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October
24, 2001
Hitch Hiker's Guide To
Weapons Grade Biological Toxins!
By Bulldog Newspaper, Staff Researchers
Anthrax.
Anthrax is an infection caused by Bacillus anthracis that occurs
primarily in herbivores. Humans become infected when B. anthracis
spores are introduced into the body by contact with infected animals
or contaminated animal products, insect bites, ingestion, or inhalation.
Aerosolized spores of B. anthracis have the potential for use
in biological warfare or bioterrorism. Cutaneous anthrax is most common
and is characterized by the development of a localized skin lesion
with a central eschar surrounded by marked nonpitting edema. Inhalation
anthrax (woolsorters' disease) typically involves hemorrhagic mediastinitis,
rapidly progressive systemic infection, and a very high mortality
rate. Gastrointestinal anthrax is rare and is associated with a high
mortality rate.
Etiologic Agent and Epidemiology B. anthracis is a large, aerobic,
spore-forming, gram-positive rod that is encapsulated and nonmotile
and grows in chains. Sporulation does not take place in living animals.
The rectangular shape of the individual bacteria gives chains of B.
anthracis a boxcar-like appearance. Virulent strains of B.
anthracis are pathogenic for animals, including mice and guinea
pigs. Spores of B. anthracis can survive for years in dry earth
but are destroyed by boiling for 10 min, by treatment with oxidizing
agents such as potassium permanganate or hydrogen peroxide, or by
dilute formaldehyde.
Most strains of B. anthracis are susceptible to penicillin.
Anthrax occurs worldwide and is most prevalent among domestic herbivores
(including cattle, sheep, horses, and goats) and wild herbivores.
Grazing animals become infected when they forage for food in areas
contaminated with spores of B. anthracis. Anthrax in herbivores
tends to be severe, with high mortality. Terminally ill animals with
overwhelming bacteremic infections often bleed from the nose, mouth,
and bowel, thereby contaminating soil or water with vegetative B.
anthracis that can sporulate and persist in the environment.
The carcasses of infected animals provide additional potential foci
of contamination. Humans are more resistant to anthrax than are herbivorous
animals. The estimated number of human cases worldwide is 20,000 to
100,000 per year.
Human cases are classified as agricultural or industrial. Agricultural
cases result most often from contact with animals that have anthrax
(e.g., during skinning, butchering, or dissecting), from bites of
contaminated or infected flies, and (in rare instances) from consumption
of contaminated meat. Industrial cases are associated with exposure
to contaminated hides, goat hair, wool, or bones.
Only three cases of cutaneous anthrax were reported to the CDC from
1984 through 1993, and gastrointestinal anthrax has never been documented
in the United States. In an epidemic in the former Soviet Union at
Sverdlovsk in 1979, cases were initially reported as cutaneous and
gastrointestinal anthrax associated with contaminated meat; however,
subsequent analysis of epidemiologic data and autopsy findings for
most of the fatal cases established that the disease was inhalational
anthrax associated with accidental airborne release of B. anthracis
from a nearby military biological weapons facility.
A massive outbreak in Zimbabwe between 1978 and the early 1980s involved
more than 9700 cases of agricultural anthrax in humans. This outbreak
occurred during wartime and was associated with disruption of the
veterinary and medical infrastructure and cessation of veterinary
anthrax vaccination programs. Pathogenesis B. anthracis can
evade phagocytosis, invade the bloodstream, multiply rapidly to a
high population density in vivo, and kill quickly.
The poly-D-glutamic acid capsule of B. anthracis confers resistance
to phagocytosis. Anthrax toxin consists of three different proteins
called protective antigen (PA), edema factor (EF), and lethal factor
(LF).
The toxin was discovered in studies demonstrating that transfer of
sterile blood from guinea pigs dying of anthrax to uninfected guinea
pigs killed the recipients. PA binds to plasma membranes of target
cells and is cleaved by a cellular protease into two fragments.
The larger fragment remains on the cell surface, displays a binding
site for a domain that is present in both EF and LF, and serves as
a specific receptor that mediates endocytic entry of EF or LF into
the target cells. The catalytic activity of EF, a calmodulin-dependent
adenylate cyclase, is expressed in the cytoplasm of human or animal
cells that contain both calmodulin and ATP.
The biologic effects of EF, which include formation of edema in anthrax
lesions and inhibition of polymorphonuclear leukocyte functions, are
mediated by the intracellular cyclic AMP that is produced by the enzymatic
action of EF. In contrast, LF is a highly specific endopeptidase that
cleaves several members of the MAP-kinase-kinase protein family and
inactivates their functions in signal transduction pathways.
Macrophages appear to be the principal targets of LF in animals, and
intoxication of macrophages by LF is associated with production of
reactive oxygen species, release of cytokines (including tumor necrosis
factor and interleukin 1), shock, and death.
Cutaneous anthrax is initiated when spores
of B. anthracis are introduced onto the skin through cuts or
abrasions or by biting flies. The spores germinate within hours, and
the vegetative cells multiply and produce anthrax toxin.
The cutaneous anthrax lesion is characterized by necrosis, vascular
congestion, hemorrhage, and gelatinous edema, but few leukocytes are
present. In inhalational anthrax, B. anthracis spores in airborne
particles <5 m in diameter are deposited directly into the alveoli
or alveolar ducts.
The spores are phagocytized by alveolar macrophages, and some are
carried to and germinate in mediastinal nodes. Hemorrhagic necrosis
of the nodes, associated with hemorrhagic mediastinitis and overwhelming
B. anthracis bacteremia, may develop rapidly. Secondary pneumonia
sometimes occurs. Gastrointestinal anthrax usually results from ingestion
of inadequately cooked meat from animals with anthrax. Primary infection
can be initiated in the intestine by organisms that survive passage
through the stomach.
An oropharyngeal form of the disease has also been described. Lesions
in the throat or intestine are usually accompanied by hemorrhagic
lymphadenitis. B. anthracis bacteremia occurs in almost all
cases of anthrax that progress to a fatal outcome. Clinical Manifestations
Approximately 95% of human cases of anthrax are the cutaneous form,
and ~5% are the inhalational form. Gastrointestinal anthrax is very
rare. Anthrax meningitis can occur as a complication of overwhelming
B. anthracis bacteremia.
Cutaneous Anthrax The cutaneous lesion in anthrax is most often found
on exposed areas of skin. A small red macule develops within days
after inoculation of B. anthracis spores into skin. During the next
week, the lesion typically progresses through papular and vesicular
or pustular stages to the formation of an ulcer with a blackened necrotic
eschar surrounded by a highly characteristic expanding zone of brawny
edema.
The early lesion may be pruritic, and the fully developed lesion is
painless. Small satellite vesicles may surround the original lesion,
and painful nonspecific regional lymphadenitis is common. Most patients
are afebrile, with mild or no constitutional symptoms; in severe cases,
edema may be extensive and associated with shock.
