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- * Introduction * Theoretical Considerations * A Historical
Perspective * Examples of Emerging & Potentially Emergent Viruses
* Arbovirus Diseases * Aetiology * Epidemiology * Transmission * Immunity
* Active Immunity * Passive Immunity * General Clinical Features * Ecological
Factors
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- CASES IN POINT: * HANTAVIRUSES: * Hantaan virus * Seoul
virus * Four Corners virus * Ebola virus * Influenza virus: A model
for emergence * Mutation Frequency * Selective Pressures & Constraints
* Conclusion * References
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- INTRODUCTION
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- Within the last decade there has been an ever increasing
awareness of the Darwinian struggle with which the human species is engaged.
Microbial and viral predators abound, in no less abundance than before,
and still present a constant threat to individual survival as well as
to the success of the population at large. Following decades of general
complacency in the antibiotic era, a startling turning point has been reached,
spurred in large part by the global ravages of the human immunodeficiency
virus (HIV) - one of the simplest of viral constructs - which still evades
cure or even true understanding. The last two years have been accented
by several striking episodes of disease emergence, such as multi-drug
resistant tuberculosis, acute coccal infections, the rodent-borne pneumonic
hantavirus in the United States, food- and waterborne outbreaks of Salmonella
infections, cholera and illnesses caused by the Shigella-like Escherichia
coli O157. Against these newer threats is a perpetual backdrop of a multiplicity
of infections, which cycle throughout their ecological niches and are
encountering opportunities in our modern world to spread with a frightening
vigour. Currently, we are experiencing the epidemic potential of HIV,
but the next epidemic of human disease may be entirely different. A few
examples of general emerging infectious diseases are shown below:
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- Examples of Emerging Infectious Diseases:
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- USA: * E. coli O157:H7 disease * Cryptosporidiosis *
Hantavirus pulmonary syndrome * Coccidioidiomycosis * Vancomycin-resistant
enterococci and multiply-resistant pneumococci
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- International: * Vibrio cholerae O139 in Asia * Vibrio
cholerae O1 in Latin America * Yellow fever virus in Kenya * Rift Valley
fever virus in Egypt E coliO157:H7 disease
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- To quote Donald A.Henderson of the U.S. Office of Science
and Technology Policy: "The recent emergence of AIDS and Dengue hemorrhagic
infections, among others, are serving usefully to disturb our ill-founded
complacency about infectious diseases. Such complacency has prevailed
in this country (USA) throughout much of my career... It is evident now,
as it should have been then, that mutation and change are facts of nature,
that the world is increasingly interdependent, and that human health and
survival will be challenged, ad infinitum, by new mutant microbes, with
unpredictable pathophysiological manifestations...How are we to detect
these at an early date so as to be able to devise appropriate preventative
and therapeutic modalities? What do we look for? What types of surveillance
and reporting systems can one devise?" (Morse 1993).
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- The Centers for Disease Control and Prevention (CDC),
in an attempt to ensure that its prevention and control programs keep
pace with the numerous and changing health problems that threaten all
segments of our diverse society, has identified four priority areas: 1.
strengthen core public health functions; 2. develop, maintain, and enrich
the capacity to respond to urgent threats to health; 3. develop a nationwide
prevention network and program; and 4. promote women's health.
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- Leading the list of urgent threats to health are new
and emerging infections. It must be recognized that the health of the
developed world's people is inextricably linked to the health of people
in other nations, infectious diseases can and do disseminate rapidly around
the globe, and global surveillance for emerging infections is vital to
public health. While it is vital for us to recognize and promote this
awareness, we too have an integral role to play in surveillance and basic
research.
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- There seems to be two stages in public health crises.
The first is, "I don't believe you." And the second is "Why
didn't you tell me?" (Dowdle 1994). Everyone tends to think in very
short terms. Although officials need to recognize and respond to the critical
`disease of the year', it is also necessary to maintain the infrastructure
needed to identify emerging diseases as well as to develop effective ways
for combating them. The problem can be made more difficult when resources
are set aside for the spotlighted problem without ensuring that the less
glamorous infrastructure needs to continue to be met. In this essay I
will attempt to address these issues, as well as to highlight appropriate
examples of emergent disease, particularly those of viral origin.
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- THEORETICAL CONSIDERATIONS
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- Joshua Lederburg has commented that viruses are humanity's
only real competitors for dominion of the planet, serving as both parasites
and genetic elements in their hosts (Lederburg 1988). Not only do they
have considerable plasticity, enabling them to evolve in new directions,
but their genetic and metabolic entanglements with cells uniquely positions
them to mediate subtle, cumulative evolutionary changes in their hosts
as well. In contrast, they are also able to decimate entire populations.
The fact that long term natural selection favours mutualism offers only
limited encouragement to our species, with millions of people suffering
before an equilibrium can be reached.
