of dengue virus 3 from its origin on the Indian subcontinent to East Africa and Latin America. Source: Messer etal. (2003).

Cb ttl

yellow fever in the Western Hemisphere occurred in 1648, and over the next 400 years epidemics were recorded across much of South and Central America, and as far north as New York City (Carter and Frost, 1931). Once Walter Reed and his colleagues had determined that A. aegypti spread yellow fever outbreaks, control focused on destroying the mosquito in the larval stage in domestic water-storage containers, and killing adult mosquitoes with insecticides - usually DDT. In 1901, William Gorgas developed the first effective control program in Havana, Cuba, which in 1904 was replicated in Panama. Over the next few years, programs were initiated in Rio de Janeiro in Brazil, Vera Cruz in Mexico, and Guayaquil in Ecuador. In 1937 a live-attenuated vaccine was developed, which was used in West Africa but not in the Americas. Nevertheless, successful mosquito control in the Americas worked to eliminate urban epidemics of yellow fever (Gubler, 2004b). With the re-expansion of A. aegypti across its former geographic range in Latin America, however, it has been dengue that has re-emerged most dramatically.

Today, yellow fever persists in three kinds of transmission cycles (Table 4.3). These cycles illustrate the process by which social-ecological factors, such as settlement patterns (including the urban expansion into rural zones and agriculture communities into forests), produce a landscape continuum from natural habitat to urban habitat. Arboviruses, because of their capability for relatively

Table 4.3 Transmission cycles for yellow fever

Type

Transmission cycle

Sylvatic or jungle yellow fever Intermediate yellow fever

Urban yellow fever

This is a disease of the rainforest in which the virus is transmitted between monkeys and wild mosquitoes; it is seen only rarely in people, in those working in logging or other activities in the rainforest This occurs in "zones of emergence," like savannah areas of Africa during the rainy season, where there is increased contact between humans and semi-domestic mosquitoes; even if a number of villages are involved simultaneously, outbreaks affect only relatively small populations

This involves domestic A. aegypti mosquitoes and produces the largest and most dangerous epidemics in cities of tropical Africa (between 15° north and 10° south of the equator); it is less common than dengue, possibly because both viruses compete for the same vector and hosts

rapid evolution (aided by a parallel domestication process exhibited by mosquitoes like A. aegypti), have the potential over time to "move" across this landscape to become major public health threats for urban areas.

At present, 33 countries in Africa with a total population of 468 million are at risk for yellow fever. Since 2000, 18 countries in Africa have reported yellow fever outbreaks, 13 of them in West Africa (World Health Organization, 2006). Given the inadequacies of the health system in these countries, it is likely that the number of reported cases is well below the actual number. Most people infected with yellow fever have no symptoms or only mild symptoms, and are not likely to see a physician who would then report their case to public health authorities. In endemic areas there also is a shortage of laboratories capable of performing virologic analyses. The major threat of epidemic yellow fever, however, is in the Americas, where over 300 million people live in urban areas infected with A. aegypti (Gubler, 2004b). So far yellow fever has not taken hold in Asia, but if urban yellow fever epidemics begin to occur, as in the Americas, a major global public health emergency will occur, because all of the Asia-Pacific region is at high risk (Gubler, 2004b).

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