Bioterrorism

Bioterrorism has recently become an important political issue in the US. Spending on medical defense and research against bioterrorism is rising exponentially. US$91m was spent in 1998, compared to a proposed budget of US$336.6m for the year 2000.1 Former President Clinton announced that he intended to ask Congress for a staggering US$2.85bn to counter the bioterrorist threat with funds distributed between the FBI, military intelligence, the National Security Agency and the medical and emergency services.2 In February 1999, the first ever national conference on defense against bioterrorism was organized by Johns Hopkins University. The conference was substantially oversubscribed and hundreds had to be turned away.2 Frightening scenarios of invisible clouds of anthrax and smallpox drifting through cities and killing thousands of people were described. Is this simply American paranoia, or should Britain also be concerned about the threat of bioterrorism? Although often perceived as a recent invention, biological weapons have been used for hundreds of years. During the siege of Kaffa (now Feodossia, Ukraine) in 1346, the Tatars catapulted the dead bodies of plague victims into the city, causing an epidemic among the inhabitants. The subsequent migration of refugees from the defeated city may have caused the second European plague pandemic.3 In the 18th century, Sir Jeffrey Amhurst deliberately caused a smallpox epidemic among hostile Native American tribes by giving them contaminated hospital blankets. The effect on the Indian population was devastating.4 Recent use of biological agents to cause deliberate harm has only rarely been described in the medical literature, with approximately one report per decade. During the 1960s, several outbreaks of typhoid and dysentery in Japanese hospitals were caused by intentional food poisoning by a bacteriologist.5 In 1970, four Canadian students developed asthma, eosinophilia and pulmonary infiltrates after consuming food deliberately infected with Ascaris suum ova.6 During a single month in 1985 in Dalles, Oregon, 751 people developed salmonella gastroenteritis after contamination of salad bars by the Rajneeshee religious cult.7 Most recently in 1996, 12 laboratory staff developed dysentery after intentional contamination of muffins by a colleague.8 Although these amateurish attempts seem relatively minor, many experts regard bioterrorism as capable of causing death and incapacitation to tens of thousands of people. The former Congressional Office of Technology Assessment reported that a small aeroplane carrying 100 kg of anthrax spores could use a crop‐sprayer to deliver a fatal dose to 3 million people.9 A report by the World Health Organization estimated that if an aeroplane released 50 kg of anthrax over a 2 km line, upwind of a population of 500 000 people, 95 000 people could be killed and 125 000 incapacitated.10 Other agents could also cause significant morbidity and mortality (Table 1). Even hoaxes alleging the use of biological agents can cause serious disruption. A series of hoaxes alleging the use of anthrax in several US states between October and December 1998 produced emergency reactions from local and state health departments, CDC and the FBI. Businesses were temporarily closed, and many people were decontaminated and given antibiotic prophylaxis before the use of anthrax was excluded.11 In the US, the threat of bioterrorism is taken extremely seriously, with the CDC, US Department of Health and Human Services, state and local health departments, federal agencies and non‐governmental organizations working together to address bioterrorism and develop response plans. In Europe, bioterrorism has received much less attention. In this article we consider whether the threat from bioterrorism is real and how affected patients might present to the hospital physician. Comparison of effects of biological agents Theoretical number of deaths and people incapacitated by release of 50 kg of biological agent along a 2 km line upwind of a population of 500 000 as calculated by a WHO expert group.10 TBE, tick‐borne encephalitis; RVF, Rift Valley fever. Comparison of effects of biological agents Theoretical number of deaths and people incapacitated by release of 50 kg of biological agent along a 2 km line upwind of a population of 500 000 as calculated by a WHO expert group.10 TBE, tick‐borne encephalitis; RVF, Rift Valley fever. Following World War I, several countries began programmes to develop biological weapons including Belgium, Britain, Canada, France, Holland, Italy, Poland and the Soviet Union.4 However the most infamous biological weapons programme was probably that begun by Japan in 1932 in occupied Manchuria. Over a 13‐year period, Chinese, Manchurian, American, British, Australian and Soviet prisoners were infected with Bacillus anthracis, Neisseria meningitidis, Shigella spp., Vibrio cholerae and Yersinia pestis. It is estimated that 3000 prisoners died at Ping Fan, the biological weapons development centre.4 Biological weapons were used in attacks on at least eleven Chinese cities, with widespread spraying from aircraft and release of millions of plague‐infected fleas. The indiscriminate nature of