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- Coevolution of viruses and host can follow several possible
lines estimated by modelling techniques, and pathogens may not always
evolve towards lower virulence. For example, a virus strain that kills
much faster will not be favoured over a less virulent strain if it has
a modest transmission advantage, but it will prevail if it is much more
readily transmitted than the less-virulent strain. In the trade-off between
transmissibility and virulence, many viruses evolve toward a middle ground,
favouring transmissibility but allowing them to retain some virulence.
Viruses that are transmitted over a long time, for example HIV, have
a selective advantage even when their effective rates of transmission are
relatively low (Anderson and May 1987).
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- However, although mathematical approaches offer useful
insights, they are often inadequate in predicting outcomes because viral
emergence and host interactions are so complex, being dependent on both
the genetics of the host and external conditions. These predictive attempts,
a true test for chaos theorists, have even more variables than say, equations
dealing with predictions of meteorological patterns, because such climatic
conditions make up just one part of the ecological picture within which
biological evolution maneuvers. Furthermore, stock market predictions,
another favourite of chaos theorists, can also be seen to form just one
piece of the puzzle that is infectious disease, as many of our responses
to the latter problem are politically and financially interwoven.
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- A HISTORICAL PERSPECTIVE
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- New patterns of human movement, leading to new contacts
across what had once been geographic boundaries, have been seen to give
rise to a variety of emergent infections. Examples are the introduction
of smallpox into the Americas and of syphilis into Europe. Yellow fever
probably emerged in the New World as a result of the African slave trade,
which brought Aedes aegypti in water containers of ships. Similarly, the
rise of Dengue hemorrhagic fever in Southeast Asia in the late 1940s is
attributed to rapid migration to cities with open water storage, which
favoured proliferation of the mosquito or other suitable vectors. Of current
concern in the USA is the fact that Aedes albopictus, an aggressive and
competent dengue virus vector, was brought to Houston in used Asian tires
and has established itself in at least 17 American states (Morse and Schluederberg
1990).
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- RECENT EXAMPLES OF EMERGING AND POTENTIALLY EMERGENT
VIRUSES
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- Most emergent viruses are zoonotic, with natural animal
reservoirs a more frequent source of new viruses than is the spontaneous
evolution of a new entity. The most frequent factor in emergence is human
behaviour that increases the probability of transfer of viruses from their
endogenous animal hosts to man. Rodents and arthropods are most commonly
involved in direct transfer, and changes in agricultural practices or
urban conditions that promote rodent or vector multiplication favour increased
incidence of human disease. Other animals, especially primates, are important
reservoirs for transfer by arthropods. Because arthropod transmission
plays a very large part in infectious animal disease, specifically potential
emergent virus epidemics, I will dedicate the next part of this essay to
a discussion of them.
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- ARBOVIRUS DISEASES
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- Approximately 100 of the more than 520 known arthropod-borne
viruses (arboviruses) cause human disease. At least 20 of these might
fulfill the criteria for emerging viruses, appearing in epidemic form
at generally unpredictable intervals (Morse and Schluederberg 1990). These
viruses are usually spread by the bites of arthropods, but some can also
be transmitted by other means, for example through milk, excreta or aerosols.
The arbovirus infections are maintained in nature principally, or to an
important extent, through biological transmission between susceptible
vertebrate hosts by blood-sucking insects; they multiply to produce viraemia
in the vertebrates, multiply in the tissues of the insects and are passed
on to new vertebrates by the bites of insects after a period of extrinsic
incubation. The names by which these viruses are known are often place
names such as West Nile or Rift Valley, or are based on clinical characteristics
like yellow fever.
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- AETIOLOGY
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- Most arboviruses are spherical, measuring 17-150 nm or
more, a few are rod-shaped, measuring 70 x 200 nm. All are RNA viruses.
Many circulate in a natural environment and do not infect man. Some infect
man only occasionally or cause only a mild illness; others are of great
clinical importance causing large epidemics and many deaths. Specifically,
these belong to the Togaviridae, the alphaviruses, flaviviruses, the Bunyaviridae,
nairoviruses, phleboviruses and other subgroups.
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- EPIDEMIOLOGY
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- Vertebrate hosts
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- Maintenance, incidental, link and amplifier hosts are
categorized according to Stickland Hunter's "Tropical Medicine"
(1991) as the following:
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- Maintenance hosts are essential for the continued existence
of the virus, usually living in symbiosis with the viruses, without actual
disease, but they do develop antibodies. These include birds such as the
prairie chicken, pigeon and wood thrush which transmit Eastern and Western
equine encephalitis; heron and egrets transmitting Japanese encephalitis
and migrating birds which travel over long distances carrying these and
other similar viruses; rodents and insectivores such as rats, hedgehogs,
lemmings and chipmunks are known to carry louping ill and Colorado tick
fever; primates such as monkeys which carry Dengue fever; Leporidae (rabbits
and hares) which carry Californian encephalitis; Ungulates (cattle and
deer) which are implicated in the transmission of European tick-borne encephalitis;
bats which carry Rio Brava virus; and marsupials, reptiles and amphibia
such as kangaroos and snakes which also harbour encephalitis-causing viruses.