Spontaneous healing occurs in 80 to 90% of untreated cases, but edema
may persist for weeks. In the 10 to 20% of untreated patients who
have progressive infection, bacteremia develops and is often associated
with high fever and rapid death. The differential diagnosis includes
staphylococcal skin infections, tularemia, plague, and orf. Cutaneous
anthrax should be considered when patients have painless ulcers associated
with vesicles and edema and have had contact with animals or animal
products.
Inhalational Anthrax The presenting symptoms of inhalational anthrax
(woolsorters' disease) resemble those of severe viral respiratory
diseases. Early diagnosis of inhalational anthrax that occurs naturally
or as a consequence of biological warfare or bioterrorism is difficult.
After 1 to 3 days, an acute phase supervenes, with increasing fever,
dyspnea, stridor, hypoxia, and hypotension usually leading to death
within 24 h. Occasionally, patients present with fulminant disease.
A characteristic radiologic finding associated with hemorrhagic mediastinitis
is symmetric mediastinal widening, which may provide an early clue
to the diagnosis of inhalational anthrax.
Gastrointestinal Anthrax Symptoms of gastrointestinal anthrax are
variable and include fever, nausea and vomiting, abdominal pain, bloody
diarrhea, and sometimes rapidly developing ascites. Diarrhea is occasionally
massive in volume. The major features of oropharyngeal anthrax are
fever, sore throat, dysphagia, painful regional lymphadenopathy, and
toxemia; respiratory distress may be evident.
The primary lesion is most often located on the tonsils. Laboratory
Diagnosis B. anthracis is present in large numbers in cutaneous
lesions of anthrax and can be demonstrated by Gram's staining, direct
fluorescent antibody staining, or culture unless the patient has been
treated with antibiotics.
A small proportion of patients with anthrax have bacteremia. Patients
with anthrax meningitis have bloody spinal fluid containing large
numbers of B. anthracis demonstrable by staining or culture. Patients
with mild disease usually have normal leukocyte counts, but those
with disseminated disease typically have polymorphonuclear leukocytosis.
Tests for antibody to B. anthracis are useful in confirming the diagnosis
of anthrax. Treatment Viable B. anthracis disappears from the lesions
of cutaneous anthrax within 5 h of the initiation of treatment with
parenteral penicillin G. The recommended regimen for adults is 2 million
units of penicillin G at intervals of 6 h until edema subsides, with
the subsequent administration of oral penicillin to complete a 7-
to 10-day course. For penicillin-sensitive adults, treatment with
ciprofloxacin, erythromycin, tetracycline, or chloramphenicol can
be substituted.
Antibiotics decrease local edema and systemic toxicity in cutaneous
anthrax but do not prevent eschar formation. Cutaneous lesions should
be cleaned and covered, and used dressings should be decontaminated.
For inhalational or gastrointestinal anthrax, high-dose penicillin
(8 to 12 million units per day in divided doses at intervals of 4
to 6 h) is recommended.
A rational case can be made for passive immunization with anthrax
antitoxin in addition to antibiotic therapy in severely ill patients
with anthrax, but no appropriate antitoxin is commercially available.
Prevention Inhalational anthrax was essentially eliminated in England
before 1940 through the development of methods to decontaminate wool
and goat hair and the improvement of working conditions for handlers
of animal products.
Nonliving vaccines consisting of alum-precipitated or aluminum hydroxide-adsorbed
extracellular components of unencapsulated B. anthracis are used in
the United States for military personnel, agricultural workers, veterinary
personnel, and others at risk of exposure to anthrax. The major active
component of these vaccines is protective antigen.
Live attenuated vaccines containing spores of B. anthracis
are used in both developed and developing countries to immunize domestic
herbivores; these preparations are also used to immunize humans in
Russia but not in the United States. The probable basis for attenuation
of the original Pasteur spore vaccine is partial loss of a plasmid
that encodes anthrax toxin.
The basis for attenuation of the current Sterne
spore vaccine is loss of a plasmid that encodes capsular polypeptide.
Improved anthrax vaccines for humans are needed because the current
vaccines are impure and chemically complex, elicit only slow onset
of protective immunity, provide incomplete protection, and cause significant
adverse reactions. In addition to agricultural and industrial anthrax,
the possible use of B. anthracis as an agent of biological
warfare or bioterrorism is a stimulus for the development of an improved
vaccine.
Current strategies for vaccine development include purification of
candidate protective antigens, expression of protective antigens in
recombinant microbial vaccines, and construction of improved live
attenuated strains of B. anthracis. Carcasses of animals that
succumb to anthrax should be buried intact or cremated. Necropsy or
butchering of infected animals should be avoided because sporulation
of B. anthracis occurs only in the presence of oxygen. Prognosis
The mortality rate is 10 to 20% for untreated cutaneous anthrax but
is very low with appropriate antibiotic therapy. In contrast, the
mortality rate for inhalational anthrax approaches 100%, and therapy
is usually unsuccessful. The mortality rate in treated gastrointestinal
anthrax is ~50%. Anthrax meningitis is usually fatal.
Botulinum Toxins.
Botulism is caused by intoxication with the any of the seven distinct
neurotoxins produced by the bacillus, Clostridium botulinum.
The toxins are proteins with molecular weights of approximately 150,000,
which bind to the presynaptic membrane of neurons at peripheral cholinergic
synapses to prevent release of acetylcholine and block neurotransmission.
The blockade is most evident clinically in the cholinergic autonomic
nervous system and at the neuromuscular junction. A biological warfare
attack with botulinum toxin delivered by aerosol would be expected
to cause symptoms similar in most respects to those observed with
food-borne botulism.
In pure form, the toxin is a white crystalline substance, that is
readily dissolvable in water, but decays rapidly in the open air.
Symptoms of inhalation botulism may begin as early as 24-36 hours
following exposure or as late as several days. Initia l signs and
symptoms include ptosis, generalized weakness, lassitude, and dizziness.
Diminished salivation with extreme dryness of the mouth and throat
may cause complaints of a sore throat. Urinary retention or ileus
may also occur. Motor symptoms usuall y are present early in the disease;
cranial nerves are affected first with blurred vision, diplopia, ptosis,
and photophobia. Development of respiratory failure may be abrupt.
Mucous membranes of the mouth may be dry and crusted. Neurological
examination shows flaccid muscle weakness of the palate, tongue, larynx,
respiratory muscles, and extremities. Deep tendon reflexes vary from
intact to absent.
The occurrence of an epidemic with large numbers of afebrile patients
with progressive ocular, pharyngeal, respiratory, and muscular weakness
and paralysis hints strongly at the diagnosis. Single cases may be
confused with various neuromuscular disord ers such as atypical Guillain-Barrè
syndrome, myasthenia gravis, or tick paralysis. The edrophonium (tensilon)
test may be transiently positive in botulism.
Respiratory failure secondary to paralysis of respiratory muscles
is the most serious complication and, generally, the cause of death.
Reported cases of botulism prior to 1950 had a mortality of 60%.
With tracheotomy and ventilator assistance, fat alities should be
<5%. Intensive and prolonged nursing care may be required
for recovery (which may take several weeks or even months).