these weapons is shown by an attack on Changteh, where the Japenese caused an estimated 10 000 casualties and 1700 deaths among their own troops.4 The US began an offensive biological weapons programme in 1942, based at Camp Detrick (later Fort Detrick). This programme continued until 1969, when President Nixon announced that all biological weapons production should stop and all existing stocks be destroyed. The US had developed a substantial biological arsenal of weaponized agents including Bacillus anthracis, botulinum toxin, Francisella tularensis, Brucella suis, Coxiella burnetii, staphylococcal enterotoxin B and Venezuelan equine encephalitis virus.4,12 Several anti‐crop agents were stockpiled but not weaponized.4 During the Cold War, the US alleged that Soviet forces used T2 mycotoxins (Yellow Rain) in Laos, former Kampuchea, and Afghanistan.4 These accusations have proved difficult to confirm or refute. However, it is known that the former Soviet Union developed biological weapons for many years after signing the 1972 biological weapons convention prohibiting such activity.13 In 1979, an epidemic of anthrax occurred in Sverdlovsk, Russia, and US agencies attributed this to inhalation of spores released from a military microbiology facility. Although this was denied by the Soviet Government, an independent epidemiological study found that the most likely cause was accidental release of spores from the military facility, and this was eventually admitted by President Yeltsin in 1992.14 During the 1970s and 1980s, the Soviet Union allegedly operated at least six biological weapons research labs and five production facilities, and employed up to 55 000 scientists and technicians.4 One of these facilities located in Koltsovo, Novosibirsk employed 4000 people and stored smallpox, Ebola, Marburg and other haemorrhagic fever viruses.13 Ken Alibek, former deputy chief of the Russian bioweapons programme, has admitted that smallpox virus was weaponized into intercontinental ballistic missiles and bombs.15 A visit to the Novosibirsk site in 1997 found that the facility was half empty and poorly guarded, and the majority of scientists had left.13 It is possible that these scientists are now using their knowledge and skills to develop biological weapons programmes for other countries or for terrorist organisations, and they may have taken stocks of smallpox virus with them. Between 1985 and 1991, Iraq developed a substantial biological weapons programme, including four aerial dispensers and 200 bombs and 25 ballistic missiles armed with biological agents.16,17 Although these weapons were not used during the Persian Gulf War, it has been alleged that they were used during the Iran‐Iraq war, and traces of anthrax and mycotoxins were found in Iranian casualties.17,18 The United Nations Special Commission (UNSCOM) inspectors only discovered the true extent of Iraq's biological weapons programme in 1995, following the defection of General Hussein al‐Kamal, Saddam Hussein's brother‐in‐law. Iraq has declared to UNSCOM that it had stored 8400 l of anthrax (with a spore/cell count of 109/ml), 19 000 l of botulinum toxin (strength unknown), 3400 l of Clostridium perfringens spores, 2200 l of aflatoxin and 10 l of ricin. Of this, 6000 l of anthrax (50 bombs and five missiles), 12 000 litres of botulinum toxin (100 bombs, 16 missiles) and an unknown quantity of aflatoxin (seven bombs, four missiles) were weaponized.16 Aflatoxin is carcinogenic and has no obvious use in biological warfare, suggesting the Iraqis may have produced it to use on civilian targets to create panic. More alarming is the suggestion that Iraq declared the aflatoxin to cover up some other, more dangerous, biological agent.17 Iraq claims to have destroyed these weapons unilaterally, but this has proved impossible for UNSCOM inspectors to verify.17 Aum Shinrikyo, the 40 000‐member cult that caused the sarin gas attack on the Tokyo subway system in 1995, is also believed to have a substantial biological weapons programme. Between 1990 and 1995, the cult unsuccessfully tried to aerosolize anthrax and botulinum toxin throughout Tokyo on eight occasions.15 The cult sent an expedition to Zaire to acquire Ebola virus samples, and has also acquired a helicopter and two radio‐controlled drones for disseminating biological and chemical agents.9 The cult is still legal despite the imprisonment of its leader. Methods for producing biological weapons are now available on the internet, and the technology involved is not beyond the resources of highly determined terrorist groups. UNSCOM's work in Iraq has revealed how difficult it is to detect biological weapons production facilities, as most equipment is of dual‐purpose design. The explosion of a conventional weapon is immediately apparent, but release of biological agents can be silent and pass undetected until victims begin presenting to medical services, perhaps several days after exposure. D.A. Henderson, former director of WHO's global smallpox eradication campaign, describes the scenario where a lightbulb filled with smallpox virus is released in a Washington subway, perhaps infecting as few as 100 people.13 The event would pass unnoticed, and it would be several days before