Clinical Findings & Epidemiology
Arboviruses That Cause Disease in the United States
Eastern Equine Encephalitis Virus
Western Equine Encephalitis Virus
St. Louis Encephalitis Virus
California Encephalitis Virus
Colorado Tick Fever Virus
West Nile Virus
Important Arboviruses that Primarily Cause Disease Outside the United States
Yellow Fever Virus
Summaries of Organisms
Practice Questions: USMLE & Course Examinations
Arbovirus is an acronym for arthropod-borne virus and highlights the fact that these viruses are transmitted by arthropods, primarily mosquitoes and ticks. It is a collective name for a large group of diverse viruses, more than 600 at last count. In general, they are named either for the diseases they cause (e.g., yellow fever virus) or for the place where they were first isolated (e.g., St. Louis encephalitis virus).
A new group of viruses called roboviruses has recently emerged. The term robo refers to the fact that these viruses are rodent-borne (i.e., they are transmitted directly from rodents to humans without an arthropod vector). Transmission occurs when dried rodent excrement is inhaled into the human lung, as when sweeping the floor of a cabin. Two roboviruses cause a respiratory distress syndrome that is often fatal: Sin Nombre virus (a hantavirus) and Whitewater Arroyo virus (an arenavirus). These viruses are described in Chapter 46.
Most arboviruses are classified in three families,1 namely, togaviruses, flaviviruses, and bunyaviruses (Table 42–1).
TABLE 42–1 Classification of Major Arboviruses
(1) Togaviruses2 are characterized by an icosahedral nucleocapsid surrounded by an envelope and a single-stranded, positive-polarity RNA genome. They are 70 nm in diameter, in contrast to the flaviviruses, which are 40 to 50 nm in diameter (see later). Togaviruses are divided into two families, alphaviruses and rubiviruses. Only alphaviruses are considered here. The only rubivirus is rubella virus, which is discussed in Chapter 39.
(2) Flaviviruses3 are similar to togaviruses in that they also have an icosahedral nucleocapsid surrounded by an envelope and a single-stranded, positive-polarity RNA genome, but the flaviviruses are only 40 to 50 nm in diameter, whereas the togaviruses have a diameter of 70 nm.
(3) Bunyaviruses4 have a helical nucleocapsid surrounded by an envelope and a genome consisting of three segments of negative-polarity RNA that are hydrogen-bonded together.
The life cycle of the arboviruses is based on the ability of these viruses to multiply in both the vertebrate host and the bloodsucking vector (Figure 42–1). For effective transmission to occur, the virus must be present in the bloodstream of the vertebrate host (viremia) in sufficiently high titer to be taken up in the small volume of blood ingested during an insect bite. After ingestion, the virus replicates in the gut of the arthropod and then spreads to other organs, including the salivary glands. Only the female of the species serves as the vector of the virus, because only she requires a blood meal in order for progeny to be produced. An obligatory length of time, called the extrinsic incubation period,5 must pass before the virus has replicated sufficiently for the saliva of the vector to contain enough virus to transmit an infectious dose. For most viruses, the extrinsic incubation period ranges from 7 to 14 days.
FIGURE 42–1 Arbovirus transmission cycle. Arboviruses typically cycle between the vertebrate reservoir host, often a bird, and the vector, often a mosquito. The infected vector can also bite other hosts, such as humans and horses, which are “dead-end” hosts because their viremia is too low to provide the vector with an infectious dose. (Modified from provider: Centers for Disease Control and Prevention.)
In addition to transmission through vertebrates, some arboviruses are transmitted by vertical “transovarian” passage from the mother tick to her offspring. Vertical transmission has important survival value for the virus if a vertebrate host is unavailable.
Humans are involved in the transmission cycle of arboviruses in two different ways. Usually, humans are dead-end hosts, because the concentration of virus in human blood is too low and the duration of viremia is too brief for the next bite to transmit the virus. However, in some diseases (e.g., yellow fever and dengue), humans have a high-level viremia and act as reservoirs of the virus.
Infection by arboviruses usually does not result in disease either in the arthropod vector or in the vertebrate animal that serves as the natural host. Disease occurs primarily when the virus infects dead-end hosts. For example, yellow fever virus cycles harmlessly among the jungle monkeys in South America, but when the virus infects a human, yellow fever can occur.
Clinical Findings & Epidemiology
The diseases caused by arboviruses range in severity from mild to rapidly fatal. The clinical picture usually fits one of three categories: (1) encephalitis; (2) hemorrhagic fever; or (3) fever with myalgias, arthralgias, and nonhemorrhagic rash. The pathogenesis of these diseases involves not only the cytocidal effect of the virus, but also, in some, a prominent immunopathologic component. After recovery from the disease, immunity is usually lifelong.
