Botulism is a potentially life-threatening clinical syndrome of descending cranial nerve and neuromuscular paralysis which is caused by a group of neurotoxins, serotypes A through G, produced by the bacterium Clostridium botulinum, and rarely by strains of Clostridium baratii and Clostridium butyricum. These are among the most potent toxins known, with an estimated human lethal dose of 0.01 micrograms per kilogram of body weight by the inhalation route, and 1.0 micrograms per kilogram orally. Endemic botulinum intoxication occurs in three main forms: food borne botulism, infant botulism, and wound botulism. In a bioterrorism attack, the routes of exposure would most likely be either oral or by inhalation. All botulism results from absorption of toxin into the circulation from a mucosal surface (GI mucosa or pulmonary epithelium) or from a wound. The toxin does not penetrate intact skin. Botulinum intoxication is not contagious and person-to-person spread does not occur.

Toxicity varies somewhat according to serotype, with type A typically causing more severe disease, and types B and E generally causing less severe disease. These toxins consist of a 100 KD heavy chain joined to a 50 KD light chain. The light chain is the active moiety, a Zn++ containing peptidase, which prevents the release of acetylcholine from pre-synaptic motor and ganglionic neurons, producing a characteristic clinical picture of bulbar palsies and flaccid muscular paralysis leading to respiratory failure. Once neuronal cells take up toxin, clinical effects may be very long lasting (weeks to months).

State-sponsored biological programs have shown interest in botulinum toxins as weapons: prior to the 1991 Persian Gulf War, Iraq weaponized more botulinum toxin than any of its other BW agents - 19,000 liters of botulinum type A toxin, with approximately 10,000 liters loaded into military weapons. The technology for producing botulinum toxins is fairly crude - well within the reach of potential biological terrorists.

Food borne Botulism - occurs when humans ingest pre-formed botulinum toxin in contaminated foods. All ages and both genders are susceptible. This form of botulism is fairly uncommon, with an average incidence of 24 cases per year in the United States. Heating inactivates the toxin, thus cases are always associated with foods that are not heated or are inadequately cooked. Many types of food have been associated with outbreaks, but cases have occurred more often in the U.S. with low-acid (higher pH), improperly canned vegetables such as beans, carrots, corn, and peppers. Cases occur more often in the western U.S., in Alaska, California, Washington, Oregon, and Colorado; interestingly, type A intoxication is more common in the west and overall, and type B cases are the predominant type in the eastern U.S. Most food borne outbreaks in Alaska and Canada are type E disease associated with native Eskimo and Inuit foods. Type F cases are rare, and type C and D outbreaks are limited to wildlife and domestic animals, but have not caused outbreaks in humans. Susceptibility in humans is assumed, however, from non-human primate studies. The food supply could be targeted in a bioterrorism attack with botulinum toxin, mimicking an endemic outbreak, but potentially much larger in terms of numbers of cases.

Infant Botulism - occurs when young infants ingest spores of Clostridium botulinum, most commonly in contaminated honey used to sweeten milk or on a pacifier. This is the most common type of botulinum intoxication in the U.S., causing nearly three-fourths of all botulism cases. The pathophysiology of infant botulism is different than that of food borne disease. Clostridial bacteria are able to survive in the infant gut, and may then produce toxin over time that is continually absorbed and causes symptoms. Affected infants exhibit poor feeding, constipation, floppiness, and failure to thrive; impaired respiratory function and death may occur in severe or untreated cases.

Wound Botulism - the least common clinical form of botulism in the U.S., causing less than 5% of cases. Usually occurs in young males with spore-contaminated open wounds. Spores of C. botulinum are ubiquitous in the environment and in soil. Clostridia produce toxin in the contaminated wound, which is absorbed into the circulation and causes the characteristic signs and symptoms of botulism.

Inhalation Botulism - does not occur naturally, but could occur in an aerosol bioterrorism attack using botulinum toxin. Botulinum toxins are rather unstable in the environment, thus the range of an aerosol attack may be limited. Cases might be clustered geographically at the time of exposure (building, work site, or focal ground location), without a common dietary exposure.

Clinical Symptoms

Botulism is an acute, symmetric, descending flaccid neuromuscular paralysis that always begins with cranial nerve (bulbar) palsies. Patients are afebrile, and most often present for care with difficulty speaking, swallowing, or with blurred or double vision. Mentation is preserved and sensation is not affected. Other signs and symptoms may include ptosis, dilated pupils, dysconjugate gaze, dry mouth, decreased gag reflex, hyporeflexia, paresthesia, arm or leg weakness, and occasionally, ataxia. In some cases, neurological signs and symptoms may be preceded by nausea, vomiting, abdominal cramping and diarrhea; these symptoms are thought to be due to co-ingestion of other non-clostridial bacteria or bacterial metabolites with the offending food. Constipation may also occur. The progression of paralysis and its severity may vary considerably among patients, probably due to the amount of toxin consumed as well as individual host factors. Some patients may only need observation, while others may require intubation and prolonged (weeks or months) ventilatory support for respiratory failure. All should be hospitalized and observed closely, as progression to respiratory failure may be rapid in some victims and is difficult to predict. The incubation period between ingestion of the toxin and first signs of intoxication is usually 12 to 36 hours, and may be the same or possibly longer for inhalation cases, based on very limited animal data.

