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Home > Back Issues (Journal) > Journal V26 N4 (Oct - Dec 2000) > A Tale of Two Cities and the Trojan Horse: Lessons in Biological Defence

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A Tale of Two Cities and the Trojan Horse: Lessons in Biological Defence
by CPT (DR) (NS) Donald Poon and CPT (DR) Khaw Seong Lin

 

History is replete with ancient civilisations decimated to virtual extinction by the introduction of novel pathogens to a uniformly vulnerable people. Unlike any projectile or explosive, infectious disease, like wildfire, is self-perpetuating until successful containment or exhaustion of substrate.

The conquest and colonisation of the New World for example, was aided in no small part by the largely inadvertent but advantageous exposure of the indigenous population to new diseases that accompanied the Europeans settlers, to which they were completely defenceless. In fact, there were occasions when this was exploited as a deliberate tactic. The American whites are documented to have offered blankets used by smallpox sufferers as peace offerings to obstinate local Indian tribes.1 Biological warfare (BW) is thus certainly not a recent invention.

International awareness of the chillingly destructive potential of biological agents has in the last decade been heightened for three reasons.

Firstly, BW and BT (biological threat) tap into the same visceral fear of emergent lethal pathogens already deeply etched in the public psyche by the bloody footprints of the human immunodeficiency virus (HIV), the architect of the most recent global pandemic.

Adding fuel to the fire has been the massive and wide-ranging nature of several recent outbreaks. For example, the 1994 salmonellosis2 outbreak traced to contaminated ice cream, affected over 250,000 Americans, while mass water contamination caused over 400,000 cases of cryptosporidiosis in Milwaukee. Meanwhile, the world has also witnessed urban epidemics of the pneumonic plague in Surat, India, Ebola haemorrhagic fever in Central Africa, avian influenza (H5N1)3 in Hong Kong, Hendra virus 4 in Australia, Nipah virus in Malaysia and Singapore, and the West Nile virus in New York City.

The second key factor has been the public confirmation during this decade of the existence of state-sponsored advanced biological weapons development programs. Firstly, post-Gulf War United Nations Special Commission (UNSCOM) investigations in Iraq have corroborated Iraqi claims of possessing at least 25 SCUD/Al-Hussein missiles, each armed with a warhead carrying 145 litres of a wide variety of biological agents including botulinum toxin, anthrax spores or clostridium perfringens spores5.

More recently has been the disclosure of the true scale of biological weapons research in the former Soviet Union, including the admission of an accidental release in 1979 of anthrax spores from a Soviet military research facility in Sverdlovsk6 , which resulted in 66 deaths. With the disintegration of the Soviet Union, the security of both the technology and products of the program has become a matter of some concern.

Most nations have the capability to develop and manufacture biological weapons in facilities which are inexpensive and inconspicuous, under the guise of legitimate commercial or research purposes. Some 18 nations are believed to have done so, including several which the US State Department lists as supporting terrorism. In addition, there are more than 1,500 biological culture libraries worldwide as well as numerous research institutions which maintain sample cultures of various BW agents7 . These constitute a broad and easily accessible reservoir of knowledge and material, which is effectively impossible to police.

Thirdly, the revelation that the Japanese cult Aum Shinrikyo8 had made repeated but failed attempts on at least 10 occasions to disperse BW agents in aerosol form, prior to their notorious 1995 sarin nerve gas attack on the Tokyo subway, shocked the world into accepting the reality of the emerging threat of BT. BT is however not new. In 1984, the Rajneeshee cult used salmonella typhimurium bacteria to contaminate restaurant salad bars in Oregon, causing 751 cases of non-fatal food poisoning. Fortunately, such incidents are rare, with only 66 criminal events and 55 terrorist events9 involving biological agents recorded between 1960 and 1999, although most (mainly hoaxes) have occurred in recent years.

There is clearly the need for an effective national biological defence system, to provide a mechanism for the early detection and containment of both naturally occuring and artificially spawned disease outbreaks. Two recent outbreaks offer useful lessons and insights into the critical prerequisites for such a system.

