- RECENT EXAMPLES OF EMERGING
AND
POTENTIALLY EMERGENT VIRUSES
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.
-
- ARBOVIRUS DISEASES
-
- Approximately 100 of the more than 520
known arthropodborne 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 viremia 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.
-
- AETIOLOGY
-
- 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.
-
- A range of arboviruses are listed in
Table 2, while some patterns of transmission are shown in Figure 1.
-
- EPIDEMIOLOGY
-
- Vertebrate hosts
-
- Maintenance, incidental, link and amplifier
hosts are categorized according to Stickland Hunter's Tropical Medicine
(1991) as the following:
-
- 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.
-
- 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.
-
- 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.
-
- Invertebrate hosts
-
- 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.
-
- TRANSMISSION
-
- 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.
-
- 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 transovarial 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.
-
- 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.
-
- IMMUNITY
-
- 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.
-
- 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 susbsequent 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
-
- 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.
-
- PASSIVE IMMUNITY
-
- 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.
-
- GENERAL CLINICAL FEATURES
-
- 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 viremia ending when antibodies appear in
the blood and the second phase when the virus is located in organs, such
as the liver or brain.
-
- 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).
-
- 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); and
-
- 7) New routing of long-distance bird
migration brought about by new man-made water impoundments (Murphy 1994).
-
- 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.
-
- 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.
-
- CASES IN POINT
-
- 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).
-
- SEOUL VIRUS
-
- 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.
-
- "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.
-
- 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.
-
- 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.
-
- 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.
-
- 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.
-
- EBOLA VIRUS
-
- Ebola virus, a member of the Filoviridae,
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).
-
- 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.
-
- 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.
-
- 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.
-
- 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.
-
- 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.
-
- 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 airborn, and contact by 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.
-
- SUMMARY of Symptoms: Fever is prominent.
Intially the patient coplains of severe aching, scratchy throat, headache,
fatigue and fever. Physicians generally diagnose "flu." However,
the fever and aching worsen. Headache rapidly becomes severe, and small
hemorrhages called petichiae appear on the skin, usually where clothing
is tight, such as the beltline and under the bra. As the virus attacks
the lining of small blood vessels, internal bleeding supervenes. Then severe
vomiting with black and red blood, and bloody diarrhea. Due to marked general
capillary hemorrhage and seepage of serum into the body spaces, there will
be progressive fall in blood pressure and shock. The organs are attacked
and dissolve rapidly. the kidneys first usually, with failure of function,
then the liver, heart, and brain with rapid onset of coma, convulsions,
shock and death. The body becomes a blackened sack of skin containing bloody
fluid, dissolved muscles and organs, and bones. TREATMENT: CONSISTS OF
ICE BAGS, MORPHINE FOR SEVERE TOTAL BODY PAIN, INTRAVENOUS FLUIDS, AND
BLOOD TRANSFUSIONS. There is no specific therapy. Antibiotics are ineffective.
Death rate in the recent outbreak in Zaire was 90%.
-
- Byron T. Weeks, MD
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