Article Review: March 30, 1998

Pile JC, Malone JD, Eitzen EM et al. Arch Intern Med March 9, 1998;158:429-434.

Although most physicians in industrialized countries have never seen a case of anthrax, the potential use of spores of Bacillus anthracis in biological warfare makes basic knowledge of the presentation and treatment of this ancient disease important. The primary threat concerns dispersal of aerosolized anthrax spores in a densely populated area, potentially causing tens of thousands of casualties. Symptoms from inhalational anthrax begin 1 to 6 days after exposure, with nonspecific manifestations such as dry cough, mild fever, myalgias, and malaise. The patient often recovers from this initial phase, only to present several days later with severe respiratory distress and shock, which rapidly and almost inevitably causes death. Chest radiograph during the preterminal stage may show widened mediastinum and pleural effusions. Meningitis occurs in as many as half the cases. Although the drugs of choice for natural anthrax include high-dose penicillin, ciprofloxacin, and doxycycline, strains manufactured for biological warfare may have been altered for resistance to standard antibiotics. The existing vaccine has not been tested for efficacy in humans, but has been shown to protect rhesus monkeys against inhalational anthrax after 2 doses. Well-fitting M17 or M40 gas masks provide respiratory protection from exposure. Postexposure treatment involves prolonged administration of antibiotics and concomitant vaccination. There is no evidence of person-to-person contagion. (67 references)

COMMENT:

Once significant symptoms of anthrax begin, almost all patients die despite treatment. Identifying an outbreak early is the key to initiating life-saving treatment, and emergency personnel will be key players in surveillance for clusters of cases. This review serves as an excellent introduction to the topic, and is important reading. (Leon M. Gussow, MD, ABMT)

LINKS: The complete text of this article is available on-line. Further information about anthrax is available from the U.S. Army , the Department of the Navy  the Department of Defense , and the Nuclear, Biological, and Chemical Web Page.  ABC News has a large feature on terrorism , and Salon Magazine has a discussion   on whether Iraq could have biologically engineered anthrax that is resistant to traditional antibiotics. The New York Times  has a superb article on the development of Iraq's biological weapons program. The site is free but requires registration. Search all articles under "anthrax", then click on the title "How Iraq's Biological Weapons Program Came to Light".

Copyright © 1997-2000. TPR Publications.
 

Disinformation in Media.

An example of the disinformation is an article in a news weekly which listed each of the supposed terrorist weapons and the cost of producing them. For $10-20,000, terrorists could supposedly kill hundreds of thousands of persons with botulism toxin, anthrax, nerve gas, etc. "60 Minutes" had an expert who said biological weapons could be produced in someone's back yard in a five gallon bucket. They said anthrax spores released from a boat on the Hudson River could kill four hundred thousand persons in New York City.

Anthrax is Trivial.

Here's the truth of the matter. Anthrax will never be used successfully as a terrorist weapon, and probably never as a military weapon. It has to be converted to spores suspended in the air, which is technically very difficult; and the lethality is nowheres near the terror that it is made out to be. It is not 100% lethal as often claimed. Wool sorters inhale anthrax spores in small quantities continually (150-700 per hour), and only if they get a large dose does an infection get started.

Only US and Russia can Weaponize it.

To use anthrax as a weapon, it must be converted to a powder which can be inhaled. Only the US and Russian militaries have succeeded in doing that. Even Iraq uses anthrax in liquid form, which is totally ineffective.

Humans are Seldom Affected.

Anthrax is a livestock pathogen. There are anthrax spores in the ground in rural areas, because they survive for about twenty years. They normally have no effect upon humans, because a few anthrax spores cannot create an infection, and they do not come up from the ground in large quantities.

Cellular Limitations.

Anthrax is what's called a "gram positive" bacterium. This means it has the type of cell walls which are harmless, unlike the cell walls of "gram negative" bacteria, which attack tissue. Therefore, anthrax can only attack tissue by producing a special toxin which it excretes. One cell or spore does not produce enough toxin to start an infection.

Studies have apparently determined that, typically, ten thousand anthrax spores must be inhaled to start an infection. That number might be someone's guess, but it is in line with the biology of the disease. It is the number which the military uses, and only the military has significantly researched such questions. It uses gas chambers for animal tests.

Anthrax normally attacks the lungs, because it must lodge in vulnerable tissue. It can invade through other routes such as cuts or undercooked meat, but it only does so under third world conditions, and those routes are not relevant to biowarfare.