A Novel Virus in Malaysia

An epidemic of viral encephalitis affecting mostly pig farm workers in the state of Perak, Malaysia, was first reported in late 1998. Early suspicions focused on Japanese encephalitis (JE), a locally endemic, mosquito-borne virus known to cause periodic outbreaks of such illness. Pigs are the natural reservoir for JE, and the disease thus tends to occur in pig farming areas.

At about the same time, a cluster of sudden severe illness and deaths among domestic pigs was noted in Ulu Piah Tambun and Ampang near Ipoh town; Sikamat Nipah, Sawah and Bukit Pelanduk in Negri Sembilan, and Sepang and Sungei Buloh in Selangor. Because of the similarity in timing and location, the pig disease was attributed to the same virus by public health authorities.10

Measures routinely used to control Japanese encephalitis, such as mosquito fogging, were stepped up, but failed to contain either the human or pig epidemics. The number of cases continued to mount, as did the number of areas affected.

From October to May 1999, 265 cases of viral encephalitis with 105 deaths were recorded, and eventually, more than 50 farms in Perak, Malacca, Penang, Selangor and Johor were identified to have been infected.

The virus was able to propagate to the extent that seven Singaporean abattoir workers developed the disease, after contact with infected pigs from Malaysia.

The lack of success of control efforts, and increasing inconsistencies in the epidemiology of the outbreak led to a search for an alternative causative agent. International assistance was sought from the Centres for Disease Control and Prevention (CDC) as well as laboratories in Australia.

This led to the discovery of a new virus, belonging to the paramyxoviridae family, which had never been encountered. It was named 'Nipah', after the village Sungei Nipah in Negri Sembilan, which was home to the first human identified to have been infected with the virus. The virus was subsequently confirmed to be the same agent responsible for the human and pig disease.

With the discovery of the etiological agent of the outbreak, an immediate 'stamping out' policy was instituted to cull all pigs in the outbreak areas. A total of 901,228 pigs from 896 farms were destroyed in the infected areas from 28 February to 26 April 1999. The culling programme was stopped when a new test was made available to identify infected farms in a national pig testing and surveillance programme. 172,750 pigs from 50 positive farms were further culled under this surveillance programme. The epidemic was successfully controlled by May 1999.

West Nile Encephalitis in New York

In late August 1999, the CDC was called in by the New York City Health Department to assist in investigating a cluster of viral encephalitis cases.11 Tests were performed on blood and spinal fluid taken from the patients, for antibodies to six insect borne viruses commonly seen in the US. They returned positive results for St Louis encephalitis, a mosquito borne viral disease usually found in south-eastern US. Immediately, a mosquito eradication campaign was launched to halt further transmission of the virus.

Since late July 1999, officials at the Bronx Zoo had been receiving calls regarding birds dying suddenly in the Bronx and Queens. Within four days of the St Louis encephalitis outbreak being declared, several exotic birds at the zoo perished. Pathological examination of the birds revealed severe brain and heart damage of an uncertain cause.

The head of the Department of Pathology at the zoo suspected a link between the bird deaths and the human encephalitis outbreak. There was however, one significant inconsistency - the St Louis encephalitis virus is not lethal to birds.

To elucidate the cause of the bird fatalities, samples from the dead birds were sent to the National Veterinary Services Lab which is a part of the US Department of Agriculture. They were however, unable to identify the causative agent. Samples were also sent to the CDC. Unable to contact anyone at the agency, she contacted a friend at the US Army Medical Research and Material Command, which usually does not handle civilian requests, for assistance. He agreed to analyse some samples, which was sent on 21 September.

Meanwhile, the CDC had also begun to make the association and requested for more samples the same day.

On 23 September, both agencies came to the conclusion that West Nile virus was the agent killing the birds in New York City. There was also a strong suspicion that it was the same virus killing humans. On 24 September, a laboratory in California, which had received brain tissue samples taken from people who had died from the outbreak, confirmed that they had been infected with the West Nile virus.

