Chapter 461: Worldwide Changes in Patterns of Infectious Disease

Pathogenic organisms have been a constant companion of humans, their livestock, and their cultivated plants throughout evolution. Over the centuries, new organisms emerged as ecology changed or as humans managed to cross ecologic barriers such as oceans and mountains. Throughout history, there have been severe epidemics of infectious diseases, with devastating consequences to human populations over vast geographic regions. From the Plague of Justinian in Europe in the sixth century, to the Black Death in the fourteenth century, to the five cholera pandemics of the nineteenth century, to the 1918 Spanish influenza pandemic, to the current HIV/AIDS pandemic, the death toll in human populations has been enormous. The concept of emerging infectious diseases arose in the 1970s and 1980s with the recognition of several “new” diseases, such as legionellosis, HIV infection, Lyme disease, and toxic shock syndrome and was later expanded to include reemerging infectious diseases, such as tuberculosis. In 1991, the Institute of Medicine (IOM) convened a multidisciplinary committee to elucidate emerging microbial threats to health, with particular reference to the United States. In its report, the committee defined an emerging infectious disease as a disease “of infectious origin whose incidence in humans has either increased within the past two decades or threatens to increase in the near future.” In the year following the publication of the committee’s report, large outbreaks of Escherichia coli O157:H7 infection, cryptosporidiosis, and hantavirus pulmonary syndrome spurred the development of a national plan to recognize and interdict emerging and reemerging infectious disease threats by the Centers for Disease Control and Prevention (CDC). Since then, the list of emerging and reemerging viral, bacterial, fungal, and parasitic diseases has grown to include multiple infections and syndromes. Examples of emerging and reemerging infectious diseases, as of 2017, are shown in Table 461-1.

The reasons for the emergence of previously unrecognized diseases and the reemergence of diseases that have previously been largely under control are legion. At its core, however, emergence has to do with genetic changes in disease agents or changes in ecology, which includes human behavior. The IOM committee listed six primary reasons for disease emergence or reemergence: human demographics and behavior, technology and industry, economic development and land use, international travel and commerce, microbial adaptation and change, and breakdown of public health measures. A disease can emerge or reemerge for one or more of these reasons. For example, the worldwide spread of severe acute respiratory syndrome (SARS) began as a species cross-over, most likely involving transmission of a previously unknown coronavirus of horseshoe bats to Himalayan palm civets that were subsequently captured and transported to live-animal (i.e., “wet”) markets in Guangzhou, China, for human consumption. The SARS coronavirus was then transmitted to humans—most likely by restaurant workers—and from them to medical personnel and eventually to individuals around the world. This spread had nothing to do with migratory patterns of bats or civets but was, instead, a consequence of human travel. The cities most effected by SARS—Hong Kong, Beijing, and Toronto—became involved because of rapid human movement via international passenger aircraft.

To this list, additional factors can now be added. Either therapeutic or acquired immunosuppression (e.g., in HIV infection) can render populations susceptible to infections that have not previously been recognized, such as that with human herpesvirus 8—the cause of Kaposi’s sarcoma. Climate change, in particular, can expand the host range of disease-transmitting vectors. In addition, the weaponization of pathogenic organisms for biological terrorism or warfare can lead, at least theoretically, to prolonged chains of human-to-human transmission. One factor is clear: the preponderance of emerging infectious diseases are zoonotic in origin. The authors of a 2008 review calculated that 60.3% of all emerging infectious disease events from 1940 to 2004 were zoonotic in origin, and 71.8% of these zoonotic events originated in wildlife.

In this chapter, we review the recent changing epidemiology of four emerging infectious viral diseases that exemplify some of the IOM’s principles for emergence: infections caused by West Nile virus, dengue virus, Ebola virus, and Zika virus. This list is clearly not exhaustive but highlights a few prominent instances of the recent emergence of infectious diseases and their root causes.

WEST NILE VIRUS (WNV)

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.

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.

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).

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.

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.

DENGUE VIRUS

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.

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.

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.

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.

EBOLA AND MARBURG VIRUSES

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.

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.

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.

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.

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.

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.

ZIKA VIRUS

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.

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.

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.

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.

Humans will continue to experience outbreaks of emerging and reemerging infectious diseases. Emerging diseases will most likely come from two sources. The first source consists of organisms that have acquired new genetic materials from other strains of the same species or from different species altogether. An example of this is influenza A virus, in which strains can acquire new genetic material through a process called reassortment. If the new gene is a hemagglutinin gene, the resulting reassortant virus will have a new surface hemagglutinin that is unrecognized immunologically by most human populations. An interesting case is influenza A H1N1 virus, which emerged in 2009 from the reassortment of H1N1 swine influenza virus with human seasonal H3N2 influenza virus, North American avian influenza virus, and Eurasian avian-origin swine influenza viruses. Despite a worldwide pandemic, people born before 1950 were relatively spared because they had earlier exposure to an H1N1 strain sufficiently similar to provide them with cross-immunity. Another example of this is E. coli O157:H7, which acquired a virulence gene from Shigella, probably as the result of horizontal genetic exchange. The resulting organism and several other serotypes of E. coli that have acquired the gene are the leading cause of hemolytic–uremic syndrome worldwide. The second source for emergence consists of existing organisms entering new ecologic niches and spreading broadly, usually through insect vectors, to immunologically naïve humans—as occurred with Zika virus. A variation on this theme is humans entering new ecosystems and becoming infected with organisms to which they have no immunity. An organism’s epidemic potential will be determined by whether it is largely incapable of leaving the human host to continue onward via human-to-human transmission (e.g., Coccidioides) or can be efficiently transmitted from human to human (e.g., HIV and Ebola virus).

In its 1994 strategic plan to address emerging infectious disease threats, the CDC listed four goals: (1) to detect, promptly investigate, and monitor emerging pathogens, the diseases they cause, and the factors influencing their emergence; (2) to integrate laboratory science and epidemiology in order to optimize public health practice; (3) to enhance communication of public health information about emerging diseases and ensure prompt implementation of prevention strategies; and (4) to strengthen local, state, and federal public health infrastructures in order to support surveillance and implement prevention and control programs. Much of this plan has been implemented. The concept of “emerging infectious diseases” has been broadly accepted, and molecular biological methods have improved to the point that, for example, the SARS coronavirus was completely sequenced in a matter of days. In addition, there has been an increasing recognition of the “one health” concept: the nexus among human, livestock, wildlife, and plant health and the development of surveillance systems to provide early warnings of emerging and reemerging infections. New vaccines and new vector-control agents are important promising weapons in the struggle to contain existing diseases; vaccines against both dengue and Ebola have been shown to be efficacious in phase 3 trials, and a new vector-control technique involving deliberate infection of the Aedes population with Wolbachia, a bacterial genus that inhibits the transmission of arbovirus from mosquito hosts, is being evaluated.

The World Health Organization has developed new international health regulations that are designed, in part, to facilitate the recognition and reporting of infectious disease threats. However, as evidenced by the 2013–2016 Ebola virus epidemic in West Africa, additional capacity and possibly new forms of global health governance and response may be required. What is clear is that humans will continue to experience new and reemerging infections, and we will need robust, flexible, and timely responses in order to control them.