Lyle R. Petersen MD, MPH1
Deputy Director for Science
Duane J. Gubler SC.D2
1Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention
2Department of Microbiology, Colorado State University; Adjunct Professor, Department of International Health, The Johns Hopkins University School of Public Health; Director, Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention
Lyle R. Petersen, M.D., M.P.H., has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Duane J. Gubler, Sc.D., has received grants for educational activities from Novartis Pharmaceutical Corp., Sanofi Pasteur SA, and Hawaii Biotech, Inc.
Zoonoses are human diseases caused by pathogens that normally infect animals. About 534 zoonotic viruses from eight taxonomic families have been identified, 120 of which are known to cause human illness [see Tables 1 and 2]. The natural hosts of zoonotic viruses are usually unaffected by the viruses. Infection in humans may cause no obvious illness, a nonspecific viral syndrome, or more severe illness that generally falls into one of three categories: hemorrhagic fever, encephalitis, or rash arthralgia [see Table 1].
Table 1 Important Viral Zoonoses That Cause Human Disease
Table 2 Principal Hantaviruses That Cause Human Disease
Transmission of Zoonotic Viruses
Zoonotic viruses replicate in the reservoir animal host and are usually transmitted to humans by direct contact or the bite of a hematophagous (blood-sucking) arthropod. Transmission by direct contact normally involves a bite by the infected reservoir animal or handling of the animal's tissues or materials contaminated by the animal's body fluids. Most viral zoonoses require a blood-sucking arthropod for transmission to humans. Mosquitoes are the most important arthropod vectors, followed by ticks, sandflies, and midges. Arthropod vector-borne viruses are called arboviruses and are maintained in complex life cycles involving a nonhuman primary vertebrate host and a primary arthropod vector [see Figure 1]. The arthropod vector usually becomes infected when it ingests virus while feeding on the blood of a viremic animal. Virus replicates in the arthropod tissues, ultimately infecting the salivary glands. The arthropod then transmits the virus to a new host when it injects infective salivary fluid while taking a blood meal. This extrinsic incubation period (i.e., the time between ingestion and transmission of the virus) is usually 8 to 12 days, depending on environmental factors, the virus, and the vector species.
Figure 1. Generalized arbovirus maintenance cycle.
Arthropod-borne viruses generally remain undetected until humans encroach on the natural enzootic focus or until the virus escapes the primary cycle via a secondary vector or vertebrate host [see Figure 1]. Although humans may become ill, they are generally considered dead-end hosts because they do not develop sufficient viremia to infect feeding vectors and thus do not contribute to the transmission cycle. Notable exceptions include dengue, yellow fever, chikungunya, and Ross River virus infection [see Table 1].
Hemorrhagic fevers are diseases, generally viral, that often cause extensive bleeding in humans. Specific laboratory diagnosis of hemorrhagic fevers usually requires special serologic or virologic tests, such as enzyme-linked immunosorbent assays (ELISAs) to detect virus-specific immunoglobulin M (IgM) or immunoglobulin G (IgG) antibody, or other tests such as hemagglutination-inhibition, complement fixation, and neutralization tests on paired serum samples taken during the acute and convalescent phases of illness. Some viruses produce viremia [see Table 1] and can be isolated from, or detected in, the acute-phase serum or cerebrospinal fluid by polymerase chain reaction (PCR) or immunohistochemistry (IHC) testing of autopsy tissues. Clinicians who suspect a hemorrhagic fever in one of their patients can have samples sent through their state health department to the Centers for Disease Control and Prevention (CDC) for testing.
VIRUSES OF THE FAMILY FLAVIVIRIDAE
The dengue virus complex (family Flaviviridae, genus Flavivirus) consists of four antigenically related serotypes (DEN-1, DEN-2, DEN-3, and DEN-4). Although there is extensive cross-reactivity between dengue virus serotypes in serologic tests, there is no lasting cross-protective immunity in humans; cross-protection lasts for only a few months. Thus, individuals can have as many as four dengue infections in their lifetime, one from each serotype.1
All four dengue virus serotypes have a worldwide distribution in the tropics and are maintained in tropical rain forests of Asia and Africa in a mosquito-monkey-mosquito cycle and in most tropical urban centers in a mosquito-human-mosquito transmission cycle.1 The forest cycle is not considered important in terms of public health. A map of countries reporting dengue can be found athttp://www.cdc.gov/ncidod/dvbid/dengue/index.htm. In many urban centers, multiple virus serotypes cocirculate (a phenomenon known as hyperendemicity). An estimated 50 to 100 million infections occur annually. The principal mosquito vector is Aedes aegypti, an African species that spread around the world during the 17th, 18th, and 19th centuries via the slave trade and shipping industry. Ae. aegyptibecame well adapted to living in intimate association with humans and is a highly efficient epidemic vector in urban settings. Secondary vectors include other Aedes (Stegomyia) species such as Ae. albopictus, Ae. polynesiensis, and Ae. scutellaris. These secondary vector species can transmit dengue viruses during outbreaks, but they are more important as maintenance vectors.
In the United States, dengue fever should be suspected in a traveler who falls abruptly ill within 2 weeks of returning from the tropics. Infection with dengue viruses can be inapparent or can cause a spectrum of clinical illness ranging from a mild, nonspecific viral syndrome to classic dengue fever to severe and fatal hemorrhagic disease. The classic form usually affects adults and older children; in young children, the illness is usually mild but may be severe. After an infective mosquito bite, there is an incubation period of 3 to 14 days (average, 4 to 7 days), followed by the sudden onset of fever (which is often biphasic—with 2 to 5 days of fever, followed by a 1- to 2-day afebrile period, and then 1 to 2 days of fever), severe headache, chills, retro-orbital pain, and generalized, severe pain in the muscles and joints. A maculopapular rash generally appears on the trunk between the third and fifth days of illness and spreads to the face and extremities. Nausea, vomiting, lymphadenopathy, anorexia, constipation, and altered taste sensation are common. Occasionally, petechiae are seen on the dorsum of the feet, legs, hands, axillae, and palate late in the illness. The illness generally lasts 5 to 7 days, after which recovery is complete, although convalescence may be prolonged. Leukopenia with a relative lymphocytosis and thrombocytopenia may occur. Liver enzyme levels may be elevated, and hemorrhagic manifestations may occur. Neurologic manifestations such as encephalopathy and seizures may occur during the disease's febrile stage.2,3
The diagnosis of dengue infections should be based on clinical signs and symptoms and on epidemiologic information such as travel history. Laboratory testing is useful only for confirmation of the clinical diagnosis. The IgM-capture ELISA is the serologic test of choice for dengue infection.
Treatment and prevention
Treatment of dengue fever is supportive; there are no antiviral agents that are effective for the disease. Prevention consists of environmental control (see below).
Dengue Hemorrhagic Fever
Dengue hemorrhagic fever (DHF) is a severe form of dengue infection that is most commonly observed in children younger than 15 years in Southeast Asia and in all age groups in the Americas and the Pacific region.4,5
The pathogenesis of DHF is still not well understood. Classic DHF with a vascular leak syndrome may have a unique immunopathologic basis that is associated with enhancement of viral infection of mononuclear phagocytes in patients with dengue antibodies from a previous infection with a different serotype (heterologous antibody).6 Infection of mononuclear phagocytes stimulates the release of vasoactive mediators, leading to a cascade of events that result in increased vascular permeability.
