http://bmj.com/cgi/content/full/324/7333/336
BMJ 2002;324:336-339 ( 9 February )
Clinical review
Biological warfare and bioterrorism
Nicholas J Beeching
a Division of Tropical Medicine, Liverpool School of Tropical
Medicine, Liverpool L3 5QA, b Public Health Laboratory,
Derriford Hospital, Plymouth PL6 8DH, c Worcestershire Acute
Hospitals NHS Trust, Kidderminster Hospital, Kidderminster DY11 6RJ, d Bristol
Public Health Laboratory, Level 8, Bristol Royal Infirmary, Bristol BS2
8HW
Correspondence to: N Beeching Nicholas.Beeching@rlbuh-tr.nwest.nhs.uk
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Summary points
Appropriate dispersion of even a
small volume of biological warfare agent may cause high morbidity and
mortality, which may be exacerbated by public panic and social disruption Early symptoms of disease induced
by a biological warfare agent may be non-specific or difficult to recognise Healthcare workers should be
alert for unusual single cases or clusters of illness, especially in
otherwise healthy adults Unusual illness should be
notified immediately to public health authorities Strategic responses to the
deliberate release of biological warfare agents must be rehearsed locally and
nationally with multiple agencies Healthcare professionals should
familiarise themselves with national and local sources of advice on
deliberate release |
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The
use of pathogens as weapons |
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Biological warfare agents are defined as "living organisms, whatever
their nature, or infected material derived from them, which are used
for hostile purposes and intended to cause disease or death in man,
animals and plants, and which depend for their efforts on the
ability to multiply in the person, animal or plant attacked."1 Many such
agents are zoonotic and have a considerable impact on agriculture as
well as on human health. Biological warfare agents are well suited
for use in bioterrorism or for attack by poorer nations against the
rich (so called "asymmetric methods" of attack2) as they
are cheap and easy to obtain and disperse, although full scale use
as a weapon may be difficult.
Infectious diseases have always played a major part in limiting military
campaigns, and invading armies may also be assisted by disease,
deliberately or inadvertently (box 1). Western powers,
including Britain,7
the United States, and Canada,8 and the
former Soviet Union9
had biological research programmes for both offensive and defensive
purposes, and several other nations are known or thought to have
such programmes. Bioterrorism, usually from within, has become
reality in both the United States10 and
Japan.11
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Essentials
of delivery |
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The criteria for a successful biological warfare agent are listed in box 2.1 Agents
that might potentially be used as biological weapons can be
classified according to their clinical characteristics and impact on
public health (see table A on bmj.com).12 Clinical
effects vary from high mortality (for example, smallpox, pneumonic plague)
to prolonged incapacity (for example, Venezuelan equine encephalitis).
The mere threat of use in a military setting will impair the
effectiveness of opposing troops
for
example, the need for alliance troops to work in full protective
(nuclear, biological, and chemical) suits in high temperatures
during the Gulf war. In a civilian setting, logistic and economic
disruption and longlasting psychological effects on the general
population may greatly outweigh the direct medical effects of
deliberate release,13
as exemplified by recent anthrax releases in the United States.
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Consistently produces a given effectIn a military setting, biological warfare agents are most
likely to be delivered by aerosol. The optimum particle size is 0.3-5.0µ
in diameter, which is small enough to reach the alveoli when it is
inhaled.14
This can be achieved by aerosol generators mounted in fixed
locations or on trucks, cars, or boats as well as from cruise
missiles and planes equipped with tanks and spray nozzles. Numerous
climatic factors affect the efficiency of such methods including
wind velocity and direction, humidity, degree of cloud protection
from direct sunlight, and rainfall. In optimum circumstances the
distribution of a biological warfare agent from a cruise missile
could cover a large enough area and produce casualties equivalent to
that due to fallout from a nuclear device.15 In the
bioterrorist setting aerosols could be disseminated the same way, by
direct delivery into ventilation or air conditioning systems or via
letters or parcels. Suicide attacks would be extremely effective for
disseminating diseases such as smallpox. Food and water are suitable
vehicles for local delivery of pathogens. The Rajneeshee cult caused
over 750 cases of salmonellosis by contamination of salads in
Oregon in 1984.10
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Effects
of delivery |
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The effects of a deliberate release will be obvious if a large number of
troops become ill with similar symptoms at the same time. It may be
less clear in a civilian population unless the incubation period is
short, when the outbreak will resemble a chemical attack or disaster
and will be obvious to local practitioners and hospital emergency
rooms. However, an unexpected covert release in an urban civilian
setting could affect individuals living in widely dispersed areas,
who may then present to several different healthcare providers.