The West Nile virus had never previously been seen in the Western hemisphere as it is usually found in Africa and Asia, with occasional outbreaks in Europe. The virus is closely related to the St Louis encephalitis virus. Both are flaviviruses, sharing a similar clinical spectrum, mode of transmission (mosquitoes) and reservoir (birds). This close relationship accounts for the early false positive tests for St Louis encephalitis. Also, the flawed initial diagnosis did not have any actual detrimental effect, as the control measures employed were entirely appropriate.

Lest We Forget

The two outbreaks share many uncanny parallels, illustrating clearly the shortcomings of the present biological threat surveillance and management systems, and present opportune lessons which demand closer scrutiny and application. A tabulated summary comparing them is as follows:

The Trojan Horse - Two Cases of Mistaken Identity

In both outbreaks, the aetiological agents were not immediately recognised. The outbreak in Malaysia was initially and erroneously thought to be caused by the JE virus, while the causative agent in the New York outbreak was first mis-diagnosed as the St Louis encephalitis virus.

The adage "common things occur commonly" is a useful guiding principle for efficient targeting of investigative efforts, but it also lays a trap for the unwary and complacent.

Nipah Virus Outbreak (October 1998 - May 1999) West Nile Virus Outbreak (August 1999 - October 1999)
Biological Agent Paramyxovirus family - newly emerged virus never before isolated, structurally similar to Hendra virus. Flavivirus family - not known to exist in New York or the Western Hemisphere before outbreak.
Animal Reservoir Pigs, bats Birds
Transmission Direct contact with infected pig's excreta and secretions. Vector borne - bite of infective mosquito belonging to Culex spp. univittatus, pipiens, molestus.
Affected Areas Malaysia and Singapore New York City
Duration of Outbreak 6 months 3 months
No of Casualties 265 54
No of Deaths 105 (40%) 7 (13%)

Twice, unknown pathogens sparked mysterious clusters of disease, and twice, health authorities were quick to attribute blame to known local pathogens. While this is usually a sound epidemiological practice, it becomes a pitfall if investigators then rest on their laurels, as they did here. They failed to question their initial conclusions until much later, even in the light of increasing inconsistencies. An example of the latter was the unusual casualty age distribution during the Nipah virus outbreak. Victims were overwhelmingly working age adults. This is epidemiologically inconsistent with JE, which tends to affect those at the extremes of age - the young and elderly.

There is the need for an open-minded and lateral approach to disease outbreaks, that appreciates the implications of increasing urbanisation and global traffic, and consequently, the effective breakdown of natural geographic barriers. Diagnostic kits targeting the usual bacteria and viruses will no longer suffice as micro-organisms skip from continent to continent, from animal to human, and from the jungle, into our cities. And of course, non-indigenous diseases may be artificially introduced in the BT and BW context.

Moreover, interpreting tests for exposure to viruses, which usually involve isolation of antibodies produced in the course of the body's defence, is often complicated by cross-reactivity - closely related but distinct viruses may induce the production of similar antibodies. Therefore, exposure to the West Nile virus may result in a positive St Louis encephalitis antibody test.

The obvious means of maximising the speed and accuracy with which outbreak-causing pathogens are identified, is to maintain diagnostic capabilities for the widest possible variety of biological agents. Investigations into the West Nile outbreak were hampered by the limited capabilities of the National Veterinary Services Lab, which was first lab to receive the bird samples. There are only about 50 candidate micro-organisms12 suitable for use in BW and BT. Once BW or BT is suspected, every possible test, as guided by clinical presentation, should be applied to all animals and human beings deemed to have succumbed to the attack.

It is an expensive proposition to stockpile a wide range of diagnostic equipment with only narrow applicability. Because of resource constraints, only a very limited number of centres will be able to maintain such capabilities. It is essential that the doors to these centres be kept open. The diagnostic technology must be made as accessible as possible to all who are in a position to sound the alarm bells.

It is an unfortunate fact of life however, that many of these personnel are not able to recognise situations in which such resources should be called into play. Most physicians in industrialised countries have never seen cases of many exotic diseases such as anthrax, and the last case of naturally acquired small pox worldwide13 was seen in October 1977. Adequate specific training is critical if our frontline personnel are to effectively operate as the first echelon of defence. Learning to maintain an open mind and awareness of the myriad manifestations of BW and BT must be reinforced. It would be ideal to have at least one BW/BT trained physician in all emergency and outpatient departments.