Although the risk of DHF is higher in patients experiencing a second dengue infection, DHF also occurs in patients who have primary infections; thus, heterologous dengue antibody (previous infection) is not a prerequisite for DHF. Furthermore, some strains of dengue viruses cannot be enhanced in vitro. Both field evidence and laboratory evidence support a more prominent role of viral factors in the pathogenesis of DHF and suggest that virus strain and serotype are also important risk factors for severe disease.1,3,6,7,8 Hemorrhage may occur without vascular leakage, suggesting another pathogenetic mechanism.3,9
DHF is characterized by sudden onset of fever, usually lasting 2 to 7 days, and nonspecific signs and symptoms.1 The critical stage of DHF occurs between 24 hours before and 24 hours after the patient's temperature falls to or below normal. During this time, hemorrhagic manifestations usually occur, and signs of circulatory failure may appear. The patient may become restless or lethargic, experience acute abdominal pain, and have cold extremities and oliguria, usually on or after the third day of illness. Clinical laboratory tests at this time will show thrombocytopenia (platelet count < 100,000/mm3), a low serum total protein level, a low albumin level, and a rise in hematocrit secondary to plasma leakage from the vascular compartment. Another indication of vascular leakage is pleural effusion. Loss of intravascular volume may result in hypovolemia, shock, and death if not corrected. The most common hemorrhagic manifestations are skin hemorrhages, but epistaxis, bleeding gums, gastrointestinal hemorrhage, and hematuria may occur.
Treatment and prevention
Early diagnosis and prompt management with fluid replacement therapy can substantially reduce case-fatality rates.10 Initial management and treatment decisions should not be delayed pending results of serologic tests. Clinical laboratory tests should be used to monitor vascular leakage.10
There is no licensed vaccine for dengue/DHF, although significant progress is being made toward the development of live attenuated and recombinant candidate vaccines using infectious clone technology.11,12 Currently, disease prevention depends exclusively on mosquito control and personal protective measures such as the use of mosquito repellents.
Yellow fever virus (family Flaviviridae, genus Flavivirus) is believed to have originated in Africa. The disease is now present in tropical America and Africa but does not occur in Asia. Like dengue, yellow fever virus has two transmission cycles: jungle and urban. The jungle or forest transmission cycle involves canopy-dwelling mosquitoes and monkeys. The urban cycle involves humans as the vertebrate host andAe. aegypti as the principal vector. In the past 30 years, Ae. aegypti has reinvaded Central and South America, putting the American tropics at the highest risk for urban epidemics of yellow fever in over 60 years. Epidemics in Africa often occur in moist savanna regions; forest or peridomestic Aedes mosquitoes and humans are the viremic hosts. In dry areas and urban centers where water storage practices promote the breeding of domestic Ae. aegypti, this mosquito is responsible for epidemic transmission. Several hundred thousand people are infected yearly, and outbreaks are frequent. Cases among unvaccinated travelers are rare; however, since 1996, six travelers have died in the United States and Europe of yellow fever acquired in South America and Africa.
Yellow fever varies from an inapparent infection to a deadly fulminating hemorrhagic disease. Three clinical stages are commonly recognized: infection, remission, and intoxication.13,14 After an incubation period of 3 to 10 days, the period of infection begins with sudden onset of fever, rigors, headache, and backache. In severe cases, the patient is intensely ill and restless, with flushed face, swollen lips, bright-red tongue, congested conjunctivae, and bleeding. There may be bradycardia relative to fever (Faget sign). This stage is followed after 2 to 3 days by a brief period of remission. Remission is often not obvious. The period of intoxication occurs on the third to sixth day after illness onset in about 15% of patients. This period consists of moderate or severe disease with jaundice. Fever returns with relative bradycardia, along with nausea, vomiting, a hemorrhagic diathesis, hypotension, albuminuria, oliguria, and anuria.
Most patients with severe disease will have leukopenia, thrombocytopenia, elevated levels of serum creatinine and liver enzymes, and coagulation defects. The jaundice, which gives the disease its name, is generally apparent only in convalescing patients. In fatal cases, death usually occurs within 7 to 10 days; case-fatality rates vary widely, but they can exceed 50% in clinically ill patients.15 At autopsy, the organs most affected are the liver, spleen, kidneys, and heart. Typically, the liver shows midzonal hyaline necrosis and Councilman inclusion bodies.
The initial diagnosis of yellow fever should be based on clinical signs and symptoms and on epidemiologic information such as vaccination history and recent travel to an endemic area [see CE:VII Health Advice for International Travelers]. Laboratory diagnosis is made by detection of virus, viral antigen, or viral nucleic acid or by serologic examination. Virus is often isolated from blood during the first 4 days of illness. Serologic tests may be negative during the first week of illness. Diagnostic testing for yellow fever may be obtained by request to the CDC through state and local health departments.
Treatment and prevention
Treatment is supportive. Yellow fever is an international reportable disease, and immunization is required for travelers to many countries of sub-Saharan Africa and tropical America. The live, attenuated 17D vaccine, delivered as a single 0.5 ml subcutaneous dose, is highly effective. Immunity is probably lifelong, but for travel certification, revaccination is recommended every 10 years. Information about indications for yellow fever vaccine and requirements for international travel are available at http://www.cdc.gov/travel/reference.htm.16,17For patients who require immunization, the locations of designated yellow fever vaccination centers can be obtained through local health departments. The CDC also provides an extensive list of yellow fever vaccination clinics on its Web site.
Although the 17D vaccine is one of the safest vaccines, rare cases of severe and fatal infection from vaccination have been reported. The elderly may experience a higher incidence of serious adverse events.18,19 Persons with documented egg allergy should not be immunized or should be skin-tested with the vaccine. The vaccine must not be given to children younger than 6 months, in whom there is a risk of postvaccinial encephalitis, and it is best to delay vaccination until 9 months of age. On theoretical grounds, persons with immunosuppression, including those with clinical AIDS, should not be immunized. Immunization during pregnancy is generally contraindicated.
Other hemorrhagic diseases caused by flaviviruses include Kyasanur Forest disease in India and Saudi Arabia and Omsk hemorrhagic fever in Russia [see Table 1]. Both are tick-borne diseases and are rare in comparison with disease from mosquito-borne flaviviruses.
VIRUSES OF THE FAMILY BUNYAVIRIDAE
Crimean-Congo Hemorrhagic Fever
Epidemiology and etiology
Crimean-Congo hemorrhagic fever (CCHF) virus (family Bunyaviridae, genus Nairovirus) is transmitted by ticks, primarily of the genusHyalomma, over a broad geographic range that includes sub-Saharan Africa, eastern Europe and Russia, the Middle East, and western China.14,20 Humans become infected after a tick bite; after parenteral exposure to, or contact with, blood from acutely ill patients20; or, on occasion, after the slaughter of sick domestic animals. Disease may be seasonal in humans, reflecting the natural abundance of ticks.
In the United States, CCHF should be suspected in a traveler who falls abruptly ill less than 2 weeks after returning from an endemic area. The incubation period for CCHF is 3 to 7 days for nosocomial infections and up to 12 days for those infected by a tick bite, followed by abrupt onset of fever, headache, myalgia, weakness, nausea, and vomiting. This initial phase may last 2 to 3 days, followed by remission of several hours' duration in one third to two thirds of patients. The second phase of illness is associated with hemorrhagic manifestations, which may last from 3 days to as long as 10 days and includes, most commonly, petechiae over the chest and abdomen, epistaxis, ecchymoses, bleeding from puncture sites, melena, and hematuria. Those surviving the hemorrhagic phase enter a convalescent phase characterized by normalization of fever, cessation of hemorrhages, occasionally transient hair loss, and prolonged fatigue and dizziness.20Mortality ranges from 9% to 40%.