The arboviral diseases occur primarily in the tropics but are also found in temperate zones such as the United States and as far north as Alaska and Siberia. They have a tendency to cause sudden outbreaks of disease, generally at the interface between human communities and jungle or forest areas.
ARBOVIRUSES THAT CAUSE DISEASE IN THE UNITED STATES
Eastern Equine Encephalitis Virus
Of the four encephalitis viruses listed in Table 42–2, eastern equine encephalitis (EEE) virus causes the most severe disease and is associated with the highest fatality rate (approximately 50%). In its natural habitat, the virus is transmitted primarily by the swamp mosquito, Culiseta, among the small wild birds of the Atlantic and Gulf Coast states. Species of Aedes mosquitoes are suspected of carrying the virus from its wild bird reservoir to the principal dead-end hosts, horses and humans. The number of cases of human encephalitis caused by EEE virus in the United States usually ranges from zero to four per year, but outbreaks involving hundreds of cases also occur. Subclinical infections greatly exceed the number of overt cases.
TABLE 42–2 Epidemiology of Important Arbovirus Diseases in the United States
The encephalitis is characterized by the sudden onset of severe headache, nausea, vomiting, and fever. Changes in mental status, such as confusion and stupor, ensue. A rapidly progressive downhill course with nuchal rigidity, seizures, and coma occurs. If the patient survives, the central nervous system sequelae are usually severe. Immunity following the infection is lifelong.
The diagnosis is made by either isolating the virus or demonstrating a rise in antibody titer. Clinicians should have a high index of suspicion in the summer months in the appropriate geographic areas. The disease does not occur in the winter because mosquitoes are not active. It is not known how the virus survives the winter—in birds, mosquitoes, or perhaps some other animal.
No antiviral therapy is available. A killed vaccine is available to protect horses but not humans. The disease is too rare for production of a human vaccine to be economically feasible.
Western Equine Encephalitis Virus
Western equine encephalitis (WEE) virus causes disease more frequently than does EEE virus, but the illness is less severe. Inapparent infections outnumber the apparent by at least 100:1. The number of cases in the United States usually ranges between 5 and 20 per year, and the fatality rate is roughly 2%.
The virus is transmitted primarily by Culex mosquitoes among the wild bird population of the western states, especially in areas with irrigated farmland.
The clinical picture of WEE virus infection is similar but less severe than that caused by EEE virus. Sequelae are less common. The diagnosis is made by isolating the virus or observing a rise in antibody titer. There is no antiviral therapy. There is a killed vaccine for horses but not for humans.
St. Louis Encephalitis Virus
St. Louis encephalitis (SLE) virus causes disease over a wider geographic area than do EEE and WEE viruses. It is found in the southern, central, and western states and causes 10 to 30 cases of encephalitis per year in the United States.
The virus is transmitted by several species of Culex mosquitoes that vary depending on location. Again, small wild birds, especially English sparrows, are the reservoir, and humans are dead-end hosts. Although EEE and WEE viruses are predominantly rural, SLE virus occurs in urban areas because these mosquitoes prefer to breed in stagnant wastewater.
SLE virus causes moderately severe encephalitis with a fatality rate that approaches 10%. Most infections are inapparent. Sequelae are uncommon.
The diagnosis is usually made serologically, because the virus is difficult to isolate. No antiviral therapy or vaccine is available.
California Encephalitis Virus
California encephalitis (CE) virus was first isolated from mosquitoes in California in 1952, but its name is something of a misnomer because most human disease occurs in the north-central states. The strain of CE virus that causes encephalitis most frequently is called La Crosse for the city in Wisconsin where it was isolated. CE virus is the only one of the four major encephalitis viruses in the United States that is a member of the bunyavirus family.
La Crosse virus is transmitted by the mosquito Aedes triseriatus among forest rodents. The virus is passed transovarially in mosquitoes and thus survives the winter when mosquitoes are not active. The clinical picture can be mild, resembling enteroviral meningitis, or severe, resembling herpes encephalitis. Death rarely occurs. Diagnosis is usually made serologically rather than by isolation of the virus. No antiviral therapy or vaccine is available.
Colorado Tick Fever Virus
Of the five diseases described in Table 42–2, Colorado tick fever (CTF) is the most easily distinguished from the others, both biologically and clinically. CTF virus is a reovirus transmitted by the wood tick Dermacentor andersoni among the small rodents (e.g., chipmunks and squirrels) of the Rocky Mountains. There are approximately 100 to 300 cases per year in the United States.