A particularly unsavoury aspect of BW/ BT is that they may not be immediately manifest, unlike conventional or chemical attacks, because of the incubation period inherent in all diseases. This facilitates the geographic dissemination of the disease.

At the forefront of a truly sensitive and responsive biological defence therefore, must be a vigilant and broad network of sentinels, providing data for consolidation and assimilation by a centralised body. Such pooling of information means not only a more accurate situation appraisal, but also facilitates more simplified and direct links with those responsible for effecting a response.

The 10 Commandments

Just as crucial as collecting adequate data is its appropriate interpretation. The following 10 epidemiological clues14 do not constitute proof of intentional use of biological agents but they can assist greatly in determining if further investigation is warranted. A biological threat must not be urgently ruled out if any of the 10 conditions prevail:

  • A large epidemic with greater case loads than expected especially in a discrete population.

  • More severe disease than expected for a suspected pathogen, as well as unusual routes of exposure.

  • A disease that is unusual for a given geographic area, is found outside the normal transmission season, has unusual spectrum of casualties or is impossible to transmit naturally in the absence of the normal vector for transmission.

  • Multiple simultaneous epidemics of different diseases.

  • A disease outbreak with animal as well as human consequences, as many of the potential threat agents are pathogenic to animals.

  • Unusual strains or variants of organisms or antimicrobial resistance patterns.

  • Association between attack rate and being predominantly indoors or outdoors during the time preceding the outbreak. This may reflect release of an aerosolised inside or outside of the building.

  • Intelligence that an adversary has access to a particular agent or agents.

  • Claims by terrorists of the release of a biologic agent.

  • Direct evidence of the release of an agent, with findings of equipment, munitions, or tampering.

Applying these principles to our two case studies, it is evident that conditions (i), (iii), (v) and (vi) were present in the two outbreaks. Condition (viii) was relevant in the New York outbreak as there were reports of Iraq experimenting with the West Nile virus for BW/BT purposes.15 Even though a deliberate source of the outbreak was categorically ruled out, a good biological defence system triggered by this association could possibly have achieved a more rapid identification of causative agent.

Of Birds and Pigs

The BW/BT frontline is not limited to human disease surveillance. Few pathogens infect humans exclusively. The great majority are far from finicky about their victims, and latent carriage in a variety of animals provides a lasting reservoir of infection. Human disease in fact, often represents the mere tip of the iceberg, in terms of the disease burden of a given locality.

In the course of investigating the two outbreaks, important clues provided by disease patterns in local animals were completely overlooked by public health professionals initially. The fact that pigs are only the amplifying hosts for the Japanese encephalitis virus, and do not die from infection was astutely pointed out by certain veterinarians and microbiologists16 . The observation to the contrary during the Nipah outbreak should have been the first vital clue that it was due to some other agent.

History repeated itself in New York. Once again, the significance of the dying birds was not immediately appreciated by human disease specialists. It took an attentive veterinary pathologist to spot the anomaly. Furthermore, her observation that emus in the Bronx zoo were thriving enabled her to eliminate another candidate pathogen - the equine encephalitis virus, which is usually lethal to that species.

The need to include professionals from all walks in a holistic biological defence system cannot be overemphasised. As illustrated in the two outbreaks, it is not only the medical care provider who is in the position to make crucial observations. Key information can come from the microbiologist seeing unusual strains of organisms, the zoo keeper noticing strange deaths in animals, pharmacists distributing more antibiotics than usual, or even funeral directors with increased business.

Once again, the common denominator must be an easily accessible and well known central surveillance agency tasked to capture such input, analyse the information and aggressively track the leads.

Most of the discussion so far has centred on an impromptu information supply rather than a proactive one. While a reactive detection system may on occasion be able to provide early warning of a health threat, proactive surveillance on strategic fronts is the key to pre-emptive intervention. Disease in animals presents one hitherto untapped area which potentially offers a wealth of invaluable data.

Dead Birds Do Tell Tales

In the month prior to the recognition of the New York City viral encephalitis outbreak, municipal health departments had received well over 1,000 reports of birds dying suddenly around the region. Investigations after the outbreak confirmed that a significant proportion of these had resulted from exposure to the West Nile virus.