patients became unwell and presented to physicians. By this time many other people would be secondarily infected, and a full‐scale epidemic could occur. The majority of physicians practising today have never seen a case of smallpox, pneumonic plague, typhoidal tularaemia, pulmonary anthrax nor many other diseases that could result from a bioterrorist attack. Diagnostic microbiology laboratories may also have difficulties in correctly identifying the organism. Delays in diagnosis would be likely and for some biological agents this could result in hospital transmission of disease. When a patient with smallpox was admitted to a German hospital in 1970, 19 hospital in‐patients developed the disease before the diagnosis was established, and hospital patients and staff had to be quarantined for 4 weeks to control further spread.19 Therefore medical practitioners need to be aware of the diseases which could be caused by bioterrorism, how to recognize them and how they might present in an atypical fashion. Although CDC has a long list of restricted biological agents (Table 2),20 relatively few could be prepared and distributed on a wide scale. The US Army Research Institute for Infectious Diseases identifies ten conditions which they feel are most suitable for bioterrorism: smallpox, anthrax, botulism, plague, tularaemia, Q fever, viral encephalitides, viral haemorrhagic fevers, brucellosis and staphylococcal enterotoxin B.21 The important features of these diseases, when acquired by inhalation, will be discussed. CDC list of restricted agents CDC list of restricted agents Smallpox is potentially the most dangerous bioterrorist weapon because of its infectivity in aerosol form, case fatality of 30% and high patient‐to‐patient transmission rate. The world's population has become increasingly susceptible to smallpox because of the discontinuation of vaccination, and probably only 20% of the population are now protected.15 Clinical features include malaise, fever, rigors, vomiting, headache, backache, delirium and an erythematous rash. Over the following week, the patient develops mucous membrane lesions, which shed virus particles, and a rash which progresses from macules to papules to pustular vesicles. In contrast to varicella, the skin lesions are all present at the same stage of development. Patients are regarded as infectious until all of the scabs separate.22 Many exposed patients may shed virus from the oropharynx without developing the disease and cause further virus transmission.23 A high degree of awareness is required to diagnose smallpox, because it can easily be confused with varicella, erythema multiforme or allergic dermatitis. Pharyngeal swabs and skin scrapings are required for virus isolation, ELISA and PCR. Samples from any suspected patient must be processed in a biosafety category 4 facility. Clinicians should not be complacent that this disease is extinct, because recognition of a single confirmed case would be an international emergency, and prompt diagnosis and appropriate precautions could save many lives. Strict quarantine, including respiratory isolation, is required for anyone in contact with the patient, as infection can occur even if the patient is 10 m away.19 There is no known treatment for smallpox, although cidofovir is effective in vitro and could be used.21 Smallpox vaccine would need to be given to all potentially exposed individuals. The US has only 5–7 million doses of smallpox vaccine stored and there is currently no facility to produce further vaccine. Therefore, if a terrorist group began a concerted campaign of releasing smallpox virus, it would not be possible to protect the population. During the Gulf War, the US stockpiled 30 million doses of ciprofloxacin in the zone of operations to protect troops in case of an anthrax attack.4 Iraq produced enormous quantities of anthrax, and it is possible that some of this is now in the possession of terrorist groups. Aerosolized anthrax spores would cause the inhalational form of disease (traditionally known as woolsorters' disease). After a 1–5 day incubation period, the patient develops a prodromal illness characterized by fever, malaise, and A day may or the patient may to disease with and inhalational anthrax is fatal despite antibiotic is by and The patient not as transmission not occur. with ciprofloxacin and are exposed to an anthrax attack prophylaxis with a of ciprofloxacin or The US military has stocks of an anthrax although there are in the of the vaccine following inhalational release of anthrax would cause for medical The of release may be to the disease incubation period, and identifying have potentially been exposed may It is possible to develop of illness up to weeks after exposure. Therefore anyone developing could be from the prodromal appropriate health would need to be and hospitals and practitioners might be by an are the most to the the release of and Between and several days after inhalational to the toxin, develop including and The disease progresses to produce a with death from respiratory The patient may be found to have mucous and the disease may many patients could before medical attention. may be confused with or is as in the toxin is not in or and is only in