The disease occurs primarily in people hiking or camping in the Rocky Mountains and is characterized by fever, headache, retro-orbital pain, and severe myalgia. The diagnosis is made either by isolating the virus from the blood or by detecting a rise in antibody titer. No antiviral therapy or vaccine is available. Prevention involves wearing protective clothing and inspecting the skin for ticks.
West Nile Virus
West Nile virus (WNV) caused an outbreak of encephalitis in New York City and environs in July, August, and September 1999. This is the first time WNV caused disease in the United States. In this outbreak, there were 27 confirmed cases and 23 probable cases, including 5 deaths. Many birds, especially crows, died as well. No human cases occurred after area-wide spraying of mosquito-control compounds and the onset of cooler weather.
In the summer of the year 2000, there were 18 cases and 1 death, and by July 2001, the virus had spread to many states along the East Coast (from New Hampshire to Florida) and as far west as Louisiana. In 2002, there was a marked increase in the number of cases. There were more than 4000 cases, 274 people died, and the virus had spread as far west as Colorado. In 2003, there were 7700 cases, of whom 166 died, and the virus had spread to California. In 2012, there were 3142 reported cases and 134 deaths. WNV has caused the highest number of deaths due to a mosquito-borne encephalitis in the United States. It is not known how WNV entered the United States, but either an infected traveler or an infected mosquito brought by an airplane seems likely to be involved.
WNV is a flavivirus that is classified in the same antigenic group as SLE virus. It is endemic in Africa but has caused encephalitis in areas of Europe and Asia as well. Wild birds are the main reservoir of this virus, which is transmitted by mosquitoes, especially Culex species. Humans are dead-end hosts. Transmission of the virus via solid organ transplants has also occurred.
The most important clinical picture is encephalitis with or without signs of meningitis, typically in a person over 60 years of age. Encephalitis occurs in about 1% of infections, fever and headache without encephalitis occur in about 20%, and roughly 80% of infections are asymptomatic.
The laboratory diagnosis can be made by either isolation of the virus from brain tissue, blood, or spinal fluid or by detection of antibodies in spinal fluid or blood. Polymerase chain reaction (PCR)–based assays are also available. No antiviral therapy or vaccine is available. In an attempt to prevent blood-borne transmission, blood banks screen donated blood for the presence of WNV using nucleic acid probes specific for the virus.
IMPORTANT ARBOVIRUSES THAT PRIMARILY CAUSE DISEASE OUTSIDE THE UNITED STATES
Although yellow fever and dengue are not endemic in the United States, extensive travel by Americans to tropical areas means that imported cases occur. It is reasonable, therefore, that physicians in the United States be acquainted with these two diseases. Both yellow fever virus and dengue virus are classified as flaviviruses. Table 42–3 describes the epidemiology of the important arboviral diseases that occur primarily outside the United States. Japanese encephalitis virus, also a flavivirus and an important cause of epidemic encephalitis in Asia, is described in Chapter 46.
TABLE 42–3 Epidemiology of Important Arboviral Diseases Outside the United States
Yellow Fever Virus
As the name implies, yellow fever is characterized by jaundice and fever. It is a severe, life-threatening disease that begins with the sudden onset of fever, headache, myalgias, and photophobia. After this prodrome, the symptoms progress to involve the liver, kidneys, and heart. Prostration and shock occur, accompanied by upper gastrointestinal tract hemorrhage with hematemesis (“black vomit”). Diagnosis in the laboratory can be made either by isolating the virus or by detecting a rise in antibody titer. No antiviral therapy is available, and the mortality rate is high. If the patient recovers, no chronic infection ensues and lifelong immunity is conferred.
Yellow fever occurs primarily in the tropical areas of Africa and South America. In the epidemiology of yellow fever, two distinct cycles exist in nature, with different reservoirs and vectors.
(1) Jungle yellow fever is a disease of monkeys in tropical Africa and South America; it is transmitted primarily by the treetop mosquitoes of the Haemagogus species. Monkeys are the permanent reservoir, whereas humans are accidental hosts. Humans (e.g., tree cutters) are infected when they enter the jungle occupationally.
(2) In contrast, urban yellow fever is a disease of humans that is transmitted by the mosquito Aedes aegypti, which breeds in stagnant water. In the urban form of the disease, humans are the reservoir. For effective transmission to occur, the virus must replicate in the mosquito during the 12- to 14-day extrinsic incubation period. After the infected mosquito bites the person, the intrinsic incubation period is 3 to 6 days.
Prevention of yellow fever involves mosquito control and immunization with the vaccine containing live, attenuated yellow fever virus. Travelers to and residents of endemic areas should be immunized. Protection lasts up to 10 years, and boosters are required every 10 years for travelers entering certain countries. Epidemics still occur in parts of tropical Africa and South America. Because it is a live vaccine, it should not be given to immunocompromised people or to pregnant women.
