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VIRAL ZOONOSES

Author(s)

DUANE J. GUBLER SC.D.
LYLE R. PETERSEN M.D., M.P.H.

August 2002

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Introduction

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].

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 (time between ingestion and transmission of the virus) is usually 8 to 12 days, depending on environmental factors, the virus, and the vector species.

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. 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

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

Dengue Fever

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

Epidemiology

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 at www.cdc.gov/ncidod/dvbid/dengue/index.htm. In many urban centers, multiple virus serotypes cocirculate (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. A. aegypti became 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 A. albopictus, A. polynesiensis, and A. scutellaris. These secondary vector species can transmit dengue viruses during outbreaks, but they are more important as maintenance vectors.

Diagnosis

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

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

Epidemiology

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

Pathogenesis

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).5 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, which suggests that 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.1,3,5-8 Hemorrhage may occur without vascular leakage, suggesting another pathogenetic mechanism.3,9

Diagnosis

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 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 Currently, disease prevention depends exclusively on mosquito control and personal protective measures such as mosquito repellents.

Yellow Fever

Epidemiology

Yellow fever (YF) 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, YF 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 and A. aegypti as the principal vector. In the past 30 years, A. aegypti has reinvaded Central and South America, putting the American tropics at the highest risk for urban epidemics of yellow fever in over 50 years. Epidemics in Africa often occur in moist savanna regions, involving forest or peridomestic Aedes mosquitoes and humans as viremic hosts. In dry areas and urban centers where water storage practices promote the breeding of domestic A. 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.

Diagnosis

YF varies from an inapparent infection to a deadly fulminating hemorrhagic disease. Three clinical stages are commonly recognized: infection, remission, and intoxication.12,13 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.14 At autopsy, the organs most affected are the liver, spleen, kidneys, and heart. Typically, the liver shows midzonal hyaline necrosis and Councilman inclusion bodies.

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