the for about after The may be in botulism, producing with mortality is but the patient may several weeks or to of is the Yersinia is by from to but can also be by respiratory or an infectious dose of Following a bioterrorist the most likely would be of pneumonic After a incubation period, there is malaise, high fever, rigors, headache, and progresses and mortality is of and the diagnosis to be are also recognition of disease is because pneumonic plague is fatal if treatment is not of for treatment include and The patient should be until he or has received 3 days Following likely aerosol to plague, or is Although a vaccine is it has following aerosol Francisella is a which can be to by of contaminated food or or by few as can produce infection the respiratory The typhoidal form of the disease develops after a day incubation with fever, and treatment the mortality is approximately is difficult because and are and as is not in Britain, may not be from or can be difficult and potentially to is but is to be in the of disease. is with or or can be used for transmission is and respiratory is Coxiella is a with high infectivity but relatively used as a biological it would be likely to have mortality but high The of Q fever are and up to of are Patients may present with or including fever, headache, malaise, and skin rash. are Q fever is an cause of but may be more with Q fever is by and with or These include Venezuelan and equine encephalitis infection is from to by but these are also infectious After an incubation of patients with develop fever, vomiting, and of patients develop and among the and have a day incubation by a prodromal illness with fever, malaise, headache, and with and is the more case fatality are high and many patients have The morbidity and mortality of these when acquired by inhalation is and may be to acquired During the of virus can be from the In the diagnosis is by is as no treatment is known to be A vaccine is available for but reactions in many There is currently no vaccine available for or This group the causing and Venezuelan haemorrhagic fevers, fever, Rift Valley fever, haemorrhagic fever, and Ebola and The to viral but include fever, and can to and mucous membrane of can disease following Patients must be to be highly infectious and in is by virus or Many of these 4 laboratory facilities for their can be used to the American haemorrhagic fevers, fever and haemorrhagic can also be used in and haemorrhagic fevers, fever and haemorrhagic to the by patient treatment of and treatment of and are between are to Brucella from and These are highly infectious in form, only to The incubation is extremely from a few days to several are and on the patients may have fever, malaise, and Most patients without although a will develop which can be is by or of the from or is for weeks with a of and to the of and a more including an is can be given for weeks to exposed There is no vaccine enterotoxin B is a cause of food is extremely by 30 is to cause incapacitation and can The incubation is the at which was released would be for other biological is a and the production of quantities of This in the of headache, fever, vomiting, and The diagnosis is difficult to Several presenting with illness should and features would aerosol from food is toxin may be in or from is and treatment is to tick‐borne encephalitis and have also been described as biological and many other and their could be Although we have on aerosol could food or or develop some other of many the would the of exposure. that bioterrorism is the cause of illness could be extremely Several features of a disease may that bioterrorism is the A disease in an where it is not should immediately diseases such as pneumonic plague, smallpox, pulmonary anthrax, typhoidal tularaemia, haemorrhagic fever, the of deliberate The diagnosis of these diseases on an them when with an need to be aware of biological agents that could be used as terrorist and the atypical in which these diseases might Many diseases caused by bioterrorism present with relatively epidemiological is required to the cause of the disease. or may that a disease is not a when anthrax occurred Sverdlovsk, all were found to have or in a of the military suggesting that it was the of the Bioterrorism will often a with all a single time This may be of the but for diseases caused by a single such as food it may not be the features of disease are this may an of infection inhalational with to a have a high of disease or in a a have a this may an high of disease may deliberate if several outbreaks occur the of should have been that deliberate contamination was the cause of the salmonella in Oregon, because of the extremely high number of the to a single of the with salad bars and the of illness among from the same salad bars at epidemiological of disease is for the of most bioterrorist diseases such as smallpox, recognition of disease and appropriate could save many and a of the and Biological Institute has that are we have to a line between the and to people that it is a for which we need to In Britain, awareness of the threat from bioterrorism is much in the US. It is that awareness is among medical practitioners and health to the effects of any attack.