Chapter 16: Arthropod-Borne and Other Zoonotic Viruses

The zoonotic viruses comprise of more than 400 viral agents, one or more of which occur in most parts of the world. Members of the group have their ultimate reservoirs in insects or lower vertebrates. They are from diverse RNA virus families that primarily include the togaviruses, flaviviruses, bunyaviruses, reoviruses, arenaviruses, and filoviruses. The zoonotic viruses discussed here are divided into two groups: Arthropod-borne (arboviruses) and nonarthropod-borne zoonotic viruses. The arthropod-borne or arboviruses are transmitted to humans by infected blood-sucking insects, such as mosquitoes, ticks, and Phlebotomus flies (sandflies). The other zoonotic RNA viruses are generally believed to be transmitted by inhalation of infected animal excretions, by the conjunctival route, or occasionally by direct contact with infected animals (nonarthropod zoonotic viruses). Rabies virus, which is commonly transmitted by animal bites, is discussed separately in Chapter 17. Certain DNA viruses (poxviruses) are also transmissible from animals to humans, which are described in Chapter 11.

VIROLOGY

In most cases, the zoonotic viruses were first named after the place or region of initial isolation or reported infection (eg, St. Louis encephalitis virus, West Nile virus, Zika virus) or after the disease produced (eg, yellow fever). More recent studies have assigned the majority to families and genera on the basis of properties including morphologic and genetic features, geographic distribution, and disease spectrum summarized in Table 16–1. The major characteristics of these arboviruses families, including togaviruses, flaviviruses, bunyaviruses, and reoviruses are summarized in the following discussion.

TOGAVIRUSES

Togaviruses are from Togaviridae family and Alphavirus genus includes arboviruses within this family that infect humans. The other genus, Rubivirus that includes rubella virus is discussed in Chapter 10. Alphaviruses have enveloped virions that measure 70 mm in external diameter and contain a positive-sense single-stranded, linear RNA genome. The RNA genome is encapsidated in an icosahedral capsid that measures approximately 40 nm. The lipid bilayer envelope contains viral-encoded glycoproteins, E1 and E2. Alphaviruses have the ability to hemagglutinate via fusion of E1 glycoprotein to lipids in erythrocyte membrane and E2 also participates in this process. The structure of an alphavirus virion is shown in Figure 16–1. Replication occurs in the cytoplasm of the cells of infected arthropods and in vertebrate hosts. Virus enters via receptor-mediated endocytosis by interacting with a variety of cellular receptors, depending on the host and the cell type. The positive-sense genomic RNA serves as the mRNA for the translation of nonstructural proteins, including RNA-dependent RNA polymerase. The RNA-dependent RNA polymerase synthesized negative-sense RNA intermediates, which is used for the synthesis of both subgenomic RNA (mRNA for synthesis of structural proteins) and new positive-sense, full-length genomic RNA. Virus assembly takes place in the cytoplasm. Virions mature by budding from cellular membranes. The effect of viral replication on invertebrate and vertebrate hosts is variable, with usually a persistent infection in invertebrate (arthropod) hosts. Viruses within the Alphavirus genus are frequently serologically related to one another but not to others. Representatives are listed in Table 16–1.

FLAVIVIRUSES

Flaviviruses come from Flaviviridae family and Flavivirus genus includes arboviruses transmitted through mosquitoes to humans. The other genus of Flaviviridae is Hepacivirus (hepatitis C virus) that is a blood-borne virus and causes hepatitis C (discussed in Chapter 13). Flaviviruses are similar to togaviruses in several respects such that they are positive-sense, single-stranded RNA, icosahedral capsid, enveloped viruses. However, the virions of flaviviruses are smaller than those of togaviruses, ranging from 40 to 50 nm in diameter. The RNA genome is surrounded by multiple copies of small basic proteins; the capsid (C) protein that covers the core and makes it icosahedral. The lipid bilayer envelope membrane contains the membrane (M) protein and envelope (E) protein, which is glycosylated in many flaviviruses. An example of a flavivirus virion is shown in Figure 16–2. Flavivirus members are serologically related, and there is cross-reactivity among members. Virus replication starts with virus entering the target cells via receptor-mediated endocytosis; flaviviruses can also bind to Fc receptors on macrophages, monocytes, and other cells coated with antibody. The enhancing antibody enhances viral adsorption and infectivity. The virus replicates like positive-sense RNA viruses, and the whole positive-sense RNA genome is translated into a polyprotein (like picornaviruses), which is cleaved into individual mature proteins, including a protease, an RNA-dependent RNA polymerase, a capsid, and envelope proteins. Virus assembly takes place in the cytoplasm and the envelope is acquired by budding into intracellular vesicles and released upon cell lysis. Like alphaviruses, flaviviruses also cause a lytic response in vertebrate hosts and a persistent infection in invertebrate hosts.

BUNYAVIRUSES

There are four genera of Bunyaviridae family: Bunyavirus (–) RNA, Phlebovirus (–) RNA, Nairovirus (+/–) ambisense RNA, and Hantavirus (–) RNA. All bunyaviruses are arboviruses, except Hantavirus, which is a nonarthropod zoonotic virus and discussed in the next section. Bunyaviruses are morphologically spherical, enveloped virions of 90 to 100 nm in external diameter containing two envelope glycoproteins, G1 and G2. Inside the virion, the single-stranded, negative-sense or ambisense RNA genome forms three helical nucleocapsids containing RNA, namely, large (L), medium (M), and small (S), associated with an RNA-dependent RNA polymerase (L) and nonstructural proteins (N) (Figure 16–3). Unlike enveloped RNA viruses, bunyaviruses are devoid of a matrix protein. The viral attachment protein (G1) interacts with cellular receptors, and the virus enters the cell via receptor-mediated endocytosis. After lysis of endosomal vesicles and release of the nucleocapsids in the cytoplasm, the negative RNA strands (L, M, S) transcribe to synthesize mRNA using virion-associated RNA-dependent RNA polymerase. The M strand encodes G1 and G2 envelope, a nonstructural protein; L strand encodes the L protein (RNA-dependent RNA polymerase); and the S strand encodes the nucleocapsid protein (NP) and a nonstructural protein. They mature by budding into smooth-surfaced vesicles in or near the Golgi region of the infected cell. The major disease-causing bunyaviruses in North America are California virus such as La Crosse virus subtype and others (arbovirus) and hantavirus (nonarthropod zoonotic virus).