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- Incidental hosts become infected, but transmission from
them does not occur with sufficient regularity for stable maintenance.
Man is usually an incidental host, often, but not always, being a dead
end in the chain. These hosts may or may not show symptoms. Link hosts
bridge a gap between maintenance hosts and man, for example, between small
mammals and man by goats (via milk) in tick-borne encephalitis. Amplifier
hosts increase the weight of infection, as is the case with pigs which
act between wild birds and man in Japanese encephalitis.
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- The populations and characters of the vertebrate hosts
and their threshold levels of viraemia are important. Small rodents multiply
rapidly and have short lives, thus providing a constant supply of susceptible
individuals. In contrast, monkeys and pigs multiply slowly, and once they
have recovered from an infection, remain immune for life. African monkeys
are relatively resistant to Yellow Fever, but Asian and American monkeys
are susceptible, probably because, unlike the African monkeys, they have
not been exposed continuously for centuries to the infection. Also, possibly
related arboviruses may offer partial immunization.
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- Invertebrate hosts
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- Mosquitoes, sandflies and ticks may imbibe virus from
a vertebrate in a state of viraemia, after which the virus undergoes an
incubation period within the arthropod, known as the extrinsic incubation
period. In mosquitoes this period is short: 10 days at 30o C ambient temperature
and longer at lower temperatures. Mosquitoes remain infective for life
without any apparent ill-effects. In fact, their infectivity appears to
increase with time after infection and their effectiveness as transmitters
depends upon the frequency with which they bite. It is also possible that
arthropods, whose mouth parts are contaminated by virus in the act of
feeding, could transmit the virus mechanically if they feed soon afterwards
on another animal. For instance, chikungunya virus can be transmitted
mechanically by A. aegypti for 8 hours after infection. In general, mosquito-borne
viruses may not use ticks as vectors nor can tick-borne viruses reside
in mosquitoes.
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- TRANSMISSION
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- Arthropod transmission involves several stages: 1. Ingestion
by the arthropods of virus in the blood (usually) or tissue fluids of the
vertebrate hosts 2. Penetration of the viruses into the tissue of the
arthropods, in the gut wall, or elsewhere after passing through the gut
barrier 3. Multiplication of the viruses in the arthropod cells, including
those of the salivary glands.
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- Stage 2 and part of stage 3 represent the extrinsic incubation
period of the disease (Hunter 1991). The quantity of blood, and therefore
the amount of virus ingested, seems to be important as each arthropod
species must ingest a minimum quantity of a given virus before multiplication
can take place. The same mosquito species can have two different thresholds
for two different viruses and if one species has a low threshold, other
species may have high thresholds or may be completely resistant. This
threshold phenomenon is extremely important in determining the efficiency
of a vector and may also vitally affect the course of an epidemic. Viruses
reportedly persist in overwintering mosquitoes, while transovarian passage
of virus has been seen in some tick species. For mosquitoes the availability
of suitable breeding places (and therefore rainfall) is a major factor.
An efficient vector may have a wide range of animals on which to feed,
but if the arthropod species is abundant, and even if it bites man only
infrequently in the presence of other (and preferred) animals, the large
numbers enable it to maintain transmission to man. For example, Culex
tritaeniorhynchus, which mostly bites birds, Bovidae, dogs and especially
porcines, and only to a limited extent man, can maintain transmission of
Japanese encephalitis from pigs to man by sheer numbers.
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- Although transmission of arboviruses usually takes place
through the bites of arthropods, Lassa virus, for example, may be transmitted
through contact with excreta of infective rodents, and others via urine
or faeces infecting the nasopharynx, some through aerosol from a patient
or others by one bird pecking another.
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- IMMUNITY
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- After a vertebrate has been infected, the arbovirus
probably multiplies first in the regional lymph glands where the earliest
formation of antibodies also probably takes place. Some do not produce
high titres of antibodies in man and some antibodies are short-lived or
appear late. In diagnosis, haemagglutination-inhibiting and complement-fixing
antibodies are important, but the only protective antibody is of the neutralizing
type, which is also the most specific.
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- Arboviruses are grouped according to antigenic characters,
but after inoculation of one virus into a fresh animal, not only the homologous
antibodies, but also heterologous antibodies reacting with other viruses
of the same group tend to appear. Recovery from an infection by a member
of one group of arboviruses may provide some degree of resistance to a
subsequent infection by another member of the same group. For example,
infection with West Nile virus may have modified the Ethiopian epidemic
of Yellow Fever in 1962. Again, the effect of prior infection with Zika,
Uganda S and other related viruses in the forest belt of Nigeria, leading
to a high incidence of related antibodies, is suggested as the explanation
of the absence of epidemic Yellow Fever in man in that area. These related
infections probably modify the disease rather than prevent infection.
