CLINICAL UPDATE
CLINICAL UPDATE
Biological agents as weapons 1: smallpox and botulism Michael Whitby, Alan C Street, Tilman A Ruff and Frank Fenner THE USE OF BIOLOGICAL AGENTS as weapons of war is not new. In the 14th-century siege of Kaffa, on the Black Sea, the attacking Tartars catapulted bodies of plague victims at the defending Genoese, who contracted the disease and The Medical Journal of Australia 0025-729X May 2002 abandoned the city. Over the pastISSN: century, many 6countries 176 9 431-433 have developed the capacity to use biological agents to ©Thecasualties Medical Journal of Australia 2002 www.mja.com.au produce in humans and domestic animals and to CLINICAL UPDATE damage crops and environmental systems. Some biowarfare programs are known to have continued despite the adoption by 144 countries of the 1972 Biological Weapons Convention, which prohibited development or acquisition of such weapons. Early recognition of unusual clinical illness by physicians is an integral part of the public health response to a biological attack. We review the features of four biological agents of greatest concern. In this article, we discuss smallpox, a disease not seen in the world for the past two decades, and botulism. A subsequent article will discuss anthrax and plague.
ABSTRACT ■
Early recognition by clinicians of illnesses suggesting a biological attack is integral to the public health response.
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The four biological agents of most concern are smallpox virus, botulinum toxin, and anthrax and plague bacteria.
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Smallpox is distinguishable from chickenpox by the prominent prodromal period and lesions that develop at the same pace and, on any part of the body, appear identical to each other, evolve slowly and are peripherally distributed.
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The degree of protection conferred by smallpox vaccination given 20 or more years ago is unknown.
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Foodborne and inhalational botulism could result from deliberate release of toxin.
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Botulism presents with cranial nerve palsies and descending paralysis in a patient with normal conscious state and no fever.
Smallpox
MJA 2002; 176: 431–433 Epidemiology
In a world declared free of smallpox in May 1980,1 this disease has characteristics that make it particularly suitable for biological warfare. It can be spread person-to-person. With the cessation of vaccination programs over 20 years ago, immunity has waned among those who have been vaccinated, while those born since 1980 are unvaccinated. The virus spreads by the respiratory route (primarily by droplet nuclei or aerosols expelled from the nasopharynx of infected people) or by direct contact (being released from ulcers on the oral mucosa from the time lesions appear on the skin and two to three days after onset of fever). It has also been transmitted by soiled clothing and blankets used by patients. Smallpox spreads rapidly between close family
Infection Management Services, Princess Alexandra Hospital, Brisbane, QLD.
contacts2 and within hospitals when no special precautions are taken.3 Smallpox as a weapon
Other features of smallpox that contribute to its suitability as a weapon are the stability of the virus in aerosol form and the likely small infective dose.4 Smallpox virus was added to the biowarfare program of the Soviet Union in 1980. Successful methods of stockpiling large amounts of this virus and delivering it from aircraft or ballistic missiles have been developed.5 With the discontinuation of the Soviet civilian biowarfare program in 1992, hundreds of experienced scientists became available to sell their services and take smallpox virus to other countries.5 The Indian strain of smallpox virus, used in the Soviet biowarfare program, causes a mortality of about 30% in unvaccinated people.
Michael Whitby, FRACP, FRCPA, Director.
Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, VIC. Alan C Street, FRACP, Deputy Director.
GlaxoSmithKline Biologicals, Melbourne, VIC. Tilman A Ruff, FRACP, Medical Director.
John Curtin School of Medical Research, Australian National University, Canberra, ACT. Frank Fenner, MD, FRS, Visiting Fellow. Reprints will not be available from the authors. Correspondence: Dr M Whitby, Infection Management Services, Princess Alexandra Hospital, Brisbane, QLD 4102.
