ARTHROPOD-BORNE ZOONOTIC ARBOVIRUSES Overview
Arboviruses are transmitted to humans through insects (arthropods) bite tropic to CNS, liver or small blood vessels and cause encephalitis, meningitis, hemorrhage or febrile illness. These RNA viruses come from viral families such as togaviruses, flaviviruses, bunyaviruses, and reoviruses. In case of CNS infection, there is a severe inflammation of the brain (encephalitis) with damage or destruction of neural cells that may be fatal or lead to permanent neurologic damage in survivors. These viruses include West Nile virus (WNV), St. Louis encephalitis virus, California virus, and Japanese B encephalitis virus. One of these viruses, WNV, has a wide disease spectrum, including no symptoms, flu-like symptoms, gastrointestinal symptoms to CNS infection such as meningitis, meningoencephalitis, and poliomyelitis. Some viruses such as dengue viruses can produce illnesses that range from mild flu-like symptoms to overwhelming shock with widespread hemorrhage into tissues, whereas others such as yellow fever virus primarily attacks liver cells leading to extensive destruction and sometimes fatal liver failure. Immunity is serotype specific. Diagnosis is done by RT-PCR or EIA. There is no specific treatment or vaccine for most of these viral infections. However, vaccines for yellow fever virus and western and eastern equine encephalitis and some other arboviruses are available but not routinely used.
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.
Virion structure of alphavirus. The single-stranded, positive-sense RNA genome is encapsidated into an icosahedral capsid (C protein) wrapped by a lipid bilayer envelope (viral membrane) containing viral-encoded glycoproteins (spikes), E1 and E2 with an external diameter of 70 nm. E1 has the ability to hemagglutinate via fusion to lipids on erythrocyte membrane and E2 also participates in this process.
Alphavirus genus of Togaviruses includes most arboviruses
✺ Positive-sense RNA viruses that have icosahedral capsid and lipid bilayer envelope
Envelope contains glycoproteins that are hemagglutinin and lipoproteins
Replicates in the cytoplasm of the infected cells
Full-length RNA encodes nonstructural proteins and subgenomic RNA encodes structural proteins
✺ Usually causes persistent infection in arthropods but acute infection in humans
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.
Virion structure of flavivirus. Two types of virions, intracellular and extracellular virions, are shown. The positive-sense, single-stranded RNA genome is packaged into an icosahedral capsid wrapped into a lipid bilayer envelope containing membrane (M) protein and spike glycoprotein (E). The prM is the precursor to M protein. The size of flavivirus virion ranges from 40 to 50 nm in diameter. There are two major differences between intracellular and extracellular virions; intracellular virions have only prM and E as monomer, whereas extracellular virions have prM and M and E as dimer.
Flavivirus genus comprises arboviruses
✺ Enveloped, positive-sense RNA, icosahedral capsid viruses
Replicates in the cytoplasm
Genomic RNA translated into a polyprotein that is cleaved into individual proteins
✺ Lytic infection in vertebrates and persistent infection in invertebrates
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).
Bunyavirus virion structure. The virions of bunyaviruses contain single-stranded, negative-sense RNA viruses that are spherical and enveloped with an external diameter of 90 to 100 nm. The envelope contains two glycoproteins, G1 and G2, and encloses 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).
Four genera, three arboviruses and one nonarthropod zoonotic virus
Enveloped, single-stranded, negative-sense or ambisense RNA viruses
Three helical nucleocapsids containing RNA: large (L), medium (M), and small (S)
✺ Replicates in the cytoplasm; ambisense RNA uses negative-sense RNA strategies for replication
M segment encodes the envelope glycoproteins (G1 and G2), L segment encodes the viral RNA polymerase, and S segment encodes the nucleocapsid (N) protein
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.
Colorado tick fever is prominent in North America
✺ Colorado tick fever is the only reovirus transmitted by ticks to humans
Naked capsid, double-stranded RNA viruses replicate in the cytoplasm
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.
Sometimes maintained by vertical transmission in vector
Multiplication in vector is required
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.
Sustained viremia required for vertebrate host to be significant reservoir for transmission
Why are arboviruses not pathogenic to insects or some lower vertebrate reservoirs but pathogenic to humans?
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.
Season-to-season survival has multiple mechanisms
✺ Three basic specific cycles of arbovirus transmission include urban, sylvatic, and arthropod sustained
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.
Urban cycle exists with dengue and yellow fever
In the sylvatic cycle, a single nonhuman vertebrate reservoir may be involved.
Think ➪ Apply 16-1. Arboviruses are less pathogenic in insects and some lower vertebrates than humans because of low level of viral replication and less cytopathic effects in these reservoirs.
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.
Sylvatic cycle occurs with many viruses
Humans are tangential hosts
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.
Arthropod sustained by tick transovarial transmission
✺ Weather, swamps, and ponds alter conditions
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.
Mosquito increases create risk for blind-end human infection
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.
