Ricin and Staphylococcal Enterotoxin B: Potential Biologic Weapons

In 1978, a ricin-filled pellet--which was injected with aspring-loaded device disguised in an umbrella--wasused to assassinate Bulgarian defector Georgi Markov.A similar device was employed unsuccessfully against asecond defector in the same year.¹

The potential arsenal of biologic weapons is not limitedto intact microorganisms, such as Bacillus anthracis,variola virus, and Yersinia pestis. Purified toxins alsopose a threat. Here, we focus on ricin and staphylococcalenterotoxin B (SEB) (Table).

RICIN
Ricin is a potentially lethal toxin derived from thebeans of the castor plant; cases of accidental intoxicationare infrequent. Ricin is purified from castor bean mash,which is a by-product of castor oil production and is approximately5% ricin by weight. Ricin toxin is a dimericprotein comprising a receptor-binding subunit and an enzymaticsubunit that inhibits host cell protein synthesisand ultimately causes cell death. Most cases of accidentalpoisoning occur in children who ingest castor or relatedbeans. Ricin is very stable and can be lethal by aerosol,enteric, or parenteral routes, although it is the aerosolroute that is most hazardous.¹

Clinical manifestations. Experience with human intoxicationis limited, but the clinical sequelae are potentiallysevere, begin within hours, and vary depending on doseand route of exposure. After inhalation of sublethal doses,symptoms include fever, tightness in the chest, cough, dyspnea,nausea, and arthralgias, beginning within 4 to 8 hours.More substantial aerosol exposures in animals lead to pulmonarynecrosis and severe edema. Human exposures ofthis type are expected to cause progressive cough with severepulmonary inflammation, cyanosis, and pulmonaryedema. In animals, death occurs within 36 to 72 hours.¹

GI exposure causes local cytotoxicity with hemorrhage,as well as hepatic, splenic, and renal necrosis. Intramuscularinjection of ricin causes severe tissue necrosisof muscle and lymph nodes as well as some distant organinvolvement.¹

Diagnosis. A case of ricin toxicity would likely bemissed without a high index of suspicion. Look for a rapidlyprogressing pulmonary syndrome that does not respondto antibiotics. In contrast to anthrax respiratory syndrome,ricin toxicity does not produce mediastinitis. ELISA testingof serum or immunohistochemical analysis of tissue samplescan be diagnostic. The chest radiograph may show bilateralinfiltrates; other features include hypoxemia andpolymorphonuclear leukocytosis.

Therapy. Treatment options currently are limited tosupportive care and management of pulmonary edema. GIdecontamination is warranted in cases of ricin ingestion.¹

STAPHYLOCOCCAL ENTEROTOXIN B
SEB is most often associated with food-borne outbreaksof GI disease; however, SEB and other staphylococcalenterotoxins are also responsible for some cases oftoxic shock syndrome. When present in the respiratorytract, SEB causes significant morbidity. Thus, it may notbe surprising that SEB and other staphylococcal enterotoxinshave been prepared as a powder for aerosol dispersalby various nations. Inhalation of SEB produces a quitedifferent clinical picture from that produced by ingestion.While exposure of this type would probably not be fatal tomost persons, victims would be rapidly incapacitated andsome might experience life-threatening symptoms.

Mechanism of action. As a biologic weapon, SEBhas the advantages of heat stability, a wide range of biologicactivities, and high potency. SEB is a "superantigen,"and as such, belongs to a family of molecules that bindwith high affinity to major histocompatibility complexclass II receptors of monocytes and macrophages and tothe T-cell receptor V βdomain.^2,3 This binding, in turn,productionof interleukin-1, tumor necrosis factor α, and interferon-μ, as well as a host of physiologic effects.

Clinical manifestations. Following aerosol exposureto SEB, symptoms begin within 3 to 12 hours, with suddenonset of fever, headache, chills, myalgias, and anonproductive cough.⁴ Dyspnea and retrosternal chestpain are sometimes evident, and a high-dose exposure canlead to hypotension, shock, multiorgan failure, and death.Toxin deposited in the mouth will be swallowed, leadingto nausea, vomiting, and diarrhea. Fever may last for upto 5 days, with or without chills.

Diagnosis. There are usually no significant physicalfindings with SEB intoxication, although in more severecases, there may be pulmonary edema with the expectedmanifestations on chest x-ray films. Laboratory findingsare generally nonspecific. Soon after exposure, SEB or itsmetabolites can be detected in swabbings of the nasalmucosa (by ELISA) and in urine.

Therapy.With supportive care, most patients make afull recovery. Aside from supportive care, there is no widelyavailable specific therapy for SEB toxicity at present; specificimmune globulin may ameliorate the disease if givenquickly. Efforts to develop a vaccine are under way⁵

REFERENCES:1. US Army Medical Research Institute for Infectious Diseases. Medical Managementof Biological Casualties Handbook. 3rd ed. Frederick, Md: USAMRIID; 1998.
2. Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives.Science. 1990;248:705-711.
3. Schlievert PM. Role of superantigens in human disease. J Infect Dis. 1993;167:997-1002.
4. Franz DR, Jahrling PB, Friedlander AM, et al. Clinical recognition andmanagement of patients exposed to biological warfare agents. JAMA. 1997;278:399-411.
5. Lowell GH, Colleton C, Frost D, et al. Immunogenicity and efficacy againstlethal aerosol staphylococcal enterotoxin B challenge in monkeys by intramuscularand respiratory delivery of proteosome-toxoid vaccines. Infect Immun.1996;64:4686-4693.
6. Relman DA, Olson JE. Bioterrorism preparedness: what practitioners need toknow. Infect Med. 2001;18:497-514.