Likewise, reports of pigs dying in Malaysia were received months before the virus spread to humans. And that these pigs were not the only animals being infected at this time is demonstrated by the results of a sero-survey done after the outbreak, which found that wild fruit bats, dogs and even pigs from farms outside the epidemic areas17 had already been exposed to the Nipah virus.

These findings point to the possible ubiquity of both viruses in the animal reservoir prior to the human outbreaks. Had this been detected earlier, they may well have been preventable.

As many biological agents may be amplified in zoonotic hosts, routine sentinel surveillance of disease in both native and imported animal species is clearly valuable. In fact, much useful intelligence may be clandestinely garnered about the health threats of a particular area by testing animals commercially imported from there.

Animal disease surveillance will also guard against wilful introduction of biological agents through livestock. Biological agents need not always be delivered by the dramatic release of millions of spores in an air drop as popularly imagined. A single bird carrying a genetically engineered agent may be enough to infect the local population of birds establishing endemicity in the ornithic reservoir before spilling over to the human population.

Maintaining sentinel flocks of birds or herds of other animals for the purpose of revealing the entry of foreign pathogens, or estimating local disease burden, is analogous to the centuries old practice of using canaries to detect poisonous gases in the coal mines, or even, in the military context, using special papers to detect toxic chemical agents.

Peeping into the Trojan Horse - Is It Worth It?

To summarise the discussion so far, the key components of any responsive bio-defence system, as demonstrated by the two outbreaks, are as follows:

i) Comprehensive diagnostic capabilities.

ii) Continuing BW/BT emergency/primary physician training.

iii) Established and accessible communication links between relevant agencies.

iv) Centralised collection and analysis of peripheral input.

v) Randomised and selective zoonotic disease surveillance.

The overall effectiveness of such a system is of course contingent upon the availability of appropriate intervention. This means that stockpiles of costly vaccines, therapeutic drugs and prophylactic drugs, and post-attack damage control plans must already be in existence. How much is such a system worth? Is it economically viable?

Using the insurance model is one way to estimate the benefits of investment in a bio-defence system18 . An actuarially fair annual premium is calculated on the basis of savings from averted health care costs, as well as the value of economically productive activities which would have been lost due to the morbidity and mortality resulting from any outbreak. The latter includes not only the human and livestock cost resulting from the disease itself, but also from control measures. After the Nipah outbreak, the standing pig population in Malaysia was reduced from 2.4 million to 1.32 million and the number of farms was reduced from 1885 to 829

In the context of bio-defence, a significant consideration which influences its cost effectiveness is the speed with which post-detection intervention can be delivered. Using these principles, an elaborate biological defence system may or may not be justifiable depending on the cost and risk assessment done by individual nations.

It must be emphasised that a bio-defence system will address not only the threat of low intensity sabotage or rogue weapons of mass destruction, but also the equally serious danger of emerging infectious diseases such as the Nipah and West Nile viruses. Thus may benefits be reaped even in the absence of biological attacks.

Last Words

In the 1500s, 95 percent of the Aztec Indian population perished within a matter of months as a result of having zero immunity to smallpox, which was unintentionally introduced by the Spanish Conquistadores19 . It happened in an age without motor highways, railroads or supersonic air travel, when physical boundaries were still formidable. With these amenities in the present age, will this tragedy be repeated on a global scale?

Endnotes

1. Hopkins, Donald, Princes and Peasants: Smallpox in History, Chicago, University of Chicago Press, 1983.

2. Documented in Journal of American Medical Association, JAMA by Torok TJ et al - A Large Community Outbreak of Salmonellosis Caused by Intentional Contamination of Restaurant Salad Bars, JAMA 1997; 278:389-95.

3. Detailed information on these outbreaks may be found in the Weekly Mortality and Morbidity Reports of Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

4. Philby AW et al, An Apparently New Virus (family Paramyxoviridae) Infectious For Pigs, Humans, and Fruit Bats, Emerging Infectious Disease 1998;4:269-71.

