Epidemiology

When the science of epidemiology of the nineteenth century was applied to the study of yellow fever, the epidemiologist was hampered by a lack of knowledge of infectious agents and of vector arthropods in the transmission cycle.

As can be seen in Table VIIL 10.3, a mysterious specificity exists between certain feeding arthropods and certain viruses; furthermore, a preferential feed­ing of certain arthropods (mosquitoes, for example) on certain food sources is shown. Some vertebrates react to a specific virus with severe disease. Yellow fever, for example, produces severe illness in hu­mans, laboratory white mice, rhesus monkeys, and Alouatta monkeys. On the other hand, yellow fever

Table VIIL 10.2. Size, morphology, structure, and composition of selected virus families or generathat contain arboviruses

Source: In part based on Theiler and Downs (1973); Field (1985); and Monath (1988).

may infect dogs, cats, Cebus monkeys, cows, and horses without producing overt disease. Among the encephalitides, eastern equine encephalitis (EEE) virus (endemic strains) can produce severe disease and death in human beings, laboratory mice, certain other vertebrates, and very specifically equines.

The resistance of various vertebrates to various arboviruses can be of use to the investigator because it permits the production of large quantities of im­mune sera in such vertebrates. Such immune sera are of minimal importance in treating disease in human beings, but are of cardinal importance in the design of specific serologic tests for virus identifica­tion. With the advent of cell culture techniques, lead­ing to the preparation of monoclonal antibodies to specific portions of a virus genome, identification work has been greatly broadened in scope and much narrowed in specificity, often providing in a matter of hours identification of a virus that would have required days or weeks for identification using older techniques.

Modem techniques, founded on studies carried out over a period of half a century, involving basic labora­tory techniques of complement fixation, precipita­tion, electrophoresis, centrifugation, hemagluti- nation inhibition, and virus neutralization, have been extended by later advances such as “tagged”

Table VIIL 10.3. Twenty-nine selected arboviruses important in causing human andJor animal diseases, with data on vectors, hosts, and geographic distributions

Table VIII.10.3. (cont.)

Abbreviations: ASF = African swine fever; CHP = Chandipura; CGL = Changuinola; CHIK = Chikungunya; CTF = Colorado tick fever; CHF = Crimean hemorrhagic fever; DENs = dengues (1,2,3,4); EEE = eastern equine encephalitis; HAN = Hantaan (Korean hemorrhagic fever); JBE = Japanese encephalitis; KFD = Kyasanur Forest disease; LAC = LaCrosse; MID = Middelburg; MVE = Murray Valley encephalitis; NSD = Nairobi sheep disease; ORO = Oropouche; PIRY = Piry; POW = Powassan; RVF = Rift Valley fever; ROC = Rocio; RR = Ross River; RSSE = Russian spring/ summer encephalitis; SFN = Naples sandfly fever; SFS = Sicilian sandfly fever; SLE = St.

Sources: Based in part on Calisher and Thompson (1985); Evans (1984); and Karabatsos (1975), among others.

antibodies - that is, the use of monoclonal anti­bodies in combination with “tagged probes” in elec­tron microscopy. Such new techniques, involving the use of specific “probes,” are presently a fertile area of research, from which is emerging a more rational and complete knowledge of the virus particle itself and its interactions with vertebrate and inverte­brate hosts.

Dengue

Geographic distribution of viruses and disease is determined by the characteristics of the vectors, rather than by the characteristics of the viruses. Taking dengue viruses (Flauiuirus genus) as an ex­ample, the limits of their distribution are defined by the limits of the distribution of the principal vector, Aedes aegypti. This mosquito, originally found in Southeast Asia, spread worldwide, traveling wher­ever humans traveled and established itself in tropi­cal and subtropical and often temperate regions, but not in Arctic and Antarctic polar extremes. The dengue viruses moved with the vectors and became established worldwide, particularly in tropical and subtropical regions. The viruses may have had, in their original territories of Southeast Asia, cycles involving A. aegypti and/or Aedes albopictus and subhuman forest primates, but as the virus left their original home, they adapted to a vector-human- vector cycle, allowing them to exist in endemic form wherever humans exist, and to appear in epidemic form at intervals.

The other Southeast Asian vector, A. albopictus, has of recent years established itself in other coun­tries such as the United States, with as yet unknown potential for involvement in the life cycles of still other viruses such as yellow fever. There are also other aedine vectors of dengue in Polynesia. The dengues are placed in four serotypes, one or more of which are associated with often fatal manifestations of dengue hemorrhagic fever and dengue shock syn­drome.

Yellow Fever

Yellow fever, a Flaviuirus serologically related to the dengues, is also capable of being transmitted from human to human by A. aegypti and can maintain itself endemically in a human population by such means. This mode of transmission occurred a cen­tury and more ago but has not been observed re­cently. The virus is found in Africa, south of the Sahara, and in the equatorial South American jun­gle regions. In both Africa and South America (here including Central America, and the West Indies), and even in the United States, Spain, France, Gi­braltar, and England, periodic outbreaks of the disease, often explosive and devastating, have been observed since A. aegypti may establish itself in sub­tropical and even temperate locales. Although A. aegypti (and A. albopictus) is prevalent in Asia and Australia, yellow fever has never established itself in these regions. With vectors present, as well as millions of nonimmune humans, there is a continu­ing threat of its introduction.