Treatment and prevention
Treatment is supportive and focuses on the hemorrhagic manifestations. The antiviral drug ribavirin has been administered to a limited number of patients with apparent success.21 Persons in endemic areas should take protective measures to prevent exposure to infected ticks, and barrier methods should be used in hospitals where patients with suspected CCHF are being treated.
Hantaviruses (family Bunyaviridae, genus Hantavirus) are rodent-borne viruses causing human diseases known as hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia and as hantavirus pulmonary syndrome (HPS) in the Americas.22 The prototype hantavirus is Hantaan virus, which causes epidemic hemorrhagic fever in China and Korea, but many different hantaviruses are now recognized. Hantaviruses are maintained in nature by chronic infection of rodent hosts, and each is principally associated with a specific rodent host [see Table 2]. Antibodies against hantaviruses are also present in domestic and wild animals such as cats, dogs, pigs, cattle, and deer. German investigators are examining whether hantaviruses can be transmitted from rats to cattle, because the incidental infection of species other than rodents has the potential to influence the pathogenicity and virulence of the virus.23
Humans are infected after aerosol exposure to infectious excreta or occasionally by bites. Apparent human-to-human transmission was noted in one outbreak with the Andes virus.24
The incidence of hantavirus infections in humans often fluctuates with rodent densities and human activities that increase contact with contaminated materials. Commonly infected groups are military personnel on field maneuvers, shepherds, woodcutters, campers, and others involved in outdoor activities.
Hemorrhagic fever with renal syndrome
Along with Hantaan virus, other hantaviruses causing HFRS are Seoul virus, Puumala virus, and Dobrava/Belgrade virus. Classic HFRS caused by Hantaan or Dobrava virus infection has a variable incubation period and is characterized by five phases: (1) a febrile phase of 3 to 7 days, with fever, malaise, headache, abdominal pain, nausea, vomiting, facial flushing, petechiae, and conjunctival hemorrhage; (2) a hypotensive phase of a few hours to 3 days, when hypotension, shock, blurred vision, hemorrhagic signs, and a drop in blood pressure occur; (3) an oliguric phase of 3 to 7 days, during which oliguria or anuria predominates and hemorrhagic manifestations may worsen; (4) a diuretic phase of days to weeks, when polyuria predominates; and (5) a prolonged convalescent phase of weeks to months.22 Mortality in classic HFRS results from shock, multiorgan hypoperfusion, or uremia and ranges from 1% to 10%. Infection with Puumala virus or Seoul virus produces milder disease, with lower mortality. Serology is the main diagnostic tool, but it should be used only for confirmatory retrospective diagnosis.22
Early treatment with ribavirin may reduce hemorrhage, renal failure, and mortality in HFRS.25 Commercially available inactivated vaccines for Hantaan virus or bivalent Hantaan/Seoul virus vaccines are produced in Korea and China; other vaccines are in development.26 Control of HFRS relies on reduction of human-rodent contact through good sanitation and waste management, rodent control, and making buildings rodent proof.
Hantavirus pulmonary syndrome
Since its discovery in 1993 during an outbreak in the southwestern United States, several hundred cases of HPS have been identified in the Americas.27 The Sin Nombre virus, which is carried by deer mice, caused the initial outbreak; subsequently, a number of related hantaviruses hosted by other sigmodontine rodents have been identified as a cause of human disease [see Table 2].
HPS should be suspected on the basis of the clinical picture, clinical laboratory results, and radiologic findings; confirmation of diagnosis is by serologic testing. Diagnostic information about HPS, including instructions on submitting suspected HPS specimens for serologic testing, can be obtained from the CDC at http://www.cdc.gov/ncidod/diseases/hanta/hps/index.htm.
The incubation period of HPS probably ranges from 9 to 33 days. Clinical disease can be divided into four phases: febrile, cardiopulmonary, diuretic, and convalescent.28 The febrile phase, typically lasting 3 to 5 days, is characterized by fever, myalgia, and malaise. Headache, dizziness, anorexia, nausea, vomiting, and diarrhea may occur. The cardiopulmonary phase is marked by pulmonary edema and shock. Once pulmonary edema develops, the rapid onset of circulatory compromise and hypoxia often leads to death. During the diuretic phase, pulmonary edema clears, along with resolution of fever and shock. The convalescent phase may last several months; complete recovery is the rule. Renal insufficiency has been reported with the Sin Nombre virus and is a more constant feature of many of the newly recognized American hantaviruses causing HPS, suggesting that HPS and HFRS are not as clinically distinct as previously thought. Thrombocytopenia is almost universally present. Mortality is approximately 40% but varies with the infecting virus.
Treatment of patients with HPS remains supportive. Early intensive care management is important, with prompt correction of electrolyte, pulmonary, and hemodynamic abnormalities. Vaccines are in development.26 Despite its in vitro activity against Sin Nombre virus, ribavirin failed to produce a dramatic reduction in case fatality in an open-label trial.29
Rift Valley Fever
Epidemiology and etiology
Rift Valley fever (RVF) is caused by the RVF virus (family Bunyaviridae, genus Phlebovirus). First described during a fatal epizootic in sheep that occurred in the Rift Valley of Kenya in 1931, RVF is a mosquito-borne disease affecting domestic ungulates, especially goats and sheep.14 Large epizootics occur during periods of heavy rainfall. Humans become infected through the bite of an infected mosquito, by infectious aerosols when sick animals are slaughtered, or by occupational exposure (e.g., veterinarians attending to infected animals). Large human outbreaks have occurred in sub-Saharan Africa, Egypt, and more recently on the Saudi Arabian peninsula.14 RVF virus is a potential agent of bioterrorism.
The incubation period in humans is 2 to 6 days. This is followed by abrupt onset of fever, headache, chills, and malaise. Uncomplicated illness usually resolves within 2 to 3 days. Retinitis, hemorrhagic fever, and encephalitis occur in rare instances.
Treatment and prevention
Treatment is supportive, although the antiviral drug ribavirin has been effective in the treatment of related viruses of the family Bunyaviridae and deserves further investigation. Inactivated and live attenuated vaccines have been produced for use in domestic animals and appear to be efficacious. No vaccine is commercially available for use in humans, although an experimental inactivated vaccine has been used to protect select populations at risk for laboratory or occupational exposure.14
VIRUSES OF THE FAMILY ARENAVIRIDAE
Significant human illnesses caused by Arenaviridae viruses include lymphocytic choriomeningitis; Lassa fever; and Argentine, Bolivian, and Venezuelan hemorrhagic fever. Arenaviruses are transmitted directly to humans after close rodent-human contact, such as touching objects or eating food contaminated with rodent excreta [see Table 3]. Human-to-human transmission of Lassa fever has occurred. Several of the arenaviruses are considered potential agents of bioterrorism.
Table 3 Arenaviruses That Cause Significant Human Illness
Arenaviral infections typically begin with fever, malaise, headache, and GI symptoms. More severe cases may involve the heart, lungs, liver, and kidneys. Fulminant and often fatal hemorrhagic shock occurs in a minority of cases (e.g., about 20% of hospitalized Lassa fever patients). Lassa fever is especially severe in pregnant women, often causing death in both mother and fetus. Hearing loss (of varying degrees) is a common sequela of Lassa fever, even in mild cases.