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- ACTIVE IMMUNITY
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- With Yellow Fever, neutralizing antibodies can be found
as early as a few days after the beginning of the disease and are found
constantly for many years in the sera. The persistence of immunity does
not depend on exogenous reinfection. It is probable that a mosquito infected
with Yellow Fever is not harmed by it, but continues to excrete the virus
throughout life. This means a continuous supply and release of virus, probably
from the epithelial cells of the salivary glands. The virus enters man
(or other animals) and gains the liver and other epithelia, provoking
the early antibodies in the blood, which neutralize circulating viruses.
But, as suggested by Hunter (1991), antibodies which can be detected for
so many years in man must stem from a continuing stimulus, and the sensitive
cells and their progeny probably have a prophase equivalent of the virus
incorporated into their genome, with occasional reversion to productive
development which provides the stimulus for further antibody formation.
A degree of immunity of this kind may possibly be provided when a related
virus invades epithelial cells.
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- PASSIVE IMMUNITY
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- Infant rhesus monkeys and human infants born of mothers
immune to Yellow Fever have transient protective antibodies in their sera
at birth which persist for several months. They are probably placentally
transferred, rather than coming from the mother's milk, because antibodies
may disappear from infant sera while they are still suckling. Passive immunity
induced by injection of homologous immune serum, has been used for protection
against tick-borne encephalitis in cases of special risk and similar sera
could be used against other infections, particularly after laboratory
or hospital accidents.
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- GENERAL CLINICAL FEATURES
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- Most arbovirus infections are inapparent, that is they
produce no symptoms or often only mild ones (fever and occasional rash).
For example, in an epidemic of Japanese encephalitis it was estimated
that for each case of apparent disease there were 500-1000 inapparent
infections. If clinical manifestations arise after infection they do so
after an intrinsic incubation period lasting from a few days to a week
or more. Some arboviruses damage the endothelial lining of the capillaries
increasing permeability which allows the virus to pass the blood brain
barrier causing meningoencephalitis. Others damage the parenchymatous
organs by direct damage to the cells in which they are situated, while
with others damage is caused by the immune system of the host from the
formation of antigen- antibody complexes and disordered complement formation
which damage the renal tubules and alter the coagulation and fibrinolytic
systems of the body causing haemorrhage (viral hemorrhagic fevers). There
is a general pattern of biphasic illness, the first phase associated with
viraemia ending when antibodies appear in the blood and the second phase
when the virus is located in organs, such as the liver or brain.
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- The onset of clinical manifestations is usually abrupt,
generally occurring after the onset of viraemia. Fever is usual and is
sometimes the only sign. In many cases the clinical manifestations last
only while the virus is disseminated, but in other cases there is remission,
short or long. If long, the disease is biphasic. After this, fever returns
with signs indicating localization of the virus in certain organs. If
the period of viraemia has been symptomless and the virus becomes localized
in the central nervous system, encephalitis appears. In hemorrhagic cases
there is a special risk of shock which can rapidly become irreversible
unless promptly treated (Hunter 1991).
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- ECOLOGICAL FACTORS
-
- Microorganisms and viruses are adapted to extremely diverse
econiches. One of the most complex sets of adaptive characteristics concern
arthropod transmission of viruses. The arthropod-borne viruses are spectacular
examples of emergence and re-emergence resulting from innocent environmental
manipulation or natural environmental change. Deforestation, amateur irrigation
and the introduction of new species (usually livestock) gives rise to
many virus disease threats of humans and animals. Important aspects of
ecological change and their relation to arbovirus life cycles are: 1.
Population movements and the intrusion of humans and domestic animals into
new arthropod habitats, particularly tropical forests 2. Deforestation,
with development of new forest-farmland margins and exposure of farmers
and domestic animals to new arthropods 3. Irrigation, especially primitive
irrigation systems, which are oblivious to arthropod control 4. Uncontrolled
urbanization, with vector populations breeding in accumulations of water
(tin cans, old tires etc.) and sewage 5. Increased long distance air travel,
with potential for transport of arthropod vectors 6. Increased long-distance
livestock transportations, with potential for carriage of viruses and arthropods
(especially ticks) 7. New routing of long-distance bird migration brought
about by new man-made water impoundments (Murphy 1994).
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- To illustrate the effect ecological change can have on
the emergence of a new disease and the course of it afterwards one can
look to dengue, one of the most rapidly expanding diseases in tropical
parts of the world, with millions of cases occurring each year. For example,
Puerto Rico had five dengue epidemics in the first 75 years of this century,
but has had six epidemics in the past 11 years, at an estimated cost of
over $150 million. Simultaneously, Brazil, Nicaragua and Cuba have had
their first major dengue epidemic in over 50 years, involving multiple
virus types. At the lethal end of the dengue spectrum is dengue haemorrhagic
fever, first occurring in the Americas in 1981. Since then, 11 countries
have reported cases, and since 1990 over 3000 cases have been reported
annually. Figure 3 illustrates the extent of dengue occurrence globally.
