Viral Zoonoses Part 2

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 genus Hyalomma, 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.

Table 3 Arenaviruses That Cause Significant Human Illness

Virus	Disease	Geographic Distribution	Primary Host in Nature
Lymphocytic choriomeningitis virus	Lymphocytic choriomeningitis	Americas, Europe, parts of Asia	Mus musculus (house mouse)
Lassa virus	Lassa fever	West Africa	Mastomys species (rodent)
Junin virus	Argentine hemorrhagic fever	Argentina	Calomys musculinus (rodent)
Machupo virus	Bolivian hemorrhagic fever	Bolivia	Calomys callosus (rodent)
Guanarito virus	Venezuelan hemorrhagic fever	Venezuela	Zygodontomys brevicauda (rodent) Sigmodon alstoni (?) (rodent)
Sabia virus	Hemorrhagic fever	Brazil	Unknown

Diagnosis 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, epi-staxis, 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.20 Mortality ranges from 9% to 40%.

Treatment and prevention Treatment is supportive and focuses on the hemorrhagic manifestations. The antiviral drug ri-bavirin 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.

Hantavirus Infections

Hantaviruses (family Bunyaviridae, genus Hantavirus) are rodent-borne viruses causing human diseases known as hemor-rhagic fever with renal syndrome (HFRS) in Europe and Asia and as hantavirus pulmonary syndrome (HPS) in the Ameri-cas.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 patho-genicity and virulence of the virus.

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.

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 Han-taan virus, other hantaviruses causing HFRS are Seoul virus, Pu-umala 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 Ameri-cas.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].

Diagnosis 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 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 peninsu-la.14 RVF virus is a potential agent of bioterrorism.

Table 4 Viral Zoonoses Endemic in the United States

Disease	Region	Vector/Host	Clinical Manifestations
Colorado tick fever	Mountainous areas of western states	Wood ticks	Flulike illness, rash, leukopenia
Eastern equine encephalitis	Focal locations along eastern seaboard, Gulf Coast, and some midwestern states	Mosquitoes	Mild flulike illness to encephalitis
Hantavirus pulmonary syndrome	Most prevalent in southwestern states	Deer mice and other rodents (aerosol exposure to infected excreta, or bites)	Febrile, cardiopulmonary, diuretic, and convalescent phases
La Crosse virus	Widespread; most prevalent in rural upper Midwest	Mosquitoes	Mild flulike illness to encephalitis, often with focal seizures
Powassan virus encephalitis	Northeastern states	Ixodes ticks	Encephalitis, with localizing neurologic signs and convulsions
Rabies	All except Hawaii	Wild carnivores, bats	Encephalomyelitis
St. Louis encephalitis	All lower 48 states; epidemics in Midwest and Southeast	Mosquitoes	Febrile headache to encephalitis
West Nile virus infection	Eastern states	Mosquitoes	Febrile illness to encephalitis
Western equine encephalitis	Western states	Mosquitoes	Mild flulike illness to encephalitis

Diagnosis 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.

Diagnosis

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 hem-orrhagic 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 are-naviral 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.

Marburg Virus

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.

Ebola Virus

Epidemiology 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, Cote 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.

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.

Diagnosis 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 hem-orrhagic 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.

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

Encephalitis

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 www.cdc.gov/ncidod/dvbid/ index.htm and through state and local health departments.

Viruses of the family bunyaviridae

La Crosse Encephalitis

Epidemiology 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 involving Ae. 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].

Diagnosis 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

Epidemiology 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 Fla-vivirus) 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.

Diagnosis 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.

Prevention 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 at 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

Epidemiology 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 fla-viviruses, 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.

Diagnosis 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.

Prevention There is no vaccine for MVE virus. Prevention relies on mosquito control and avoidance of mosquito bites.

Saint Louis Encephalitis

Epidemiology St. Louis encephalitis (SLE) virus (family Fla-viviridae, 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.

Diagnosis 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 meningis-mus, 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 quadri-paresis, 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.