Several cases of Lassa fever have been imported into Europe, Japan, and the United States in recent years. Consequently, the clinician should consider the diagnosis in patients who experience a febrile illness within 3 weeks after travel to endemic countries in West Africa (i.e., Nigeria, Guinea, Liberia, and Sierra Leone). South American arenaviruses should be considered in the differential diagnosis of hemorrhagic fever in patients with a history of travel to that region. Because its symptoms are varied and nonspecific, arenavirus infection can be confirmed by serology, most commonly with ELISA, which can be requested from the CDC through state and local health departments.
Treatment and Prevention
The antiviral drug ribavirin reduces mortality from Lassa fever, especially if started within the first 6 days after the onset of fever. Ribavirin may be of value in the treatment of other arenaviral infections as well, although efficacy cannot be fully validated because of a lack of clinical experience.30 A live, attenuated vaccine of proven efficacy has been developed for Junin virus and is available in Argentina31; vaccine candidates for Lassa fever are in development.
VIRUSES OF THE FAMILY FILOVIRIDAE
Marburg and Ebola viruses are among the most severe and mysterious viral pathogens to emerge in the 20th century.32 Filoviruses share common morphology as long, pleomorphic rods but are antigenically and genetically distinct. Current understanding of these agents is largely restricted to investigations of human outbreaks and limited experimental studies conducted at the few laboratories worldwide that are able to safely handle filoviruses.
There is no vaccine or effective chemotherapy for any known filovirus. Marburg and Ebola viruses are considered potential agents of bioterrorism.
African green monkeys, Cercopithecus aethiops, imported from Uganda for use in research and vaccine production, were the source of the initial 31-person outbreak that led to the discovery of the Marburg virus in 1967. Human fatality was 23%.32 In 2005, the World Health Organization confirmed an outbreak of Marburg virus infection in 124 persons in Angola.33 Information for travelers to Angola is available from the CDC at http://www.dcd.gov/travel/other/marburg_vhf_angola_2005.htm. The ecology of Marburg virus remains virtually unknown. Marburg virus disease presents as an acute febrile illness; it can progress within 6 to 8 days to severe hemorrhagic manifestations. Clinical manifestations include fever, chills, headache, myalgia, maculopapular rash, nausea, vomiting, chest pain, and abdominal pain. Signs and symptoms can become increasingly more severe. Clinicians should consider the diagnosis of Marburg virus for febrile patients who, within 10 days before onset of fever, have traveled in northern Angola, had direct contact with blood or other body fluids of a person suspected of having hemorrhagic fever, or have worked in a laboratory that handles hemorrhagic fever viruses. No vaccine or curative treatment is available; treatment is supportive.
At least 1,000 persons have died from Ebola virus infection since its discovery in Sudan in 1976. Of the four known genetic subtypes of Ebola virus—Zaire, Côte d'Ivoire, Sudan, and Ebola-Reston—the first three have been associated with human disease in West and central Africa.32 Ebola-Reston was discovered in macaques imported from the Philippines for medical research.34 Occupational exposure to Ebola-Reston from nonhuman primates is infrequent and results in asymptomatic infection.35
The natural history of Ebola virus remains a mystery. Outbreaks of Ebola hemorrhagic fever are associated most often with the introduction of the virus into the community by one infected person, followed by dissemination by person-to-person transmission, often within medical facilities.32,36
Ebola virus infection has an incubation period of approximately 6 days, which is commonly followed by two clinical phases.37 Early symptoms include fever, asthenia, diarrhea, nausea and vomiting, anorexia, abdominal pain, headaches, arthralgia, and back pain. Bilateral conjunctivitis, nonpruritic rash, and sore throat with odynophagia, when present, suggest Ebola virus infection. The second phase, characterized by hemorrhagic manifestations, neuropsychiatric abnormalities, and oligoanuria, portends a worse outcome. In recent outbreaks, bleeding occurred in a minority of patients.32,36 Mortality during outbreaks typically exceeds 50%.
The clinical diagnosis is challenging, because the presentation is nonspecific. To exclude other infections, patients with clinical manifestations consistent with Ebola virus infection should have a blood smear examination for malaria, a blood culture, and a stool culture if they have bloody diarrhea. ELISA, PCR, and virus isolation can be used to confirm Ebola virus infection within a few days of the onset of symptoms.38 Detailed diagnostic information is available from the CDC athttp://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/ebola.htm.
Treatment and prevention
Treatment is supportive. Outbreak control rests on initiation of case finding, case isolation, and other infection-control practices, including barrier nursing procedures.32,36
Viral encephalitis is caused by a number of arboviruses belonging to the families Flaviviridae, Togaviridae, Bunyaviridae, and Reoviridae, as well as other zoonotic viruses. Specific laboratory diagnosis of encephalitis from zoonotic viruses requires special serologic tests, such as hemagglutination-inhibition, complement fixation, and neutralization tests. ELISAs are used to detect virus-specific IgM or IgG antibody in serum or CSF samples. As with the flaviviruses, serologic tests must be cautiously interpreted, because there is considerable serologic cross-reactivity among many of these viruses of the same genus. Viruses can also be isolated and detected by PCR or immunohistochemistry in autopsy tissue. Assistance with serologic diagnosis can be obtained from the CDC at http://www.cdc.gov/ncidod/dvbid/index.htm and through state and local health departments.
VIRUSES OF THE FAMILY BUNYAVIRIDAE
La Crosse Encephalitis
La Crosse (LAC) virus (family Bunyaviridae, genus Bunyavirus) is the most pathogenic member of the California encephalitis serogroup, which includes the California encephalitis, trivittatus, snowshoe hare, and Jamestown Canyon viruses. LAC is maintained in a cycle involvingAe. triseriatus mosquitoes and a number of mammalian hosts, including the eastern chipmunk, tree squirrels, and foxes.
Human infections occur in the central and eastern United States, mostly as sporadic cases in school-age children from July through September [see Table 4].39
Table 4 Viral Zoonoses Endemic in the United States
Most infections are asymptomatic. After an incubation period of 3 to 7 days, headache, fever, and vomiting develop. Seizures are a presenting finding in about half of cases, and focal neurologic abnormalities in about one fifth.39 The combination of fever, focal signs, and focal seizures may mimic herpes simplex encephalitis. Mortality is 1%. About 10% of children have residual neurologic sequelae, including focal neurologic deficits and decreased intelligence. Diagnosis can be confirmed serologically by the CDC on the request of state and local health departments.
Treatment and prevention
Treatment is supportive; management of cerebral edema and seizures is important [see 11:XVI Acute Viral Central Nervous System Diseases]. Ribavirin has been used, but efficacy is unproved.39 Prevention rests on avoidance of mosquito bites.
VIRUSES OF THE FAMILY FLAVIVIRIDAE
Japanese encephalitis (JE) is the most important global cause of arboviral encephalitis; 30,000 to 45,000 cases are reported annually. JE virus (family Flaviviridae, genus Flavivirus) is widespread throughout Asia. In recent years, the disease has been detected in Australia and other areas in the Pacific region. Epidemics occur in late summer in temperate regions, but the virus is enzootic and occurs throughout the year in many tropical areas of Asia. JE virus is maintained in a natural enzootic cycle involving Culex mosquitoes and water birds. The virus is transmitted to humans by Culex mosquitoes, primarily C. tritaeniorhynchus and related species, which breed in rice fields. Pigs are the primary amplifying hosts in the peridomestic environment.
