Does The Yellow Fever Still Exist

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Where Does Yellow Fever Still Exist

FIGURE 3.24 Crystal structure (ribbon diagram) of the dimer of the E protein of tick-borne encephalitis virus. This is a top view, looking down onto the surface of the virion. Numbered sites are those in which mutations alter the virulence of the virus. [From Rey et al. (1995).]

organ, causes the major symptoms of disease and the symptoms from which the name of the virus derives, jaundice following destruction of liver cells. The virus also replicates in other organs, such as kidney and heart, and causes hemor-rhaging. Illness is accompanied by high fever. Death occurs in 20-50% of serious infections, usually on days 7-10 of illness and usually as a result of extensive liver necrosis.

YFV is present today in Africa and Latin America. It originated in Africa and spread to the Americas with European colonization and the introduction of slaves. The virus is maintained in two different cycles. In an endemic or sylvan cycle, it is maintained in Aedes africanus and other Aedes mosquitoes in Africa and in Haemogogus mosquitoes in the Americas. Monkeys form the vertebrate reservoir. In this cycle, forest workers and other humans who enter deep forests are at risk. Infection of humans can lead to the establishment of an epidemic or urban cycle in which the virus is transmitted by the mosquito A. aegypti and man is the vertebrate reservoir. In this cycle, all urban dwellers are at risk. Aedes aegypti is a commensal of man, breeding around human habitation. It is widespread in the warmer regions of the world, including the southern United States, Central America and the Caribbean, large regions of South America, sub-Saharan Africa, the Indian subcontinent, southeast Asia, Indonesia, and northern Australia.

In the 1800s, YFV was continuously epidemic in the Caribbean region, where it had a pronounced influence on the development and settlement of the Americas by the Europeans. Caucasians and Native Americans are very sensitive to yellow fever, usually suffering a serious illness with a high death rate. Black Africans, who were brought as slaves to the New World to replace Native American slaves who had died in large numbers from European diseases, in general suffer less severe disease following yellow fever infection, presumably having been selected for partial resistence by millenia of coexistence with the virus. Their relative resistance to yellow fever resulted in the importation of even more black slaves into yellow fever zones. The high death rate among French soldiers sent to the Caribbean region to control black slaves was probably responsible for the decision by Napoleon to abandon the Louisiana territory by selling it to the United States. The high death rate among French engineers and workers in the 1880s under de Lesseps, who had previously supervised the construction of the Suez Canal, led to the abandonment of the attempt by the French to build a canal through Panama. The Panama Canal through Panama was built by the United States only after yellow fever was controlled.

From its focus in the Caribbean, yellow fever regularly spread to port cities in the southern and southeastern United States and as far north as Philadelphia, New York, and Boston. Epidemic yellow fever even reached London. The virus also spread up the Mississippi river from New Orleans. The virus was transported from its focus in the

Caribbean by ships, which carried freshwater in which mosquitoes could breed. If there was yellow fever on the ship, the disease was maintained and could be transmitted by the mosquitoes or by infected individuals to ports at which the ships called. Yellow fever epidemics could afflict most of the population of a city and result in death rates of 20% or more of the city's original population.

One telling account of an epidemic in Norfolk, Virginia, in 1855 is described in the report of a committee of physicians established to examine the causes of this epidemic. Quarantine procedures to prevent the introduction of yellow fever were often thwarted by captains who concealed the presence of the disease to avoid a lengthy quarantine, even going to the extreme of secretly burying crew members who died while in quarantine. On June 6, 1855, the steamer Ben Franklin arrived from St. Thomas and anchored at the quarantine ground. The health officer, Dr. Gordon, visited the ship and was told that there was no disease on the ship. After 13 days in quarantine the ship was allowed to dock and yellow fever soon appeared in Norfolk. The first cases were crew and passengers from the ship. A number of early cases among the citizens of the town were ascribed to the ship passing within a half mile of their homes, and it is possible that infected mosquitoes were blown ashore. The disease then spread in all directions at a uniform rate of about 40 yards per day until it encompassed the whole city. The epidemic peaked at the end of August and died out after October. During the epidemic, an estimated 10,000 cases of yellow fever occurred in a population of 16,000, and 2000 died of the disease. The report established two other facts about the disease: Persons who had had yellow fever previously were immune, and the epidemic was not spread by person-to-person contact.