REOVIRUSES

Reoviruses are spherical, naked capsid icosahedral, double-stranded segmented RNA viruses that measure about 80 nm in diameter. The details about virus structure and replication of another member of the Reoviridae family, Rotavirus, are described in Chapter 15. The double-stranded segmented RNA genome of reoviruses replicate in the cytoplasm by utilizing the negative-stranded RNA of the double strand for transcription and replication using their virion-associated RNA-dependent RNA polymerase. However, the reoviruses described here are arboviruses that are transmitted through insect (tick) bites. The most important North American arbovirus of this family, which is a member of the genus Coltivirus, causes Colorado tick fever in humans. The other arboviruses from the Reoviridae family are Orbivirus which includes African horse sickness and bluetongue viruses, mainly causing disease in animals.

ARBOVIRUS DISEASE

EPIDEMIOLOGY

Arboviruses of major importance in human disease are listed in Table 16–1 with summaries of their geographic distribution, the arthropod vectors that transmit them, and the usual disease syndromes that can result from infection.

With the exception of urban dengue and urban yellow fever, in which the virus may simply be transmitted between humans and mosquitoes, other arboviral diseases involve nonhuman vertebrates. These are usually small mammals, birds, or, in the case of jungle yellow fever, monkeys. Infection is transmitted within the host species by arthropods (eg, mosquitoes or ticks) that become infected. In some cases, the infection can be maintained from generation to generation in the arthropod by transovarial transmission. Infection in the arthropod usually does not appear to harm the insect; however, a period of virus multiplication (termed extrinsic incubation period) is required to enhance the capacity to transmit infection to vertebrates by bite.

The consequences of infection transmitted from the arthropod to susceptible vertebrate hosts are variable; some develop illness of varying severity with viremia, whereas others have long-term viremia without clinical disease. Vertebrate hosts are then a source of further spread of the virus by amplification, in which noninfected arthropods feeding on viremic hosts acquire the virus, thereby increasing the risk of transmission. The general features of this overall transmission cycle are illustrated in the following discussion.

Transient viremia is a feature of many of these infections in hosts other than their reservoir; those affected, including humans and higher vertebrates (eg, horses and cattle), are often referred to as blind-end hosts. In contrast, if viremia is sustained for longer periods (eg, weeks to months in a variety of togavirus, flavivirus, and bunyavirus infections of lower vertebrates), the vertebrate host becomes highly important as a reservoir for continuing transmission. Viremia may last a week or more in human dengue and yellow fever infections, and humans may then serve as a reservoir in urban disease.

Obviously, the typical arthropod vectors are rarely present during all seasons. The question then arises as to how the arboviruses survive between the time the vector disappears and the time it reappears in subsequent years. Several mechanisms can operate to sustain the virus between transmission periods (often referred to as overwintering): (1) sustained viremia in lower vertebrates such as small mammals, birds, and snakes, from which newly mature arthropods can be infected when taking a blood meal; (2) hibernation of infected adult arthropods that survive from one season to the next; and (3) transovarial transmission, whereby the infected female arthropod can transmit virus to its progeny.

Urban

As the term suggests, the urban cycle is favored by the presence of relatively large numbers of humans living in close proximity to arthropod (usually mosquito) species capable of virus transmission. The cycle is:

Examples of the urban cycle include urban dengue, urban yellow fever, and occasional urban outbreaks of St. Louis encephalitis.

Sylvatic

In the sylvatic cycle, a single nonhuman vertebrate reservoir may be involved.

In this situation, the human, who becomes a tangential host through accidental intrusion into a zoonotic transmission cycle, is not important in maintaining the infection cycle. An example of this cycle is jungle yellow fever.

In other sylvatic cycles, multiple vertebrate reservoirs may be involved:

Examples include western equine encephalitis, eastern equine encephalitis, and California viruses. In some situations, such as St. Louis encephalitis and yellow fever, the urban and sylvatic cycles may operate concurrently.

Arthropod Sustained

Arthropods, especially ticks, may sustain the reservoir by transovarial transmission of virus to their progeny, with amplification of the cycle by spread to and from small mammals:

Tick-borne encephalitis in Russia is transmitted by the arthropod-sustained cycle. In temperate climates such as the United States, arboviruses are major causes of disease during the summer and early fall months, the seasons of greatest activity of arthropod vectors (usually mosquitoes or ticks). When climatic conditions and ecologic circumstances (eg, swamps and ponds) are optimal for arthropod breeding and egg hatching, arbovirus amplification may begin.

An example of amplification is provided by western equine encephalitis. When the mosquito vectors become abundant, the level of transmission among the basic reservoir hosts (birds and small mammals) increases, and the mosquitoes also turn to other susceptible species such as the domestic fowl. These hosts experience a rapidly developing asymptomatic viremia, which permits still more arthropods to become infected on biting. At this point, spread to blind-end hosts such as humans or horses and the development of clinical disease become likely. This occurrence depends on the accessibility of the host to the infected mosquito and on mosquito feeding preferences which, for unknown reasons, vary from one season to another.

PATHOGENESIS

There are three major manifestations of arbovirus diseases in humans associated with different tropisms of various viruses for human organs, although overlap can occur. In some, the central nervous system (CNS) is primarily affected, leading to aseptic meningitis or meningoencephalitis. A second syndrome involves many major organ systems, with damage to the liver, as in yellow fever. The third syndrome is manifested by hemorrhagic fever, in which damage is particularly severe to the small blood vessels, with skin petechiae and intestinal and other hemorrhages.

Infection of the human by a biting of an infected arthropod is initiated by viral replication at the site of bite probably in Langerhan cells of skin and mononuclear cells followed by viremia, which is apparently amplified by extensive virus replication in the reticuloendothelial system and vascular endothelium. After replication, the virus becomes localized in various target organs, depending on its tropism, and illness results. The viruses produce cell necrosis with resultant inflammation, which leads to fever in nearly all infections. If the major viral tropism is for the CNS, virus reaching this site by crossing the blood–brain barrier or along neural pathways can cause meningeal inflammation (aseptic meningitis) or neuronal dysfunction (encephalitis). The CNS pathology consists of meningeal and perivascular mononuclear cell infiltrates, degeneration of neurons with neuronophagia, and occasionally destruction of the supporting structure of neurons.

In some infections, especially yellow fever, the liver is the primary target organ. Pathologic findings include hyaline necrosis of hepatocytes, which produces cytoplasmic eosinophilic masses called Councilman bodies. Degenerative changes in the renal tubules and myocardium may also be seen, as may microscopic hemorrhages throughout the brain. Hemorrhage is a major feature of yellow fever, largely because of the lack of liver-produced clotting factors because of liver necrosis.

