Risk of deliberately used anthrax
RISK OF DELIBERATELY INDUCED ANTHRAX OUTBREAK
The Lancet, October, 2001
The spate of cases of anthrax associated with spores delivered by mail to offices and the House of Representatives in the USA in the wake of the terrorist attack on the World Trade Centre in New York has put the world on special alert about the possibility of biological and chemical warfare. This zoonotic infection is acquired from herbivores and caused by the gram-positive, spore-forming, bacterium Bacillus anthracis.
Cutaneous anthrax, now extremely rare in UK and USA, is by far the commonest form of illness and is an occupational hazard for workers who handle animals or their products (eg, wool and goat-hair). Manifesting as a black painless pustule, it is the mildest form of the disease and is the most likely one to be acquired from spores delivered in the post. With appropriate treatment, it is rarely fatal, but without such treatment the infection can spread systemically. The inhalational form of the disease is fatal in 90% of cases unless treated in the prodromal phase. The spores inhaled are transported via lymphatics to mediastinal lymph nodes, where the bacteria germinate. Germination can range from a few days to about 2 months, and after their release the bacteria rapidly cause overwhelming disease. Oropharyngeal anthrax and intestinal anthrax (which is extremely rare) can be fatal in up to half of the cases.
Replicating bacteria release at least three powerful toxins, which cause haemorrhage, oedema, and necrosis. These toxins are coded by the pX01 plasmid and include the 83 kDa lethal factor, the 89 kDa oedema factor (adenylate cyclase interacting with calmodulin), and the 85 kDa protective antigen, which also contains the 20 kDa host-cell-receptor component.1 The protective antigen PA is vital for the function of the other two proteins, which it protects until they enter the host cells. The expression of the bacterial capsule (encoded by plasmid pX02) is vital for the pathogenicity of B anthracis; the capsule inhibits phagocytosis by the host’s leucocytes.
Diagnosis is by gram stain and culture of exudates (from skin lesions), blood (for pulmonary anthrax), and faeces (for intestinal form). Smears should be fixed chemically instead of by the usual brief flame-heating, which may not kill the spores. Culture results are available overnight. Screening for infection in people exposed is by culture of nasal swabs.
Large anthrax epizootics in herbivores have been reported. During a 1945 outbreak in Iran, a million sheep died. The biggest two recent outbreaks among human beings occurred in Zimbabwe, where over 10 000 cases, mostly cutaneous, arose between 1979 and 1985, and in Sverdlovsk, Russia, where an accident in a biological weapon plant in 1979 released aerosols of spores and led to tens (if not hundreds) of cases of pulmonary anthrax.2 In the USA, 224 cases of cutaneous anthrax were reported between 1944 and 1994 and only 18 cases of inhalational anthrax between 1900 and 1978, most occurring in special-risk groups, such as people working with goat hair, goatskin, or wool, or those working in tanneries. Two of these cases were laboratory associated. No cases of pulmonary anthrax had been reported in the USA since 1978.
Strains in bioweapons
There are diverse strains of B. anthracis, which have been typed phenotypically and genetically. The recent outbreak in the USA is thought to have originated from a single source and to be a derivative of the virulent Ames strain, which is used by researchers around the world. It will have changed considerably through subsequent passages and subculturing since its first isolation in the 1950s from a dead animal in Ames, Iowa. Anthrax, like most chemical and biological weapons, is used largely to terrify rather than to kill. In modern times most biological agents are poor weapons in battle zones because soldiers fight in chemical and biological protection suits and have generally been vaccinated against anthrax. It is thus puzzling why member states of the United Nations are producing and stockpiling them.
The long-dreaded concern that chemical and biological weapons might reach terrorist hands is now a reality. Of the list of bioweapons, anthrax is probably the most serious because it needs the simplest of manufacturing infrastructure and is most durable and suitable for many forms of delivery, including, as is the case now, by mail. An anthrax-vaccinated terrorist with basic microbiology skills can easily manufacture quantities of anthrax spores from local animal isolates. A few litres of standard broth culture of anthrax, prepared in a kitchen, can produce sufficient quantities of anthrax to infect a few people when sent in the post in powder form. Lyophilising cultures into powder also requires only simple equipment. More complicated biotechnological equipment is required for ultra-refining the spores to remove unwanted (sticky) material and reducing spores to fine (inhalable) powder, hence the issue of weapon-grade anthrax that was extensively debated by American experts in the recent incidents. Such refinement is thought by American experts to be beyond the capability of small groups. At least 17 countries are believed to possess chemical and biological weapons programmes.