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- The primary reason that dengue is emerging and re-emerging
is vector control. National priority lists are political in nature and
tend to emphasize daily problems, not episodic ones. Expensive mosquito
control tends to fall off the bottom of the list. Meanwhile, as older
cheaper chemicals lose effectiveness or are banned, new and expensive chemicals
replace them. Before 1970, A. aegypti, the vector of dengue and Yellow
Fever, was targeted for regional or even global eradication through the
use of DDT (dichlorodiphenyltrichloroethane) (Murphy 1993). Obviously,
this solution is no longer applicable, but nothing has effectively supplanted
it.
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-
- CASES IN POINT
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- HANTAAN VIRUS
-
- The hantavirus (mentioned above) is also the focus of
much international attention. During the Korean War of 1950-1952, thousands
of United Nations troops developed a mysterious disease marked by fever,
headache, hemorrhage and acute renal failure; the mortality rate was 5-10%.
Despite much research, the agent of this disease remained unknown for
28 years, when a new virus, named Hantaan virus, was isolated in Korea
from field mice. Recently, related viruses have been found in many parts
of the world in association with different rodents and as the cause of
human diseases with a variety of little-known local names. Epidemic haemorrhagic
fever, one of the most important diseases in China, causes more than 100000
cases per year. Transmission to humans is primarily by inhalation of aerosolized
excreta. In May 1993 a cluster of deaths in the southwestern United States
set in motion a multiagency local, state and federal investigation that
led to the discovery of a highly pathogenic hantavirus and to the definition
of a new clinical syndrome (Peters 1994).
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- SEOUL VIRUS
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- Another virus of current interest in the USA, Seoul virus,
was identified about 10 years ago in Korea as a Hantaan-like virus whose
natural host is the urban rat. Serologic surveys detect it worldwide,
including seroprevalence rates of 12% in urban rats in Philadelphia and
about 64% in Baltimore rats (Le Duc 1986). Although acute hemorrhagic fever
was not identified in inner-city Baltimore, 1.3% of 1148 local residents
were antibody-positive and the possibility of viral association with chronic
renal disease is under study.
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- "FOUR CORNERS VIRUS"
-
- The disease hantavirus pulmonary syndrome (HPS), is
characterized by an initial fever followed by the abrupt onset of acute
pulmonary edema and shock. After recognition of the initial cases by observant
clinicians in the Southwest, investigations were swiftly mounted by local
university and public health workers but, in spite of efficient and competent
studies, failed to find the cause. By the time the CDC became involved,
a number of possible causative agents had been ruled out, leading most
of the investigators to believe they were dealing with a new entity. This
observation led to a broadly based approach to the field epidemiology
and the laboratory study of the disease. Samples from the field investigations
were distributed among many different laboratories of the National Center
for Infectious Disease (NCID) for analysis by the most sensitive classic
and modern molecular biological tests for a wide range spectrum of infectious
agents.
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- Somewhat surprisingly, successful results were obtained
after only a few days of straightforward serologic tests for hantaviruses.
The hemoconcentration, thrombocytopenia and shock observed in some of
the patients had raised speculation about the involvement of these viral
agents; however they had been previously known as associated with renal
syndromes only. The serologic results came from established techniques
such as indirect fluorescent-antibody assays and enzyme-linked immunosorbent
assays. The next steps utilized reverse transcription and PCR amplification
of RNA in postmortem tissue samples (60% of confirmed cases to date have
been fatal), using consensus primers based on known hantavirus RNA sequences.
These yielded products with sequences typical of hantavirus but clearly
different from any known member of the genus. This provided additional
evidence for the hantavirus etiology and linked the new hantavirus closely
to the human disease by its presence in the tissues of people dying of
the infection. Using the genomic sequences from human tissues, investigators
were subsequently able to implicate the deer mouse as the principle reservoir
of the virus.
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- Hantaviruses have traditionally been difficult to propagate,
and this one was no exception. Thus a full-length cDNA clone of the small
RNA segment of the virus was synthesized. This technique provided a diagnostic
reagent of increased sensitivity that could be made widely available.
Eventually, full length RNA sequences were developed for the medium segment
and a partial sequence was determined for the large segment, permitting
the definitive determination that the new virus, isolated weeks later
and registered as Muerto Canyon virus, was not a reassortant of any known
hantavirus.
-
- Immunohistochemical identification of hantavirus antigens
and in situ hybridization with genomic sequences also confirmed the hantavirus
etiology of the syndrome. The extensive presence of antigen in pulmonary
capillaries provided an explanation for the pathophysiology and target
organ specificity differing from that of other known disease-causing hantaviruses.
This method, when applied to paraffin- imbedded tissues, has also served
as a retrospective diagnostic tool, firmly identifying fatal cases from
10 to 15 years ago.
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- The rapid recognition of the hantavirus etiology of this
disease was important in that it alleviated heightened fear among the
general American population, and saved lives by focusing public health
recommendations on the avoidance of contact with potentially infected
rodents. Different hantaviruses have been isolated in Louisiana, Florida
and also Brazil, indicating the uncommon, yet widespread nature of this
disease. Recently (Diglisic 1994), isolation of a hantavirus from Mus
musculus captured in Yugoslavia was reported.