Although dengue is not endemic in the United States, some tourists to the Caribbean and other tropical areas return with this disease. In recent years, there were 100 to 200 cases per year in the United States, mostly in the southern and eastern states. No indigenous transmission occurred within the United States. It is estimated that about 20 million people are infected with dengue virus each year worldwide. Dengue is the most common insect-borne viral disease in the world.
Classic dengue (breakbone fever) begins suddenly with an influenzalike syndrome consisting of fever, malaise, cough, and headache. Severe pains in muscles and joints (breakbone) occur. Enlarged lymph nodes, a maculopapular rash, and leukopenia are common. After a week or so, the symptoms regress but weakness may persist. Although unpleasant, this typical form of dengue is rarely fatal and has few sequelae.
In contrast, dengue hemorrhagic fever is a much more severe disease, with a fatality rate that approaches 10%. The initial picture is the same as classic dengue, but then shock and hemorrhage, especially into the gastrointestinal tract and skin, develop. Dengue hemorrhagic fever occurs particularly in southern Asia, whereas the classic form is found in tropical areas worldwide.
Hemorrhagic shock syndrome is due to the production of large amounts of cross-reacting antibody at the time of a second dengue infection. The pathogenesis is as follows: The patient recovers from classic dengue caused by one of the four serotypes, and antibody against that serotype is produced. When the patient is infected with another serotype of dengue virus, an anamnestic, heterotypic response occurs, and large amounts of cross-reacting antibody to the first serotype are produced. There are two hypotheses about what happens next. One is that immune complexes composed of virus and antibody are formed that activate complement, causing increased vascular permeability and thrombocytopenia. The other is that the antibodies increase the entry of virus into monocytes and macrophages, with the consequent liberation of a large amount of cytokines. In either scenario, shock and hemorrhage result.
Dengue virus is transmitted by the A. aegypti mosquito, which is also the vector of yellow fever virus. Humans are the reservoir for dengue virus, but a jungle cycle involving monkeys as the reservoir and other Aedes species as vectors is suspected.
The diagnosis can be made in the laboratory either by isolation of the virus in cell culture or by serologic tests that demonstrate the presence IgM antibody or a fourfold or greater rise in antibody titer in acute and convalescent sera. A PCR assay that detects virus in the blood is also available.
No antiviral therapy or vaccine for dengue is available. Outbreaks are controlled by using insecticides and draining stagnant water that serves as the breeding place for the mosquitoes. Personal protection includes using mosquito repellent and wearing clothing that covers the entire body.
1. An outbreak of dengue hemorrhagic fever (DHF) recently occurred in two Central American countries. Regarding dengue and DHF, which one of the following is the most accurate?
(A) Humans are dead-end hosts for dengue virus.
(B) DHF occurs primarily in individuals who are deficient in the late-acting complement components.
(C) Dengue virus is transmitted by Aedes mosquitoes, and monkeys are an important natural reservoir.
(D) The vaccine containing live, attenuated dengue virus is recommended for those living or traveling in endemic areas.
(E) DHF occurs more often in people infected for the first time than when they are reinfected because antibody protects against reinfection.
2. Yellow fever still exists in many tropical areas of the globe. Which one of the following is the best reason yellow fever still exists?
(A) Sewage disposal is inadequate in many areas.
(B) Both humans and monkeys are reservoirs for yellow fever virus.
(C) The virus has mutated, so the existing vaccine is no longer effective.
(D) The vaccine has been withdrawn because it was found to have unacceptable side effects.
(E) The people in developing countries cannot afford to take amantadine when they enter endemic areas.
3. Regarding West Nile virus (WNV), which one of the following is the most accurate?
(A) Rodents are the main reservoir for WNV.
(B) WNV does not cause disease in the United States.
(C) WNV is transmitted primarily by Ixodes ticks.
(D) Most infections are asymptomatic, but the elderly are at risk for encephalitis.
(E) The live, attenuated vaccine should be administered to elderly adults in endemic areas.
SUMMARIES OF ORGANISMS
Brief summaries of the organisms described in this chapter begin on page 648. Please consult these summaries for a rapid review of the essential material.
PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS
Questions on the topics discussed in this chapter can be found in the Clinical Virology section of PART XIII: USMLE (National Board) Practice Questions starting on page 703. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.
1A few arboviruses belong to two other families. For example, Colorado tick virus is a reovirus; Kern Canyon virus and vesicular stomatitis virus are rhabdoviruses.
2Toga means cloak.
3Flavi means yellow, as in yellow fever.
4“Bunya” is short for Bunyamwera–the town in Africa where the prototype virus was located.
5The intrinsic incubation period is the interval between the time of the bite and the appearance of symptoms in the human host.