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original
source: Federation of American Scientist's Bio-Warefare Analysis
http://www.fas.org/nuke/intro/bw/agent.htm
Biological
Warfare Agents
* Anthrax
* Botulinum Toxins
* Brucellosis
* Cholera
* Clostridium Perfringens Toxins
* Crimean-Congo Hemorrhagic Fever
* Melioidosis
* Plague
* Q Fever
* Ricin
* Rift Valley Fever
* Saxitoxin
* Smallpox
* Staphylococcal Enterotoxin B
* Trichothecene Mycotoxins
* Tularemia
* Venezuelan Equine Encephalitis
Many
products are currently considered investigational new drugs (IND).
This indicates that the product (drug, vaccine, antitoxin, etc.)
has been shown to be safe and effective in animal studies and has
been approved for limited use as an investigational product in humans.
In general, IND products must be obtained through official channels
from the government of the producing nation and administered under
a research protocol approved by a recognized institutional review
board.
Anthrax
Anthrax
is a zoonotic disease caused by Bacillus anthracis. There are two
types of this disease: cutaneous anthrax and inhalation anthrax.
About 95% of the human anthrax cases in the United States have been
in the former category. Cutaneous anthrax develops when a bacterial
organism from infected animal tissues becomes deposited under the
skin. When a patient contracts cutaneous anthrax, he develops a
small elevated lesion on his skin which becomes a skin ulcer, frequently
surrounded by swelling or edema. The lymph gland near the lesion
may also swell from the infection. If the lesion occurs on the neck
or on or about the eye, it may cause complications. The incubation
period for cutaneous anthrax is from one to seven days. When a patient
does not receive an effective antibiotic, the mortality rate for
cutaneous anthrax is 10-20%. With treatment, the mortality rate
falls to less than 1%.
Inhalation
anthrax develops when the bacterial organism is inhaled into the
lungs. A progressive infection follows. Since inhalation anthrax
is usually not diagnosed in time for treatment, the mortality rate
in the United States is 90-100%. A biological warfare attack with
anthrax spores delivered by aerosol would cause inhalation anthrax,
an extraordinarily rare form of the naturally occurring disease.
A
lethal dose of anthrax is considered to be 10,000 spores; 80 percent
of a population that inhaled such a dose would die. Less than one
millionth of a gram is invariably fatal within five days to a week
after exposure. According to an estimate by the US Congress's Office
of Technology Assessment, 100 kilograms of anthrax, released from
a low-flying aircraft over a large city on a clear, calm night,
could kill one to three million people.
The
disease begins after an incubation period varying from 1-6 days,
presumably dependent upon the dose of inhaled organisms. Onset is
gradual and nonspecific, with fever, malaise, and fatigue, sometimes
in association with a nonproductive cough and mild chest discomfort.
In some cases, there may be a short period of improvement. The initial
symptoms are followed in 2-3 days by the abrupt development of severe
respiratory distress with dyspnea, diaphoresis, strider, and cyanosis.
Physical findings may include evidence of pleural effusions, edema
of the chest wall, and meningitis. Chest x-ray reveals a dramatically
widened mediastinum, often with pleural effusions, but typically
without infiltrates. Shock and death usually follow within 24-36
hours of respiratory distress onset.
An
epidemic of inhalation anthrax in its early stage with nonspecific
symptoms could be confused with a wide variety of viral, bacterial,
and fungal infections. Progression over 2-3 days with the sudden
development of severe respiratory distress followed by shock and
death in 24-36 hours in essentially all untreated cases eliminates
diagnoses other than inhalation anthrax. The presence of a widened
mediastinum on chest x-ray, in particular, should alert one to the
diagnosis. Other suggestive findings include chest-wall edema, hemorrhagic
pleural effusions, and hemorrhagic meningitis. Other diagnoses to
consider include aerosol exposure to SEB; but in this case onset
would be more rapid after exposure (if known), and no prodrome would
be evident prior to onset of severe respiratory symptoms. Mediastinal
widening on chest x-ray will also be absent. Patients with plague
or tularemia pneumonia will have pulmonary infiltrates and clinical
signs of pneumonia (usually absent in anthrax).
Almost
all cases of inhalation anthrax in which treatment was begun after
patients were symptomatic have been fatal, regardless of treatment.
Historically, penicillin has been regarded as the treatment of choice,
with 2 million units given intravenously every 2 hours. Tetracycline
and erythromycin have been recommended in penicillin-sensitive patients.
The vast majority of anthrax strains are sensitive in vitro to penicillin.