A pentavalent toxoid of Clostridium botulinum types A, B, C,
D, and E is available under IND status. This product has been administered
to several thousand volunteers and occupationally at-risk workers
and induces serum antitoxin levels that co rrespond to protective
levels in experimental animal systems. The currently recommended schedule
(0, 2, and 12 weeks, then a 1 year booster) induces solidly protective
antitoxin levels in greater than 90 percent of those vaccinated after
1 year.
Brucellosis.
Brucellosis is a systemic zoonotic disease caused by one of four species
of bacteria: Brucella melitensis, B. abortus, B. suis, and B. canis;
virulence for humans decreases somewhat in the order given. These
bacteria are small gram-negative, ae robic, non-motile coccobacilli
that grow within monocytes and macrophages. They reside quiescently
in tissue and bone-marrow, and are extremely difficult to eradicate
even with antibiotic therapy. Their natural reservoir is domestic
animals, such as goats , sheep, and camels (B. melitensis);
cattle (B. abortus); and pigs (B. suis). Brucella
canis is primarily a pathogen of dogs, and only occasionally causes
disease in humans. Humans are infected when they inhale contaminated
aer osols, ingest raw (unpasteurized) infected milk or meat, or have
abraded skin or conjunctival surfaces that come in contact with the
bacteria. Laboratory infections are quite common, but there appears
to be no human-to-human transmission; isolation of inf ected patients
is, therefore, not required. Brucella species long have been
considered potential candidates for use in biological warfare. The
organisms are readily lyophilized, perhaps enhancing their infectivity.
Under selected environmental cond itions (for example, darkness, cool
temperatures, high C02), persistence for up to 2 years
has been documented. When used as a biological warfare agent, Brucellae
would most likely be delivered by the aerosol route; the resulting
infecti on would be expected to mimic natural disease.
Brucellosis presents after an incubation period normally ranging from
3-4 weeks, but may be as short as 1 week or as long as several months.
Clinical disease presents typically as an acute, non-specific febrile
illness with chills, sweats, headache, f atigue, myalgias, arthralgias,
and anorexia. Cough occurs in 15-25%, but the chest x-ray usually
is normal. Complications include sacroiliitis, arthritis, vertebral
osteomyelitis, epididymo-orchitis, and rarely endocarditis. Physical
findings include Iymphadenopathy in 10-20% and splenomegaly in
20-30% of cases. Untreated disease can persist for months to
years, often with relapses and remissions. Disability may be pronounced.
Lethality may approach 6% following infection with B. me litensis,
but the disease is rarely fatal (0.5% or less) after infection
with other serotypes (usually after endocarditis develops).
The initial symptoms of brucellosis are usually nonspecific, and the
differential diagnosis is therefore very broad and includes bacterial,
viral, and mycoplasmal infections. The systemic symptoms of viral
and mycoplasmal illnesses, however, are usuall y present for only
a few days, while they persist for prolonged periods in brucellosis.
Brucellosis may be indistinguishable clinically from the typhoidal
form of tularemia or from typhoid fever itself. The disease in humans
is characterized by a multitud e of somatic complaints, including
fever, sweats, anorexia, fatigue, malaise, weight loss, and depression.
Localized complications may involve the cardiovascular, gastrointestinal,
genitourinary, hepatobiliary, osteoarticular, pulmonary and nervous
system s. Without adequate and prompt antibiotic treatment, some patients
develop a ‘chronic’ brucellosis syndrome with many features of the
‘chronic fatigue’ syndrome.
The recommended treatment is doxycycline (200 mg/day) plus rifampin
(900 mg/day) for 6 weeks. Alternative effective treatment consists
of doxycycline (200 mg/day) for 6 weeks plus streptomycin (1 gm/day)
for 3 weeks. Trimethoprimsulfamethoxazole given for 4-6 weeks is less
effective. In 5-10% of cases, there may be relapse or treatment
failure. Laboratory infections with brucellosis are quite common,
but there is no human-to-human transmission and isolation is not required.
Killed and live attenuated human vaccines have been available in many
countries but are of unproven efficacy. There is no information on
the use of antibiotics for prophylaxis against human brucellosis.
Cholera.
Cholera is a diarrheal disease caused by Vibrio cholera, a
short, curved, gram-negative bacillus. Humans acquire the disease
by consuming water or food contaminated with the organism. The organism
multiplies in the small intestine and secretes an enterotoxin that
causes a secretory diarrhea. When employed as a BW agent, cholera
will most likely be used to contaminate water supplies. It is unlikely
to be used in aerosol form. Without treatment, death may result from
severe dehydration, hypovole mia and shock. Vomiting is often present
early in the illness and may complicate oral replacement of fluid
losses. There is little or no fever or abdominal pain.
Watery diarrhea can also be caused by enterotoxigenic E. coli,
rotavirus or other viruses, noncholera vibrios, or food poisoning
due to ingestion of preformed toxins such as those of Clostridium
perfringens, Bacillus cereus, or Staphylococcus aureus.
Treatment of cholera depends primarily on replacement of fluid
and electrolyte losses. This is best accomplished using oral dehydration
therapy with the World Health Organization solution (3.5 g NaCL,
2.5 g NaHC03, 1.5 g KC1 and 20 g glucose per liter) . Intravenous
fluid replacement is occasionally needed when vomiting is severe,
when the volume of stool output exceeds 7 liters/day, or when severe
dehydration with shock has developed. Antibiotics will shorten the
duration of diarrhea and thereby reduce fluid losses.
Improved oral cholera vaccines are presently being tested. Vaccination
with the currently available killed suspension of V. cholera
provides about 50% protection that lasts for no more than 6
months. The initial dose is two injections given at least 1 week
apart with booster doses every 6 months.
Clostridium Perfringens Toxins.
Clostridium perfringens is a common anaerobic bacterium
associated with three distinct disease syndromes; gas gangrene or
clostridial myonecrosis; enteritis necroticans (pig-bel); and clostridium
food poisoning. Each of these syndromes has very specific requirements
for delivering inocula of C. perfringens to specific sites
to induce disease, and it is difficult to imagine a general scenario
in which the spores or vegetative organisms could be used as a biological
warfare agent. There are , however, at least 12 protein toxins elaborated,
and one or more of these could be produced, concentrated, and used
as a weapon. Waterborne disease is conceivable, but unlikely. The
alpha toxin would be lethal by aerosol. This is a well characterized,
hi ghly toxic phospholipase C. Other toxins from the organism
might be co-weaponized and enhance effectiveness. For example, the
epsilon toxin is neurotoxic in laboratory animals.
Gas gangrene is a well-recognized, life-threatening emergency. Symptoms
of the disease may be subtle before fulminant toxemia develops,
and the diagnosis is often made at postmortem examination. The bacteria
produce toxins that create the high mortali ty from clostridial
myonecrosis, and which produce the characteristic intense pain out
of proportion to the wound. Within hours signs of systemic toxicity
appear, including confusion, tachycardia, and sweating. Most Clostridia
species produce lar ge amounts of CO2 and hydrogen that cause intense
swelling, hence the term "gas" gangrene, resulting in gas in the
soft tissues and the emission of foul-smelling gas from the wound.