At the turn of the century, there was much debate as to the mechanism by which yellow fever spread. The Department of the Army sent an expedition, under the command of Walter Reed, to Cuba, recently acquired by the United States from Spain, to study the disease. The commission undertook to test the thesis that the virus was transmitted by mosquitoes, using themselves as human volunteers. Mosquitoes were allowed to feed on yellow fever patients and then on volunteers. At first there was a lack of understanding about the fact that mosquitoes are infected only by feeding on patients early in their disease, before an effective immune response arises, and about the necessity for an extrinsic incubation period in the mosquito, during which the virus establishes an infection in the salivary glands, before it can transmit the virus. Ultimately, however, the investigation team did succeed in proving mosquito transmission and one member of the commission, Dr. Jesse Lazear, died of it. Fortunately, his was the only death recorded in these experiments. It is of note that in the days before the introduction of a vaccine, most researchers who studied yellow fever in the field or in the laboratory ultimately contracted the disease and many of them died.

With the discovery that the virus was mosquito-borne, the U.S. Army began a campaign in Havana to eliminate mosquito breeding places by eliminating sources of water around human habitation. It was (and still is) common for drinking water to be stored around houses throughout Latin America in large pots that served as excellent breeding places for A. aegypti. The campaign succeeded in breaking the mosquito transmission cycle and yellow fever as an epidemic agent disappeared from Havana within months. This approach was later exported to other areas with great success, including Panama. It was at first believed that yellow fever could be eradicated, but the discovery of the endemic cycle of yellow fever dispelled this idea. Forest workers who cut down trees and brought the mosquitoes down from the upper canopy, where they transmit the disease to monkeys, were particularly at risk. Once infected, a person is able to bring the disease back to town where it can get into the A. aegypti population and start an urban epidemic.

In the late 1920s, yellow fever virus was successfully propagated in Rhesus monkeys, in which it causes a lethal disease and in which it can be experimentally passed from monkey to monkey. One such strain was derived from an infected human named Asibi. Theiler and Smith passed the Asibi strain of yellow fever in chicken cells, and after approximately 100 passages, it was found that the resulting virus was no longer virulent for Rhesus monkeys. After additional passages, this virus, called 17D, was ultimately used as a live virus vaccine in man and has proven to be one of the best and most efficacious vaccines ever developed. The vaccine virus causes very few side reactions and is essentially 100% effective in providing long-lasting protection against yellow fever. This vaccine is routinely given to travelers to regions where yellow fever is endemic and is used to control the spread of epidemic yellow fever in Latin America and, with less success, in Africa. The success of this vaccine has served as a model for the development of other live virus vaccines, namely, passing the virus in cultured cells from a non-native host.

Although not as wide ranging as previously, yellow fever continues to cause epidemics in Africa and South America as illustrated in Fig. 3.25. On an annual basis, 50-300 cases

Yellow Fever Virus

FIGURE 3.25 Cumulative number of cases of yellow fever reported to the World Health Organization for the years 1982 through 1995, by country. It is suspected that cases in Africa may be underreported by at least a factor of 10. Immunization coverage in Africa has remained low and the disease has recently emerged after more than a decade, with cases reported in Kenya (1992), Ghana (1993), Gabon (1994), and Liberia (1995). [From Fields et al. (1996, p. 1014) and the WHO web site: fever.htm.]

FIGURE 3.25 Cumulative number of cases of yellow fever reported to the World Health Organization for the years 1982 through 1995, by country. It is suspected that cases in Africa may be underreported by at least a factor of 10. Immunization coverage in Africa has remained low and the disease has recently emerged after more than a decade, with cases reported in Kenya (1992), Ghana (1993), Gabon (1994), and Liberia (1995). [From Fields et al. (1996, p. 1014) and the WHO web site: fever.htm.]

are officially reported in South America and up to 5000 cases in Africa, but these figures are significantly under-reported. Between 1986 and 1991, annual outbreaks of yellow fever occurred in Nigeria that probably resulted in hundreds of thousands of cases. Epidemics of yellow fever has also occurred in Peru and Bolivia in recent years. There was one imported case of yellow fever in the United States in 1996, in which an American who visited the jungles of Brazil along the Amazon River without being immunized returned to the United States with yellow fever and died of the disease. Because of the endemic cycle in which monkeys are the reservoir, it is probably impossible to eradicate the virus as has been done with smallpox and as is planned for poliovirus and measles virus.

