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Heptavalent Botulinum Antitoxin to be Acquired by HHS

By Clarence Lam and Luciana Borio, M.D., August 3, 2006

On June 1, 2006, the U.S. Department of Health and Human Services (HHS) issued a contract for the purchase of 200,000 doses of heptavalent botulism antitoxin from Cangene Corporation (Winnipeg, Manitoba, Canada) at a price of $363 million with delivery to the Strategic National Stockpile scheduled to begin in 2007. [1] The heptavalent antitoxin is expected to be effective against all known types of botulinum toxin.

The Most Poisonous Substance Known to Man

Botulinum toxins are the most poisonous substances known to man. [2] They prevent the release of acetylcholine from neuromuscular junctions and at muscarinic peripheral autonomic synapses, which results in flaccid muscle paralysis and autonomic dysfunction.

There are 7 types of botulinum toxin, designated A through G based on antigenic differences. A, B, and E most commonly affect humans, and most of the antitoxin stockpiled by the Centers for Disease Control and Prevention (CDC) and available through state health departments is trivalent—effective against those 3 types. Botulinum toxin F may also cause human disease, whereas types C and D affect primarily animals. Type G has not been associated with naturally occurring disease.

Clinical Course

Botulinum poisoning typically presents within 1 to 5 days after ingestion of the toxin as a symmetric, descending flaccid paralysis. [3] Wound botulism occurs after spores contaminate a wound and germinate to produce toxin. The incubation period and rate of clinical progression following delivery of aerosolized botulinum toxin in a bioterrorist attack is unknown, but past cases of toxin exposure after inhalation indicated that symptoms of botulinum poisoning occurred in approximately 72 hours. [2, 4]

Bilateral cranial nerve palsies occur first and may present as diplopia and ptosis. Further progression results in bulbar nerve dysfunction, with dysphagia and dysarthria, and subsequent skeletal muscle paralysis leads to respiratory failure and death in the absence of mechanical ventilation. Mentation is normal, and sensory deficits, other than blurred vision, do not occur. Patients are afebrile. The cornerstones of management include airway protection, mechanical ventilation, botulinum antitoxin, and supportive therapy.

Administration of Antitoxin

Botulinum antitoxin should be administered by slow intravenous infusion. Published data on adverse events from past botulinum antitoxin use indicates mild reactions, including serum sickness, utricaria, and anaphylaxis. [3] The U.S. Army used heptavalent immunoglobulin in a type E food borne outbreak in Egypt, with published reports of mild hypersensitivity reactions and serum sickness. [5] Diphenhydramine and epinephrine should be available for administration in the event of adverse reaction.

Conclusion

Botulinum antitoxin is the only effective therapeutic against botulinum poisoning. Patients suspected of botulism should be provided with antitoxin immediately, without waiting for confirmatory laboratory testing. Although treatment with antitoxin will not reverse any manifested paralysis, it will prevent its progression. This is critical in the event of an attack, because patients who do not receive antitoxin and progress to respiratory failure may require mechanical ventilation for prolonged periods (mean of 58 days for type A ingestion). [6] The medical infrastructure is not equipped to deliver mechanical ventilatory support to a large number of patients for a protracted time period.The CDC and certain state and local health departments currently retain stocks of a licensed trivalent antitoxin against types A, B, and E. Because it is effective against all known botulinum toxins, a heptavalent botulinum immunoglobulin affords greater protection from a bioterrorist attack since the type of toxin used may not be known.

References

  1. HHS Awards BioShield Contract For Botulism Antitoxin. Available at http://www.dhhs.gov/news/press/2006pres/20060601.html. Accessed on July 17, 2006.

  2. Arnon SS, Schechter R, Inglesby TV, et al. Botulinum toxin as a biological weapon: medical and public health management. JAMA 2001;285(8):1059-70.

  3. Horowitz BZ. Botulinum Toxin. Crit Care Clin. 2005;21(4):825-39, viii.

  4. Holzer VE. Botulism from inhalation [in German]. Med Klin. 1962;57:1735-38.

  5. Hibbs RG, Weber JT, Corwin A, et al. Experience with the use of an investigational F(ab')2 heptavalent botulism immune globulin of equine origin during an outbreak of type E botulism in Egypt. Clin Infect Dis 1996;23(2):337-40.

  6. Seals JE, Snyder JD, Edell TA, et al. Restaurant-associated type A botulism: transmission by potato salad. Am J Epidemiol. 1981;113(4):436-44.