Livestock eat from the ground, so they have their faces in the ground where the spores are, and they can inhale ten thousand spores. How does anyone get ten thousand spores into the lungs of humans?

Technical Obstacles to Weaponizing.

The first requirement would be to aerosolize the spores. The spores would have to be converted to a dry powder, because a liquid would create globs which would fall to the ground rather than staying suspended in the air.

To create a powder, the spores would first have to be washed several times in an array of very large and expensive centrifuges. Then a drying apparatus would have to be used; and it would require spraying a mist into a vacuum, which is how powders are created from liquids. Otherwise, everything globs up into hard rocks.

How do workers clean the equipment without getting spores everywhere? A likely procedure would be to enclose the equipment in a pressure chamber and steam sterilize it for several days. Such an operation costs hundreds of millions of dollars, considering related facilities and development. Only countries do that, not radical groups, and not in five gallon buckets.

It won't stay in the Air.

Even in powder form, the spores would fall to the ground rapidly in the absence of wind. Anthrax is not adapted for airborne dissemination. It needs to stay on the ground until inhaled by livestock. So it would not stay in the air like mold spores but would fall out easily, about like flour. In the presence of wind, the spores would be carried away rapidly and would not stay in one place long enough for anyone to get more than a few inhaled.

Once the spores were on the ground, they would not affect humans significantly, because they would not come up from the ground in large enough quantities.

Foggers are Propaganda.

There is some talk about using liquids with fogging devices for dispersion of biological agents such as anthrax. It's not realistic. First, there is no mention of the purity that would be required to prevent globbing and plugging of nozzles. At least, a lot of expensive centrifuging would be required to remove debris.

Then agricultural spraying demonstrates that a mist drops rapidly to the ground. It does that because air can only hold a small amount of water, which causes sprays to precipitate.

Another problem is that spores would rapidly settle to the bottom of a liquid and form a gum due to sticky cell debris and their tendency to clump.

A chemical mist is different, because chemicals vaporize, while cells do not. Cells in a mist would clump together as the liquid vaporizes. To create free spores would require very clean material, high dilution, ultra fine mist and a vacuum for rapid evaporation. Foggers can't do the same thing.

For these reasons, anthrax would be difficult to use; and it could hardly kill more than a few hundred persons under the most ideal conditions, not the hundreds of thousands which are claimed. On top of that, antibiotics are effective for it during the early stage of the illness. It is not contagious for humans.

Glib Journalism is Unrealistic.

Innumerable journalists have been insisting that anthrax can be produced in a simple laboratory with little expertise. To the contrary, no countries but the U.S. and Russia can convert anthrax to a usable weapon. Iraq cannot.

Consider what the journalists fail to recognize. Growing a large quantity of anthrax would result in a fermenter full of slop which is extremely slimy and viscous with large amounts of debris and metabolic products mixed with the nutrient medium. That slop has to be washed and converted to a medium which will induce spores to form. Much research and knowledge would be required to get a reasonable yield of spores. Then the cells would have to be fragmented with something like a blender to get the spores out of the cells. Then much differential centrifugation would be required to separate the spores from the debris. Then spray drying of spores in a vacuum would be required.

Accomplishing all of that would require several Ph.Ds. and much developmental type research in addition to expensive equipment and a very large building. It isn't a matter of growing something in a kettle and pouring it into a rocket, as journalists and weapons inspectors seem to be assuming.

Grinding is Another Absurdity.

The latest contrivance is that terrorists might weaponize anthrax by drying a slurry and grinding it to particles 1-5 microns in size. (The bacteria are 1 by 3 microns.)

The first problem is that the gunk would dry like glue; and after grinding, it would still be glue. Even if it were washed first, the bacteria would be sticky and would dry like glue.

The second problem is that bacteria do not tolerate grinding. They are as fragile as egg shells. Grinding is how they are broken apart for biochemical tests. Even if only 1% were broken, the result would be a sticky gum, not a powder; and more like 99% would be broken before getting 5 micron particles.

Journalists keep mentioning how many anthrax spores can be gotten onto the head of a pin. It's not a question of how many can be gotten onto the head of a pin but how many can be gotten into someone's lungs.

Planes cannot Dust a City.

A scenario which is often mentioned is that someone might use a plane to dust a large city with anthrax during the night. It's unrealistic. First, no one in buildings would be harmed by anthrax. The few spores that entered buildings would settle on surfaces, and few would enter the air, and even fewer would be inhaled. At most, someone might inhale a few dozen spores per hour. That's not the ten thousand that are needed.