Clinical features include necrosis, dark red serous fluid, and numerous
g as filled vesicles. The infection may progress upto 10 cm per
hour, and early diagnosis and therapy are essential to prevent rapid
progression to toxemia and death. Pulmonary findings might lead
to confusion with staphylococcal enterotoxin B (SEB) initia lly.
Liver damage, hemolytic anemia, and thrombocytopenia are not associated
with SEB and the pulmonary findings should be reversible in SEB.
No specific treatment is available for C. pefringens intoxication.
Early antibiotic treatment is effective, if undertaken before significant
amounts of toxins have accumulated in the body. If not treated the
bacteria enter the bloodstream caus ing fatal systemic illness.
The organism itself is sensitive to penicillin, and consequently,
this is the current drug of choice. Recent data indicate that clindamycin
or rifampin may suppress toxin production and provide superior results
in animal models . Prompt surgical debridement and broad spectrum,
intravenous antibiotics are the mainstay of therapy. Hyperbaric
oxygen has not been proven effective in prolonging survival.
There is no available prophylaxis against most C. perfringens
toxins. Toxoids are being used to prevent enteritis necroticans
in humans, and veterinary toxoids are in wide use.
Congo-Crimean Hemorrhagic Fever.
Congo-Crimean hemorrhagic fever (CCHF) is a viral disease caused by
CCHF virus. The virus, first isolated in the Congo, is transmitted
by ticks, principally of the genus Hyalomma, with intermediate vertebrate
hosts varying with the tick species. The disease, next found in the
Crimea, occurs also in the Middle East, the Balkans, the former USSR,
and eastern China. In 1969 it was recognised that the pathogen causing
Crimean haemorrhagic fever was the same as that responsible for an
illness identified in 195 6 in the Congo, and linkage of the 2 place-names
resulted in the current name for the disease and the virus. Little
is known about variations in the virus properties over the huge geographic
area involved. Humans become infected through tick bites, crush ing
an infected tick, or at the slaughter of viremic livestock. Even in
epidemics, cases do not show narrow clustering and person-to-person
spread is rare. CCHF would probably be delivered by aerosol if used
as a BW agent.
The length of the incubation period for illness appears to depend
on the mode of acquisition of the virus. Following infection via tick
bite, the incubation period is usually one to three days, with a maximum
of nine days. The incubation period followi ng contact with infected
blood or tissues is usually five to six days, with a documented maximum
of 13 days. Typical cases present with sudden onset of fever and chills
3-12 days after tick exposure. There is severe headache, lumbar pain,
nausea and vomi ting, delirium, and prostration. Fatal cases are associated
with extensive hemorrhage, coma, and shock. Mortality among cases
recognized as hemorrhagic fever is 15-30%, with death occurring
in the second week of illness. In those patients who recove r, improvement
generally begins on the ninth or tenth day after onset of illness.
Convalescence in survivors is prolonged with asthenia, dizziness,
and often hair loss.
Diagnosis of suspected CCHF is performed in specially-equipped, high
biosafety level laboratories. Other viral hemorrhagic fevers, meningococcemia,
rickettsial diseases, and similar conditions may resemble full-blown
CCHF. Most fatal cases and half the others will have detectable antigen
by rapid enzyme-linked immunosorbant assay (ELISA) testing of acute
serum samples. IgM ELISA antibodies occur early in recovery.
Supportive therapy with replacement of clotting factors is indicated.
Crimean-Congo hemorrhagic fever virus is sensitive to ribavirin in
vitro and clinicians have been favorably impressed in uncontrolled
trials. Immune globulin has also been re commended but is available
only in Bulgaria.
When patients with CCHF are admitted to the hospital, there is a risk
of nosocomial spread of infection. In the past, serious outbreaks
have occurred in this way and it is imperative that adequate infection
control measures be observed to prevent this disastrous outcome. Patients
with suspected or confirmed CCHF should be isolated and cared for
using barrier nursing techniques. Because of several well-defined
outbreaks within hospitals, protective measures for medical personnel
are an issue. The weigh t of evidence points to large droplets or
fomites as the mediators of transmission and so strict barrier nursing
is indicated and probably sufficient for the care of naturally acquired
disease. The virus is aerosol-infectious and additional precautions
(f or example, respirators) might be considered in a biological warfare
setting.
Although there is little field experience and no definitive data on
efficacy, the sensitivity of the virus to ribavirin and the severity
of disease suggests that prophylaxis of high-risk exposures is indicated.
In the case of a suspected biological att ack, ribavirin could be
considered for prophylaxis, but there is insufficient information
to make a firm recommendation for dosing. An inactivated mouse-brain
vaccine is used in Bulgaria, but there is no general experience with
this product.
Ebola Haemorrhagic Fever
Ebola Haemorrhagic Fever is one of the most virulent viral disease
known to humankind, causing death in 50-90% of all clinically-ill
cases. Consequently, it has figured prominently in popular discussions
of biological warfare, although its practical appli cations as an
biological warfare agent remain speculative. The disease has its origins
in the jungles of Africa and Asia and several different forms of Ebola
virus have been identified and may be associated with other clinical
expressions, on which furthe r research is required.
The Ebola virus is transmitted by direct contact with the blood, secretions,
organs or semen of infected persons. Transmission through semen may
occur up to 7 weeks after clinical recovery, as with Marburg haemorrhagic
fever. Health care workers have f requently been infected while attending
patients. In the 1976 epidemic in Zaire, every Ebola case caused by
contaminated syringes and needles died.
After an incubation period of 2 to 21 days, Ebola is often characterised
by the sudden onset of fever, weakness, muscle pain, headache and
sore throat. This is followed by vomiting, diarrhoea, rash, limited
kidney and liver functions, and both internal and external bleeding.
Specialized laboratory tests on blood specimens (which are not commercially
available) detect specific antigens or antibodies and/or isolate the
virus. These tests present an extreme biohazard and are only conducted
under maximum c ontainment conditions.
No specific treatment or vaccine exists for Ebola haemorrhagic fever.
Severe cases require intensive supportive care, as patients are frequently
dehydrated and in need of intravenous fluids. Experimental studies
involving the use of hyperimmune sera on animals demonstrated no long-term
protection against the disease after interruption of therapy.
Suspected cases should be isolated from other patients and strict
barrier nursing techniques practised. All hospital personnel should
be briefed on the nature of the disease and its routes of transmission.
Particular emphasis should be placed on ensuri ng that high-risk procedures
such as the placing of intravenous lines and the handling of blood,
secretions, catheters and suction devices are done under barrier nursing
conditions. Hospital staff should have individual gowns, gloves and
masks. Gloves and masks must not be reused unless disinfected. Patients
who die from the disease should be promptly buried or cremated.
