Most arboviruses are maintained in natural cycles of infection between vector insects or ticks and vertebrate hosts, with seasonal variations in cycle amplitudes related to extremes of humidity, temperature, and other environmental factors. The viruses may be carried through the winter or dry months by vertical transovarial transmission in vector mosquitoes, by transtadial transmission in ticks (across tick developmental stages, such as larval to nymphal to adult stage), or in persistently infected vertebrates; in tropical locations, transmission may occur continuously. A common pattern of enzootic transmission in a bird–mosquito cycle is illustrated in Figure 184.1. Human infections are most likely to occur in circumstances of intense viral transmission, when the virus “spills over” from the enzootic cycle. The enzootic foci of certain “place-specific” diseases, such as sylvatic yellow fever and Venezuelan equine encephalitis, may be maintained in relatively remote or inaccessible locations, so that humans are infected when they impinge on these otherwise isolated locations. Epizootic or bridging vectors are required to transmit infection to humans or other dead-end hosts in such diseases as EEE, for which the enzootic vector exhibits a narrow “biting preference” limited to the amplifying host. A different vector, therefore, is needed to deliver the virus to humans. Vertebrate-amplifying hosts must sustain viremias of sufficient titers (e.g., 10⁴ pfu/mL or higher) and for sufficient periods (e.g., 3 to 5 days) to provide sufficient opportunity for enzootic vectors to become infected. Certain arboviruses, notably yellow fever, dengue, chikungunya, and Oropouche viruses, produce sufficient viremias in humans that anthroponotic (vector-borne interhuman) transmission is possible, with the possibility of pure human-driven epidemics occurring. In Africa, yellow fever epidemics arise when viremic persons traveling from areas of enzootic virus transmission introduce the virus into urban areas, where peridomestic breeding Aedes aegypti mediate a human–mosquito–human cycle.

The transmission cycles of many arboviruses are complex and not understood fully. (More detailed characterizations of the individual viruses are given in the Suggested Readings.) Several of the diseases mentioned in this chapter are zoonoses in which infections arise through direct contact with infectious material (e.g. blood, excreta, respiratory secretions) from a reservoir host. The arenaviruses, which cause Lassa and other hemorrhagic fevers and lymphocytic choriomeningitis, and the hantaviruses are spread from persistently infected rodents to humans. Human infection acquired from bats with Rio Bravo virus, Duvenhage virus, and Issyk-kul virus, and from shrews with Mokola virus are examples of uncommon viral zoonoses. Omsk hemorrhagic fever has been transmitted from infected muskrats to trappers during skinning, and RVF and Congo-Crimean hemorrhagic fever (CCHF) from infected livestock to herders and to butchers during slaughter, as well as by contact with the infectious ticks. Person-to-person transmission of CCHF and Ebola, Marburg, and Lassa viruses has led to sizable outbreaks associated with high mortality rates (some greater than 90%). Person-to-person transmission is facilitated in settings or by occupations associated with very close contact, especially health care delivery.

Effective clinical diagnosis of these viral infections requires a detailed case history to determine the patient’s possible exposures and their relationships to established incubation periods for these infections. In general, arboviral infections are acute and preceded by an incubation period ranging from several days to no more than several weeks. A longer interval suggests an alternate diagnosis. A detailed list should be made of the dates and places of travel, the kinds of habitats encountered, dwellings occupied, and the activities in which the patient was engaged, in addition to any history of military service and residence in tropical areas (where previous asymptomatic infections may have been acquired). The evaluation should include a careful assessment of immunization history, including yellow fever, JE, or other arboviral vaccines.

Most arboviral infections produce a nonspecific febrile illness, and specific laboratory tests are needed to confirm their diagnosis. Often, patients are seen after the acute phase of illness, and serology is the only means by which the diagnosis can be made; however, several arboviruses, including those of dengue, chikungunya, yellow fever, Venezuelan equine encephalitis, and Colorado tick fever, can circulate in the blood for several days, whence they can be recovered in the acute febrile phase of the illness. Suckling mice, primary duck embryo cells, and continuous mosquito cell lines (e.g., C636) are especially sensitive systems for recovering most arboviruses, but Vero cells, which are more widely available, are an adequate system for viral culture in most cases. The intrathoracic inoculation of Toxorhynchites mosquitoes is a sensitive system for the isolation of dengue and yellow fever viruses. Neurotropic arboviruses should be sought by real-time polymerase chain reaction (PCR) of cerebrospinal fluid (CSF). Viral culture, immunohistochemical studies, or electron microscopy should be undertaken when a brain biopsy is obtained from patients with suspected viral encephalitis.