5. Carus S. Bioterrorism and Biocrimes: The Illicit Use of Biological Agents in the 20th Century, Washington: Center for Counterproliferation Research, National Defense University; 1998, Page 230.

6. Meselson M et al. The Sversdlovsk Anthrax Outbreak of 1979, Science 1994;266:1202-8..81

7. US Department of State. 1996 Patterns of Global Terrorism Report. Available from URL: http://www.state.gov.

8. WuDunn S, Miller J, Broad WJ. How Japan Germ Terror Alerted World. New York Times 1998 May 26;Sect A:1 (col 1), A:10 (col 1-5).

9. Jonathan B. Tucker, Director of the Chemical and Biological Weapons Nonproliferation Project, Center for Nonproliferation Studies, Monterey Institute of International Studies.

10. A succinct summary of the Nipah outbreak is found in Centers for Disease Control and Prevention, Mortality and Morbidity Weekly Reports 1999;48:265-269.

11. The West Nile Virus episode was closely covered in the New York Times National from 29/9/1999 - 11/10/1999. We are indebted to the Military Adviser Office, Singapore Mission to the UN for sending the relevant articles to HQMC on a regular basis.

12. As listed in Departments of the Army, Navy, and Airforce NATO Handbook on the Medical Aspects of NBC Defensive Operations. Washington, The Department;1996.

13. World Health Organisation Group of Consultants. Health Aspects of Chemical and Biological Weapons Geneva, The Organisation;1990.

14. Noah DL et al. Biological Warfare Training: Infectious Disease Outbreak Differentiation Criteria Military Medicine 1998;163:198-201.

15. Jennifer Steinhauer and Judith Miller in an article in the New York Times dated 10 October 1999 first drew attention to the fact that the West Nile virus was allegedly experimented on by Saddam Hussein as a potential biological weapon. CIA later concluded that the West Nile outbreak is not related to bio-terrorism.

16. This view was widely held by several virologists, including the late Professor Chan YC (former Head of Microbiology Department in National University of Singapore), in his capacity as regional moderator for Asia in the highly respected Internet website renowned for expeditious reports of infectious disease outbreaks in the world -Program for Monitoring Emerging Diseases (ProMED). ProMED covered the Nipah outbreak very closely and critically. Their role in providing accurate and prompt information during the Nipah outbreak was acknowledged in the international medical journal, Lancet.

17. Field et al. Nipah Virus - The Search for a Natural Reservoir. A working paper for WHO Meeting on Zoonotic Paramyxoviruses, Kuala Lumpur, Malaysia, 19-21st July1999.

18. Arnold F. Kaufmann, former US Public Health Officer, who developed an insurance analogy economic model to provide justification for the investment of US Federal funds in a bio-defence system for USA. The US President has since proposed $230 million in his Fiscal Year 2000 budget to prepare for biological terrorism and warfare.

19. Henry Dobyns' work 'Their Number Became Thinned' (Knoxville: University of Tennessee Press, 1983) marshals evidence for the view that European-introduced diseases killed 95 percent of all native Americans.

Bibliography

1. Zajtchtchuk R and Bellamy RF (eds), Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare, Office of the Surgeon General, Department of the Army, Washington, DC; 1997.

2. Committee on R&D Needs for Improving Civilian Medical Response to Chemical and Biological Terrorism Incidents, Institute of Medicine, National Academy of Sciences. Chemical and Biological Terrorism. Research and Development to Improve Civilian Medical Response, Washington, National Academy Press; 1999.

3. Morse, Stephen, ed., Emerging Viruses, New York, Oxford University Press, 1993.

4. Ewald, Paul, Evolution of Infectious Diseases, New York, Oxford University Press, 1994.

5. Special Issue on Biological Terrorism and Warfare, Emerging Infectious Diseases Journal published by the US National Centre for Infectious Diseases, Vol 5, No. 4.

 

CPT (DR) (NS) Donald Poon (left) holds an MBBS from NUS. CPT (DR) Khaw Seong Lin (right) is a staff officer with HQ Medical Corps and holds an MBBS (Hons) from the University of Adelaide.

 
Last updated: 03-Jul-2006


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