However, penicillin-resistant strains exist naturally, and one has
been recovered from a fatal human case. Moreover, it is not difficult
to induce resistance to penicillin, tetracycline, erythromycin,
and many other antibiotics through laboratory manipulation of organisms.
All naturally occurring strains tested to date have been sensitive
to erythromycin, chloramphenicol, gentamicin, and ciprofloxacin.
Vaccines
are available against some forms of anthrax, but their efficacy
against abnormally high concentrations of the bacteria is uncertain.
A licensed, alum-precipitated preparation of purified B.anthracis
protective antigen (PA) has been shown to be effective in preventing
or significantly reducing the incidence of inhalation anthrax. Limited
human data suggest that after completion of the first three doses
of the recommended six-dose primary series (0, 2, 4 weeks, then
6, 12, 18 months), protection against both cutaneous and inhalation
anthrax is afforded. As with all vaccines, the degree of protection
depends upon the magnitude of the challenge dose; vaccine-induced
protection is undoubtedly overwhelmed by extremely high spore challenge.
If
there is information indicating that a biological weapon attack
is imminent, prophylaxis with ciprofloxacin (500 mg po bid), or
doxycycline (100 mg po bid) is recommended. If unvaccinated, a single
0.5 ml dose of vaccine should also be given subcutaneously. Should
the attack be confirmed as anthrax, antibiotics should be continued
for at least 4 weeks in all exposed.
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. Initial 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 usually 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 disorders 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, fatalities 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 correspond 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
Characteristics.
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, aerobic, 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 aerosols, 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 infected 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 conditions (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 infection 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, fatigue, 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. melitensis, 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. The differential
diagnosis is therefore very broad and includes bacterial, viral,
and mycoplasmal infections. The systemic symptoms of viral and mycoplasmal
illnesses, however, are usually 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
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, hypovolemia 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,
highly 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 mortality 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 large
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 gas 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) initially. 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 causing 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.
Crimean-Congo
Hemorrhagic Fever
Crimean-Congo
hemorrhagic fever (CCHF) is a viral disease caused by CCHF virus.
The virus is transmitted by ticks, principally of the genus Hyalomma,
with intermediate vertebrate hosts varying with the tick species.
The disease was first recognized in the Crimea, but occurs over
most of Africa, the Middle East, the Balkans, the former USSR, and
eastern China. Little is known about variations in the virus properties
over the huge geographic area involved. Humans become infected through
tick bites, crushing 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.
Typical
cases present with sudden onset of fever and chills 3-12 days after
tick exposure. There is severe headache, lumbar pain, nausea and
vomiting, delirium, and prostration. Fatal cases are associated
with extensive hemorrhage, coma, and shock. Mortality among cases
recognized as hemorrhagic fever is 15-30%. Convalescence in survivors
is prolonged with asthenia, dizziness, and often hair loss.
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 recommended but is available only in Bulgaria.
Because
of several well-defined outbreaks within hospitals, protective measures
for medical personnel are an issue. The weight 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 (for 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 attack, 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.
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 fulminant, 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 virtually 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 well. 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 potential exposure before
the onset of clinical symptoms.
Plague
Plague
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 flea, 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
could 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 can 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 mortality 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 enterotoxin 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 possible 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 maintain 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 chest 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 progressive 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 wide, 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 vascular 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 and 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 serum, 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 become 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 expected 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 mosquito 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 contaminate
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 flaccid 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 inhalation 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 respiratory 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 cases (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, the 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 approximately 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 to 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 sporadic, 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 malignant 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; appearance 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 incubation
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®) afforded 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 significant 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 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 epidemic
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 present 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. Secondary 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 agricultural 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 with 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 rapid 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 upon 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 management 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 bites 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
disease 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 required 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 without 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 gastrointestinal 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 fulminant, 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 discomfort, 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
tularemia. 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 tularemia 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 generally 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-acquired 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 severe 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 encephalitis 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 patients 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 children
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 neutralizing 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 presently
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.
Sources and Methods
*
NATO HANDBOOK ON THE MEDICAL ASPECTS OF NBC DEFENSIVE OPERATIONS
PART II - BIOLOGICAL
* The"Bad Bug Book" Foodborne Pathogenic Microorganisms and Natural
Toxins Handbook U.S. Food & Drug Administration Center for Food
Safety Applied Nutrition
Georg
Schoefbaenker
advisory bord AEC Symposium Life Science
arms control analyst
schoefbaenker@magnet.at
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