Only about one in 250 infections results in symptomatic illness. The incubation period of JE is 5 to 14 days. Symptomatic illness is primarily seen in children. Mild clinical illness, such as aseptic meningitis and simple febrile illness with headache, usually goes undetected. In severe cases, the onset of symptoms is usually sudden, with fever, headache, and vomiting. The illness resolves in 5 to 7 days if there is no central nervous system involvement. Patients with CNS involvement commonly are lethargic, with expressionless faces, and have sensory and motor disturbances affecting their speech, eyes, and limbs. They may have confusion and delirium progressing to coma; in children, convulsions are sometimes a presenting sign. Weakness and paralysis may affect any part of the body. Neck rigidity and a positive Kernig sign are found, and reflexes are abnormal. Signs of extrapyramidal involvement are characteristic. Initial leukocytosis is followed by leukopenia. Mortality is 5% to 30%, with higher case-fatality rates in young children. Approximately one third of patients who recover have neurologic sequelae. The diagnosis can be confirmed serologically by the CDC on request of state and local health departments.
A formalin-inactivated mouse brain vaccine prepared with the Nakayama strain of JE virus is used internationally. Vaccination is recommended to residents in JE-endemic areas and to certain travelers to those areas. The risk to travelers is generally low, but vaccination is recommended for visitors to endemic or epidemic areas during the transmission season, especially when potential exposure will be prolonged and when there is a high likelihood of exposure to vectors.40 Treatment is supportive. Interferon alfa was not effective against JE in a double-blind, placebo-controlled trial.41 Further information on JE is available athttp://www.cdc.gov/ncidod/dvbid/jencephalitis/index.htm. Mosquito control and improved animal husbandry and rice-growing practices are needed to decrease transmission risk in endemic areas.
Murray Valley Encephalitis
Murray Valley encephalitis (MVE) virus (family Flaviviridae, genus Flavivirus) was first isolated in 1951. MVE occurs only in Australia and New Guinea.42 Like other flaviviruses, MVE virus is believed to be maintained in a natural cycle involving water birds and Culex mosquitoes. Viremia has not been documented in humans, who are likely dead-end hosts.
Only one in 1,000 to 2,000 infections results in clinical illness. Clinical illness resembles JE. Illness is characterized by the sudden onset of fever, headache, nausea and vomiting, anorexia, and myalgias, followed by drowsiness, malaise, irritability, mental confusion, and meningismus. In severe cases, there may be hyperactive reflexes, spastic paresis, convulsions, coma, and death. Of patients with neurologic disease, approximately one third die and one quarter have residual neurologic deficits.
There is no vaccine for MVE virus. Prevention relies on mosquito control and avoidance of mosquito bites.
Saint Louis Encephalitis
St. Louis encephalitis (SLE) virus (family Flaviviridae, genus Flavivirus) is prevalent throughout the Western Hemisphere from Canada to Argentina. In North America, the infection is maintained between wild birds and Culex mosquitoes. Although clinical illness has been sporadically reported throughout much of this region, most infections occur in North America during sporadic epidemics in the Midwest and Southeast.
The ratio of infection to clinical illness is high, ranging from 800 to 1 in children younger than 10 years to 85 to 1 in persons older than 60 years. Illness ranges from fever with headache to aseptic meningitis to encephalitis. Advanced age is the strongest risk factor for both symptomatic disease and severe encephalopathy. SLE should be considered in the differential diagnosis of adult viral encephalitis cases during the summer months in the United States. After an incubation period of 4 to 21 days, the illness begins with fever, headache, chills, nausea, and dysuria. Within 1 to 4 days, CNS signs appear, with meningismus, tremor, abnormal reflexes, ataxia, cranial nerve palsies, convulsions (especially in children), stupor, and coma. About 25% of very young infants have residual mental deficits, personality changes, muscle weakness, and paralysis. Overall, the case-fatality rate is about 6%, but the disease is generally milder in children (case-fatality rate of those younger than 5 years is 1%). The diagnosis can be confirmed serologically by the CDC on request of state and local health departments.
Treatment and prevention
Treatment is supportive; no specific therapy is available. A pilot study indicated that early initiation of therapy with interferon alfa-2b may reduce the severity and duration of complications such as quadriplegia and quadriparesis, but a randomized trial is required to better assess the efficacy of this therapy.43 No vaccine is available. Prevention is aimed at mosquito-bite avoidance and mosquito abatement.
Epidemiology and etiology
Tick-borne encephalitis (TBE) is caused by two closely related viruses of the family Flaviviridae, genus Flavivirus.44 The eastern subtype of the TBE virus is transmitted by Ixodes persulcatus and causes Russian spring-summer encephalitis, which occurs from Eastern Europe to China. The western subtype is transmitted by I. ricinus and causes Central European encephalitis, which occurs from Scandinavia in the north to Greece and Serbia and Montenegro in the south. Of the two subtypes, Russian spring-summer encephalitis is the more severe infection, having a mortality of 5% to 20%, compared with less than 2% for the western subtype. Both viruses are maintained in natural cycles involving a variety of mammals and ticks. Human exposure occurs through work or recreational activities in the spring and summer months in temperate zones and in fall and winter in the Mediterranean, when the ticks are most active. Infection may also occur through the ingestion of raw milk or cheese from cows, sheep, or goats.
The incubation period of TBE is usually 7 to 14 days. The western subtype typically produces a biphasic illness. Infection usually presents as a mild, influenzalike illness lasting 2 to 7 days, followed by an afebrile or relatively asymptomatic period lasting 2 to 10 days. Approximately one third of patients then develop higher fevers with aseptic meningitis or meningoencephalitis. The eastern subtype usually progresses without an asymptomatic phase. Permanent paresis develops in 2% to 10% of patients with the western subtype and in 10% to 25% of patients with the eastern subtype. Rarely, cases occur in United States citizens who visit enzootic areas. Infections can be confirmed serologically by the CDC on request of state and local health departments.
Treatment and prevention
Treatment of TBE is supportive. Inactivated vaccines against both eastern and western subtypes of TBE viruses are available in Europe, but they are not commercially available in the United States44; candidate vaccines are in development in the United States.45 Prevention strategies include avoiding tick bites and pasteurizing milk.
West Nile Virus
Epidemiology and etiology
West Nile virus (family Flaviviridae, genus Flavivirus), first isolated in 1937 in the West Nile district of Uganda, has historically had a wide geographic distribution in Africa, Asia, the Middle East, and Europe.46 The virus was first recognized in the Western Hemisphere during an epizootic among birds and horses and a human encephalitis outbreak in the New York City area in 1999.47 From the 1950s to the 1970s, human outbreaks were reported infrequently, mostly in the Middle East. However, since the mid-1990s, outbreaks of neurologic disease in humans and horses, with an increase in death rates, may have marked the evolution of a new West Nile virus variant.46,48 By 2002, the virus's known geographic distribution extended to southeastern Canada, the Grand Cayman Islands, and throughout the eastern United States.48,49 Up-to-date maps of the virus's spread in the United States are available athttp://www.cdc.gov/ncidod/dvbid/westnile/surv&control.htm. The virus has a natural maintenance cycle involving wild birds and Culexmosquitoes and is thought to spread via migrating birds.46,48 In temperate climates, the incidence of infection peaks during late summer and early fall; however, year-round transmission is possible in more tropical areas. Human infections result primarily from infectious mosquito bites; however, in 2002, five new modes of transmission were recognized: blood product transfusion, organ transplantation, transplacental transmission, breast-feeding, and occupational exposure in laboratory workers.48
The incubation period of West Nile virus ranges from 3 to 14 days. Serologic surveys during recent outbreaks suggest that approximately 20% of persons who are infected develop a systemic febrile illness.50 Common symptoms are fever; headache; myalgia; GI complaints; and an erythematous macular, papular, or morbilliform skin rash.46,47 Lymphadenopathy may be present, but it has been reported less frequently in recent outbreaks. Overall, fewer than 1% of infected persons develop encephalitis.50 Older persons are at increased risk for meningitis or encephalitis; once these complications develop, such individuals have a higher case-fatality rate and a higher incidence of residual neurologic deficits.47 Of note, muscle weakness and flaccid paralysis, when present, may provide a clue to a West Nile virus etiology. Overall, case-fatality rates in severe cases are about 10%. The diagnosis is most efficiently confirmed serologically; testing can be obtained through state and local health departments.
