arsenal in the 1950s and 1960s, and was weaponized by Iraq in the 1980s. The
Aum Shinrikyo cult in Japan tried unsuccessfully to disseminate botulinum toxin
before deciding to release sarin in the Tokyo subway system.
Pathophysiology. Botulinum toxins are produced by certain strains of
Clostridium botulinum, a strictly anaerobic spore-forming gram-positive rod
commonly found in soil. Most cases of naturally occurring botulism result from
ingestion of preformed toxin (food poisoning) or intestinal toxin formation (infant
form). Infant botulism has additional unique epidemiologic considerations; more
extensive discussion of this disease, and of botulism in general, may be found
elsewhere in this text (see Chapters 82 Weakness and 97 Neurologic Emergencies
). The botulinum neurotoxins are the most toxic substances known to man. These
toxins function at the peripheral cholinergic presynaptic nerve terminals,
principally the neuromuscular junction, by preventing the release of acetylcholine
and thereby leading to a generalized flaccid paralysis and autonomic symptoms.
In keeping with the fact that toxins are chemical poisons produced by biologic
organisms, it is important to keep in mind that cases of botulism arising from a
terrorist attack represent intoxication rather than infection caused by replicating
C. botulinum organisms.
Clinical Manifestations. Following a latent period ranging from 24 hours to
several days, victims begin to experience cranial nerve dysfunction, manifesting
as bulbar palsy, ptosis, photophobia, and blurred vision owing to difficulty in
accommodation. Symptoms progress to include dysarthria, dysphonia, and
dysphagia. Ultimately, a descending, symmetric, flaccid paralysis ensues,
although sensorium and sensation are not affected primarily. The mucous
membranes are dry; this fact, along with mydriasis, the nature of the paralysis
(lack of initial fasciculations), and the latent period, all differentiate botulism
from nerve-agent intoxication. A solitary case of botulism must also be
differentiated from myasthenia gravis, Guillain–Barré syndrome, tick paralysis,
and a few other uncommon neurologic disorders. The presence of multiple
casualties with similar symptoms should raise the concern for botulism.
Management. Supportive care, with meticulous attention to ventilatory support,

remains the mainstay of botulism management. Patients may require such support
for several months, making the management of a large-scale botulism outbreak
especially problematic in terms of medical resources. A heptavalent (types A to
G) despeciated (Fab2) equine botulinum antitoxin was licensed in 2013 for the
management of noninfant botulism and is available through the CDC. Although


administration of antitoxin is unlikely to reverse disease (the antitoxin is most
effective when given during the clinically asymptomatic, or latent, period), it may
be useful in preventing progression when administered to exposed persons. In
addition, a licensed human botulinum immunoglobulin is available to treat infant
botulism. While the product (BabyBIG) contains antibody against botulinum
toxin types A to E, it has only been studied, and is thus only licensed, to treat type
A and B intoxication. Botulism is not contagious, and standard precautions are
adequate for patient care.
Tularemia
Tularemia is a highly infectious plague-like disease caused by the gram-negative
coccobacillus Francisella tularensis. Several clinical forms of naturally occurring
tularemia are known, but pneumonic tularemia would presumably be the most
likely clinical presentation in the event of an intentional aerosol release of F.
tularensis. The onset of symptoms may be abrupt and include fever,
nonproductive cough, substernal tightness, pleuritic chest pain, occasional
hemoptysis, chills, headache, malaise, anorexia, and fatigue. Chest radiographs
may show infiltrates, hilar adenopathy, pleural effusion, or miliary infiltrates
(may mimic tuberculosis).
Tularemia is not contagious, and standard precautions are adequate in patient
care. However, because of the very low infectious dose by aerosol, processing
tularemia bacterial cultures is an extreme health risk to laboratory staff, who
therefore must be notified of a suspected case, and special precautions are
warranted. See Table 132.3B for detailed treatment recommendations for

children.

VIRAL HEMORRHAGIC FEVERS
The viral hemorrhagic fevers are a heterogeneous group of illnesses caused by
infection with lipid-enveloped RNA viruses belonging to the families
Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. These viruses may
cause deadly, fulminant illnesses with fever, hypotension, and bleeding diatheses.
A high mortality rate, with a capacity for human-to-human transmission by direct
contact with body fluids makes the filoviruses (e.g., Ebola and Marburg viruses)
and arenaviruses (e.g., Lassa fever virus) particularly concerning. Bunyaviridae
such as Crimean-Congo Hemorrhagic Fever virus can also be transmitted to
healthcare providers. Supportive care remains the cornerstone of therapy for most
of the viral hemorrhagic fevers. Intravenous ribavirin appears somewhat
efficacious in treating disease due to the Arenaviridae.