As the primary mode of person-to-person transmission is contact with
contaminated blood, secretion or body fluids, any person who has had
close physical contact with patients should be kept under strict surveillance,
i.e. body temperature checks twice a day, with immediate hospitalization
and strict isolation recommended in case of temperatures above 38.3
C (101 F). Casual contacts should be placed on alert and asked to
report any fever. Surveillance of suspected cases should continue
for three weeks a fter the date of their last contact. Hospital personnel
who come into close contact with patients or contaminated materials
without barrier nursing attire must be considered exposed and put
under close supervised surveillance.
The Ebola virus was first identified in a western equatorial province
of Sudan and in a nearby region of Zaire in 1976 after significant
epidemics in Yamkubu, northern Zaire, and Nzara, southern Sudan. Between
June and November 1976 the Ebola virus inf ected 284 people in Sudan,
with 117 deaths. In Zaire there were 318 cases and 280 deaths in September
and October. An isolated case occurred in Zaire in 1977, a second
outbreak in Sudan in 1979. In 1989 and 1990, a filovirus, named Ebola-Reston,
was isola ted in monkeys being held in quarantine in a laboratory
in Reston (Virginia), Alice (Texas) and Pennsylvania. In the Philippines,
Ebola-Reston infections occurred in the quarantine area for monkeys
intended for exportation, near Manila. A large epidemic o ccurred
in Kikwit, Zaire in 1995 with 315 cases, 244 with fatal outcomes.
One human case of Ebola haemorrhagic fever and several cases in chimpanzees
were confirmed in Côte d'Ivoire in 1994-95. In Gabon, Ebola haemorrhagic
fever was first documented in 19 94 and recent outbreaks occurred
in February 1996 and July 1996. In all, nearly 1,100 cases with 793
deaths have been documented since the virus was discovered. The natural
reservoir of the Ebola virus seems to reside in the rain forests of
Africa and Asi a but has not yet been identified.
Different hypotheses have been developed to try to uncover the cycle
of Ebola. Initially, rodents were suspected, as is the case with Lassa
Fever whose reservoir is a wild rodent (Mastomys). Another hypothesis
is that a plant virus may have caused the infection of vertebrates.
Laboratory observation has shown that bats experimentally infected
with Ebola do not die and this has raised speculation that these mammals
may play a role in maintaining the virus in the tropical forest.
Melioidosis.
Melioidosis is an infectious disease of humans and animals caused
by Pseudomonas pseudomallei, a gram-negative bacillus. It is
especially prevalent in Southeast Asia but has been described from
many countries around the world. The disease has a variable and inconstant
clinical spectrum. A biological warfare attack with this organism
would most likely be by the aerosol route.
Infection by inoculation results in a subcutaneous nodule with acute
lymphangitis and regional lymphadenitis, generally with fever. Pneumonia
may occur after inhalation or hematogenous dissemination of infection.
It may vary in intensity from mild to f ulminant, usually involves
the upper lobes, and often results in cavitation. Pleural effusions
are uncommon. An acute fulminant septicemia may occur characterized
by rapid appearance of hypotension and shock. A chronic suppurative
form may involve virtual ly any organ in the body.
Antibiotic regimens that have been used successfully include tetracycline,
2-3 g/day; chloramphenicol, 3 g/day; and trimethoprim-sulfamethoxazole,
4 and 20 mg/kg per day. Ceftazidine and piperacillin have enjoyed
success in severely ill patients as wel l. In patients who are toxic,
a combination of two antibiotics, given parenterally, is advised.
There are no means of immunization. Vigorous cleansing of abrasions
and lacerations may reduce the risk of disease after inoculation of
organisms into the skin. There is no information available on the
utility of antibiotic prophylaxis after a potenti al exposure before
the onset of clinical symptoms.
Plague.
lague is a zoonotic disease caused by Yersinia pestis. Under
natural conditions, humans become infected as a result of contact
with rodents, and their fleas. The transmission of the gram-negative
coccobacillus is by the bite of the infected fl ea, Xenopsylla
cheopis, the oriental rat flea, or Pulex irritans, the
human flea. Under natural conditions, three syndromes are recognized:
bubonic, primary septicemia, or pneumonic. In a biological warfare
scenario, the plague bacillus coul d be delivered via contaminated
vectors (fleas) causing the bubonic type or, more likely, via aerosol
causing the pneumonic type.
- In bubonic plague, the incubation period ranges from 2 to 10
days. The onset is acute and often fulminant with malaise, high
fever, and one or more tender lymph nodes. Inguinal lymphadenitis
(bubo) predominates, but cervical and axillary lymph nodes c an
also be involved. The involved nodes are tender, fluctuant, and
necrotic. Bubonic plague may progress spontaneously to the septicemia
form with organisms spread to the central nervous system, lungs
(producing pneumonic disease), and elsewhere. The mort ality is
50 percent in untreated patients with the terminal event being
circulatory collapse, hemorrhage, and peripheral thrombosis.
- In primary pneumonic plague, the incubation period is 2 to 3
days. The onset is acute and fulminant with malaise, high fever,
chills, headache, myalgia, cough with production of a bloody sputum,
and toxemia. The pneumonia progresses rapidly, resulting in dyspnea,
strider, and cyanosis. In untreated patients, the mortality is
100 percent with the terminal event being respiratory failure,
circulatory collapse, and a bleeding diathesis.
In cases where bubonic type is suspected, tularemia adenitis, staphylococcal
or streptococcal adenitis, meningococcemia, enteric gramnegative
sepsis, and rickettsiosis need to be ruled out. In pneumonic plague,
tularemia, anthrax, and staphylococcal en terotoxin B (SEB) agents
need to be considered. Continued deterioration without stabilization
effectively rules out SEB.
Plague may be spread from person to person by droplets. Strict isolation
procedures for all cases are indicated. Streptomycin, tetracycline,
and chloramphenicol are highly effective if begun early. Significant
reduction in morbidity and mortality is p ossible if antibiotics
are given within the first 24 hours after symptoms of pneumonic
plague develop.
A formalin-killed Y. pestis vaccine is produced in the United
States and has been extensively used. Efficacy against flea-borne
plague is inferred from population studies, but the utility of this
vaccine against aerosol challenge is unknown.To m aintain immunity,
boosters every 1-2 years are required. Live-attenuated vaccines
are available elsewhere but are highly reactogenic and without proven
efficacy against aerosol challenge.
Q Fever.
Q fever is a zoonotic disease caused by a rickettsia, Coxiella
burnetii. The most common animal reservoirs are sheep, cattle
and goats. Humans acquire the disease by inhalation of particles contaminated
with the organisms. A biological warfare attack would cause disease
similar to that occurring naturally.
Following an incubation period of 10-20 days, Q fever generally occurs
as a self-limiting febrile illness lasting 2 days to 2 weeks. Pneumonia
occurs frequently, usually manifested only by an abnormal chest x-ray.
A nonproductive cough and pleuritic c hest pain occur in about onefourth
of patients with Q fever pneumonia. Patients usually recover uneventfully.