Secondly, anthrax spores would not diffuse uniformly through the air like a gas. They will either drop too fast or blow away. A few dozen persons might be killed, but that's not the terror that is being hyped in the media. And more than anything, nobody is producing the spores in powder form but the U.S. and Russia.

Journalists seem to assume that an anthrax cell anywhere will kill someone someplace. Putting words alongside each other on a page is not the same thing as getting cells into humans on the ground. There are millions of square miles of space on the ground which do not show up with the words.

Iraq did not Weaponize Anthrax.

Saddam Hussein is said to have produced anthrax. If so, the reason is because it is stable and easy to handle, not because it is effective when used. Iraq is unsophisticated to a point of ineptness in its approach to biological weapons.

It is said that Iraq uses anthrax in liquid form and puts it in missiles in liquid form. In liquid form, anthrax is almost as safe as cotton candy. Therefore, Iraq poses no anthrax threat.

In fact, military and UN inspectors only found two Iraqi warheads with anthrax in them (in liquid form). If Iraq had anthrax in an effective form, it would have had it in hundreds of warheads, as they did with nerve gas. So Iraq knew its anthrax was useless.

For about a billion dollars, Iraq could probably get enough experts together to develop anthrax as a weapon. But the reason why it doesn't is that researchers already know that anthrax would be next to worthless after it was developed.

The Whole Concept is Flawed.

Biological warfare is a flawed concept. The only route usually considered is airborne, because bombs and missiles create the delivery system. There is no disease in existence which is propagated in that manner. Even the airborne diseases require close contact with the source. The reason is because wind disperses the agents too thinly, and gravity brings them down too rapidly. Increasing the quantities massively will get a few persons, but only a few.

And then, very few of the diseases which are mentioned as biowarfare agents are suitable for airborne dissemination. Brucellosis is not. It is disseminated through body fluids. Plague is not. It is carried by insects from the blood of one animal to another. The insects do not pick it up from the ground.

Motives Taylor the Truth at every Level.

Biowarfare is promoted through a combination of ignorance and propaganda. The researchers, who should know better and often do, are getting paid to produce the agents, so they do not want to admit the futility of it. The nonresearchers cannot realistically evaluate the claims, and they have propaganda motives. They want to militarize society, and scare tactics go a long ways in that direction.

The only way biological warfare agents can be used in a significant manner to create disease is to inject them into the victims. If they are then contagious, they go a lot farther. The U.S. military has been focusing on contagious diseases. Since the water runs downhill in that direction, the agents are or will be used in that manner. With the motives for population control which the military has acquired, it can be expected to use its bio agents in that manner.

The point here is not that large countries cannot make a lot of persons miserable with biological weapons. It's that the small countries and terrorists cannot do so on their own; and it cannot be done on a large scale and in some magical way as described in the media.
 

Web Link to McAlvany Intelligence Advisor.
 

Web Link to Vaccines and the Military

History

Anthrax is derived from the Greek word for coal which describes its typical black eschar of cutaneous disease. The fifth Egyptian plague is thought to have been due to anthrax, approximately 4000 years ago. Virgil recorded a lyrical description of anthrax around 25 BC, and the disease became known as the "Black Bane" during the Middle Ages. In the 1870s, Robert Koch did studies on anthrax and subsequently became the first to demonstrate the bacterial origin of a specific disease. Shortly afterward, John Bell established Bacillus anthracis as a cause of wool sorter's disease. He recognized the clinical syndrome of inhalational anthrax and became instrumental in establishing wool disinfection processes. In 1880 the first successful immunization of livestock against anthrax was done by William Greenfield. Louis Pasteur closely followed suit and tested a heat-cured anthrax vaccine in sheep, which has been usually remembered as the initial use of a live vaccine.

Epidemiology

Anthrax is a disease of herbivores, infecting sheep, goats cattle and swine. It is caused by B anthracis, a gram positive, sporulating bacillus. The reservoir of B anthracis is the soil and the organism is distributed worldwide. It exists in the infected host as the bacillus and in the environment as a spore. The spore is very durable and can survive adverse environmental conditions and remain dormant for decades. Animals contract the spores while grazing. Humans contract anthrax via innoculation of minor skin lesions with spores, from ingestion of contaminated meat or inhalation of the spores. Another mechanism that has been described is biting flies. The spores can be found in live animals as well as their hides, wool or other products.