In view of the apparent sensitivity of the clinical isolates in the USA to penicillin and doxycycline, they are unlikely to have originated from Soviet plants, because Russian scientists are known to have engineered strains resistant to these antibiotics.2 The existence of such strains is the main reason why ciprofloxacin was recommended as antibiotic of first choice until laboratory confirmation of sensitivity to antimicrobials. Ciprofloxacin-resistance genes can be introduced in the organism but has not been done. Ciprofloxacin is not licensed for use prophylactically against anthrax and is not free from side-effects, some of which (eg, convulsions or allergic reactions) can be serious albeit rare. The US Food and Drug Administration has just issued a reminder that doxycyline is suitable for prophylaxis and for treatment of all forms of the disease. It is also approving new labelling for the use of several antibiotics for the treatment of anthrax. Health authorities are strongly discouraging the prescription of antibiotics for the prevention of anthrax without clear indication of exposure. To be effective, treatment (including prophylaxis) has to be taken at full dose for 2 months because antibiotics are not effective against the spores.
Although the LD50 for human beings is thought to be only a few thousands of inhaled anthrax spores, maximum damage (an epidemic of pulmonary anthrax) is believed to be achievable only if high quantities are air-borne. WHO has suggested that 50 kg of anthrax spores (which would require massive fermenters and several months of fermentation) released from an aircraft over an urban population of 5 million would cause 250 000 cases of the disease. Another report estimated that releasing a cloud of 100 kg of spores upwind of Washington DC could cause between 130 000 and 3 million deaths. The Aum Shinrikyo cult of Japan, which poisoned Tokyo underground commuters with sarin, is reported to have failed to deliver anthrax in and around the city despite repeated attempts. Speculation about how much spores the terrorists in the recent incidents possess was prompted by a report that one of the hijackers in the New York attack had inquired about crop (dusting planes), so such planes have been grounded in the USA.
The best defence against biological terrorism is knowledge combined with a high state of alert. Procedures for dealing with outbreaks of illness due to biological or chemical terrorism are no different from those for outbreaks of illness occurring naturally or by accident. Good public-health systems should have in place policies for controls of outbreaks, including those induced deliberately, and be revised in the light of the current events. Defence against biological warfare will be further strengthened by informing and reassuring the public because just threats of such attacks can cause damage by disrupting everyday activities. Anthrax does not spread from person to person and remains susceptible to many antibiotics. Shortage of antibiotic supply is unlikely. Vaccine supply is not an issue because vaccination will be considered for only a selected few—eg, those who handle investigations or specimens, including environmental samplers and laboratory and mortuary staff. The most important component of vaccines is the protective antigen, and a full six-dose course of acellular vaccine containing this antigen is more than 90% effective.
Once a point-source and the exposed population are identified, the outbreak can be tackled as planned. The biggest task for public-health authorities is to communicate the news skillfully enough to prevent panic and to avoid overwhelming the health service. Important elements in such information include an assessment of the method of delivery of the biological agent and the likely size and severity of the outbreak.
The possibility of chemical and biological warfare has long been recognised, and discussions among nations since 1925 have led to several conventions and treaties related to chemical and biological warfare. The treaty of 1972 was considered inadequate, and after 21 years of further discussions The Convention on the Prohibition of the Production, Stockpiling and Use of Chemical Weapons and on Their Destruction, was signed in Paris in 1993. However, little progress has been made in its implementation. The 17 countries (including Iraq, Iran, Russia, India, Yugoslavia, and USA) known or strongly believed to possess chemical and biological weapons are all signatories of the 1993 treaty. Iraq is the only country recorded by the United Nations to have breached the treaties and is known to have used chemical weapons against Iran and the Kurdish population within Iraq (where 15 000 Kurds were reportedly poisoned). Therefore, it is the urgent task of the United Nations to put an end to the production, proliferation, and use of biological weapons.
The Lancet, 27 October, 2001,Vol 358, pages 1386-8
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3 Dalton R. Genetic sleuths rush to identify anthrax strains in mail attacks. Nature 2001; 413: 657–58.
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5 Office of Technology Assessment, US Congress. Proliferation of Weapons of Mass Destruction. Washington, DC: US Government Printing Office; 1993:53-55. Publication OTA-ISC-559.