JOURNAL OF THE ROYAL SOCIETY OF MEDICINE
Influenza as a bioweapon
Mohammad Madjid MD 3,4 Scott Lillibridge MD 1
J R Soc Med 2003;96:345–346
Two years ago, we published a case–control study with the
surprising finding that influenza immunization reduced the
risk of recurrent myocardial infarction by 66%.1
Simultaneously, Siscovick and colleagues reported that
influenza immunization was associated with a 49%
reduction in the risk of sudden cardiac death.2 A subsequent
report described a 50% reduction in risk of stroke in
association with influenza immunization,3 and later a
randomized control trial pointed to a 50–75% reduction
in the risk of adverse endpoints and cardiovascular death.4
Furthermore, an ecological study suggests that the 1918
influenza pandemic may have contributed to the epidemic of
coronary heart disease mortality registered in the 20th
century.5
These data caused us to re-examine the usual estimate
that, in the USA, influenza kills 20 000 a year.6 From more
recent studies of all-cause mortality, we suspect that the
total is closer to 90 000. The Spanish flu epidemic in 1918
killed 20–40 million people.7 Less severe epidemics were
the Asian flu in 1957, Russian flu in 1977, and Hong Kong
flu in 1978.7 In addition to such spontaneous mutations, we
must, since the terrorist attacks of September and October
2001, consider the possibility of malicious genetic
engineering to create more virulent strains. Sequencing of
the genome of the 1918 Spanish influenza virus is nearly
complete; once it is published, unscrupulous scientists
could presumably utilize candidate virulence sequences.8,9
Recently, the possibility of synthesizing an infectious agent
solely by following instructions from a written sequence has
moved from theory to practice.10
Influenza is usually transmitted by direct contact but can
also be transmitted by aerosol (e.g. on a passenger plane).11
Indeed, international transmission is increasingly frequent.
Notably, aerosol transmission of influenza requires up to
27 000 times fewer virions to induce equivalent disease.12
Taken together with the fact that influenza virus is readily
accessible and may be causing more deaths than previously
suspected, the possibility for genetic engineering and
School of Medicine, 1Center for Biosecurity and Public Health, 2Office of
Biotechnology, University of Texas–Houston Health Center; 3Texas Heart
Institute, Houston, Texas; and 4President Bush Center for Cardiovascular
Health, Memorial Hermann Hospital, Houston, Texas, USA
Correspondence to: Ward Casscells MD, 6431 Fannin, MSB 1.254, Houston
TX77030, USA
E-mail: S.Ward.Casscells@uth.tmc.edu
Volume 96 July 2003
SPECIAL ARTICLES
Parsa Mirhaji MD 2 Ward Casscells MD 2,3,4
aerosol transmission suggests an enormous potential for
bioterrorism.
Influenza is a very different virus from smallpox, and the
public health implications of influenza as a bioweapon differ
from those for smallpox: influenza is readily available,
whereas known stocks of smallpox are secured at the Centers
for Disease Control and Prevention in Atlanta and at a facility
in Russia (though there is reason to suspect its leakage to
weapons programmes elsewhere). Secondly, because influ-
enza occurs naturally, a cluster of cases would not prompt an
investigation, and an epidemic would have a considerable
head start on public health authorities. A third difference is
that the incubation period for influenza is short (1–4 days)
versus 10–14 days for smallpox. Immunization after
exposure to influenza is therefore not protective, and even
the neuraminidase inhibitors such as oseltamivir must be
administered before symptoms develop or within the first 48
hours after their appearance. Fourth, influenza is harder to
eradicate, because of avian, murine, and swine reservoirs.
Fifth, influenza outside of pandemics, has lower case-fatality
(2.5% versus 25%, though the newly recognized triggering
of cardiovascular events suggests that the true mortality may
be much higher in ill or elderly persons). Finally, influenza
poses a greater threat to world leaders than does smallpox,
because they are older and prone to influenza and its
cardiovascular complications, have some residual immunity
to smallpox (whereas unvaccinated youth have none), and
are often in public places.
Even a natural epidemic of influenza can devastate our
healthcare system and render society vulnerable to terrorist
attacks of any kind.13 In addition, because of the similarity
between early symptoms of influenza and other bioterror
agents (such as anthrax), clinicians need to understand the
differences in symptoms and signs and be aware of the initial
screening tests for anthrax and influenza. Since the two
diseases could coexist it is unfortunate that there are, to
date, no point-of-care tests to diagnose both and thus
minimize confusion and panic. We have seven proposals to
address these issues.