Environmental persistence of spores is due to increased nitrogen levels in the soil, organic contents in soil, pH greater than 6.0 and an ambient temperature of greater than 15°C. Triggers of spore germination and environmental spread include drought, heavy rain as well as dissemination via biting flies and vultures. B. anthracis is endemic in Africa and Asia. Sporadic outbreaks have occurred, as a result of both agricultural and military breakdown. In Zimbabwe in 1978-80, during the Rhodesian civil war, vaccinations couldn't be maintained and infected animals caused an epidemic of anthrax, with 6500 infected, 100 dead. In 1979, in Sverdiovsk, (now Yekaterinburg) of the former Soviet Union, there was a mishap at a military microbiology facility that resulted in 66 deaths. First reported as gastrointestinal, forensic experts from other countries described inhalational disease. The youngest person that died was 24 years old , which demonstrates an age- related predilection of the disease. Exposures are usually agricultural (laborers in contact with animals/products) or industrial (infected animal products). Worldwide incidence in 1958 was 20,000 to 100,000. This number is difficult to estimate, because it has not been a reportable disease in Africa. The US incidence has been less than one case per year over the last 20 years. There were 235 cases described between 1955-1994, of which 224 were cutaneous, 11 inhalational and 20 were fatal.

Of greater and more immediate concern is the threat of anthrax as an agent of biological warfare. Biological weapons have been described as the "poor man's nuclear bomb." In 1991, the US was involved in the Persian Gulf War with thousands of troops. In 1995, Iraqi military officers revealed that during the war Iraq had produced and prepared to use 19,000 liters of botulinum toxin and 8,500 liters of anthrax.

Human Disease

There are no convincing data to suggest that human to human transmission has ever taken place and thus, anthrax is primarily zoonotic. 95% of disease worldwide is cutaneous, about 5% is inhalational and 0-5% is gastrointestinal.

Inhalational anthrax was first described as wool sorter¹s disease which occurred in the textile and tanning industries among workers handling contaminated wool, hair and hides. The minimum infective dose ranges from 4,000 to 80,000 spores, based on nonhuman primate studies. Inhaled spores are ingested by pulmonary macrophages and then carried to hilar and mediastinal lymph nodes. The incubation period is 1 to 6 days after exposure. The spores undergo germination and multiplication and begin to elaborate toxins. They soon overwhelm the clearing ability of the lymph nodes. The host undergoes bacteremia and subsequent death. The chest X-ray is typically without infiltrates but may reveal a widened mediastinum with pleural effusions, which may be hemorrhagic. Meningitis, often hemorrhagic, has been reported in up to 50% of cases. Untreated, the mortality rate of inhalational anthrax is about 95%.

Cutaneous anthrax occurs through entry of the spores through cuts and abrasions of the host, or via biting flies. Incubation is 2 to 5 days after exposure. It begins as a nondescript papule that becomes a 1-2 cm vesicle in 24-48 hours. The lesion is associated with an occasional severe edema, which can lead to airway compromise in the head and neck area. Germination is at the site of exposure in the macrophages. Locally there is edema and tissue necrosis but no purulence. The organism is easily isolated from the vesicular fluid and is evident on gram stain. The nonpainful occasionally pruritic lesion ruptures after one week and then its ulcer progresses to its characteristic black eschar. The differential diagnosis includes tularemia, plague, cutaneous diphtheria, staphylococcal disease, rickettsial infection and orf, a viral disease of livestock. It usually remains localized but without treatment, can disseminate systemically in 5-20% of cases. With treatment mortality is only 1%. Antibiotics prevent dissemination but do not affect the natural history of the lesion.

Gastrointestinal anthrax begins with ingestion of contaminated meat. The spores are transported to mesenteric or regional lymph nodes, where they undergo replication and dissemination. The incubation period is 2-5 days after ingestion. The host subsequently becomes bacteremic with a high mortality rate. A subset of this disease is oropharyngeal anthrax.

Pathogenesis

Bacillus anthracis is a large (1-1.5 x 3-10 microns) gram positive sporulating rod. It grows in gray white colonies of 4-5mm, with characteristic comma shaped or "comet-tail" protrusions. B anthracis is characterized and thus differentiated by the absence of the following: hemolysis, motility, growth on phenylethyl alcohol blood agar, gelatin hydrolysis and salicin fermentation.

