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WEST NILE VIRUS (WNV)
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WNV is a flavivirus that was originally discovered in Uganda in 1937 and emerged as a cause of neurologic disease in humans and equines. WNV exists in nature in an enzootic cycle that involves certain birds and mosquitoes, particularly those of the genera Culex and Aedes. Humans, horses, and other vertebrates are incidental hosts and, except through blood transfusion, are unlikely to transmit WNV because levels of viremia are insufficiently high to infect mosquitoes. When originally described, WNV was believed to cause a mild febrile illness, but subsequent experience showed that it caused neuroinvasive disease in some cases. The first cases of neuroinvasive disease were described in an outbreak among elderly patients in Israel and subsequently in humans and horses in the Mediterranean basin, India, and South Africa. By the 1990s, outbreaks had been reported from Romania, Russia, and Central Asia; these outbreaks were probably a result of seasonal bird migrations from endemic Mediterranean countries, with introduction of infected mosquitoes and the establishment of infection in local bird species.
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An explosive outbreak of WNV infection began in the United States in the summer of 1999 and initially involved infection of birds of the family Corvidae (e.g., the American crow and blue jay) that were susceptible to neuroinvasive disease. The first human cases appeared in New York City that same summer. Subsequently, sufficient numbers of birds more resistant to neuroinvasive disease and mosquitoes of the genus Culex became infected and an enzootic cycle was established in North America. Over the next 3 years, WNV spread across the continental United States, Canada, and Mexico and became an important cause of human and equine neurologic disease. The WNV clade causing the North American outbreak was the same (clade 1a) as that causing disease in the Middle East, Europe, North Africa, and parts of Asia.
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In 2016, 2038 cases of WNV infection in humans, including 1140 cases of neuroinvasive disease, were reported in the United States; these figures are certainly gross underestimations of the actual number of cases. There were 94 deaths, primarily among the elderly. An additional 377 cases were reported in horses from 32 states despite the availability of a reasonably protective equine vaccine. Human cases were reported from 44 states, with only Alaska, Delaware, Hawaii, Maine, New Hampshire, and West Virginia free of the disease. Infected mosquito pools were even more widespread; Maine was the only state in the continental United States to be free of all WNV activity. Thus, from an initial introduction into New York City, WNV has successfully established itself across North America and infected an estimated 2.6–6.1 million people in the United States (1.1% of the population).
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Why did this happen? First, microorganisms and larger organisms, such as plants and animals, have been exchanged between the Old and New Worlds since the initial voyages of exploration in the fifteenth and sixteenth centuries. However, it is the advent of modern high-speed transportation that allows vectors, such as mosquitoes, to move between continents in hours or days as opposed to months or years. In the most likely scenario for the introduction of WNV into North America, a single viremic mosquito was accidentally transported from an area endemic for clade 1a to New York City in the cargo hold of an airplane in 1999. The original strain associated with the 1999 outbreak (NY99) had caused outbreaks in Tunisia and Israel in 1997 and 1998, respectively; this information suggests that one of those countries was the source. The imported strain in turn infected crows, which in turn infected more competent mosquitoes, establishing an enzootic life cycle in North America with at least three Culex species and multiple species of birds involved. This scenario represents a successful invasion of WNV into a new ecologic niche.
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The likelihood that WNV will gradually disappear is low. The virus has many avian hosts and more than one mosquito vector; it has undergone at least one successful mutation in the North American outbreak, thereby becoming infectious to Culex piperans and Culex tarsalis—mosquitoes with a broad range in the western United States. Moreover, the occurrence of outbreaks in 17 consecutive years in North America suggests that WNV has been successfully introduced onto the continent and will remain endemic for years to come.
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Dengue is the most important of the human arboviral infections, with almost half of the world’s population at risk. Occurring in the range of Aedes mosquitoes, dengue virus infection imposes a heavy burden of morbidity and mortality worldwide, with as many as 50–200 million infections, 500,000 severe cases, and 20,000 deaths annually. Dengue virus is a flavivirus and exists in four serotypes (DENV1–4) that circulate independently of one another; immunity to one serotype does not confer immunity to the others.