Treatment and prevention
Treatment of West Nile virus infection is supportive. Prevention relies on mosquito control and protection from mosquito bites. There is no human vaccine for West Nile virus infection. An equine vaccine is available.
Powassan virus (family Flaviviridae, genus Flavivirus) is related to the Eastern Hemisphere's tick-borne encephalitis viruses. It was thought to be a rare cause of encephalitis in eastern Canada and the northern United States; however, West Nile virus surveillance has increased the recognition of this pathogen.51 The case-fatality rate is 5% to 10%, with a high incidence of residual neurologic dysfunction in survivors. Serologic surveys indicate an antibody prevalence of 1% to 4%. The virus is transmitted between Ixodes ticks and rodents; humans become infected via tick bites. The clinical features are those of viral encephalitis, with localizing neurologic signs and convulsions.44 There is no specific treatment or vaccine.
VIRUSES OF THE FAMILY TOGAVIRIDAE
Eastern Equine Encephalitis
Eastern equine encephalitis (EEE) virus (family Togaviridae, genus Alphavirus) is widely distributed throughout North, Central, and South America and the Caribbean; however, little is known about the epidemiology of EEE outside North America. In the United States, human infections are usually sporadic, and small outbreaks occur each summer, mostly in the upper Midwest and along the Atlantic and Gulf coasts. In North America, wild birds and Culiseta melanura (a mosquito found in swamp areas that support cedar, red maple, and loblolly bay trees) maintain the virus. In central Alabama, high rates of EEE virus infection were found in Uranotaenia sapphirina, a mosquito that commonly feeds on amphibians and reptiles, which suggests that species other than birds may serve as a reservoir for EEE in hardwood swamps in the southeastern United States and elsewhere.52
The incubation period of EEE exceeds 1 week; onset is abrupt, with high fever. About 2% of infected adults and 6% of infected children develop encephalitis. EEE causes the most severe of the arboviral encephalitides, with a mortality of 50% to 75%. Symptoms and signs include dizziness, decreasing level of consciousness, tremors, seizures, and focal neurologic signs. Death can occur within 3 to 5 days after onset. Sequelae, which are common in nonfatal encephalitis, include convulsions, paralysis, and mental retardation. Illness from EEE in South America is less severe. Infection can be confirmed serologically by the CDC on request of state and local health departments.
Treatment and prevention
No specific treatment is available. Prevention focuses on avoidance of mosquito bites and mosquito control in suburban areas. Inactivated vaccines have been used successfully in horses, and an inactivated vaccine has been used in laboratory workers or others at high risk of exposure, but it is not commercially available.
EEE is a potential agent of bioterrorism through the aerosol route.
Venezuelan Equine Encephalitis
In the Venezuelan equine encephalitis (VEE) virus (family Togaviridae, genus Alphavirus) complex, six subtypes (I to VI) have been identified. Five antigenic variants exist in subtype I (IAB, IC, ID, IE, and IF). These subtypes and variants are classified as epizootic or enzootic on the basis of their apparent virulence and epidemiology. Epizootic variants of subtype I (IAB and IC) cause equine epizootics and are associated with more severe human disease. Enzootic strains (ID to IF, II [Everglades], III [Macambo, Tonate, Paramana], IV [Pixuna], V [Cabassou], VI [unnamed]) do not cause epizootics in horses, but they may produce sporadic disease in man. Epizootic strains are transmitted by many different types of mosquitoes; enzootic strains are transmitted by culicine mosquitoes. VEE has a widespread geographic distribution, from Florida to South America, where it is an important veterinary and public health problem. Focal outbreaks occur periodically, but occasionally, large regional epizootics occur, with thousands of equine and human infections.
VEE is infectious via aerosols, making it an occupational risk to certain laboratory workers and a potential agent of bioterrorism.
After an incubation period of 1 to 6 days, there is a brief febrile illness of sudden onset, characterized by malaise, nausea or vomiting, headache, and myalgia.53 Fewer than 0.5% of adults and fewer than 4% of children develop encephalitis. Long-term sequelae and fatalities are uncommon.
Treatment and prevention
Treatment is supportive. Effective prevention of both human and equine disease can be accomplished by immunizing horses and other equine animals, which serve as the primary amplification host for the epizootic VEE viruses and without which there would be little human disease. During epidemics, mosquito vectors can be controlled by insecticides. Live attenuated and inactivated vaccines have been used for laboratory workers; however, human vaccines are not commercially available.
Western Equine Encephalitis
Western equine encephalitis (WEE) virus (family Togaviridae, genus Alphavirus) is a complex of closely related viruses found in North and South America. Flooding, which increases breeding of culicine mosquitoes, may precipitate summer outbreaks of WEE. Large outbreaks in humans and horses occurred in the western United States in the 1950s and 1960s; however, a declining horse population, equine vaccination, and improved vector control have reduced disease incidence. The younger the patient, the greater the likelihood of symptomatic infection: the ratio of asymptomatic to symptomatic infection is less than 1:1,000 in adults but increases to 1:1 in infants.
After an incubation period of about 7 days, headache, vomiting, stiff neck, and backache are typical in WEE. In children, restlessness and irritability are seen, and convulsions are common. Neurologic sequelae are relatively common in infants, but they are rare in older children and adults. The case-fatality rate is 3% to 7%. The diagnosis can be confirmed serologically by the CDC on request of state and local health departments.
Treatment and prevention
No specific treatment is available for WEE. Prevention focuses on mosquito control and personal measures to avoid mosquito bites. Inactivated vaccine is available for horses. Although inactivated vaccine has been used for laboratory staff and others at high risk for exposure, it is not commercially available for use in humans. WEE is a potential agent of bioterrorism through the aerosol route.
VIRUSES OF THE FAMILY RHABDOVIRIDAE
The rabies virus (family Rhabdoviridae, genus Lyssavirus) occurs worldwide. Dogs remain the major source of human rabies worldwide. In the United States, however, vaccination has sharply limited canine rabies, and consequently, wildlife rabies has increased in importance. About 90% of all reported cases of animal rabies in the United States now occur in wildlife, particularly wild carnivores (e.g., raccoons, skunks, foxes, coyotes, and bobcats) and bats.54,55
The major wildlife reservoir for rabies in the United States is the raccoon, which accounts for 37% of all reported cases of rabies in animals; skunks (29%), bats (17%), and foxes (6%) represent the other major reservoirs for animal rabies.54 Raccoon rabies is the most prevalent in the eastern states; skunk rabies is predominant in the central and western states.54 Rodents (e.g., squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, and mice) and lagomorphs (rabbits and hares) are rarely infected and have not been identified as sources of human rabies in the United States.55 In the United States since 1990, indigenous rabies virus variants associated with insectivorous bats and foreign canine rabies virus variants have accounted for 30 of the 32 human cases. Although 74% of the 32 cases since 1990 have been attributed to bat-associated variants of the virus, a history of a bite was established in only three cases.56
Etiology and pathogenesis
In most cases of rabies, an infected animal inoculates saliva containing rabies virus into the patient, and the virus may replicate in muscle cells near the bite. After replication, the virus spreads via retrograde axoplasmic flow in unmyelinated motor or sensory nerves to the CNS. It then replicates in the brain before moving via the nerves into other tissues, including the salivary glands, from which it can be shed.