Hemorrhagic fevers other than those related to primary hepatic destruction have a somewhat different pathogenesis, which has been studied most extensively in dengue infections. In uncomplicated dengue fever, which is associated with a rash and influenza-like symptoms, there are changes in the small dermal blood vessels. These alterations include endothelial cell swelling and perivascular edema with mononuclear cell infiltration. More severe infection, as in dengue hemorrhagic fever, often complicated by shock, is characterized by perivascular edema and widespread effusions into serous cavities such as the pleura and by hemorrhages. The spleen and lymph nodes show hyperplasia of lymphoid and plasma cell elements, and there is focal necrosis in the liver. The pathophysiology seems related to increased vascular permeability and disseminated intravascular coagulation, which is further complicated by liver and bone marrow dysfunction (eg, decreased platelet production and decreased production of liver-dependent clotting factors). The major vascular abnormalities may be provoked by circulating virus–antibody complexes (immune complexes), which mediate activation of complement and subsequent release of vasoactive amines. The precise reason for this phenomenon is not clear; it may be related to intrinsic virulence of the virus strains involved and to host susceptibility factors.

Two hypotheses are based on the existence of four distinct but antigenically related serotypes of dengue virus, DEN1, DEN2, DEN3, and DEN4 any of which can generate group-specific cross-reacting antibodies that are not necessarily protective against other serotypes. One possibility is that preexisting group-specific antibody at a critical concentration serves as “enhancing” rather than neutralizing antibody. In the presence of enhancing antibody, virus–antibody complexes are more efficiently adsorbed to and engulfed by monocytes and macrophages. Subsequent replication leads to extensive spread throughout the host. Alternatively, or in concert with this, activation of previously sensitized T cells by viral antigen present on the surfaces of macrophages may result in release of cytokines, which mediate the development of shock and hemorrhage.

IMMUNITY

The usual humoral responses (hemagglutination inhibition, IgM, neutralization) in relation to onset of illness are illustrated in Figure 16–4. The rise in antibody titer generally correlates with recovery from infection. Neutralizing antibodies, which are the most serotype-specific, generally persist many years after infection. The presence of IgM-specific antibodies indicates that primary infection likely occurred within the previous 2 months. Cellular immunity and humoral immunity to reinfection are serotype specific and appear to be permanent.

SPECIFIC ARBOVIRUS DISEASES

Western Equine Encephalitis

Western equine encephalitis virus (Alphavirus/Togavirus) causes western equine encephalitis that is prevalent in the central valley of California, eastern Washington (Yakima valley), Colorado, and Texas. It has also been responsible for outbreaks in Midwestern states (Minnesota, Wisconsin, Illinois, Missouri, and Kansas) and as far east as New Jersey. The virus is transmitted through mosquito (Culex tarsalis) bites. Horses and humans represent blind-end hosts; both are susceptible to infection and illness, commonly manifested as encephalitis. Although human infection in endemic areas is commonplace, overall only 1 of 1000 infections causes clinical symptoms. However, in young infants, 1 of every 25 infections may produce severe illness. The attack rates are therefore far higher in young infants than in other groups. The disease spectrum may range from mild, nonspecific febrile illness to aseptic meningitis or severe, overwhelming encephalitis. Mortality rate is estimated at 5% for cases of encephalitis. It is a very serious disease in infants less than 1 year of age; as many as 60% of survivors have permanent neurologic impairment.

Eastern Equine Encephalitis

The eastern equine encephalitis virus (Alphavirus/Togavirus) is largely confined to the Atlantic Seaboard states from New England down the coasts of Central America and South America. The mosquito vector (principally Culiseta melanura) generally restricts its feeding to horses and birds, although occasional outbreaks among humans have occurred. Increasing numbers of human infections have been observed in 2005 and 2012, which is a cause of concern. The virus can cause severe encephalitis in horses and also in wild birds. The mortality rate for eastern equine encephalitis among humans is estimated at 33% for individuals of all ages, and the incidence of severe sequelae among survivors is high.

St. Louis Encephalitis

The St. Louis encephalitis virus (Flavivirus) is a major cause of arbovirus encephalitis in the United States. Its major mosquito vector is C tarsalis similar to those of western equine encephalitis, but St. Louis encephalitis has been much more prevalent in eastern and central states and in Texas, Mississippi, and Florida. The incubation period is from 5 to 15 days. Most people infected with the virus have no symptoms and less than 1% develop clinical symptoms. Symptoms include fever, headache, dizziness, nauseas, and malaise. However, some infected people develop CNS symptoms such as stiff neck, confusion, disorientation, dizziness and tremors, including coma in severe cases. The highest attack rates, are among adults more than 40 years of age. Infants and young children are relatively spared. About 40% of infected children develop fever and headache or mild meningitis, whereas 95% of infected elderly develop encephalitis. Overall mortality is between 5% and 15%.

California Virus or La Crosse Virus Encephalitis

Although California virus (Bunyavirus) was first isolated in the State of California, its major distribution in the United States has been in the Midwest; outbreaks due to the La Crosse virus subtype are particularly prevalent in Wisconsin, Ohio, Minnesota, Indiana, and West Virginia. In Wisconsin and Minnesota, California virus is considered an important cause of encephalitis. However, studies elsewhere in North America and throughout the world, indicate that California virus or closely related agents are present nearly everywhere. The primary mosquito vector (Aedes triseriatus) is commonly encountered in suburban or rural environments. The reservoir host is the chipmunk; transovarial transmission by mosquitoes to their larvae also serves to sustain the virus in nature. Unlike western equine, eastern equine, and St. Louis encephalitis viruses, the highest attack rates of California virus are seen in those aged 5 to 18 years. The incubation period is 5 to 15 days followed by symptoms such as fever, headache, nausea, vomiting, tiredness, and lethargy. Severe neuroinvasive diseases are often characterized by abrupt onset of encephalitis, frequently with seizures.

Japanese B Encephalitis

Japanese B encephalitis virus (Flavivirus) causes Japanese B encephalitis that is prevalent on the eastern coast of Asia, on its offshore islands (Japan, Taiwan, and Indonesia), and in India. Its transmission cycle resembles that of the St. Louis encephalitis and western equine encephalitis viruses in the sense that the mosquito vector is from the genus Culex but more specifically, Culex tritaeniorhynchus. The virus uses pigs and birds as vertebrate hosts. A high proportion of human infections are subclinical, especially in children; less than 1% of the infected people develop clinical disease and when encephalitis does develop it is severe and often fatal. After infection, the virus generally multiplies for 5 to 15 days (incubation period) followed by initial symptoms such as fever, headache, and vomiting. In the next few days other symptoms develop that include mental status changes, neurologic issues, weakness, movement disorders, and seizures (common in children).