Q fever usually presents as an undifferentiated febrile illness, or
a primary atypical pneumonia, which must be differentiated from pneumonia
caused by mycoplasma, legionnaire's disease, psittacosis or Chlamydia
pneumonia. More rapidly progressi ve forms of pneumonia may look
like bacterial pneumonias including tularemia or plague.
Tetracycline (250 mg every 6 hr) or doxycycline (100 mg every
12 hr) for 5-7 days is the treatment of choice. A combination of
erythromycin (500 mg every 6 hr) plus rifampin (600 mg per day)
is also effective.
Vaccination with a single dose of a killed suspension of C. burnetii
provides complete protection against naturally occurring Q fever and
>90% protection against experimental aerosol exposure in human
volunteers. Protection lasts for at least 5 years. Administration
of this vaccine in immune individuals may cause severe cutaneous reactions
including necrosis at the inoculation site. Newer vaccines are under
development. Treatment with tetracycline during the incubation period
will delay but not prevent the onset of illness.
Ricin.
Ricin is a glycoprotein toxin (66,000 daltons) from the seed of
the castor plant. It blocks protein synthesis by altering the rRNA,
thus killing the cell. Ricin's significance as a potential biological
warfare agent relates to its availability world wi de, its ease
of production, and extreme pulmonary toxicity when inhaled.
Overall, the clinical picture seen depends on the route of exposure.
All reported serious or fatal cases of castor bean ingestion have
taken approximately the same course: rapid onset of nausea, vomiting,
abdominal cramps and severe diarrhea with vascu lar collapse; death
has occurred on the third day or later. Following inhalation, one
might expect nonspecific symptoms of weakness, fever, cough, and
hypothermia followed by hypotension and cardiovascular collapse.
The exact cause of death is unknown an d probably varies with route
of intoxication. High doses by inhalation appear to produce severe
enough pulmonary damage to cause death.
In oral intoxication, fever, gastrointestinal involvement, and
vascular collapse are prominent, the latter differentiating it from
infection with enteric pathogens. With regard to inhalation exposure,
nonspecific findings of weakness, fever, vomiting, cough, hypothermia,
and hypotension in large numbers of patients might suggest several
respiratory pathogens.
Therapy is supportive and should include maintenance of intravascular
volume. Standard management for poison ingestion should be employed
if intoxication is by the oral route. There is presently no antitoxin
available for treatment.
There is currently no prophylaxis approved for human use. Active
immunization and passive antibody prophylaxis are under study, as
both are effective in protecting animals from death following exposure
by intravenous or respiratory routes.
Rift Valley Fever.
Rift Valley Fever (RVF) is a viral disease caused by RVF virus.
The virus circulates in sub-Saharan Africa as a mosquito-borne agent.
Epizootics occur when susceptible domestic animals are infected,
and because of the large amount of virus in their ser um, amplify
infection to biting arthropods. Deaths and abortions among susceptible
species such as cattle and sheep constitute a major economic consequence
of these epizootics, as well as providing a diagnostic clue and
a method of surveillance. Humans be come infected by the bite of
mosquitoes or by exposure to virus-laden aerosols or droplets. The
human disease appears to be similar whether acquired by aerosol
or by mosquito bite. A biological warfare attack, most likely delivered
by aerosol, would be ex pected to elicit the rather specific spectrum
of human clinical manifestations and to cause disease in sheep and
cattle in the exposed area. If disease occurred in the absence of
heavy vector populations or without domestic animals as amplifiers
of mosqui to infection, a BW attack would also be a likely cause.
The incubation is two to five days and is usually followed by
an incapacitating febrile illness of similar duration. The typical
physical findings are fever, conjunctival injection, and sometimes
abdominal tenderness. A few petechiae or epistaxis may occur. A
small proportion of cases (approximately one percent) will progress
to a viral hemorrhagic fever syndrome; mortality in this group is
roughly 50 percent. A small number of infections will lead to a
late encephalitis. After apparent recovery from a typical febrile
illness, the patient develops fever, meningeal signs, obtundation,
and focal defects. These patients may die or often have serious
sequelae.
The occurrence of an epidemic with febrile disease, hemorrhagic
fever, eye lesions, and encephalitis in different patients would
be characteristic of RVF. Demonstration of viral antigen in blood
by ELISA is rapid and successful in a high proportion of acute cases
of uncomplicated disease or hemorrhagic fever.
In hemorrhagic fever, supportive therapy may be indicated for hepatic
and renal failure, as well as replacement of coagulation factors.
The virus is sensitive to ribavirin in vitro and in rodent
models. No studies have been performed in human or the more realistic
monkey model to ascertain whether administration to an acutely ill
patient would be of benefit.
Avoidance of mosquitoes and contact with fresh blood from dead
domestic animals and respiratory protection from small particle
aerosols are the mainstays of prevention. An effective inactivated
vaccine is available in limited quantities.
Saxitoxin.
Saxitoxin is the parent compound of a family of chemically related
neurotoxins. In nature they are predominantly produced by marine
dinoflagellates, although they have also been identified in association
with such diverse organisms as blue-green algae , crabs, and the
blue-ringed octopus. Human intoxications are principally due to
ingestion of bivalve molluscs which have accumulated dinoflagellates
during filter feeding. The resulting intoxication, known as paralytic
shellfish poisoning (PSP), is known throughout the world as a severe,
life-threatening illness requiring immediate medical intervention.
In a BW scenario, the most likely route of delivery is by inhalation
or toxic projectile. In addition, saxitoxin could be used in a confined
area to cont aminate water supplies.
After oral exposure, absorption of toxins from the gastrointestinal
tract is rapid. Onset of symptoms typically begins 10-60 minutes
after exposure, but may be delayed several hours depending upon
the dose and individual idiosyncrasy. Initial symptoms are numbness
or tingling of the lips, tongue and fingertips, followed by numbness
of the neck and extremities and general muscular incoordination.
Nausea and vomiting may be present, but typically occur in a minority
of cases. Respiratory distress and fl accid muscular paralysis are
the terminal stages and can occur 2-12 hours after intoxication.
Death results from respiratory paralysis. Clearance of the toxin
is rapid and survivors for 12-24 hours will usually recover. There
are no known cases of inhalat ion exposure to saxitoxin in the medical
literature, but data from animal experiments suggest the entire
syndrome is compressed and death may occur in minutes.
Routine laboratory evaluation is not particularly helpful. Cardiac
conduction defects may develop. Differential diagnosis may require
toxin detection. Diagnosis is confirmed by detection of toxin in
the food, water, stomach contents or environmental samples.
Management is supportive and standard management of poison ingestion
should be employed if intoxication is by the oral route. Toxins
are rapidly cleared and excreted in the urine, so diuresis may increase
elimination. Incubation and mechanical respirat ory support may
be required in severe intoxication. Timely resuscitation would be
imperative, albeit very difficult, after inhalation exposure on
the battlefield.
No vaccine against saxitoxin exposure has been developed for human
use.
Smallpox.