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Many biological warfare agents cause illness that could be
mistaken for common diseases such as influenza. Delay in recognition will
be further enhanced during natural cyclical epidemics, such as
respiratory illness in winter. If the incubation period of clinical
illness is long, and especially if secondary transmission to
contacts occurs from index cases, huge epidemic spread may have already
occurred before the release is recognised. This has recently been
demonstrated by the catastrophic epidemic of foot and mouth disease
in British farm animals. The same would hold true for release of
smallpox into a non-immune population.
Genetic engineering of biological warfare agents can alter their
pathogenicity, incubation periods, or even the clinical syndromes they
cause. Resistance to antimicrobial drugs may be enhanced or added,
and strains may be produced that evade the host response induced by
conventional immunisation.9
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Clinical
features |
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Many of the major clinical syndromes produced by biological warfare agents
start with a non-specific febrile illness (see table B on bmj.com). Pneumonic
and gastrointestinal illness may be mistaken for naturally occurring
sporadic or epidemic infections. Few clinicians will have seen
illness caused by biological warfare agents, and induced syndromes
may be atypical. For example, pulmonary consolidation and effusions
are said to be unusual in inhalational anthrax, which was thought to
have a mortality exceeding 90% if not diagnosed and treated
immediately. Yet in the recent cases of inhalational anthrax in the
United States six of 10 people survived.16
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Anthrax |
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Anthrax is a zoonosis caused by Bacillus anthracis, to which man is
relatively resistant (ID50 8×103
4×104
spores), but one deep breath of weaponised aerosol may contain as
many as 105 spores.17
Inhalational anthrax usually develops within one week of exposure,
but incubation periods of up to 43 days were described after
the accidental release at Sverdlovsk in 1979.18 Septicaemia
and rapid progression to shock and respiratory failure are common,
and mortality is substantial even with access to full intensive care
facilities, which would not be sustainable in a large scale attack. 16 19 There
are many differential diagnoses, and the supposedly pathognomonic x
ray feature of hilar lymphadenopathy may be absent or
overlooked.16
Unlike in pulmonary plague, person to person spread of inhalational
anthrax does not occur and protection to prevent secondary cases is
not necessary. However, spillage of blood and contaminated body
fluids from severely ill patients or corpses could pose some risk as
organisms will sporulate in contaminated areas and may cause an
infection hazard by secondary aerosol.
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Additional
educational resources
Chapters from the book, specific links to New England
Journal of Medicine and extensive links to other primary sources and
major websites
Detailed chapters including potential biological agents.
Information complements that in other major infectious disease textbooks.
The bioterrorism section of the main CDC website. Best
information is gained by going to "Biological" in the "Agents
and Threats" index. Includes extensive links, patient information
sheets, downloadable presentations, and indexed press releases/advisory
notes, etc. Separate index listing MMWR reports on anthrax and other
bioterrorism agents at www.cdc.gov/mmwr/indexbt.html
Expanding site with full British protocols for several
biological and chemical agents, general advice, and patient information leaflets.
Teaching slide sets still on secure website only at time of going to press
Information for general public, online publications including
2002 second edition of Health aspects of biological and chemical
weapons and downloadable photographs and presentations
Collected links with emphasis on microbiological aspects
Several good articles and many links available from home
page. Also has a number of slide presentations available for download
Combination of policy, politics, debate, and outputs of
exercises and think tanks, together with both medical and political links
Another site providing collated links to primary sources, and
downloadable presentations
Large collection of military and political links as well as
US military medical manuals online
Informal consultative gathering of over 30 nations committed
to ridding the world of chemical and biological weapons. Policy statements,
press releases, external links to websites concerned with export controls of
many countries
Debate, videos to download, and reports on effects of
suspension of Fifth Review Conference of the Biological and Toxin Weapons
Convention |
Cutaneous anthrax, caused by local inoculation of spores
through damaged skin, is much less likely to produce septicaemia and
death and has a wide differential diagnosis (see table B on bmj.com).