1. The World Health Organization and the Centers for
Disease Control and Prevention (CDC) should bring
together experts in influenza, bioterrorism, health policy,
international law, and ethics to study this matter.
Authorities should recognize that smallpox-based lessons
drawn from exercises such as Dark Winter are not all 345
 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE
applicable to weaponized influenza. Depending on their
other public health needs and resources and their likelihood
of being targeted, countries might consider only some of
the steps listed below, which are suggested in particular for
the USA. CDC should advance influenza as a critical agent
in priority as a bioterrorism threat.
2. Physicians, nurses and their organizations, insurers,
and health officials should increase efforts to immunize
those for whom immunization is currently recommended.
The policy might be extended to mandatory immunization
of medical personnel, or even universal immunization.
3. Increase the security of laboratories conducting
influenza research, and of manufacturers and distributors of
vaccines and antivirals.
4. Stockpile antiviral drugs and increase capacity to
develop and produce vaccine. These might also be added to
the ‘push-packs’ for urgent distribution by the US
Department of Health and Human Services.
5. Consider a Federal influenza gene-sequencing and
vaccine development programme, based at high-security
government, pharmaceutical and university laboratories.
6. Expand active sero-epidemiological surveillance and
offer incentives to reporting of clinical cases. The recently
developed influenza assays make serological surveillance
simple and fast, yet are little used by clinicians. New
syndromic surveillance systems are required, capable of
detecting incipient epidemics.
7. Consider Federal programmes to develop antiviral
filters, biosensors, and inactivation systems (e.g. ultraviolet)
for ventilation systems. Such efforts could be part of a
broader viral protection programme.
Acknowledgment This work is supported in part by the
US Army’s Disaster Relief and Emergency Medical Services
(DREAMS) grant #DAMD 17-98-1-8002.
346
Volume 96 July 2003
REFERENCES
1 Naghavi M, Barlas Z, Siadaty S, Naguib S, Madjid M, Casscells W.
Association of influenza vaccination and reduced risk of recurrent
myocardial infarction. Circulation 2000;102:3039–45
2 Siscovick DS, Raghunathan TE, Lin D, et al. Influenza vaccination and
the risk of primary cardiac arrest. Am J Epidemiol 2000;152:674–7
3 Lavallee P, Perchaud V, Gautier-Bertrand M, Grabli D, Amarenco P.
Association between influenza vaccination and reduced risk of brain
infarction. Stroke 2002;33:513–18
4 Gurfinkel EP, de la Fuente RL, Mendiz O, Mautner B. Influenza
vaccine pilot study in acute coronary syndromes and planned
percutaneous coronary interventions: the FLU Vaccination Acute
Coronary Syndrome (FLUVACS) Study. Circulation 2002;105:2143–7
5 Azambuja MI, Duncan BB. Similarities in mortality patterns from
influenza in the first half of the 20th century and the rise and fall of
ischemic heart disease in the United States: a new hypothesis
concerning the coronary heart disease epidemic. Cad Saude Publica
2002;18:557–77
6 Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH,
Schonberger LB. The impact of influenza epidemics on mortality:
introducing a severity index. Am J Publ Health 1997;87:1944–50
7 Laver WG, Bischofberger N, Webster RG. Disarming flu viruses.
Sci Am 1999;280:78–87
8 Webster RG. Virology. A molecular whodunit. Science
2001;293:1773–5
9 Basler CF, Reid AH, Dybing JK, et al. Sequence of the 1918 pandemic
influenza virus nonstructural gene (NS) segment and characterization
of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad Sci
USA 2001;98:2746–51
10 Cello J, Paul AV, Wimmer E. Chemical synthesis of poliovirus cDNA:
generation of infectious virus in the absence of natural template. Science
2002;297:1016–18
11 Hammond GW, Raddatz RL, Gelskey DE. Impact of atmospheric
dispersion and transport of viral aerosols on the epidemiology of
influenza. Rev Infect Dis 1989;11:494–7
12 Alford RH, Kasel JA, Gerone PJ, Knight V. Human influenza resulting
from aerosol inhalation. Proc Soc Exp Biol Med 1966;122:800–4
13 Schoch-Spana M. Implications of pandemic influenza for bioterrorism
response. Clin Infect Dis 2000;31:1409–13