To date, the most severe Ebola outbreak in history began in Guinea in 2013 and
spread to West African neighbors Liberia and Sierra Leone. Before being
declared extinguished in 2016, over 28,000 cases and 11,000 deaths occurred. A
few cases were imported to the United States, revealing issues with medical
readiness for imported viral hemorrhagic fevers. Ebola, depending on the strain,
typically has a case fatality rate of 50% to 80% in African nations, raising
concerns regarding its intentional release by terrorists. A recombinant Ebola
vaccine tested in Guinea during the outbreak has shown great promise in
preventing spread of disease to close contacts.

Ricin
The distinction between biologic agents, which are living organisms capable of
causing infections, and chemical agents, which are nonliving poisons, is obvious.
Toxins such as ricin, however, are chemical poisons produced by biologic

organisms and occupy a somewhat nebulous niche between chemical and biologic
(infectious) agents. Although discussed with biologic agents, it should be kept in
mind that they cause intoxication (poisoning) rather than infection, do not
replicate in hosts, and do not produce communicable, or contagious, conditions.
Ricin is a toxin derived from the castor bean, and its production is not
technologically challenging. It is quite toxic if ingested, and far more so if
injected or inhaled. It is infamous as a homicidal weapon of espionage used by
the Bulgarian secret service in London during the Cold War against defector
Georgi Markov. More recently, in February 2004, it was discovered in a U.S.
Senate office building, apparently having been delivered through the mail. At
least 16 persons required decontamination, although no one became ill. Ricin is
an inhibitor of cellular protein synthesis via enzymatic attack on the 28S
ribosomal subunit.
The clinical presentation of ricin intoxication depends on the route of exposure.
Exposures due to aerosols produce dose-dependent symptoms. Four to 8 hours
after inhalation, fever, chest tightness, cough, dyspnea, nausea, and arthralgias
can occur, followed within 36 hours by progressive cough, dyspnea, cyanosis, and
pulmonary edema resulting in respiratory failure. If ingested, necrosis of the GI
epithelium, local hemorrhage, and hepatic, splenic, and renal necrosis can be
expected followed by vascular collapse and death. If injected, severe local
necrosis of muscle and regional lymph nodes with moderate visceral organ
involvement are seen.
Patients with ricin poisoning are not contagious. Establishing a diagnosis of
ricin intoxication may be challenging: Early postexposure (0 to 24 hours) nasal or
throat swabs and respiratory secretions may be submitted for toxin assay for


epidemiologic purposes, although positive nasal swabs do not prove penetration
of toxin to the lungs, and negative swabs do not exclude exposure in any given
patient. In addition, assays for the presence of toxin, as well as measurement of

an antibody response, can be performed on serum. Management is primarily
supportive, although the U.S. military has found that postexposure prophylaxis
with an investigational toxoid is efficacious in animal trials.

OTHER AGENTS
Numerous other agents may present bioterrorist threats of varying degrees. In
addition to previously discussed incidents, terrorists and belligerents have
attempted to use Salmonella, Shigella, glanders, cholera, typhus, and probably
many other organisms or toxins to induce disease. Many of these agents are
discussed adequately elsewhere in this and other texts; a few warrant additional
comment here.
Venezuelan equine encephalitis makes an attractive weapon because of its high
infection-to-disease ratio; virtually all those who are not immune become
symptomatic. In infants and young children the disease can be severe, with as
many as 4% developing overt encephalitis, often leading to permanent sequelae
or death.
Staphylococcal enterotoxin B (SEB) is a bacterial toxin that has been
weaponized in the past. Although familiar to many clinicians as a common cause
of food poisoning, SEB would also be a potent incapacitating toxin if delivered
by aerosol. Symptoms produced in this manner would begin 3 to 12 hours after
exposure and consist of fever, headache, chills, myalgias, and nonproductive
cough. Dyspnea and chest pain accompany the inhalation of high dosages of
inhaled toxin. Nausea, vomiting, and diarrhea may occur as a result of
inadvertently swallowed toxin. Treatment is supportive; meticulous attention
should be paid to fluid management. Patients may be ill for as long as 2 weeks
with aerosol exposure.
Various fungal toxins, such as the trichothecene mycotoxins, have been
mentioned in a biowarfare or bioterrorism context. After the Vietnam War, the
U.S. government accused the Soviets of using a trichothecene toxin, T-2
mycotoxin (otherwise known as “yellow rain”), against Hmong tribesmen. The

Iraqis are known to have weaponized another fungal toxin, aflatoxin, which in
addition to acute clinical effects, is a potent hepatic carcinogen. Symptoms
produced by various mycotoxins are variable and depend on the route of
exposure. The trichothecene mycotoxins are different from virtually all other
bioterrorist agents in that they are dermally active. Treatment is supportive.