There is no specific treatment. However, avoiding mosquito bites may reduce the risk of transmission. Inactivated Japanese encephalitis virus vaccine is licensed and available for use in the United States for people above 2 months of age. The vaccine is given in two doses, 28 days apart, and may need a booster after 1 year for those above 17 years of age. This vaccine is recommended for travelers in endemic area.

West Nile Virus (Febrile Illness or Encephalitis)

West Nile virus (WNV), a member of flaviviruses, was first detected in 1937 in Uganda, Africa. During the summer of 1999 in the Northeastern United States, human WNV infections appeared for the first time in the Western Hemisphere. A subsequent outbreak occurred again in 2000. Together, these outbreaks resulted in 78 hospitalized patients and 9 deaths, mostly among the elderly. More widespread activity was observed in 2001 (66 human cases); then in 2002 (4156 cases) and 2003 (9862 cases) saw a dramatic increase in virus spread across the United States (in 46 states) and 4 Canadian provinces. WNV has now been detected in all states in the continental United States, except Alaska. In the last 10 years, between 2000 to 3000 cases of WNV are reported every year in the United States, of which more than 50% are neuroinvasive diseases. Before 1999, outbreaks of human WNV infections were primarily confined to eastern Africa, the Middle East, eastern Europe, west Asia, and Australia. Now it is distributed throughout Africa, the Middle East, parts of Europe, the former USSR, North America, South America, Asia, India, and Indonesia.

WNV is antigenically related to St. Louis encephalitis and Japanese encephalitis. The vector for transmission is mosquito and the principal vertebrate host is bird. Crows are particularly affected; virus has been detected in dead crows found as far south as Florida, and more recently in the Midwestern United States. Transmission is from infected mosquitoes that feed from infected birds and then transmit the virus to humans and other animals. WNV can also be spread through transfusion, transplants, breastfeeding, and from mother to child. After mosquito bite, the virus multiplies in Langerhans cells of skin with an incubation period of 2 to 14 days (average 2-6 days) followed by viremia and spread of the virus to the peripheral organs and in some cases the CNS.

Three outcomes of the infection have been observed: asymptomatic, West Nile fever, or severe West Nile disease. (1) Asymptomatic: Approximately 80% of WNV-infected people do not get any symptoms. (2) West Nile fever: 20% of the infected people develop WNV fever. The typical case is mild, characterized by fever, headache, backache, muscle pain, joint pain, generalized myalgia, and chills. Rash appears in half of the cases, involving the chest, back, and upper extremities. Generalized lymphadenopathy is a common finding. Pharyngitis and gastrointestinal symptoms (nausea, vomiting, abdominal pain) may occur. The disease runs its course from 3 to 6 days, followed by recovery. Children generally experience milder illness than adults. (3) Severe West Nile Disease: About 1 in 150 people infected with WNV develop severe West Nile disease. The virus in this case evades the nervous system causing aseptic meningitis, meningoencephalitis, encephalitis, or West Nile poliomyelitis, especially in the elderly, and in some cases may result in death. Symptoms of severe disease include headache, fever, stiff neck, disorientation, coma, tremors, convulsions, muscle weakness, and paralysis. Severe disease may last for weeks and cause permanent injury or, in some cases, death. The symptoms may last for several weeks; neurologic effects may be permanent and may also result in death. The fatality rate is 10%. Serious illness can occur in people over the age of 50 years and the immunocompromised. In addition, people with other medical conditions such as cancer, diabetes, hypertension, kidney disease, and organ transplant recipients have also risk of serious disease. Chemokine receptor, CCR5 that acts as a coreceptor to HIV, provides resistance to WNV infection, whereas Δ32CCR5 homozygosity that provides resistance to HIV is significantly associated with severe West Nile disease.

Clinical laboratory findings include leukopenia and, in cases with CNS signs, CSF pleocytosis, and elevated protein. Diagnosis: serology (antibody to WNV), confirmation by polymerase chain reaction (PCR). The treatment is supportive and vaccine development is underway.

Yellow Fever

Geographically, yellow fever virus (Flavivirus) is distributed throughout the Caribbean and Central America, the Amazon valley in South America, and a broad central zone in Africa from the Atlantic Coast to the Sudan and Ethiopia. Thirty-four countries in Africa and 13 countries in Central and South America have endemic areas. In 2013, 84 000 to 170 000 severe cases and 29 000 to 60 000 deaths were estimated in an African modeling study. In November 2016, an outbreak of yellow fever started in Brazil that continued toward the Brazil’s Atlantic coast in early 2017. It continues to be a potential threat to the Southeastern United States because of an urban vector (Aedes aegypti) in that area. The incubation period is 3 to 6 days, and majority of infected people are either asymptomatic or have mild symptoms. The clinical disease is characterized by abrupt onset of fever, chills, headache, back pain, body ache, nausea, vomiting, fatigue, and weakness. After a short remission of hours to a day, 15% of cases develop serious disease such as high fever, jaundice, bradycardia, hemorrhage, bleeding shock, and failure of multiple organs. Severe vomiting sometimes causes gastric hemorrhage. If the patient recovers from the acute episode, there are no long-term sequelae. However, the fatality of the severe disease is 20% to 50%. A live, attenuated vaccine (17-D) is available and recommended for travelers to endemic areas.

Dengue

Dengue virus (Flavivirus) has four related serotypes (DEN 1-4), any of which may exist concurrently in a given endemic area. There are more than 100 countries where dengue has become endemic. These viral agents are widespread throughout the world, particularly Africa, the Americas, the Eastern Mediterranean, South Asia, South-east Asia and the Western Pacific, the Middle East, Africa, the Far East, and the Caribbean Islands. They have invaded the United States in the past with an outbreak in south Texas in 2005. All dengue cases in the continental United States are imported. Globally, it is estimated that about 100 million people are infected by dengue virus, 500 000 dengue hemorrhagic fever cases, and 22 000 deaths mostly in children every year. The mosquito vector (A aegypti) is the same as the domestic vector of yellow fever. The known transmission cycle is human–mosquito–human, although a sylvatic cycle involving monkeys may also exist. The incubation period is 4 to 7 days.

The symptoms last for 3 to 10 days. The characteristic clinical illness usually results in high fever, an erythematous rash, and severe pain in the back, head, eyes (behind eyes), muscles, bone and joints. There is also sometimes mild bleeding manifestation such as nose or gum bleed, petechiae, or bruising. Especially in the Far East (Philippines, Thailand, and India), dengue has periodically assumed a severe form characterized by shock, pleural effusion, severe abdominal pain and vomiting, and hemorrhage often followed by death.