In most instances, the detection of viral-specific IgM in serum is the most rapid approach to making a presumptive laboratory diagnosis. Its detection in the CSF, reflecting an intrathecal antibody response, is diagnostic of acute central nervous system (CNS) infection, whereas IgM in a single serum specimen provides only a presumptive diagnosis, because specific IgM may persist beyond a single transmission season in some individuals. Infection is confirmed serologically by demonstrating seroconversion (i.e., fourfold or greater change in titer) in appropriately timed serum specimens. The diagnosis is considered presumptive if a high titer is present in a serum pair or in a single serum specimen. Indirect immunofluorescence (IF) is used widely to measure IgM and IgG antibodies. Although IgG assays are sensitive, serologic cross-reactions to viruses within a taxonomic group frequently are encountered. The hemagglutination inhibition (HI) test, using goose erythrocytes, is a sensitive but broadly reactive assay for those arboviruses that exhibit the property of hemagglutination. Heterologous reactions may be encountered in patients previously infected by related viruses. The complement fixation (CF) test is more specific but is not entirely sensitive, because the antibody response is slow and unpredictable, and it can result in false-negative results. Although, in general, neutralization tests provide the highest specificity, they are inconvenient to perform.

The direct detection of viral genomic material or antigens in blood or other fluids is an important alternative to serology in diagnosing Ebola and other hemorrhagic fevers. Circulating antibodies against theses viruses may not be detectable for several weeks, and infection may cause death before the patient has had time to develop detectable antibodies. Establishing the diagnosis rapidly in the acute phase of illness is important for timely decisions to be made regarding both therapeutic management of the individual patient and public health and infection-control requirements to prevent additional cases. PCR analysis of acute serum samples is a sensitive and specific approach to laboratory diagnosis of dengue fever, Venezuelan equine encephalitis, O’nyong nyong, Ebola, and other infections producing relatively high viremia levels. In addition, viral particles can be visualized by electron microscopy on tissue culture supernatant after successful viral culture, offering useful information for several pathogens with distinctive morphologies. Viral antigens also can be visualized directly by immunohistochemistry in fixed or frozen tissues.

Serologic diagnostic testing is available through several private diagnostic laboratories, state health department laboratories, some university laboratories, and the U.S. Army Medical Research Institute of Infectious Diseases. Assays for all these agents, including viral isolation and viral antigen or genomic detection, are available after consultation from the Centers for Disease Control and Prevention (CDC). Until the specific etiology of a viral hemorrhagic fever is determined, all testing is performed best in a biosafety level 4 facility, because most of these agents are aerosol-infectious in a laboratory setting.

Cases of arboviral encephalitis should be reported to state health departments. Available public health control measures can reduce their transmission and epidemic threat. Because of the possibility of nosocomial transmission occurring and the availability of diagnostic assays, all suspect cases of viral hemorrhagic fever should be reported to the Special Pathogens Branch, CDC. Until the specific etiology of a viral hemorrhagic fever is determined, all testing should be performed in a biosafety level 4 (BSL-4) because of the high risk of occupational laboratory transmission occurring and the possibility of person-to-person spread of some of these viruses. High-risk laboratory procedures, such as centrifugation, which can generate infectious aerosols, require special precautions. All wastes and exhaust from BSL-4 facilities are sterilized before leaving the facility. Inactivated aliquots of a specimen can be removed from the BSL-4 facility for further assessment. Because of the transmissibility and potential severity of illnesses caused by many of these pathogens, appropriate reporting of cases is an important aspect of diagnosing. The laboratory diagnoses of arboviral encephalitis should be reported to the state health department so that public health measure (e.g., vector control) can be applied to reduce the risk of further transmission and a possible epidemic. Any suspected case of viral hemorrhagic fever poses a high risk of health care–associated transmission
(e.g., to other patients, health care personnel, and laboratory personnel) and should be reported immediately to the viral Special Pathogens Branch, CDC, for appropriate diagnostic assessment.

Research on therapeutic modalities has focused on the treatment of the hemorrhagic fevers because of their high case-fatality rates. In controlled trials of adults, ribavirin reduced mortality and morbidity rates in Lassa fever and hemorrhagic fever with renal syndrome (HFRS), and anecdotal experience suggests possible efficacy in Argentine hemorrhagic fever and CCHF. Immune plasma is an effective therapy for Argentine hemorrhagic fever, and passive immunization has been used empirically in the therapy or prophylaxis of other hemorrhagic fevers and after laboratory exposure to certain arboviruses. Immune globulins are available for CCHF and for tickborne encephalitis (TBE), but use of the latter in post-exposure prophylaxis and treatment of TBE has been associated with exacerbated illness in some cases. Although similar adverse experiences have not been reported in a limited number of JE and WNE cases treated with passive immunization, caution should be exercised. In one controlled trial, interferon alpha-2a therapy failed to improve the outcome of JE cases.