The infectivity of rabies virus varies with the site and mode of transmission. A bite on the face presents a 60% chance of disease; a bite on the hand or arm reduces the chance of disease to between 15% and 40%, and a bite on the leg presents only a 3% to 10% chance of disease. The risk of disease from a bite is almost 50 times greater than the risk from scratches by a rabid animal. Although a less common mode of transmission, the virus also can be inhaled, which accounts for rabies in laboratory workers exposed to viral aerosols and in a few explorers of bat-infested caves.
The incubation period of rabies ranges from 12 days to many years and probably averages 30 to 90 days or less. The clinical course is quite variable. The initial clinical presentation is a prodromal phase typically lasting a day or two. It is marked by pain and paresthesias in the area of the bite, GI and upper respiratory symptoms, irritability, apprehension, and a sense of impending death. Hydrophobia and aerophobia occur in some patients and, like the history of a bite, call attention to this disease. Thereafter, the patient enters an excitation state, marked by hyperventilation, hyperactivity, disorientation, and even seizures. During the next few days, the patient becomes lethargic and begins to show paralysis, particularly in areas innervated by the cranial nerves and in the somatic muscles, bladder, and bowels. Gradual involvement of cardiac muscles and paralysis of respiratory muscles lead to death. Rabies virus infection in humans is uniformly fatal once symptoms occur.
Rabies should be considered if classic signs of hydrophobia, aerophobia, and excited behavior are present or in any case of encephalitis or myelitis of unknown etiology, even in the absence of an exposure history. The CSF shows nonspecific elevation in levels of leukocytes and protein, as occurs in other viral encephalitides. Fluorescent antibody staining, virus isolation, and reverse transcriptase/PCR constitute the most accurate means of diagnosing rabies infection.57 Circulating antibodies may be detected in unvaccinated persons as early as the sixth day of illness and usually appear within the first 2 weeks after infection. Rabies virus can be isolated from the second day through the second week of illness from a throat swab or saliva sample, as well as from tears, urine sediment, and CSF.
Treatment and prevention
Three rabies vaccines are currently available in the United States: human diploid cell rabies vaccine (HDCV), rabies vaccine absorbed (RVA), and purified chick embryo cell vaccine (PCEC).58 Each is licensed for preexposure or postexposure vaccination. Clinical trials with RVA and PCEC have demonstrated immunogenicity equivalent to that of HDCV.58 Corticosteroids, other immunosuppressing agents and conditions, and antimalarials may interfere with the development of active immunity after vaccination. Preexposure prophylaxis is indicated for persons in high-risk groups such as certain laboratory workers, persons whose occupation puts them in frequent contact with animal species at risk for having rabies, and certain international travelers.58
Disease onset can be prevented by prompt postexposure prophylaxis. Postexposure prophylaxis begins with immediate and thorough washing of all bite wounds with soap and water and irrigation with a virucidal agent such as a povidone-iodine solution. Previously unimmunized persons should receive human rabies immunoglobulin and rabies vaccine. Guidelines for the indications and dosing schedules for postexposure prophylaxis are available from the CDC at http://www.cdc.gov/ncidod/dvrd/rabies/.55 Local or state public health officials should be consulted if questions arise about the need for rabies prophylaxis.
At present, therapy for clinical rabies is supportive. In unvaccinated patients, the disease is invariably fatal. A patient with rabies or suspected rabies should be kept in isolation, and standard infection control precautions should be followed, although laboratory-confirmed person-to-person transmission has not been documented.
VIRUSES OF THE FAMILY PARAMYXOVIRIDAE
Nipah virus (family Paramyxoviridae) is closely related to the Hendra virus, which has rarely caused fever, pneumonia, and encephalitis in persons exposed to ill horses in Australia. Nipah virus was newly discovered in Malaysia during an outbreak involving 265 persons, with 105 deaths in 1998 and 1999; in 2004, outbreaks involving 25 persons occurred in Bangladesh.59 Most affected persons had contact with live pigs and were pig farmers. The reservoir for Nipah virus is believed to be fruit bats, and it is thought that humans are infected by contact with an infected bat or by contact with an intermediate animal host such as pigs.
The incubation period is unknown, but more than 90% of the hospitalized Malaysian patients had had contact with pigs in the previous 2 weeks. Among hospitalized patients, fever was almost invariably present, with headache, dizziness, and vomiting common presenting symptoms. Predominant neurologic symptoms were decreased level of consciousness, segmental myoclonus, meningismus, and seizures. Pneumonia was noted in 25% of the patients in Singapore, but it was not prominent in the Malaysian patients. The diagnosis can be confirmed serologically by viral culture or by detection of viral nucleic acid.
Treatment is supportive. An open-label trial suggested that ribavirin reduced mortality.60 Prevention is avoidance of pig farms.
VIRUSES OF THE FAMILY REOVIRIDAE
Colorado Tick Fever
The Colorado tick fever virus (family Reoviridae, genus Coltivirus) is transmitted to humans in the western United States and Canada mainly by the wood tick, Dermacentor andersoni. Human incidence corresponds to the wood tick's geographic distribution in mountainous areas at elevations of 4,000 to 10,000 ft. Transmission occurs from March to September, but it peaks from April to June.
The mean incubation period for Colorado tick fever virus is 3 to 4 days. In 90% of cases, the patient reports a tick bite or tick exposure. Fever, chills, myalgias, and prostration are common presenting symptoms. A petechial or maculopapular rash occurs in 15% of patients.61Although acute symptoms last about a week, fever may recur several days later. Fatigue is often prolonged. Meningitis or encephalitis develops in 5% to 10% of children; fatal cases with hemorrhage and shock have been rarely reported. Leukopenia is very common. The virus infects marrow erythrocytic precursors, which accounts for the ability to recover the virus from peripheral blood up to 6 weeks after illness onset. Transmission via blood transfusion has been reported. The diagnosis can also be confirmed serologically by the CDC on request through state and local health departments.
Treatment is supportive. Prevention rests on avoiding tick bites in endemic areas.
VIRUSES OF THE FAMILY TOGAVIRIDAE
Several alphaviruses belonging to the family Togaviridae can cause a viral syndrome associated with rash and arthralgias or arthritis. Diagnosis requires serologic testing of paired acute-phase and convalescent-phase serum. Virus can also be isolated from or detected in acute-phase serum samples.
There are no vaccines available for general use against alphaviruses. Prevention depends on mosquito control and decreasing exposure to mosquitoes.
Barmah Forest Virus
Barmah Forest virus (family Togaviridae, genus Alphavirus) causes sporadic disease and epidemics in Australia.42 Clinically, Barmah Forest virus causes a Ross River virus-like illness, but the rash tends to be more florid, and true arthritis is less common. Outbreaks have coincided with Ross River virus outbreaks, and Barmah Forest virus has been identified in the same mosquito species as Ross River virus.42,62
Chikungunya (CHIK) virus (family Togaviridae, genus Alphavirus) is found in Africa and Asia and is transmitted by Aedes mosquitoes. After a 20-year hiatus, outbreaks of CHIK virus infection occurred in Indonesia from September 2001 to March 2003, suggesting a reemergence of the virus.63 In urban settings, the virus is transmitted from human to human via A. aegypti mosquitoes. Explosive urban epidemics occur during the rainy season. The native name for the disease means “doubled up,” because of the excruciating joint pains.