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- As stated by C.J. Peters, chief of the Special Pathogens
Branch of the Division of Viral and Rickettsial Diseases at NCID, the
crucial role of modern techniques in virology was possible only in a context
of past hantavirus research, and as part of efforts of a multidisciplinary
team of clinicians, epidemiologists, field ecologists and classic microbiologists.
The need for basic research is highlighted by the applied practical success
which resulted from it, as was the case in identifying a new strain of
hantavirus. Future research will need to investigate the molecular mechanisms
for induction of pulmonary edema and an appropriate blocking therapy.
The evolutionary relationships of the hantaviruses and their rodent host
specificity must be understood to predict the future course of transmission,
and finally the basis for the different tropisms of the viruses must be
examined at a molecular level.
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- EBOLA VIRUS
-
- Ebola virus, a member of the <Filoviruses.htmlFiloviridae,
burst from obscurity with spectacular outbreaks of severe, haemorrhagic
fever. It was first associated with an outbreak of 318 cases and a case-fatality
rate of 90% in Zaire and caused 150 deaths among 250 cases in Sudan. Smaller
outbreaks continue to appear periodically, particularly in East, Central
and southern Africa. In 1989, a haemorrhagic disease was recognized among
cynomolgus macaques imported into the United States from the Philippines.
Strains of Ebola virus were isolated from these monkeys. Serologic studies
in the Philippines and elsewhere in Southeast Asia indicated that Ebola
virus is a prevalent cause of infection among macaques (Manson 1989).
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- These threadlike polymorphic viruses are highly variable
in length apparently owing to concatemerization. However, the average
length of an infectious virion appears to be 920 nm. The virions are 80
nm in diameter with a helical nucleocapsid, a membrane made of 10 nm projections,
and host cell membrane. They contain a unique single-stranded molecule
of noninfectious (negative sense ) RNA. The virus is composed of 7 polypeptides,
a nucleoprotein, a glycoprotein, a polymerase and 4 other undesignated
proteins. Proteins are produced from polyadenylated monocistronic mRNA
species transcribed from virus RNA. The replication in and destruction
of the host cell is rapid and produces a large number of viruses budding
from the cell membrane.
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- Epidemics have resulted from person to person transmission,
nosocomial spread or laboratory infections. The mode of primary infection
and the natural ecology of these viruses are unknown. Association with
bats has been implicated directly in at least 2 episodes when individuals
entered the same bat-filled cave in Eastern Kenya. Ebola infections in
Sudan in 1976 and 1979 occurred in workers of a cotton factory containing
thousands of bats in the roof. However, in all instances, study of antibody
in bats failed to detect evidence of infection, and no virus was isolated
form bat tissue.
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- The index case in 1976 was never identified, but this
large outbreak resulted in 280 deaths of 318 infections. The outbreak
was primarily the result of person to person spread and transmission by
contaminated needles in outpatient and inpatient departments of a hospital
and subsequent person to person spread in surrounding villages. In serosurveys
in Zaire, antibody prevalence to Ebola virus has been 3 to 7%. The incubation
period for needle- transmitted Ebola virus is 5 to 7 days and that for
person to person transmitted disease is 6 to 12 days.
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- The virus spreads through the blood and is replicated
in many organs. The histopathologic change is focal necrosis in these
organs, including the liver, lymphatic organs, kidneys, ovaries and testes.
The central lesions appear to be those affecting the vascular endothelium
and the platelets. The resulting manifestations are bleeding, especially
in the mucosa, abdomen, pericardium and vagina. Capillary leakage appears
to lead to loss of intravascular volume, bleeding, shock and the acute
respiratory disorder seen in fatal cases. Patients die of intractable
shock. Those with severe illness often have sustained high fevers and
are delirious, combative and difficult to control.
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- EBOLA SEROLOGY
-
- The serologic method used in the discovery of Ebola was
the direct immunofluorescent assay. The test is performed on a monolayer
of infected and uninfected cells fixed on a microscopic slide. IgG- or
IgM-specific immunoglobulin assays are performed. These tests may then
be confirmed by using western blot or radioimmunoprecipitation. Virus
isolation is also a highly useful diagnostic method, and is performed on
suitably preserved serum, blood or tissue specimens stored at -70oC or
freshly collected.
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- TREATMENT OF EBOLA
-
- No specific antiviral therapy presently exists against
Ebola virus, nor does interferon have any effect. Past recommendations
for isolation of the patient in a plastic isolator have given way to the
more moderate recommendation of strict barrier isolation with body fluid
precautions. This presents no excess risk to the hospital personnel and
allows substantially better patient care, as shown in Table 2. The major
factor in nosocomial transmission is the combination of the unawareness
of the possibility of the disease by a worker who is also inattentive
to the requirements of effective barrier nursing. after diagnosis, the
risk of nosocomial transmission is small.