Epidemiologic Indicators

Sporadic endemic cases are recognized by the characteristic clinical picture, common dietary exposure to offending food or drink items in two or more affected individuals, and/or a history of risk factors for infant or wound botulism. Indicators of a bioterrorism attack may be: large numbers of cases exposed to a widely distributed commercial food item or common potential food source; an outbreak of botulinum intoxication cases with a common geographic factor but without a common dietary exposure (aerosol attack); multiple simultaneous outbreaks without a common source; an outbreak of intoxication caused by a toxin type unusual in humans (C, D, F, and G, or E not associated with an aquatic food).

Diagnosis

Botulinum intoxication is a clinical diagnosis, and is a public health emergency, whether endemic or due to bioterrorism. Waiting for laboratory results prior to treatment to confirm the presence of toxin in an offending food, GI secretions, or in blood is not appropriate. Immediate actions at clinical diagnosis should include notification of local public health officials, a request for polyvalent antitoxin either locally or from CDC, hospitalization in an ICU setting and careful monitoring for progression and respiratory failure, and preparations to treat symptomatic patients with antitoxin as early as possible.

Diagnostic samples should include: 1) Serum or blood for serology, 2) Culture and toxin testing of gastric aspirate, feces, or food (specimens should be refrigerated). Generally larger state laboratories, as well as CDC and USAMRIID, are capable of performing appropriate diagnostic tests.

Differential Diagnosis

Misdiagnoses of other neurological, psychiatric, neoplastic, inflammatory, and infectious syndromes are unfortunately common in some larger botulinum outbreaks, delaying treatment. However, there are very few other etiologic causes that may actually closely mimic the exact clinical features of botulism. Diagnoses which may be close enough clinically to be confused with botulinum poisoning include Guillain-Barre syndrome (Miller-Fisher variant), myasthenia gravis, Eaton-Lambert Syndrome, and tick paralysis, all of which are less common than botulism and have differentiating clinical features.

Isolation/Decontamination Precautions: Standard Precautions. In an aerosol attack, botulinum toxin would be expected to degrade in the environment within 1 to 2 days. If contaminated, clothing and skin should be washed with soap and water, and contaminated surfaces may be cleaned with a 0.1% hypochlorite (bleach) solution prior to natural degradation. Healthcare providers are generally not at risk unless a patient is heavily contaminated.

Treatment

Several antitoxins are available for treatment of botulism cases, as follows:

1) Licensed Bivalent Anti-AB equine antitoxin, Aventis-Pasteur.
2) IND Univalent Anti-E equine antitoxin, Aventis-Pasteur
3) IND Heptavalent despeciated (Fab'2) equine Anti-ABCDEFG antitoxin, U.S. Army
4) Licensed Anti-AB human antitoxin for infant botulism (HBIG - human botulinum immune globulin, sometimes referred to as "Baby-BIG")

The first three products are available from CDC on a 24-hour basis. Healthcare providers who suspect a case of botulinum intoxication (or their hospital epidemiologist or infection control practitioner) should call their local or state health department's emergency 24-hour number. Local or state health departments should call CDC at 770-488-7100. After a clinical telephone consultation with a Foodborne and Diarrheal Disease branch physician, antitoxin will be immediately released if indicated.

HBIG for infant botulism is available from the California Department of Health Services, Infant Botulism Treatment and Prevention Program (Dr. Steven Arnon) at 510-231-7600.

Treatment of patients showing early signs and symptoms of botulism should be initiated as soon as possible. Antitoxin used early may slow or halt progression of paralysis to respiratory failure by binding remaining circulating antitoxin; after respiratory failure requiring artificial ventilation is present, antitoxin is unlikely to have any beneficial effect. The recommended dose of antitoxin for a single patient is one vial (10 ml) of antitoxin diluted 1:10 in 0.9% saline administered by slow intravenous infusion. Additional doses are usually not required. Treating healthcare providers should be prepared to treat allergic reactions including anaphylaxis. Allergy/Immunology specialist bedside consultation is recommended during treatment, if available.

Intensive supportive care may be required for extended periods with all forms of human botulism.