[email protected]
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Clinical features and diagnosis
The incubation period of 10–14 days ends with sudden onset of fever, headache and backache, usually severe enough to confine the patient to bed. Fever usually continues as the rash develops, with pain associated with pustule growth. Scabs develop and gradually separate, leaving pitted scars. The rash is the most important feature allowing early recognition of smallpox (Box 1). Most cases have been “ordinary type” smallpox, which has pustular lesions, but 431
CLINICAL UPDATE
1: Smallpox lesions in an unvaccinated child Evolution of smallpox lesions from papules (top left; three days after onset of fever) to vesicles and pustules (bottom right; nine days after onset of fever). For the first two to three days, the rash of smallpox resembles that of chickenpox, but the two can be differentiated by the following: ■ Smallpox lesions appear after two to three days of
prominent prodromal symptoms (fever, headache and backache) and develop slowly (over nine to 10 days). Chickenpox lesions develop rapidly after a one- to two-day prodrome (fever and malaise). ■ All smallpox lesions develop at the same pace and, on any part of the body, appear identical. Chickenpox lesions are much more superficial and develop in crops over a two- to four-day period, with scabs, vesicles and pustules seen simultaneously on adjacent areas of skin. ■ Smallpox lesions are most concentrated on the
face, arms and legs, and may occur on the palms or soles. Chickenpox lesions are most dense over the trunk and almost never found on the palms or soles.
variant forms (“flat” and “haemorrhagic type” smallpox) occurred rarely and were almost always fatal. Modified smallpox occurred in people with waning immunity after vaccination and those who were vaccinated very early in the incubation period, and comprised a few skin lesions, which evolved more rapidly than those in unvaccinated people. Clinical diagnosis can be confirmed by electron microscopy of vesicular or pustular fluid or scabs, which should be collected and processed under maximum containment conditions.
Botulism Epidemiology
Botulism is extremely rare in Australia, with no reported foodborne cases since 1991.7 The causative organism, Clostridium botulinum, is an anaerobic, spore-forming, grampositive rod found in soil (Box 2). It produces a potent neurotoxin that causes paralysis of skeletal and smooth muscle by interfering with acetylcholine release at the neuromuscular junction. Botulism as a weapon
Management and prevention
The only proven effective treatment for smallpox is vaccination before or within three days of exposure, which may abort or modify the severity of an attack. Other treatment is supportive only, plus antibiotic therapy if secondary bacterial infection develops. Strict quarantine with respiratory isolation for 17 days is required of all cases and direct contacts of index cases. Vaccination with vaccinia virus is effective in preventing smallpox for at least five years and may prevent or modify infection for a much longer period, but this varies greatly from person to person. However, very few doses of vaccine are available worldwide at present. Furthermore, smallpox vaccination is associated with more severe adverse effects than any other type of vaccination: for example, encephalitis occurs at a rate of one per 300 000 primary vaccine doses and a quarter of cases are fatal, with some survivors having permanent neurological deficits.4 Therefore, both the World Health Organization and the United States Centers for Disease Control and Prevention have recommended that it should be used only to contain suspected cases and not for mass vaccination.6 432
Botulinum toxin was first developed as a biological weapon over 60 years ago; it can be aerosolised, or used to contaminate food,8 and the estimated lethal oral dose is 70 g. The Aum Shinrikyo cult released aerosolised toxin in Japan in the 1990s, but fortunately no cases of botulism resulted. The Soviet Union and Iraq have produced large amounts of botulinum toxin, and Iraq loaded toxin into missiles and bombs.8 Clinical features
Two forms of botulism could arise from deliberate release of botulinum toxin — foodborne and inhalational botulism. In contrast, gastrointestinal (infant) and wound botulism arise from infection with C. botulinum, rather than ingestion or inhalation of toxin, and are unlikely to occur in a biological attack. Foodborne botulism, the most common natural form of the disease, results from ingestion of preformed toxin that is produced when food contaminated with C. botulinum has been stored under anaerobic conditions. Cases are mostly associated with improperly home-bottled or preserved MJA