Severity of the dengue disease is seen more in children. The treatment is supportive and there is no vaccine available for protection. Avoiding mosquito bites is the best preventive measure. Protection after recovery is serotype specific. People who recover from infection of a serotype are protected for life against the same serotype. There is some cross-reactive immunity to other serotypes, which is only temporary and partial. More importantly, subsequent infections with other serotypes increase the risk of developing severe dengue disease, most likely by antibody-dependent enhancement (enhancing antibodies) that do not neutralize the virus rather enhance viral entry into the host cells.

Zika Virus

Zika virus, a Flavivirus, was discovered in 1947 in a monkey in the Zika forest, Uganda and in 1952 in human. Before 2015, Zika virus outbreaks occurred in Africa, Southeast Asia, and the Pacific Islands. In 2015, Zika virus cases were reported in Brazil, and since then Zika is now distributed in Central and South America, the Caribbean, Cape Verde (Africa), Singapore and Vietnam (Southeast Asia), the Pacific Island, Puerto Rico, and all states of the United States. In the United States, 5109 Zika cases were reported between January 2015 and March 2017, whereas 38 099 cases were reported in the U.S. territories (American Samoa, Puerto Rico, U.S. Virgin Islands).

Zika virus is transmitted to humans through mosquitoes (Aedes agypti) bite, mother-to-child (during pregnancy), sexual, and blood transfusion. The incubation period is 2 to 14 days. Many people infected with Zika virus do not develop any symptoms. However, the most common symptoms include fever, rash, joint pain, muscle pain, headache, conjunctivitis. Symptoms last for several days to a week (2-7 days). The severity in Zika virus infection during pregnancy can cause brain defects such as microcephaly and other fetal brain defects and defects of the eye, hearing deficits, and impaired growth. Infants born with microcephaly has been linked with several problems such as seizures, developmental delay, intellectual disability, problems with movement and balance, feeding problems, hearing loss, visual problems. In adults, Zika infection may also cause Guillain-Barré syndrome (GBS).

The pathogenesis of Zika infection is not understood but believed to involve an interaction with the immune cells. After the mosquito bite, the virus probably replicates in the skin cells such as Langerhans cells, dendritic cells, and other cells. The virus interacts with innate immune cells molecules (TLR-3, RIG-1) causing stimulation of IFN-α/β and IFN-γ and several other pro-inflammatory cytokines. The mechanism of Zika’s association with microcephaly is not known but the possibility could be the cytoxic effects of viral replication in neural progenitor cells.

The diagnosis of Zika virus infection is done by detecting viral RNA by RT-PCR (blood and other bodily secretions) and/or IgM antibody. Supportive treatment is indicated. Asprin is contraindicated unless dengue is ruled out. There is no vaccine but development is underway.

Chikungunya Fever

Chikungunya (a native term for “that which bends up”) is an Alphavirus (Togaviruses) transmitted by mosquitoes (A aegypti and some other species), particularly in urban areas of Asia, Africa, and most recently in limited areas of Southern Europe and the Caribbean. The virus may be maintained in a sylvatic subhuman primate reservoir. The incubation period is between 2 and 12 (average 3-7) days and a majority of infected people develop some symptoms. Illness is characterized by an abrupt onset of fever, accompanied by excruciating myalgia and polyarthritis. Infected people may experience additional symptoms such as headache, myalgia, arthritis, conjunctivitis, nausea, vomiting, or maculopapular rash. Symptoms usually last 1 week, but the musculoskeletal complaints can sometimes persist for weeks to months. The disease is usually not fatal. Imported cases have been diagnosed in the United States and the number has been increasing every year, but there is no evidence that the virus has established itself in North America. Diagnosis is done by detecting IgM or RNA by RT-PCR. There is no specific treatment or vaccine.

Powassan Virus

Powassan virus is the only known tick-borne Flavivirus species of North America. First isolated in Ontario from a fatal human case of encephalitis, it has been found in infected ticks in Ontario, British Columbia, and Colorado. Its significance to humans is not yet established; only a few patients have been described as having encephalitis proved to be caused by this agent. However, serologic evidence suggests that the virus is prevalent in many areas of North America.

Colorado Tick Fever

The tick-borne Coltivirus genus that causes Colorado tick fever has been found throughout the western United States, including Washington, Oregon, Colorado, and Idaho, and even Long Island. It is frequently found in Dermacentor andersoni, which are also vectors for Rickettsia rickettsii. The typical illness, which occurs 3 to 6 days after the tick bite, is characterized by a sudden onset with headache, muscle pains, fever, and occasionally encephalitis. Leukopenia is a consistent feature of infection. It is estimated that no more than one clinical illness occurs for every 100 infections with this agent.

CLINICAL ASPECTS

DIAGNOSIS

Arboviral infection diagnosis is mainly done by detecting IgM antibody by ELISA or EIA within 1 to 2 weeks and IgG after 2 to 4 weeks of infection in serum or cerebrospinal fluid (CSF) of symptomatic people, which will differentiate between acute versus convalescent serum. Because of cross reactivity among arboviruses, antibodies test require confirmation. Therefore, RT-PCR is utilized to detect viral RNA in serum or CSF depending on the type of specific arbovirus being sought. The viruses may be found in the blood (viremia) from a few days before onset of symptoms through the initial 1 to 2 days of illness. The arboviruses may be isolated in various culture systems. Attempts at isolation from the blood are generally useful only when viremia is prolonged, as in dengue, Colorado tick fever, and some of the hemorrhagic fevers. Virus is not present in the stool and is rarely found in the throat; viral recovery from CSF is also difficult, although virus can be detected in CSF or affected tissue by reverse-transcriptase PCR (RT-PCR), and sometimes by culture during the acute phase of illness.

TREATMENT AND PREVENTION

There is generally no specific treatment for arboviral infections other than supportive care; ribavirin has been used on occasion, but controlled studies have not been reported to support or refute its effectiveness. Prevention is primarily avoidance of contact with potentially infected arthropods, a task that can be extremely difficult even with the use of adequate screening and insect repellents. In some settings, vector control can be accomplished by elimination of arthropod-breeding sites (stagnant pools and the like) and sometimes by attempts to eradicate the arthropods with careful use of insecticides. Such measures have been highly effective in the control of urban yellow fever, in which elimination of urban breeding sites and other measures to eradicate the principal mosquito vector species (A aegypti) have been used. Viruses maintained in complex sylvatic cycles are infinitely more difficult to control without risking major environmental disruption and inestimable expense.