-
- PREVENTION AND CONTROL OF EBOLA
-
- The basic method of prevention and control is the interruption
of person to person spread of the virus. However, in rural areas, this
may be difficult because families are often reluctant to admit members
to the hospital because of limited resources and the culturally unacceptable
separation of sick or dying patients from the care of their family. Experience
with human disease and primate infection suggests that a vaccine inducing
a strong cell- mediated response will be necessary for virus clearance
and adequate protection. Neutralizing antibodies are not observed in convalescent
patients nor do they occur in primates inoculated with killed vaccine.
A vaccine expressing the glycoprotein in vaccinia is being prepared for
laboratory evaluation.
-
- INFLUENZA VIRUS: A MODEL FOR VIRAL EMERGENCE
-
- Influenza, both human and avian, would be very high on
the list of disease with epidemic potential. Up to 20% of the population
has been seen to become ill during a single epidemic, with 50000 deaths
per year in the United States (Murphy 1994). In the 1918 pandemic more
than 500000 people throughout the world died.
-
- The probability of interspecies transfer can be increased
not only by increased contact between humans and an animal reservoir,
but also by increased opportunity for viral genetic reassortment or recombination
within animal or insect hosts. Because influenza virus has an eight-segmented
genome, it has considerable freedom for such a genetic reassortment. While
small epidemics may arise from mutation (antigenic drift), all known human
pandemic strains have been the result of reassortment, mostly involving
the hemagglutinin (H) gene. Kida et al.(1988) and also Scholtissek and
Naylor (1988) state that influenza virus maintained in shore and migrating
birds infect ducks raised on farms and reassort in pigs, from which new
strains emerge to infect humans.
-
- Virulent strains of influenza virus can also arise from
a single mutation, even if pandemic strains have not generally arisen
this way. For example, in 1983 a single mutation in a relatively avirulent
strain gave rise to an H5N2 strain that caused a fatal epidemic in chickens
in Pennsylvania. The point mutation in the H gene changed threonine to
lysine, exposing a previously glycosylated site. Similarly, and remarkably,
if pigs are infected experimentally with an avirulent mutant, the swine
virulent parental phenotype emerges within a few days, indicating rapid
evolution and emergence in vivo of the virulent form (Kilbourne et al.
1988).
-
- For viruses with non-segmented genomes, recombination
provides another genetic avenue for emergent diseases. For instance, viral
genetic sequence analysis revealed that Western equine encephalomyelitis
virus, an alphavirus, arose from a recombination event that seems to have
involved a Sindbis-like virus and Eastern equine encephalomyelitis virus,
probably occurring some 100-200 years ago (Hahn et al. 1988). Genetic recombination
also seems to have occurred between the envelope protein genes of human
T lymphotropic virus (HTLV)-I and HTLV-II (Doolittle et al. 1989).
-
- MUTATION FREQUENCY
-
-
- The mutation rate of any genome is inversely proportional
to its size. However, RNA viruses usually have higher mutation rates than
do DNA viruses of the same genome size. This is generally ascribed to
the lack of error-correcting mechanisms in RNA synthesis. High mutation
rates have been reported in influenza genes. The changes occurred in the
non-structural protein (NS) gene of influenza A virus during a single cycle
of replication in tissue culture. A mutation rate of approximately 10-5
changes per nucleotide site per replication cycle was observed (Parvin
et al. 1986). Similar tissue culture experiments revealed mutation rates
of about 10-fold lower for poliovirus and 10-fold higher for Rous sarcoma
virus. Also, the evolution rate of influenza virus has been considered,
this is in contrast to the mutation rate as it takes place when the viruses
are passaged into humans. The evolution rate of the influenza A virus
NS gene is 1.95 x 10-3 changes/site/year, several orders of magnitude
greater than that of eukaryotic genes.
-
- Doolittle et al. (1989) looked at the evolutionary rates
of change of ten genes from retroviruses. Overall, the reverse transcriptase
showed the slowest rate of change and the outer portion of the envelope
protein the most rapid, evolving three times faster. The core portion
of the gag protein changed about 1.6 times as fast as the transcriptase,
the proteinase 1.8 times as fast, and the 140 amino acids at the amino
terminal of gag 2.5 times as fast. The viral proteinase is pepsin-like,
and that from HIV is as similar to that of visna virus as human pepsin
is to its fungal homologue. The proteinases of HIV and HTLV-I differ from
one another even more than human pepsin does from the fungal proteinase.
In other words, the retroviruses are changing extraordinarily rapidly.
Most species of RNA viruses actually consist of a population of genomes
showing considerable variation around a master sequence (Domingo et al.
1988). The population concept is important, as in experimental systems,
defective members of the genomic population can play a significant role
in viral expression.
-
- SELECTIVE PRESSURES AND CONSTRAINTS
-
- It is of interest to determine, what, if any, limits
are placed on virus variation. Despite high mutation rates and opportunities
for genetic reassortment, many factors act to minimize emergence of new
influenza A epidemics (Morse and Schluederberg 1988). even though avian
and human influenza viruses are widespread (in humans an estimated 100
million infections yearly), pandemic influenza viruses emerge infrequently
(every 10-40 years). Powerful constraints appear to exist since pandemic
human influenza strains vary in their H gene, whereas the neuraminidase
and most other genes are conserved.