A reason yellow fever has been able to maintain itself in tropical South America and Africa is that the virus can utilize a different set of vectors: the forest canopy-frequenting Haemagogus mosquitoes of the New World, as well as A. aegypti and Aedes africanus, Aedes simpsoni, Aedes taylori, Aedes furcifer, and other aedines in Africa, often with and often without A. aegypti. Using the endemic Haemagogus or Aedes species, the virus remains established as an endemic virosis in various subhuman primates of these re­gions. This maintenance cycle is referred to as “syl­van” or “jungle” yellow fever. The sylvan Haemago- gus or Aedes can and often does bite humans, and thus can transfer the virus out of the mosquito­monkey-mosquito cycle into a mosquito-human- mosquito cycle.

A completely effective attenuated yellow-fever vac­cine (17D) has been available since 1935, but govern­ments in regions where yellow fever is endemic have as yet failed to react adequately in getting the popula­tion at risk immunized. The blame for this rests not on technical failure (the vaccine itself), nor on diffi­culties in administration of same, but in the inability of governments to establish adequate bureaucratic- administrative procedures to protect the health of the people. Aedes control projects, often employed for disease control, again suffer from a bureaucratic in­ability to maintain effective programs at a high level of efficiency over periods of years.

Encephalitides

Another group of the arboviruses, the encephalitides (Venezuelan, eastern, western, St. Louis, Japanese, Murray Valley, Russian spring-summer encephali­tis), present mechanisms quite different from the dengue or yellow fever models. The vectors in question — mosquitoes or ticks - are of themselves geographically delimited, and therefore, the specific viruses associated with specific vectors are geo­graphically delimited, with little chance of spread beyond natural ecological barriers. The viruses themselves have a basic vertebrate cycle in birds or small mammals. Certain of the viruses, such as Vene­zuelan equine encephalitis, eastern equine encepha­litis, and western equine encephalitis, can escape from the mosquite-small vertebrate-mosquito cycle and spread like wildfire in one or another of the larger vertebrates, causing widespread mortality, and humans may be thus involved.

In the central United States, a recent arrival on the virus scene, La Crosse virus, a member of the California virus group, has established its position as the commonest arboviral cause of encephalitis. This endemic disease has some unusual features. It is transmitted by woodland aedine mosquitoes, and has as vertebrate hosts certain small mammals of the region. It has been further established that the virus can be transmitted transovarially (TOT) from mosquito to mosquito, vertically, through the egg, and laterally, from female to male or from male to female during copulation. This mechanism has been hypothesized to explain the long persistence of virus in a vector, serving to carry it over periods of inclem­ent weather or drought. Similar TOT has been shown for dengue, Japanese encephalitis, and yellow fever.

Tick-bome encephalitis (Russian spring-summer encephalitis, RSSE) in the Eurasian continent and Powassan virus encephalitis in America are delim­ited by the range of specific tick vectors; these vi­ruses are endemic in small mammals and present themselves in humans as sporadic cases, often not distinguished from encephalitis caused by other vi­ruses or of unknown etiology except by special labo­ratory studies.

Epidemiology of arboviruses can be conceptual­ized as a huge, multidimensional matrix, involving many viruses on one axis, many vectors on another, many vertebrate hosts on another, and yet another axis for ecological, ethological, meteorological, cul­tural, and edaphic influences impinging on vectors and hosts.

Clinical Manifestations and Diagnosis

The early days of onset of most arboviral infections are usually accompanied by fevers, aching, and gen­eral malaise, and cannot be distinguished from early stages of other very common diseases such as influ­enza, malaria, measles, pneumonias, meningitis, other respiratory afflictions, and even Lassa fever and smallpox. As diseases progress in their course, specific later manifestations may provide aid in dif­ferential diagnosis. Such specific manifestations in­clude rashes, eruptions, nausea and vomiting, diar­rhea, cough, and encephalitis.

Sporadic cases in a population may be quite impos­sible to diagnose specifically. But as epidemics prog­ress, specific features may appear and provide the clue to diagnosis. Malaria in the tropics and influ­enza in temperate regions and the tropics serve as “coverup” or “umbrella” diagnoses that often block out recognition of arbovirus illness.

Definitive diagnosis demands the assistance of ex­perienced virologists working in adequate laboratory diagnostic facilities. There exist only a few dozen such facilities in the world, supported by the World Health Organization, governments, armed forces military establishments, and, in a few instances, pri­vate philanthropy. Such laboratories usually com­bine laboratory diagnostic methodology and facilities for carrying out field epidemiological studies.

Specific diagnosis can only rarely benefit the pa­tient, but is of vital importance in alerting health departments of the presence of a potentially threat­ening epidemic. Appropriate control procedures di­rected at the vectors can then be applied on an emer­gency basis. In the special case of yellow fever, mass immunization of exposed populations can success­fully halt an epidemic in its tracks. Such an immuni­zation campaign is usually combined with emer­gency mosquito control.