Vaccines are available for immunization of horses against western, eastern, and Venezuelan equine encephalitis virus infections, and the latter has also been used for some laboratory personnel who work with the virus. Another arbovirus vaccine in general use for humans is a live attenuated yellow fever virus vaccine (17-D strain), which is used to protect rural populations exposed to the sylvatic cycle and international travelers to endemic areas. In fact, many countries in tropical Africa, Asia, and South America require proof of yellow fever vaccination before allowing travelers to enter. There is also a vaccine for human tick-borne encephalitis virus (TBEV), which is endemic in areas of Western Europe; inactivated Japanese B encephalitis vaccines are widely used in endemic areas of eastern Asia and adjacent southern Pacific countries and are also licensed in the United States.

ARENAVIRUSES

VIROLOGY

The arenaviruses of the family Arenaviridae are enveloped, bisegmented, containing a large (L), single-stranded, negative-sense (–) and a small (S) ambisense (–/+) RNA genome with pleomorphic morphology ranging in size from 50 to 300 (mean 110-130) nm in diameter (Figure 16–5). There are two separate helical nucelocapsids, L and S, encapsidating L and S RNA segments, respectively. The envelope contains two viral surface glycoproteins, G1 and G2. The virion contains host cell ribosomes in their interior. These ribosomes confer a granular appearance to the viruses; hence their name (from the Latin arenosus for “sandy”). The most significant arenavirus infections in humans are the hemorrhagic fevers caused by Lassa virus in West Africa. In addition, the South American hemorrhagic fevers are caused by arenaviruses, including Junin virus, Machupo virus, Guanarito virus, and Sabia virus. LCMV is occasionally transmitted to humans from infected mice and other rodents, and associated with CNS infection that may persist for several months.

Arenaviruses replicate in the cytoplasm of the infected host cell using the strategy of negative-sense RNA genomes. Viral attachment protein G1 interacts with a cell surface receptor (αDG), and the virions are internalized in vesicles. Viral fusion protein G2 mediates fusion, resulting in the release of nucleocapsids. Virion-associated RNA-dependent RNA polymerase (L protein, Figure 16–5) mediates transcription, and the L RNA segment encodes the polymerase (L) protein and a Z protein, which may help the virus in assembly and release. The S RNA segment, which has ambisense (–/+) polarity, encodes NP and envelope glycoproteins G1 and G2, using a negative-sense RNA strategy for transcription. The ambisense RNA strategy allows arenaviruses to regulate their gene expression, first encoding the N and later the G proteins. Like bunyaviruses, arenaviruses also lack a matrix protein, a characteristic of enveloped viruses. They mature by budding from the host cell plasma membrane. Arenaviruses cause persistent infection in rodents and are also transmitted to humans from the excreta of infected rodents.

EPIDEMIOLOGY

A common feature of the arenaviruses is their zoonotic reservoir, particularly small rodents, in which they may be sustained for long periods. Primary infection (horizontal transmission) in mature rodents often results in disease and death, whereas intrauterine or perinatal infection (vertical transmission) usually leads to chronic lifelong viremia with persistent shedding of virus into the feces, urine, and respiratory secretions. Although chronically infected rodents are somewhat tolerant to the virus (ie, infection is persistent without causing illness), they produce antibodies, and evidence of deleterious effects can be found in older hosts, usually in the form of immune complex glomerulonephritis. The viruses are perpetuated by vertical transmission from infected mothers to their offspring. When environmental contact becomes close, spread from the rodent reservoir to humans (and, in some instances, subhuman primates) can occur via aerosols; through exposure to infective urine, feces, or tissues; or directly by rodent bites. This contrasts with the arthropod spread of arboviruses.

CLINICAL DISEASE

Arenaviruses Associated With Hemorrhagic Fevers

The agents of arenavirus hemorrhagic fevers are transmitted from infected rodents to humans in the manner described earlier, although person-to-person spread by contact with secretions and body fluids also occurs readily. The viruses in this group include the South American hemorrhagic fever agents (the Junin virus, the cause of Argentinean hemorrhagic fever, and the Machupo virus, the cause of Bolivian hemorrhagic fever), Sabia virus (Brazilian hemorrhagic fever), Lassa virus, the cause of Lassa fever in West Africa, Chapare virus, the cause of Chapare (Bolivia) hemorrhagic fever and Lugo virus, the cause of Lujo (South Africa) hemorrhagic fever.

Arenaviruses have pathogenic and pathologic features similar to those described for the arboviruses that cause hemorrhagic fevers; however, the mechanism involved in the coagulation abnormalities is not understood. All are characterized by fever, usually accompanied by hemorrhagic manifestations, shock, neurologic disturbances, and bradycardia. Lassa fever also frequently causes hepatitis, myocarditis, exudative pharyngitis, and acute deafness. The last deficit may persist after recovery. Mortality rate is estimated to be 10% to 50% for Lassa fever and 5% to 30% for the other viruses. All are considered highly dangerous in terms of infectivity. Importation of cases to nonendemic areas has occurred, with significant risk of spread to medical and laboratory personnel.

The diagnosis of an arenavirus infection is suggested primarily by the recent travel history of the patient and the clinical syndrome. Although viral antibodies (IgM, IgG) and viral antigens (in some cases) by ELISA, viral RNA by RT-PCR, and virus isolation diagnosis may be performed, these procedures should not be attempted in a hospital diagnostic laboratory but in a containment laboratory facility. Any patient suspected of having such an infection should be immediately isolated and public health authorities notified. Because of the high risk of spread of infection from body fluids and excreta, even routine laboratory studies are best deferred until the diagnosis and proper disposition of specimens can be resolved. Viremia can persist 1 month, and virus shedding in the urine may continue more than 2 months after the onset of illness. Treatment is primarily supportive; however, intravenous ribavirin, if begun within 6 days of illness onset, has been shown to be helpful in Lassa fever.

Arenaviruses Associated With CNS Infections—Lymphocytic Choriomeningitis Virus

Infection with LCMV is particularly common in hamsters and mice. In the United States, most human illnesses have been traced to contact with rodent breeding colonies in research or pet supply centers and to pet hamsters in the home. The illness usually consists of fever, headache, and myalgia, although meningitis or meningoencephalitis also occurs occasionally. Such CNS infections may persist as long as 3 months. There is also evidence that transplacental infection can occur in humans, resulting in fetal death, hydrocephalus, or chorioretinitis. No person-to-person transmission of infection has been documented.

The diagnosis of lymphocytic choriomeningitis is suggested by a history of rodent contact. The virus may be isolated in the early stages of disease by cell culture or intracerebral inoculation of blood or CSF into weanling mice or young guinea pigs. Serologic testing of acute and convalescent sera is usually performed by indirect immunofluorescence. RT-PCR to detect viral RNA is also available.