Natural cutaneous infection is common in many parts of the tropics
and responds to penicillin. However, the Iowa strain of B
anthracis used in the recent releases in the United States produces
an inducible 
lactamase
and a cephalosporinase.20
This is one reason why drugs other than penicillin, such as ciprofloxacin
or doxycycline, are preferable for prophylaxis after exposure, especially
after a high inoculum exposure, although there were no significant
differences between these drugs in prophylaxis in non-human
primates. 21
22 Use
of penicillin is inappropriate after exposure to an unknown powder
or aerosol because it would not cover plague or tularaemia. Lactamase
production by B anthracis means that treatment for systemic
disease should include either a fluoroquinolone or a tetracycline.
Recent cases were treated with a combination of antimicrobial drugs.16
Empirical treatment for undiagnosed pulmonary syndromes induced by
biological warfare should include aminoglycosides, tetracyclines, or
fluoroquinolones to cover plague23 and
tularaemia.24
UK and US vaccines are known to provide protection against anthrax
when they are given before exposure, but their recent use by the
military has given rise in some quarters to concerns over possible
side effects.25
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Smallpox |
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Smallpox has proved potential as a biological warfare agent even before any
possible genetic enhancement in weapons programmes.26 Although
it was declared to have been defeated in 1980, virus stocks are
believed to exist in laboratories other than the two designated for
this purpose in the United States and in Russia. The usual
incubation period is about 12 days (range 7-17), but strains
produced by the Russian biological warfare programme had much
shorter incubation periods in non-human primates.9 Abrupt
onset of fever and headache may initially be mistaken for influenza.
Two to three days later, however, a non-specific erythematous rash
develops (see table B on bmj.com). In non-immune populations this
may be the only skin manifestation as the illness rapidly progresses
to multisystem failure and death. In most patients, flat skin
lesions evolve into pocks in crops that all appear at the same time
and in the same form and are concentrated more on the face and
peripheral limbs than on the trunk; the eyes and pharynx may also be
affected. There is no practical antiviral treatment and over 30% of
patients die, depending on the population and the infecting strain.
Vaccination before exposure is effective, but the vaccine has
measurable side effects and immunity fades after 10-20 years or
earlier in some people. Vaccination after exposure is moderately
effective if it is given within four days. The infection is highly
contagious. Modelling has confirmed the potentially disastrous
effects on the general population if smallpox were to be released. 27 28
International stocks of vaccine are acknowledged to be inadequate,
and the WHO has urged countries to consider means of increasing
these stocks.
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Response
and preparedness |
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Over the past decade the possibility of biological warfare and especially
bioterrorism attacks has been taken increasingly seriously by
Western governments. Theoretical models of deliberate aerosol
release of agents such as smallpox or anthrax in urban settings have
shown that regional infrastructures would rapidly be overwhelmed. 29 30 Recent
experience on both sides of the Atlantic with genuine release
episodes, and with many more hoaxes and false alarms, has revealed
logistic weaknesses and false assumptions in treatment and
prevention strategies. Planning needs to improve horizontal and
vertical liaison between medical providers, public health, and
veterinary agencies. Interagency, intersectoral, and international
cooperation are also essential. Vaccines and antimicrobials may need
to be stockpiled so that they can be mobilised rapidly and
distributed to large numbers of people. Protocols to deal with
expected scenarios have to be prepared and tested in exercises. The
major challenges are to conduct and learn from these exercises and
to provide adequate education, especially at grass roots level, about
the resources available and their uses.
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Recognition of covert release of biological warfare agents
requires a continued state of awareness of the possibility of abnormal disease
patterns in humans, animals, and plants. Clinicians, microbiologists, and
public health doctors should be vigilant for unusual pathogens in
sterile sites or for unusual patterns of febrile illness, with or
without features of septicaemia or respiratory, gastrointestinal, or
dermatological manifestations. Awareness should be high if previously
healthy young adults are affected, especially if mortality is high
or there is clustering of cases. Immediate notification of suspect
cases or outbreaks should prompt rapid epidemiological investigation
with a level of laboratory investigation and empirical prevention
measures appropriate to the determined risk.31 Early
prevention measures have to take into account the risk:benefit ratio
of off-licence use of antimicrobial drugs and vaccines, and include
education of the public about such risks. Such guidelines are
increasingly available in the public domain in the United Kingdom as
well as in the United States.
Meanwhile, current international agreements designed to limit the use of
biological warfare agents need strengthening. In particular, methods
of verification need to be agreed, analogous to those used for
verifying compliance with chemical weapon treaties.14
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Footnotes |
Competing interests: NB is joint recipient of an unrestricted
educational grant from Bayer to support annual meetings at the
Liverpool School of Tropical Medicine.
Two tables on categories of
biological warfare agents and clinical syndromes can be found on bmj.com
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