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Dengue is transmitted primarily by Aedes aegypti and secondarily by Aedes albopictus. The original life cycle of dengue virus was most likely similar to that of yellow fever, consisting of sylvatic transmission from mosquitoes to nonhuman primates and back to mosquitoes; over the past few centuries, the virus has adapted to an urban and periurban mosquito–human–mosquito cycle as well. Dengue and its more severe manifestations, dengue hemorrhagic fever and dengue shock syndrome, were first described in outbreaks in Japan in 1943 and Hawaii in 1945. However, clinically similar diseases had been reported during the previous two centuries in a geographic band extending from India south to Queensland, Australia, and east through Polynesia; in addition, there had been occasional outbreaks in areas as disparate as Greece, Panama, and southern Texas.
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The ecology of dengue changed dramatically in the second half of the twentieth century, led by the successful invasion by A. aegypti of the global tropics after World War II, with the postwar dispersion of troops and materiel. From its ancestral roots in Southeast Asia, all four dengue serotypes spread globally in the tropics. DENV2 had been introduced into West Africa by the 1960s and established both sylvatic enzootic nonhuman primate and urban endemic human cycles. Travel and commerce facilitated importations, probably through both viremic human hosts and infected mosquitoes. In the Americas in particular, a campaign to eradicate A. aegypti, which is also the principal vector of yellow fever, failed in the mid-1970s, and both A. aegypti and dengue virus, especially DENV2, rapidly reinvaded their prior habitat; thus dengue reemerged as a major arboviral disease extending from the southern United States in the north, through northern Argentina in the south. Recent outbreaks have occurred along the U.S.–Mexico border and in the state of São Paulo in Brazil, where DENV1, DENV2, and DENV4 are co-circulating.
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Dengue’s emergence and spread have been intimately linked to human activity. In particular, globalization, with the movement of viremic people and mosquitoes through modern transportation of both passengers and goods, has been critical to dengue’s success. One particular adaptation has also facilitated its urban spread: Aedes is able to breed in standing water associated with human habitation, such as cisterns, ornamental ponds, puddles, and water trapped in abandoned tires. This ability of Aedes has allowed dengue to be one of the only two known arboviruses (the other being Zika) that are adapted to an urban environment and can replicate entirely in a mosquito-to-human cycle. Together, these factors have led to widespread dengue transmission in a band extending across the tropics worldwide.
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EBOLA AND MARBURG VIRUSES
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Ebola virus is a filovirus that most likely exists in a sylvatic cycle in bats in Central and West Africa. Four strains are known to cause human disease. The first outbreak was described in Zaire in 1976. Since then, 29 outbreaks have been reported across tropical Africa, ranging in size from tens of cases to tens of thousands of cases in the West African outbreak of 2013–2016.
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The life cycle of Ebola virus in the wild is not fully understood. There is evidence for sustained transmission in fruit bats, with occasional nonhuman primate spillover infections. It has been speculated that humans become infected from contact with infected bats or nonhuman primates, but, once an index case has occurred, essentially all transmission is from human-to-human contact with blood and other body fluids. Preparing bodies for burial has been an especially efficient means of transmission. In addition, health care providers who do not wear adequate personal protective equipment while caring for Ebola patients are particularly vulnerable to acquiring infection. In the West African epidemic, there was only a single zoonotic introduction and all subsequent transmission was from human to human.
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The principal cause of Ebola outbreaks prior to the West African outbreak was the migration of humans into sylvatic areas, with enzootic transmission and accidental infection. In West Africa, only a single case had been recognized in Côte d’Ivoire before the 2013–2016 outbreak in the Republic of Guinea, Liberia, and Sierra Leone. It has been speculated that cultivation of palm oil attracted fruit bats, who feed on palm fruit; if so, environmental modification from dense tropical forest to palm oil plantations may have been a contributory cause. Other evidence suggests that the index patient—a 2-year-old boy—was exposed to insectivorous free-tailed bats (Mops condylurus). Whatever the initial event, the explosive amplification that occurred in these countries and the seven countries to which cases were exported was due to an inadequate medical and public health infrastructure. In fact, when Ebola virus was imported to countries with more functional public health systems, such as Nigeria, transmission was extinguished within three generations.