FILOVIRUSES

VIROLOGY

Filoviruses come from the virus family Filoviridae that have two genera, Marburgvirus and Ebolavirus that cause Marburg and Ebola fevers, the two known highly fatal hemorrhagic fevers. Although no subtypes or species of Marburg virus has been found, Ebola virus exits as four subtypes (species), including Zaire, Sudan, Tai Forest (formerly known as Ivory Coast), and Reston (no known disease in humans). Filoviruses are enveloped, helical, single-stranded, negative-sense RNA viruses with filamentous and highly pleomorphic virions, averaging 80 nm in diameter and 300 to 14 000 nm in length (Figure 16–6). There are seven viral genes that are sequentially arranged on a 19 kb RNA genome. The NP has a helical symmetry, and the envelope is derived from plasma membrane as a result of budding. The envelope contains 10 nm peplomers or spikes, and the glycoprotein (GP), which mediates virus entry into susceptible cells.

Viral GP surface protein mediates virus entry into target cells. RNA-dependent RNA polymerase directs the synthesis of mRNA from a linear negative-sense RNA genome, like other negative-sense RNA viruses (rhabdoviruses, paramyxoviruses). Seven monocistronic mRNAs are generated followed by translation of viral proteins. Translation of NP triggers the switch from transcription to genome replication. The NP binds to the RNA genome to form the nucleocapsid, which is enclosed in a matrix protein and buds from plasma membrane containing viral GPs.

EPIDEMIOLOGY AND CLINICAL DISEASE: MARBURG AND EBOLA VIRUSES

The association of the Marburg virus with serious disease did not become apparent until 1967, when 26 cases of hemorrhagic fever occurred among persons in Germany and Yugoslavia who were handling a group of African monkeys imported from central Uganda. The agent was later identified as Marburg virus and was apparently transmitted by the infected monkeys. In 1975, the virus was associated with a similar disease in three travelers in South Africa, and in 1980 in Kenya.

In 1976, severe outbreaks of hemorrhagic fever occurred in northern Zaire and southern Sudan, with case fatality rates of 90% and 50%, respectively. The illnesses were similar to those described for Marburg virus, but were later shown to be caused by an antigenically different agent known as Ebola virus, named after a river in Zaire. In 1990, another filovirus (Reston) serologically related to Ebola virus was isolated from monkeys during an epizootic of simian hemorrhagic fever at a U.S. quarantine facility with no human infection. The reservoir was determined to be monkeys imported from the Philippines. However, in 1990 and 2008, few human asymptomatic cases with evidence of antibodies against the virus were reported. Reston-Ebola does not cause any disease in humans but could be the cause for disease in monkeys. In 1994, a scientist was infected with a new strain of Ebola virus, Ebola-Ivory Coast (Cote d’Ivoire), in Tai Forest (Cote d’Ivoire) from a chimpanzee’s autopsy and was successfully treated and survived. The latest and the largest outbreak in history started in West Africa in March 2014 that severely affected countries such as Guinea, Liberia, and Sierra Leone. It also affected several other countries with few cases through travelers such as Nigeria, Senegal, Spain, United States, Mali, United Kingdom, and Italy. In this long outbreak or epidemic that lasted almost 2 years reported 28 652 estimated and confirmed cases, 15 261 laboratory-confirmed cases, and 11 325 deaths. On March 31, 2016, WHO terminated the public health emergency concern (PHEIC) for the Ebola outbreak in West Africa. The average fatality rate is around 50% but has varied from 25% to 90% in previous outbreaks.

While filoviruses are zoonotic, it is not known how these viruses are primary transmitted from infected animals (fruit bats or primates like apes or monkeys or duikers) to humans. The reservoir, though uncertain, is thought to be in bats. After the virus is transmitted from animals to humans, person-to-person transmission is probably the way by which further infections occur (secondary transmission), most likely through direct contacts such as broken skin or mucous membranes in eyes, nose or mouth to blood or body fluids (urine, saliva, sweat, feces, vomit, breast milk, semen and others) of infected, sick or deceased persons. Sexual transmission (oral, vaginal or anal) and contaminated objects like needles and syringes have been shown. The incubation period is between 2 and 21 days (average 4-10 days) followed by flu-like illness characterized by fever, headache, joint and muscle pain, sore throat, diarrhea, vomiting, and stomach pain. In some patients, a purplish-red, maculopapular rash, hiccups, and internal and external bleeding are seen. Patients who develop severe disease have hemorrhages of the gastrointestinal tract and other sites, including shock and multi-organ failure. Numerous patients who die do not have a significant immune response at the time of death. However, some people recover from Ebola infection and mechanisms of recovery are not known, recovery is most likely related to patient’s immune response. Survivors had Ebola antibody response for 10 years. Some survivors have long-term complications like joint and eye problems. Ebola virus persists in semen for 3 to 9 months in some men and also in eye, amniotic fluid, placenta, breast milk and CNS.

The reasons why these viruses can cause such fulminant, lethal hemorrhagic disease with shock in humans are not entirely clear. There is evidence that Marburg virus replicates in vascular endothelial cells, with subsequent necrosis. Ebola virus replicates at a remarkably high rate shutting off the host cell synthesis and immune responses. Both innate and adaptive immunity is suppressed most likely due to infection of monocytes/macrophages and dendritic cells. Some studies have shown that Ebola virus may exert its effects via its GP, synthesized in either a secreted or transmembrane form. The secreted GP interacts with neutrophils to inhibit early activation of the inflammatory response and alter the innate immune response. The GP allows the virus to infect monocytes/macrophages and dendritic cells causing cell damage and cytokine release associated with inflammation and fever. Viral entry into reticuloendothelial cells causes damages to vascular integrity, including cytokines release, which contribute to exaggerated inflammatory responses that are not protective. There is damage to the liver, combined with massive viremia, leading to disseminated intravascular coagulopathy. The virus eventually infects microvascular endothelial cells and compromises vascular integrity. This contributes to the hemorrhagic fever because the virus targets the reticuloendothelial network and the lining of blood vessels. The terminal stages of Ebola virus infection usually include diffuse bleeding, and hypotensive shock accounts for many fatalities. Antibody titers against Ebola virus GPs are readily detectable in patients who recover from Ebola virus infection. Serosurveys of humans residing in the areas where outbreaks have occurred suggest that human infections may be relatively common; as much as 7% of the survey group had antibodies, indicating past infection. In symptomatic infections, the mortality rate for both Marburg and Ebola viruses is extremely high but higher for Zaire-Ebola virus (50-90%) than other species of Ebola viruses or Marburg viruses.