Supportive therapy for patients with encephalitis necessitates close attention to monitoring intracranial pressure (ICP), cardiorespiratory function, and fluid and electrolyte balance. Inappropriate secretion of antidiuretic hormone and hyponatremia is a frequent complication of arboviral encephalitis. Although patients with EEE, JE, and other arboviral infections of the CNS frequently exhibit clinical signs of elevated ICP, one controlled study of JE demonstrated that dexamethasone therapy did not improve outcome. Convulsions may be the initial presentation in some arboviral CNS infections, and status epilepticus is a complication in some cases; appropriate cardiorespiratory support, correction of metabolic disorders, and anticonvulsant therapy with lorazepam should be instituted promptly.

Vaccines licensed in the United States or Europe are available for three arboviral infections: yellow fever, JE, and TBE. Attenuated yellow fever vaccine and inactivated JE vaccine (produced in Japan) are licensed and commercially available in the United States for use by travelers. Inactivated vaccines for TBE are produced in Europe and are used widely in some countries. Because the risk of acquiring TBE is low for most travelers, vaccination is not recommended routinely, and the vaccine is not available in the United States. Vaccines to prevent hemorrhagic fever with renal syndrome and Kyasanur Forest disease are licensed in Asia. Vaccine development is under way for WNE, dengue, and Ebola hemorrhagic fever, although not necessarily
for travelers’ use. Inactivated, canarypox-vectored and noted DNA equine vaccines for WNE are available commercially.

Vector-borne infections can be prevented by avoiding at-risk locations during transmission seasons or at high-risk times of the day (e.g., avoiding outdoor activity during the period when mosquito vectors are active). Use of protective clothing and repellents can reduce arthropod exposure and bites. Repellents containing picaridin (also known as icaridin or Autan^® internationally) and DEET are the most effective formulations; oil of lemon eucalyptus may be as effective as low concentrations of DEET but it should not be used in children <3 years. N, N-diethyltoluamide (DEET)-containing repellents have been used widely since the 1960s, but picaridin, a designer molecule based on DEET, has equal or better repellent activity. In high concentrations, DEET can irritate the skin and produce deep ulcerations. Cases of encephalopathy, including fatal cases, have been reported in children from ages 17 months to 8 years after exposures to formulations containing as little as 10% DEET. Although percutaneous exposure was prolonged in most cases, small quantities and limited exposure have been associated with encephalopathy.

Permethrin [0.5%, Permanone (Louiston International Corp., Easton, PA)] sprayed on clothing and bed nets effectively repels and kills mosquitoes and ticks, and impregnated material remains effective even after several washings. Permethrin shampoo [1%, Nix (Warner Lambert, Morris Plains, NJ)] and permethrin cream [5%, Elimite (Allergen, Inc., Research Triangle Park, NC)] are approved for use on children older than 2 years of age to treat head lice and scabies, and permethrin has been used topically in powders and soaps to repel or kill body lice and other insects. Presumably, these preparations could be used on skin as protection against mosquitoes and ticks. Citronyl, derived from citronella oil, may be more effective than DEET in repelling certain sandflies.

Other simple measures that reduce exposure to vector mosquitoes include covering exposed areas with clothing, avoiding outdoor activities at dusk and dawn when certain vectors are most active, and using mosquito bed nets and insecticidal room sprays. Ordinary insect nets and screens do not have a mesh sufficiently fine to exclude sandflies, which require finer meshes or permethrin-impregnated nets or clothing. When traveling in tick-infested areas, frequent inspection to remove adherent ticks from clothing, gear, and the body (including the scalp) is recommended.

From a public health perspective, arboviral diseases can be prevented or controlled by combining several approaches, including the elimination or reduction of vector mosquito–breeding sources, periodic application of larvicides or adulticides to reduce mosquito populations, and the emergency application of adulticides to lower vector populations in the face of an epidemic. Specific strategies are tailored to the breeding habitat and habits of individual vectors (Table 184.4).

Several arboviruses (e.g., WNE and St. Louis encephalitis) are transmitted to human populations only after an extensive period of amplification in natural reservoirs (e.g., birds). Surveying transmission in mosquitoes and birds helps to anticipate the likelihood of epidemic transmission occurring, allowing emergency vector control measures to be instituted at an early stage.

Certain arboviral and related zoonotic diseases of public health significance have been grouped below according to the major syndromes with which these agents generally are associated, although overlapping syndromes are common findings.

Viral hemorrhagic fever (VHF) is a loosely defined category that includes infections from a number of viruses causing similar clinical syndromes and sharing a similar severity of disease. However, these viruses are dissimilar in many ways, including their taxonomy, reservoir hosts, and, thus, geographic distributions. Risk factors for exposure also vary among the infections, and specific control methods are required. Although the signs and symptoms of individual VHFs may overlap, their pathogenesis may not; thus, therapeutic approaches may differ as well.