✺ CNS, visceral, and hemorrhagic fever are major syndromes
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.
After bite and initial viral replication, viremia and viral tissue tropism define disease
✺ In CNS, aseptic meningitis and encephalitis follow cell injury
How does arboviruses cause viremia in humans after a mosquito bite?
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.
Liver often the target, with necrosis of hepatocytes
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.
✺ Dengue hemorrhagic fevers involve perivascular and endothelial injury, may progress to shock
Lymphoid hyperplasia seen
Virus–antibody complexes may trigger complement activation
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.
✺ Antigenically related serotypes generate group specific cross-reacting antibodies that are not protective against other serotypes but may enhance infection
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.
Typical patterns of antibody response after arbovirus infection. These patterns begin to appear about 3 days after onset and decline after about 6 weeks. HI, hemagglutination inhibition antibodies; IgM, immunoglobulin M antibodies.
✺ Serotype specific neutralizing antibodies protective and last for years
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.
Human and equine illness
Prevalent in the Western United States, outbreaks in the Midwestern United States
✺ Encephalitis is more likely in young infants
Think ➪ Apply 16-2. Arbovirus is transmitted through mosquito bite and replicates in the skin Langerhans cells to amplify its inoculum followed by replication in mononuclear cells and viremia.
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.
New England to South America
Mosquito vector feeds on horses and birds
Occasional outbreaks in humans with encephalitis in all ages
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%.
✺ Major cause of arboviral encephalitis in the United States with highest attack rates among adults above the age of 40 years
Prevalent in eastern, central, and southern United States
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.
✺ La Crosse virus distributed in the Midwestern United States
Virus and vector common in suburban and rural areas
Mosquito vector and chipmunk reservoir host
✺ Highest attack rate in those aged 5 to 18 years
✺ Abrupt onset of encephalitis and frequent seizures
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).
Transmission is by mosquito bites similar to St. Louis and western equine encephalitis
Less than 1% of infected people develop clinical disease
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.
First appeared in United States in 1999
Most important arbovirus in North America
Distributed throughout Africa, Asia the Middle East, parts of Europe, the former USSR, North and South America, 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.
Transmission vector: Mosquito; principal vertebrate host: Bird
✺ Transmitted from mosquitoes to humans and other animals
Dead crows often herald spread of virus in nature
✺ Incubation period: 2 to 14 days (average 2-6 days)
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.
✺ WNV infection is asymptomatic (80%), West Nile fever (20%), or severe West Nile disease (less than 1%)
✺ Rash appears in half of the cases of West Nile fever and disease runs its course (3-6 days)
✺ Severe West Nile disease includes aseptic meningitis, meningoencephalitis, encephalitis, or West Nile poliomyelitis
✺ Serious illness in people above the age of 50 years and the immunocompromised
How does West Nile virus damage the CNS?
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.
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.
Widespread in tropical areas
Vector persists in United States
✺ Sudden onset of fever, chills, headache, and hemorrhage
✺ Patients may progress to vomiting, bradycardia, jaundice, and shock
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.
Distributed worldwide with 100 endemic countries
About 100 million people infected annually
Mosquito vector (A aegypti) same as yellow fever
✺ High fever, rash, and severe pain in back, head, eye, muscles, and joints
Think ➪ Apply 16-3. The CNS inflammation due to West Nile virus may be due to viral-induced cytopathic effects and cytokines-mediated damage.
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.
Severe form results in shock, pleural effusion, severe abdominal pain, and hemorrhage
✺ Lifelong immunity is serotype specific
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.
Cross-immunity to other serotypes short-term and incomplete
✺ Subsequent infections with other serotypes increase severity of dengue disease
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 identified in a monkey in 1947 and in humans in 1952
Zika is distributed in Central and South America, the Caribbean, the Pacific Islands, Puerto Rico, and the United States
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).
Transmitted through mosquito (Aedes agypti) bite, incubation period 2-14 days
Many infected people remain asymptomatic
✺ Symptoms of Zika infection are fever, rash, joint pain, muscle pain, headache, conjunctivitis
✺ Women infected during pregnancy have increased risks of infants with birth defects such as microcephaly
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.
✺ Risk of Gullain-Barre syndrome (GBS) in infected adults
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.
✺ Pathogenesis involves interaction with immune cells
✺ Diagnosis by RT-PCR (viral RNA) and/or IgM (serology)
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.
Major problem in Asia and Africa
Risk to tourists traveling in endemic areas
✺ Fever, accompanied by excruciating myalgia and polyarthritis
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.
Tick borne, but uncertain human importance
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.
Tick borne, throughout western United States
Most infections asymptomatic
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.
Blood is best source but must be early in disease
Diagnosis by IgM followed by IgG in acute and convalescent serum
Viral RNA by RT-PCR is detected for diagnosis and/or confirmation
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.
Treatment is supportive only
Protection from bites and vector control are primary prevention
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.
Yellow fever, TBEV, and Japanese B encephalitis vaccines are available