Smallpox virus, an orthopoxvirus with a narrow host range confined
to humans, was an important cause of morbidity and mortality in
the developing world until recent times. Eradication of the natural
disease was completed in 1977 and the last human case s (laboratory
infections) occurred in 1978. The virus exists today in only 2 laboratory
repositories in the U.S. and Russia. Appearance of human cases outside
the laboratory would signal use of the virus as a biological weapon.
Under natural conditions, t he virus is transmitted by direct (face-to
face) contact with an infected case, by fomites, and occasionally
by aerosols. Smallpox virus is highly stable and retains infectivity
for long periods outside of the host. A related virus, monkeypox,
clinically resembles smallpox and causes sporadic human disease
in West and Central Africa.
The incubation period is typically 12 days (range, 10-17 days).
The illness begins with a prodrome lasting 2-3 days, with generalized
malaise, fever, rigors, headache, and backache. This is followed
by defervescence and the appearance of a typical skin eruption characterized
by progression over 7-10 days of lesions through successive stages,
from macules to papules to vesicles to pustules. The latter finally
form crusts and, upon healing, leave depressed depigmented scars.
The case fatality rate is app roximately 35% in unvaccinated
individuals. Permanent joint deformities and blindness may follow
recovery. Vaccine immunity may prevent or modify illness.
The eruption of chickenpox (varicella) is typically centripetal
in distribution (worse on trunk than face and extremities) and characterized
by crops of lesions in different stages on development. Chickenpox
papules are soft and superticial, compared t o the firm, shotty,
and deep papules of smallpox. Chickenpox crusts fall off rapidly
and usually leave no scar. Monkeypox cannot be easily distinguished
from smallpox clinically. Monkeypox occurs only in forested areas
of West and Central Africa as a spor adic, zoonotic infection transmitted
to humans from wild squirrels. Person-to-person spread is rare and
ceases after 1-2 generations. Mortality is 15%. Other diseases that
are sometimes confused with smallpox include typhus, secondary syphilis,
and malign ant measles. Skin samples (scrapings from papules, vesicular
fluid, pus, or scabs) may provide a rapid identification of smallpox
by direct electron microscopy, agar gel immunoprecipitation, or
immunofluorescence.
There is no specific treatment available although some evidence
suggests that vaccinia-immune globulin may be of some value in treatment
if given early in the course of the illness.
Vaccinia virus is a live poxvirus vaccine that induces strong crossprotection
against smallpox for at least 5 years and partial protection for
10 years or more. The vaccine is administered by dermal scarification
or intradermal jet injection; appearan ce of a vesicle or pustule
within several days is indication of a "take." Vaccinia-immune
human globulin at a dose of 0.3 mg/kg body weight provides >70%
protection against naturally occurring smallpox if given during
the early in cubation period. Administration immediately after or
within the first 24 hours of exposure would provide the highest
level of protection, especially in unvaccinated persons. The antiviral
drug, n-methylisatin ß-thiosemicarbazone (Marboran®) aff
orded protection in some early trials, but not others, possibly
because of noncompliance due to unpleasant gastrointestinal side
effects.
Patients with smallpox should be treated by vaccinated personnel
using universal precautions. Objects in contact with the patient,
including bed linens, clothing, ambulance, etc.; require disinfection
by fire, steam, or sodium hypochlorite solution.
Staphylococcal Enterotoxin B. [SEB]
Staphylococcal Enterotoxin B (SEB) is one of several exotoxins produced
by Staphylococcus aureus, causing food poisoning when ingested.
A BW attack with aerosol delivery of SEB to the respiratory tract
produces a distinct syndrome causing signi ficant morbidity and potential
mortality.
The disease begins 1-6 hours after exposure with the sudden onset
of fever, chills, headache, myalgia, and nonproductive cough. In more
severe cases, dyspnea and retrosternal chest pain may also be present.
Fever, which may reach 103-106° F, has lasted 2-5 days, but cough
may persist 1-4 weeks. In many patients nausea, vomiting, and diarrhea
will also occur. In moderately severe laboratory exposures, lost duty
time has been <2 weeks, but, based upon animal data, it is anticipated
that severe exp osures will result in fatalities.
In foodborne SEB intoxication, fever and respiratory involvement are
not seen, and gastrointestinal symptoms are prominent. The nonspecific
findings of fever, nonproductive cough, myalgia, and headache occurring
in large numbers of patients in an epide mic setting would suggest
any of several infectious respiratory pathogens, particularly influenza,
adenovirus, or mycoplasma. In a BW attack with SEB, cases would likely
have their onset within a single day, while naturally occurring outbreaks
would prese nt over a more prolonged interval.
Treatment is limited to supportive care. No specific antitoxin for
human use is available. There currently is no prophylaxis for SEB
intoxication. Experimental immunization has protected monkeys, but
no vaccine is presently available for human use.
Trichothecene Mycotoxins
The trichothecene mycotoxins are a diverse group of more than 40 compounds
produced by fungi. They are potent inhibitors of protein synthesis,
impair DNA synthesis, alter cell membrane structure and function,
and inhibit mitochondrial respiration. Sec ondary metabolizes of fungi,
such as T-2 toxin and others, produce toxic reactions called mycotoxicoses
upon inhalation or consumption of contaminated food products by humans
or animals. Naturally occurring trichothecenes have been identified
in agricultu ral products and have been implicated in a disease of
animals known as moldy corn toxicosis or poisoning.
There are no well-documented cases of clinical exposure of humans
to trichothecenes. However, strong circumstantial evidence has associated
these toxins with alimentary toxic aleukia (ATA), the fatal epidemic
seen in Russia during World War II, and wit h alleged BW incidents
("yellow rain") in Cambodia, Laos and Afghanistan.
Consumption of these mycotoxins results in weight loss, vomiting,
skin inflammation, bloody diarrhea, diffuse hemorrhage, and possibly
death. The onset of illness following acute exposure to T-2 (IV or
inhalation) occurs in hours, resulting in the rapi d onset of circulatory
shock characterized by reduced cardiac output, arterial hypotension,
lactic acidosis and death within 12 hours.
Clinical signs and symptoms of ATA were hemorrhage, leukopenia, ulcerative
pharyngitis, and depletion of bone marrow. The purported use of T-2
as a BW agent resulted in an acute exposure via inhalation and/or
dermal routes, as well as oral exposure upo n consumption of contaminated
food products and water. Alleged victims reported painful skin lesions,
lightheadedness, dyspnea, and a rapid onset of hemomhage, incapacitation
and death. Survivors developed a radiation-like sickness including
fever, nausea , vomiting, diarrhea, leukopenia, bleeding, and sepsis.
Specific diagnostic modalities are limited to reference laboratories.
Because of their long "half-life" the toxin metabolizes
can be detected as late as 28 days after exposure.
General supportive measures are used to alleviate acute T-2 toxicoses.
Prompt (within 5-60 min of exposure) soap and water wash significantly
reduces the development of the localized destructive, cutaneous effects
of the toxin. After oral exposure mana gement should include standard
therapy for poison ingestion.