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foods, but could potentially Clostridium botulinum result from intentional addition of toxin to food. Botulism after inhalation of aerosolised toxin is an unnatural, man-made form of the disease, and would be the intended result of toxin delivery by missiles, bombs or aerosolisation devices. Only one instance of inhalational botuGram-positive rods with lism has been reported, characteristic subterminal involving accidental exposure spores (Gram stain; original of three veterinary personnel magnification x1000). to toxin re-aerosolised from (Picture courtesy Microbiological animal fur.8 Diagnostic Unit, Public Health Laboratory, University of The incubation period for Melbourne, VIC.) gastrointestinal botulism and probably also inhalational botulism (based on animal studies) is usually 12 to 72 hours. All forms of botulism have identical clinical features, with the exception that foodborne botulism may be preceded by gastrointestinal symptoms (nausea, vomiting, diarrhoea, abdominal cramps).8 The pattern of illness is characteristic: onset with cranial nerve palsies of bulbar distribution, followed by descending motor weakness (from head and chest muscles to upper, then lower, limbs) in a patient with a normal conscious state and no fever.9 Absence of sensory changes is another important negative feature. Reflexes are preserved early, but may be lost with time. Dilated pupils, blurred vision, dry mouth and constipation indicate parasympathetic involvement. Severity of the weakness and its rate of progression vary, depending on the amount of toxin ingested. With modern medical therapy, mortality of foodborne botulism is less than 10%.
toxin is an equine preparation, serum-sickness-like reactions may occur in some recipients, but anaphylaxis is rare. Otherwise, treatment is supportive. Close respiratory monitoring is essential, and patients should be admitted to an intensive care or high-dependency unit. In one foodborne outbreak, 20% of patients required mechanical ventilation. An investigational toxoid vaccine has been given to laboratory and military personnel in the United States but is not available for more widespread use. References 1. Fenner F, Henderson DA, Arita I. Smallpox and its eradication. Geneva: World Health Organization, 1988. 2. Gani R, Leach S. Transmission potential of smallpox in contemporary populations. Nature 2001; 414: 748-751. 3. Wehrle FF, Poach J, Richter KM, et al. An airborne outbreak of smallpox in a German hospital and its significance with respect to other recent outbreaks in Europe. Bull WHO 1970; 43: 669-679. 4. Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon. Medical and public health management. JAMA 1999; 281: 2127-2137. 5. Alibek K, Handelman S. Biohazard. New York: Random House, 1999. 6. Smallwood RA, Merianos A, Mathews JD. Bioterrorism in Australia. Med J Aust 2002; 176: 251-253. 7. Paterson DL, King M, Boyle R, et al. Severe botulism after eating homepreserved asparagus. Med J Aust 1992; 157: 269-270. 8. Working Group on Civilian Bio-Defense. Botulinum toxin as a biological weapon: medical and public health management. JAMA 2001; 285: 1059-1170. 9. Hatheway CL. Botulism: The present status of the disease. Curr Top Microbiol Immunol 1995; 195: 55-75. (Received 15 Feb, accepted 11 Mar 2002)
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Diagnosis
Diagnosis is initially clinical. The principal differential diagnoses are the Miller–Fisher variant of Guillain–Barré syndrome (a demyelinating condition causing cranial nerve palsies and absent deep tendon reflexes) and disorders of the neuromuscular junction, such as myasthenia gravis. These and other conditions can be differentiated from botulism on the basis of clinical signs (eg, impaired consciousness in brainstem stroke or infection), analysis of the cerebrospinal fluid (infection and Guillain–Barré syndrome), neuroimaging (stroke) and electromyography (myasthenia gravis). Laboratory testing for botulism is complicated and time consuming and is available only through selected public health laboratories. To detect toxin, mice are inoculated with serum, faeces or vomitus; the organism, if present, can also be cultured from these specimens. Results are not available soon enough to assist initial diagnosis or management. Management and prevention
Prompt administration of botulinum antitoxin, available in the US but not Australia, lessens disease severity. As the MJA
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