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Other filovirus outbreaks have involved the transport of infected primates for medical research. The original Marburg virus outbreak, which occurred in Marburg and Frankfurt, West Germany, and Belgrade, Yugoslavia, in 1967, was likely caused by the importation of African vervet monkeys (Cercopithecus aethiops) from Uganda for medical research. This outbreak resulted in 31 human cases and 7 deaths. In addition, an outbreak among five crab-eating macaques (Macaca fascicularis) imported from the Philippines and infected with Reston Ebola virus—a strain nonpathogenic for humans—led to an epizootic in northern Virginia in 1989, eventually resulting in the culling of more than 500 primates. This outbreak, however, had no human cases associated with it, although epidemiologic investigation identified a handful of asymptomatic primate handlers who were seropositive for Reston Ebola virus. Since 1989, four additional outbreaks have been recognized in Cynomolgus monkeys imported from the Philippines to the United States and Italy.
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A new reservoir of Ebola virus infection has now been identified: the semen of patients who have survived Ebola infection. The occurrence of several small clusters of sexually transmitted cases developing up to 284 days after symptom onset indicates prolonged carriage of Ebola virus in the testes. Moreover, the virus may remain viable over the long term in the vitreous humor.
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Thus, Ebola represents a spillover event to humans and nonhuman primates from their interaction with certain species of infected and infectious bats. Contact with either the bats themselves or an infected nonhuman primate leads to infection of an index patient, which leads in turn to ongoing transmission from humans to humans. Several factors clearly contribute to the continued transmission. First, medical and public health systems are weak in severely affected countries. As experience with Ebola grows and the capacity for surveillance and response improves, numbers of secondary cases can fall; for example, in five outbreaks in Uganda stretching from 2000 to 2012, the numbers of secondary cases and the geographic spread of the outbreaks decreased with each new introduction. Second, behavioral factors contribute, in particular funeral practices that bring mourners into close contact with infectious blood and tissues during preparation of a body for burial. Third, the areas in which the initial waves of transmission occur are often remote; thus, recognition of the outbreak can be delayed and, in the case of the West African outbreak, highly mobile populations can travel to larger cities to seek care.
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Zika virus is a flavivirus that is transmitted by Aedes mosquitoes and was originally described as an infection of nonhuman primates in Uganda in 1947. The first human cases were reported in Uganda in 1962 and 1963. Zika was thought to be an illness causing a mild rash and fever in humans in tropical Africa and southern Asia. The clinical and serologic similarity of Zika infection to dengue virus infection may have led to missed outbreaks. Since 2007, an Asian lineage of Zika virus has spread from the Western Pacific (initially, Yap Island) through Polynesia and on to Easter Island, Chile, where it was documented in 2014. From Polynesia, it also spread to Brazil, most likely through viremic travelers attending the world Va’a World Sprint Championships (Polynesian canoe racing) in Rio de Janeiro in the late summer of 2014. From there, Zika virus has spread hemisphere-wide, following the host range of A. aegypti. Forty-eight countries in the Americas have now reported autochthonously transmitted Zika virus infections.
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In tropical Africa and Asia, Zika virus is most likely transmitted in a nonhuman primate–mosquito sylvatic cycle. Other animals may be involved in Zika’s life cycle as well. A number of Aedes species are competent vectors, although A. aegypti may be the source of the majority of infections worldwide.
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As Zika virus spread through Latin America and the Caribbean, a parallel epidemic of fetal microcephaly appeared; this epidemic was both temporally and geographically associated with the spread of Zika virus. More than 1.6 million cases of Zika virus infection, including 41,473 cases in pregnant women and 1950 cases of Zika-associated microcephaly, were reported from Brazil alone in 2015 and 2016. Data from a large registry of Zika-exposed pregnancies in the U.S. territories show that the overall risk of microcephaly following confirmed Zika virus infection is ~5%, ranging from 8% for infection in the first trimester to 4% for infection in the third trimester. Other fetal complications include stillbirth, neural tube defects, eye abnormalities, and sensorineural deafness. Complications in adults occur in about one of every thousand cases and include Guillain-Barré syndrome, encephalitis, leukopenia, and thrombocytopenic purpura. Moreover, it is now recognized that Zika virus can be transmitted sexually and via blood transfusion.
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Thus, the introduction of Zika into the Americas represents viral invasion of a new ecosystem already widely populated by a highly competent mosquito host with an established urban habitat and an immunologically inexperienced human population. The invasion by Zika virus is in many ways similar to the original dengue invasion in the Americas in the 1950s and to the introduction of WNV into North America in 1999. Both the original importation of Zika virus and its establishment of new foci in the Americas (e.g., Florida and the Caribbean) were consequences of modern travel. Zika’s spread has also been linked to climate variations, deforestation, and urban poverty.