The diagnosis of infection by these agents is suggested by symptoms and recent travel history. Person-to-person transmission occurs in Ebola virus infections and may be possible with Marburg virus. Diagnosis can be confirmed in a reference center by isolation of virus, antigen capture by ELISA, IgM antibody detection by ELISA and genome amplification by RT-PCR. The virus can be identified in specimens from deceased patients by immunofluorescence or RT-PCR. However, as with the arenavirus-associated hemorrhagic fevers, utmost care in isolation precautions and prompt notification of public health authorities are mandatory for suspected cases before any diagnostic attempts are made. There is no specific therapy for the infections. Supportive care is recommended. There is no vaccine but research is underway to understand the mechanisms of immunity in Ebola virus infection.

HANTAVIRUSES

Hantavirus, a negative-sense RNA, enveloped virus, is the only Bunyavirus that is a nonarthropod-transmitted zoonotic virus. Other bunyaviruses are arboviruses that are discussed in the previous section. Hantaviruses have several species that cause different diseases based on geographic distribution, including the old world hantavirus causing the hemorrhagic fever with renal syndrome (HFRS) found across the world and the new world species of hantavirus (Sin Nombre virus) causing hantavirus pulmonary syndrome (HPS) found in the United States.

Hantavirus Hemorrhagic Fever With Renal Syndrome

The hantavirus causing hemorrhagic fever with renal syndrome (HFRS) includes disease such as Korean hemorrhagic fever (KHF), epidemic hemorrhagic fever, and nephropathia epidemica. These hantavirus species are Hantaan, Dobrava, Saaremaa, Seoul, and Puumala. These viruses are distributed or are endemic in various countries, including Asia, Western and Central Europe, Scanvandia, and the Balkins (Table 16-2). It is an important cause of hemorrhagic fever, often complicated by varying degrees of acute renal failure. In the 1950s, thousands of military personnel developed the disease during the Korean War and given the name Korean hemorrhagic fever (KHF). The first reported isolation of KHF was in 1978, when the antigen was detected in the lung tissues of wild rodents (Apodemus species) by indirect immunofluorescence using convalescent sera from affected patients. No illness was apparent in the rodents, suggesting a reservoir mechanism and mode of transmission like those described for the arenaviruses.

The virus is transmitted through inhalation of excreta of the rodents by the conjunctival route or by direct contact with skin breaks. People may also be infected with aerosolized urine, droppings, or saliva of infected rodents or after exposure to dust from their nests. Rodents’ bite has also been reported to transmit the virus. The incubation period is 1 to 2 weeks, and initial symptoms are headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Patients later develop low blood pressure, acute shock, vascular leakage, and acute renal failure. The severity of the disease also depends on the species, with Hantaan and Dobrava causing severe disease, whereas Seoul, Saaremaa, and Puumala cause moderate disease. Recovery takes weeks or months. The fatality rate for Hantaan is 5% to 15% and for other species is less than 1%.

Diagnosis is performed through serology (IgM), viral antigen or viral RNA (RT-PCR). Treatment is supportive with fluid and electrolyte balance and management of other underlying condition. Dialysis may be required to correct fluid overload. Intravenous ribavirin has shown some benefits, if used early in infection. There is no vaccine. Contact with rodents should be avoided to prevent infection.

Other Hantavirus Infections: Hantavirus Pulmonary Syndrome

It has been known for some time that rodents in the United States may be infected with a Hantavirus, but no associated human disease was recognized. In early 1993, an outbreak of fulminant respiratory disease with high mortality (around 56%) occurred in the Southwestern United States. This syndrome (hantavirus pulmonary syndrome, or HPS) has been related to at least three Hantaviruses, of which Sin Nombre virus is the most common. The host of the Sin Nombre virus is the deer mouse (Peromyscus maniculatus) found in the western and central United States and Canada. Several other species of Hantaviruses can cause HPS in the United States, including the New York hantavirus (host: white footed mouse) in the Northeastern United States and Black Creek hantavirus (host: cotton rat) in the Southeastern United States. Infections are associated with an increased population of infected mice in and around human habitations. From 1993 to 2016, active surveillance in the United States has documented over 690 cases that have occurred in residents of 34 states, with most having been acquired in the Southwest region. Overall the average mortality rate from 1993 to 2106 is around 36%. Hantaviruses causing HPS has been reported in Canada and South America, including Argentina, Bolivia, Brazil, Chile, Panama, Paraguay, and Uruguay.

The virus is believed to be transmitted to humans most often by inhalation of infectious rodent excreta, by the conjunctival route, or by direct contact with skin breaks. Human-to-human spread has not been encountered. The incubation period may be between 1 and 5 weeks followed by early symptoms, including fever, fatigue, chills, headaches, aches in large muscle group (thighs, hips, back, shoulder), abdominal problems (vomiting, diarrhea). The second phase of the HPS starts 4 to 10 days after early symptoms that include coughing, shortness of breath, and heaviness around the chest as lungs fill with fluid (Figure 16–7). The diagnosis is done on clinical grounds. There is no specific treatment or vaccine for HPS. Treatment has involved aggressive respiratory support in intensive care unit. Public health measures to inform inhabitants of routes of spread and to reduce the rodent population appear to have controlled the outbreak. While intravenous ribavirin has shown some benefit in HFRS (Korean hemorrhagic fever), but no evidence of efficacy in US strains causing HPS. As noted, the mortality rate is high around 38%.

ORTHOMYXOVIRUSES

Avian and animal (pigs and horses) influenza viruses may infect humans. In the past 10 years, avian influenza viruses (bird flu), including H5N1, H7N2, H7N3, H7N7, H9N2, and H9N7, and pig reassortant influenza virus (H1N1 in 2009) have been documented to cause infections in humans. See Chapter 9 for avian influenza virus pathogenesis.

HENIPAVIRUSES

Two zoonotic paramyxoviruses involving humans and animals appeared in Australia and Southeast Asia during the late 1990s. These are Hendra and Nipah viruses, now classified in the Henipavirus genus of the Paramyxoviridae family.

Hendra virus has been detected in Australia in two small outbreaks involving horses that also affected humans. The human cases were characterized by pneumonia and encephalitis. However, large Nipah virus outbreaks have occurred in India, Bangladesh, Malaysia, and Singapore, affecting pigs, dogs, and humans. The human illnesses were similar to Hendra virus, as were outcomes (more than 50% fatality rate for both). The reservoir of henipaviruses is the Pteropus species of fruit bats (“flying foxes”) and spread to humans and animals occurs via aerosols.

VESICULAR STOMATITIS VIRUS

A rhabdovirus, vesicular stomatitis virus causes outbreaks of disease in cattle, pigs, and horses that can be transmitted between animals by arthropods. Human infection is acquired by contact with infected animals, but is unusual; it consists of a self-limited febrile illness and occasional herpes-like eruptions over the lips and oral mucosa.