Ascorbic acid (400-1200 mg/kg, inter-peritoneal (ip)) works to decrease
lethality in animal studies, but has not been tested in humans. While
not yet available for humans, administration of large doses of monoclinal
antibodies directed against T-2 and metabolizes have shown prophylactic
and therapeutic efficacy in animal models.
Tularemia
Tularemia is a zoonotic disease caused by Francisella tularensis,
a gram-negative bacillus. Humans acquire the disease under natural
conditions through inoculation of skin or mucous membranes with blood
or tissue fluids of infected animals, or b ites of infected deerflies,
mosquitoes, or ticks. A BW attack with F. tularensis delivered
by aerosol would primarily cause typhoidal tularemia, a syndrome expected
to have a case fatality rate which may be higher than the 5-10%
seen when dise ase is acquired naturally.
A variety of clinical forms of tularemia are seen, depending upon
the route of inoculation and virulence of the strain. In humans, as
few as 10-50 organisms will cause disease if inhaled or injected intradermally,
whereas 108 organisms are r equired with oral challenge.
Under natural conditions, ulceroglandular tularemia generally occurs
about 3 days after intradermal inoculation (range 2-10 days), and
manifests as regional lymphadenopathy, fever, chills, headache, and
malaise, with or withou t a cutaneous ulcer. Gastrointestinal tularemia
occurs after drinking contaminated ground water, and is characterized
by abdominal pain, nausea, vomiting, and diarrhea. Bacteremia probably
is common after primary intradermal, respiratory, or gastrointesti
nal infection with F. tularensis and may result in septicemia
or "typhoidal" tularemia. The typhoidal form also may occur
as a primary condition in 5-15% of naturally-occurring cases;
clinical features include fever, prostration, and weight loss, but
without adenopathy. Diagnosis of primary typhoidal tularemia is difficult,
as signs and symptoms are nonspecific and there frequently is no suggestive
exposure history. Pneumonic tularemia is a severe atypical pneumonia
that may be fulmi nant, and can be primary or secondary. Primary pneumonia
may follow direct inhalation of infectious aerosols, or may result
from aspiration of organisms in cases of pharyngeal tularemia. Pneumonic
tularemia causes fever, headache, malaise, substernal disc omfort,
and a non-productive cough; radiologic evidence of pneumonia or mediastinal
lymphadenopathy may or may not be present. A biological warfare attack
with F. tularensis would most likely be delivered by aerosol,
causing primarily typhoidal tu laremia. Many exposed individuals would
develop pneumonic tularemia (primary or secondary), but clinical pneumonia
may be absent or non-evident. Case fatality rates may be higher than
the 5-10% seen when the disease is acquired naturally.
The clinical presentation of tularemia may be severe, yet nonspecific.
Differential diagnoses include typhoidal syndromes (e.g., salmonella,
rickettsia, malaria) or pneumonic processes (e.g., plague, mycoplasma,
SEB). A clue to the diagnosis of tularem ia delivered as a BW agent
might be a large number of temporally clustered patients presenting
with similar systemic illnesses, a proportion of whom will have a
nonproductive pneumonia. Identification of organisms by staining ulcer
fluids or sputum is gen erally not helpful. Routine culture is difficult,
due to unusual growth requirements and/or overgrowth of commensal
bacteria.
Streptomycin (1 gm q 12 intramuscular (IM) for 10-14 days) is the
treatment of choice. Gentamicin also is effective (3-5 mg/kg/day parenterally
for 10-14 days). Tetracycline and chloramphenicol treatment are effective
as well, but are associated with a significant relapse rate. Although
laboratory-related infections with this organism are very common,
human-to-human spread is unusual and isolation is not required.
A live, attenuated tularemia vaccine is available as an investigational
new drug (IND). This vaccine has been administered to more than 5,000
persons without significant adverse reactions and is of proven effectiveness
in preventing laboratory-acquire d typhoidal tularemia. Its effectiveness
against the concentrated bacterial challenge expected in a BW attack
is unproven. The use of antibiotics for prophylaxis against tularemia
is controversial.
Venezuelan Equine Encephalitis
Eight serologically distinct viruses belonging to the Venezuelan equine
encephalitis (VEE) complex have been associated with human disease;
the most important of these pathogens are designated subtype 1, variants
A, B and C. These agents also cause sev ere disease in horses, mules,
and donkeys (Equidae).
Natural infections are acquired by the bites of a wide variety of
mosquitoes; Equidae serve as the viremic hosts and source of mosquito
infection. In natural human epidemics, severe and often fatal ence
phalitis in Equidae always precedes that in humans. A BW attack with
virus disseminated as an aerosol would cause human disease as a primary
event. If Equidae were present, disease in these animals would occur
simultaneously with human disease. Secondary spread by person-to-person\contact
occurs at a negligible rate. However, a BW attack in a region populated
by Equidae and appropriate mosquito vectors could initiate an epizootic/epidemic.
Nearly 100% of those infected suffer an overt illness. After
an incubation period of 1-5 days, onset of illness is extremely sudden,
with generalized malaise, spiking fever, rigors, severe headache,
photophobia, myalgia in the legs and lumbosacral area. Nausea, vomiting,
cough, sore throat, and diarrhea may follow. This acute phase lasts
24-72 hours. A prolonged period of aesthenia and lethargy may follow,
with full health and activity regained only after 1-2 weeks. Approximately
4% of patien ts during natural epidemics develop signs of central
nervous system infection, with meningismus, convulsions, coma, and
paralysis. These necrologic cases are seen almost exclusively in children.
The overall case-fatality rate is <1%, but in childr en with
encephalitis, it may reach 20%.
An outbreak of VEE may be difficult to distinguish from influenza
on clinical grounds. Clues to the diagnosis are the appearance of
a small proportion of neurological cases or disease in Equidae, but
these might be absent in a BW attack.
There is no specific therapy. Patients who develop encephalitis may
require anticonvulsant and intensive supportive care to maintain fluid
and electrolyte balance, adequate ventilation, and to avoid complicating
secondary bacterial infections.
An experimental vaccine, designated TC-83 is a live, attenuated cellculture-propagated
vaccine which has been used in several thousand persons to prevent
laboratory infections. Approximately 10% of vaccinees fail to
develop detectable neutralizi ng antibodies, but it is unknown whether
they are susceptible to clinical infection if challenged.
A second investigational product that has been tested in humans is
the C-84 vaccine, prepared by formalin-inactivation of the TC-83 strain.
The vaccine is p resently not recommended for primary immunization,
on the basis of animal studies indicating that it may not protect
against aerosol infection.
In experimental animals, alpha-interferon and the interferon-inducer
poly-ICLC (lysine-polyadenosine) have proven highly effective for
post-exposure prophylaxis of VEE. There are no clinical data on which
to assess efficacy in humans.
[Editor's Note: See
The"Bad Bug Book" Foodborne Pathogenic Microorganisms and Natural
Toxins Handbook U.S. Food & Drug Administration Center for
Food Safety & Applied Nutrition.]
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