-
- These constraints on viral evolution are not surprising
when one considers the selective pressures imposed by the host at each
stage of the virus life cycle. Tissue tropism determinants, include site
of entry, viral attachment proteins, host cell receptors, tissue- specific
genetic elements (for example promoters), host cell enzymes (like proteinase),
host transcription factors, and host resistance factors such as age, nutrition
and immunity. Host factors contribute significantly: sequences such as
hormonally responsive promoter elements and transcriptional regulatory
factors can link viral expression to cell state.
-
- The interaction of virus and host is thus complex but
highly ordered, and can be altered by changing a variety of conditions.
Unlike bacterial virulence, which is largely mediated by bacterial toxins
and virulence factors, viral virulence often depends on host factors, such
as cellular enzymes that cleave key viral molecules. Because virulence
is multigenic, defects in almost any viral gene may attenuate a virus.
For example, some reassortments of avian influenza viruses are less virulent
in primates than are either parental strain, indicating that virulence
is multigenic (Treanor and Murphy 1990).
-
- Viral and host populations can exist in equilibrium until
changes in environmental conditions shift the equilibrium and favour rapid
evolution (Steinhauer and Holland 1987). It seems reasonable to expect
that new viruses will emerge occasionally, but the stochastic and multifactorial
nature of viral evolution makes it difficult to predict such events. According
to Doolittle, retrovirus evolution is sporadic, with retroviruses evolving
at different rates in different situations. For instance, the human endogenous
retroviral element is shared with chimpanzees, indicating no change in
over 8 million years, whereas strains of HIV have diverged in mere decades.
Endogenous retroviruses carried in the germline evolve slowly compared
with infective retroviruses. Generation of new viral pathogens is rare,
and often possible only because of high mutation rates that permit many
neutral mutations to accumulate before selective pressure forces a change.
The seeming unpredictability of these events ensure that recognition of
new pathogens must await their emergence.
-
- CONCLUSION
-
- The proposed American fiscal budget for 1995 allows allocations
for the CDC which remain basically the same as those for past years and
the $11.5 billion budget for the National Institutes of Health includes
only a modest increase for non-AIDS infectious and immunological diseases
research (Cassell 1994). In view of the magnitude of the problem, this
budget is unacceptable. Currently, infectious diseases remain the leading
cause of death worldwide. In the United States infectious diseases directly
account for 3 and indirectly account for 5 of the 10 leading causes of
death, AIDS is the ninth leading cause. Infectious diseases account for
25% of all visits to physicians in the United States. In total, the annual
cost of AIDS and other infectious diseases reached $120 billion in 1992,
about 15% of the nation's total health-care expenditure. The expanding
pool of immunodeficient patients due to the AIDS epidemic, cancer treatment,
transplant recipients, and hemodialysis has caused an explosion of opportunistic
infections due to a number of fungal, parasitic, viral and bacterial agents.
-
- According to the Gail H. Cassel, president of the American
Society of Microbiology, the public health system is not prepared to meet
the challenges of new and re-emerging infections. Perhaps the most obvious
defect is inadequate disease surveillance and reporting. In America, only
one-quarter of the states have a professional position dedicated to surveillance
of food-borne and waterborne diseases. In 1992, only $55000 was spent on
federal, state and local levels tracking drug-resistant bacterial and viral
infections. In addition, the public health laboratories are eroding. Overall,
CDC's budget for infectious diseases unrelated to AIDS has declined approximately
20% in the last decade. This is the case in the developed world of the
United States, and we in developing South Africa are certainly no better
off in terms of disease surveillance and concomitant protection. It should
be clear that a mixture of basic and applied research related to infectious
disease is needed. Coupled with this, better diagnostic techniques, prevention
strategies and risk factor analysis is needed. Finally, enhanced communication
among health care professionals and the public is integral in coming to
terms and dealing with this issue. The American National Institute of
Allergy and Infectious Diseases (NIAID) plans to develop a research and
training infrastructure to elucidate the mechanisms of molecular evolution
and drug resistance and to learn more about actual disease transmission
through molecular and environmental studies and to continue their emphasis
on vaccine development. For example, NIAID-funded research has already
led to the creation of a new Haemophilus influenzae type B vaccine which
is expected to save nearly $400 million in health-care costs each year.
Similarly, the NIH spent less than $27 million dollars to find the connection
between Helicobacter pylori and chronic peptic ulcers, yet using antibacterial
therapy for the disease will save $760 million dollars in health care costs
annually.
-
- Given the diverse nature of threats from infectious diseases,
it is not adequate merely to face each crisis as it emerges, as this may
provide a strategy which proves to be too little and too late. Instead,
a more holistic approach is required. This must include a global perspective
as well as the need to address the issue of infectious disease within the
context of shared environmental responsibility. Improved health care derived
from socioeconomic betterment is crucial, as are long term policies involving
systems thinking as opposed to the limiting nature of long term over-specialization.
-
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