Dengue Viruses

The four dengue viruses have recently undergone a dramatic expansion in range and cause tens to hundreds of millions of case of dengue fever in humans each year. Uncomplicated dengue fever is characterized by headache, fever, rash, myalgia (muscle pain, from myo = muscle and algia = pain), bone pain, and prostration. The disease may be mild or it may be extremely painful, but it is almost never fatal. However, the virus can cause illnesses characterized by hemorrhage (dengue hemorrhagic fever or DHF) or shock (dengue shock syndrome or DSS), which have mortality rates of several percent. Up to 250,000 cases of DHF and DSS are recorded each year, most of them in Southeast Asia, and DHF and DSS are a leading cause of mortality in children in southeast Asia. It is hypothesized that DHF and DSS are caused by immune enhancement in which infection by one serotype of dengue virus expands the population of cells that can be infected by a second serotype. In this model, infection with one serotype predisposes a person to shock or hemorrhage on infection with a second serotype when the second infection occurs within a limited time period, usually 1-2 years. For this reason, the development of vaccines against dengue has progressed slowly, because of the possibility that immunizing against one serotype might put a person at risk for a more serious illness. Current efforts in Thailand are directed toward developing a quadrivalent attenuated virus vaccine that would immunize against all four serotypes simultaneously. U.S. scientists are independently attempting to develop vaccines for the viruses, based either on attenuated dengue viruses or on the development of chimeric flaviviruses that express dengue envelope antigens in a yellow fever vaccine background.

Dengue viruses are maintained in A. aegypti in urban settings in most of the world, but also in Aedes albopictus in Asia, and man is the primary vertebrate reservoir. Forest cycles have been documented in Africa and Madagascar in which the vertebrate reservoir is monkeys and other mos quito species maintain the virus. Such a forest cycle does not exist in the Americas.

Dengue viruses, which have been continuously active over large areas of Asia and the Pacific region for a long time, have recently expanded their range in the Americas, as illustrated in Fig. 3.26. The viruses may have caused large epidemics in the Americas, including the United States, in the 1800s and into the early 1900s. However, it is impossible to determine with certainty from descriptions of the disease written at the time whether dengue was the causative agent of these epidemics or whether other viruses that cause similar illnesses might have been responsible. Dengue almost died out in the Americas largely because of efforts to control A. aegypti. In the mid-1900s, a serious effort was made in the Americas to eradicate A. aegypti from large regions, in order to control viral diseases spread by these mosquitoes. These efforts succeeded in eliminating the mosquito from large areas of Central and South America, as illustrated in Fig. 3.26A. However, by 1970 these efforts were abandoned because of the expense involved and the detrimental effects of DDT on the environment, and the mosquito reestablished itself over most of the region. The reintroduction of multiple dengue strains into the Americas from foci in Asia after the reestablishment of A. aegypti resulted in the outbreak of huge epidemics of dengue fever (Fig. 3.26B). Furthermore, as multiple strains have become epidemic, the incidence of DHF and DSS has started to rise, so that dengue diseases now constitute a major plague throughout Central and South America and the Caribbean region.

Japanese Encephalitis Virus and Related Viruses

The Japanese encephalitis (JE) complex of flaviviruses includes a number of related viruses, many of which cause encephalitis. In addition to JE, these include St. Louis encephalitis (SLE), Murray Valley encephalitis (MVE), Kunjin, and West Nile viruses. The close relationships of these viruses are illustrated in Fig. 3.27. Notice in this dendrogram that the the viruses do not always group by place of isolation. Kunjin virus, found in Australia and the South Pacific, is more closely related to West Nile virus, found in Africa and Europe, than it is to Murray Valley encephalitis virus, an Australian virus. Thus, circulation of these viruses has been widespread, as is also true for the dengue viruses described in the preceding section.

JE virus is distributed throughout Asia, including Japan, India, Southeast Asia, Indonesia, the Philippines, and Borneo (Fig. 3.28). Reported cases of JE encephalitis average 35,000 per year with 10,000 deaths, but the disease is greatly underreported. Only 1 JE virus infection in 200 or 300 results in encephalitis, with children and the elderly being at higher risk. The fatality rate following JE

A. Aedes Aegypti in the New World

Yellow Fever Virus Pictures

B. Dengue fever and dengue hemorrhagic fever(DHF) in the New World

1967-1971 1987-1991

Aedes Aegypti Species

FIGURE 3.26 Changing distribution of dengue virus, DHF, and the vector for dengue in the New World. (A) Distribution of the vector mosquito A. aegypti in the Americas in 1970 and 1994. Aedes aegypti spread rapidly during the 1970s and 1980s due to the collapse of mosquito control programs and urbanization. (B) Increase and spread of dengue fever and DHF, and the introduction of multiple dengue serotypes between 1967 and 1991. Size of circles indicates the size of the epidemics. Although data shown are primarily for dengue 1 and dengue 2, dengue 3 and dengue 4 have also been active recently in the Americas. [Redrawn from Fields et al. (1996, pp. 1001 and 1021, respectively).]

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