In patients with CHIK, after an incubation period of 2 to 4 days, there is a sudden onset of fever and crippling joint pains, accompanied by chills, flushed face, headache, myalgias, backache, and photophobia. Arthralgias are polyarticular, are migratory, and mostly involve the small joints. Papular or maculopapular skin rashes, typically on the trunk and limbs, usually occur during the second to fifth day of illness. The clinical picture resembles that of dengue fever, with which chikungunya is often confused.64 Most infections are probably asymptomatic. Arthralgias may last several months. In Asia, but not Africa, mild hemorrhagic manifestations have been reported; CHIK virus is not a cause of severe hemorrhagic disease. The diagnosis can be confirmed serologically by the CDC on request through state and local health departments. Confirmation by culture or detection of viral nucleic acid is possible early in illness.
There is no specific treatment for CHIK. Anti-inflammatory drugs may relieve arthralgia. Chloroquine phosphate has been used for refractory arthralgias. Prevention depends on mosquito control and decreasing mosquito exposure.
Mayaro (MAY) virus (family Togaviridae, genus Alphavirus) is closely related to CHIK virus and causes a similar illness. The virus has been isolated from mosquitoes (mostly Haemagogus) in various countries in the Caribbean and South America. Little is known about the natural history of the disease. MAY virus causes febrile illness with headache, backache, myalgias, epigastric pain, chills, nausea, photophobia, arthralgias, and maculopapular rash. Polyarthritis occurs and may persist for several weeks. Arthralgia may recur, as indicated in a report of a patient with a previous case of MAY virus infection.65 Cases of MAY disease have been imported into the United States.66 MAY virus infection should be considered in the differential diagnosis in patients with a recent travel history to South America. Diagnosis can be confirmed serologically by the CDC on request through state and local health departments.
O'nyong-nyong (ONN) virus (family Togaviridae, genus Alphavirus) was first isolated during an epidemic in Uganda in 1959 and spread to an estimated two million people in neighboring countries by 1962. Another ONN epidemic began in south-central Uganda in 1996.67 ONN virus is transmitted to humans by Anopheles and other mosquitoes. Clinically, ONN fever is similar to CHIK, although fever is less pronounced and lymphadenopathy is more common in ONN.
Ross River Fever
Ross River virus (family Togaviridae, genus Alphavirus) has caused so-called epidemic polyarthritis in Australia, southwestern Pacific Islands, and Fiji.42 Several species of Aedes and Culex mosquitoes are important vectors.42 The natural maintenance cycle of Ross River virus is not fully known. Although the magnitude, regularity, seasonality, and locality of outbreaks are wide ranging, rainfall seems to be the single most important risk factor.68 Humans have significant viremia, and the virus may follow a human-mosquito-human transmission cycle.69
After an incubation period of 2 to 21 days, the illness begins suddenly with myalgia and marked arthralgias in the small joints of the hands and feet. True arthritis occurs in over 40% of patients. A maculopapular rash occurs in 50% of patients within 2 days after onset. Myalgia, headache, anorexia, nausea, and tenosynovitis are common, but temperature is only slightly elevated. Arthralgia frequently persists for several weeks or longer—sometimes for longer than a year.
VIRUSES OF THE FAMILY FLAVIVIRIDAE
In addition to their role in hemorrhagic fever (see above), dengue viruses are a common cause of rash and arthralgia.70
OTHER VIRUSES CAUSING RASH AND ARTHRALGIA
There are a number of other viral zoonoses that cause similar nonspecific febrile illness in humans, but they occur infrequently or are rare. These include Igbo-Ora (family Togaviridae, genus Alphavirus) in Africa; Sindbis and Sindbis-like viruses (family Togaviridae, genusAlphavirus) in Africa, Asia, Australia, and Europe; Group C arboviruses (family Bunyaviridae, genus Bunyavirus) in South America; Oropouche (family Bunyaviridae, genus Bunyavirus) in South and Central America; Sandfly fever (family Bunyaviridae, genus Phlebovirus) in the Mediterranean, Middle East, West Asia, and South America; Zika virus (family Flaviviridae, genus Flavivirus) in Africa and Asia; and vesicular stomatitis virus (family Rhabdoviridae, genus Vesiculovirus) in the Americas.
Miscellaneous Viral Zoonoses
MONKEY B VIRUS DISEASE
Monkey B virus (Herpesvirus simiae or B virus) causes persistent latent infections in at least 70% of captive adult macaques. Monkey B virus disease in humans usually results from macaque bites or scratches; most documented infections have occurred in laboratory personnel working with apparently healthy rhesus, cynomolgus, or African green monkeys or their tissues, including kidney cell cultures.71 Human infection from a mucocutaneous exposure to the eye and one human-to-human transmission have been reported. In humans, monkey B virus causes acute ascending myelitis and fulminant meningoencephalitis, which leads to death within days.
Infection can be diagnosed in humans by demonstrating a rise in antibody titer and by isolating the virus from the CNS. Cardiopulmonary support is the most important aspect of management. Human infection carries a high mortality; however, patients treated early with intravenous acyclovir or ganciclovir have survived. Significant neurologic residua are common in survivors. Monkey handlers should wear protective clothing and a face mask.72 Bites, scratches, or mucosal surfaces exposed to macaque biologic materials should be cleansed thoroughly.69 Postexposure management should include referral to a medical consultant knowledgeable about monkey B virus.
RUMINANT AND PRIMATE POXVIRUS DISEASES
Several ruminant and primate poxviruses rarely cause human illness. Cowpox (vaccinia virus) is an orthopoxvirus related to variola. In humans, it produces vesicular lesions on the hands. Generalized infections are rare. Monkeypox, the only other orthopoxvirus of significance to humans, is enzootic in monkeys and squirrels in western and central Africa; infection in humans is sporadic and produces a vesicular rash similar to variola. Secondary infections occur. The case-fatality rate is 1.5%.73 Tanapox virus is a yatapoxvirus that causes vesicular lesions in monkeys along the Tana River in Kenya and Zaire. It produces a monkeypoxlike illness in humans. The parapoxviruses produce disease in humans through direct contact with infected animals. These include bovine papular stomatitis virus, milkers' nodule (pseudocowpox) in cattle, and orf in sheep and goats. Infection results in vesicles that progress to pustules and scabbing at the site of contact with the original infected species or contaminated objects.
NEWCASTLE DISEASE VIRUS INFECTION
Newcastle disease is an often fatal systemic infection of poultry that is caused by a paramyxovirus. The virus is occasionally transmitted to humans from infected birds or in the laboratory, presumably by direct inoculation. In humans, the illness appears as acute, sometimes hemorrhagic conjunctivitis without corneal involvement. It can be accompanied by lymphangitis, headache, malaise, and chills but is usually self-limited. Patients recover within 2 weeks.
VESICULAR STOMATITIS VIRUS INFECTION
Vesicular stomatitis virus is a rhabdovirus whose structure resembles that of rabies virus. The agent is responsible for oral ulcers in cattle. Occasionally, laboratory workers become infected and experience fever, vesicular enanthemas, headache, and myalgias.
Foot-and-mouth disease is a highly infectious viral infection of cloven-hoofed animals. The causative agent of the disease is aphthovirus, a member of the family Picornaviridae that is indistinguishable morphologically from rhinovirus. Persons contacting infected animals occasionally have fever, vesicular lesions on the hands, and an increase in neutralizing and complement-fixing titers. The infection is mild and transient, but relapses occur.
Editors: Dale, David C.; Federman, Daniel D.