Virulence depends on the bacterial capsule and the anthrax toxin complex. The capsule is a poly-D-glutamic acid that prevents phagocytosis and lysis. Experiments in the 20th century by Sterne showed that an unencapsulated strain attenuates anthrax. The anthrax toxins are composed of 3 entities, the protective antigen, lethal factor and edema factor. The protective antigen is a 83 kd protien that binds to the target cell receptors. Once bound, a 20 kd fragment is proteolysed, thus exposing an additional binding site. This binding site can combine with either edema factor (89-kd protein) to form edema toxin, or lethal factor (90-kd protein), to form lethal toxin. The toxin complex is then transported to the cytosol where edema toxin acts by converting adenosine triphosphate to cyclic adenosine monophosphate. Cellular cyclic adenosine monophosphate levels are increased, leading to the edema characteristic of disease. Lethal factor is not as well understood, but recent work supports that it may be a zinc metalloprotease responsible for inhibiting neutrophil phagocytosis, lysing macrophages and inducing the release of tumor necrosis factor and interleukin 1 via inactivation of mitogen-activated protien-kinase-kinases (MAPKKs).

Testing for exposure uses blood; diagnostic assays include gram stain and an ELISA (enzyme linked immunosorbent assay).

Management

Standard precautions should be observed with patient isolation. The anthrax vaccine is produced by the Michigan Biologic Products Institute and has been licensed by the FDA since 1970. It is a sterile filtrate of cultures of an avirulent strain that elaborates protective antigen. No controlled trials are available. The current US vaccine (now given to military personnel) raises strong humoral immunity specifically to lethal toxin antigens and protects against natural anthrax exposure. Its efficacy in inhalation (biowarfare) anthrax is questionable. In industries that actively vaccinate, anthrax has not occurred in those who have received more than two doses of the vaccine and has occurred in some unvaccinated workers. In rhesus monkeys, vaccination has been highly effective against a lethal aerosol challenge. The dose is 0.5 ml SC at 0, 2, 4 weeks and at 6, 12, 18 months, then annual boosters. For post exposure prophylaxis, the vaccine is given promptly and again in 2 weeks, concomitantly with an appropriate antibiotic.

Cutaneous anthrax may be treated orally, Antibiotic treatment is ciprofloxacin 400 mg IV q8-12 h, doxycycline 200 mg IV, then 100 mg IV q8-12 h, or penicillin 2 million units IV q 2h plus streptomycin 30 mg/kg IM qd (or gentamicin). Pre-exposure prophylaxis is ciprofloxacin 500 mg PO bid x 4 weeks. For post-exposure prophylaxis, begin initial dose of vaccine, or doxycycline 100 mg PO bid x 4 wk plus vaccination. Alternates for therapy include gentamicin, erythromycin and chloramphenicol. Under investigation is the potential role of new lethal factor protease inhibitors in combating anthrax as a weapon, as well as inhibitors of LF and cytokine-modulating agents to limit the pathogenesis associated with anthrax infection.

Biological Weapons

Biological warfare is the use of microorganisms (bacteria, viruses and fungi) or toxins (poisons produced by living organisms) to produce death or disease in humans, animals and plants. Unlike chemical agents, which typically lead to violent disease syndromes within minutes at the site of exposure, diseases from biological agents have incubation periods of days. Therefore, it is up to the physician to recognize the first evidence of the results of a biological attack. The potential impact of attack is well illustrated by a 1970 World Health Organization publication. It is estimated that 50 kg of aerosolized B. anthracis spores, dispensed by an airplane 2 km upwind of a population center of 500,000 unprotected people in ideal meteorological conditions would travel more than 20 km and kill or incapacitate up to 220,000 people, nearly half of those in the path of the biological cloud. In the 1950 s and 60s, the US weaponized anthrax before the program was terminated.

Anthrax is favorable as a weapon of destruction because: The spore of the bacterium is stable especially in aerosol form. (17) The insidious nature of spread and resulting confusion is appealing to terrorists. The US Secretary of Defense, William Cohen, raised a 5 lb bag of sugar on television to demonstrate the amount of anthrax spores that could kill 50% of Washington Œs population. Treatment with high doses of penicillin, fluoroquinolone or tetracycline is of limited benefit but a vaccine is available for key personnel. Economically, the consequences would be staggering: $26.2 billion per 100,000 exposed. Epidemiological clues to a biological weapon attack: Unusual geographical area of occurrence, vector-borne disease in an area without these vectors, <1 epidemic simultaneously, more morbidity and mortality than expected, decreased rates in protected personnel (in buildings, vaccinated, discovery of a potential delivery mechanism, location of casualties, animals infected, unusual presentation, high disease rates, and increased respiratory disease rates.

The Future

140 countries have signed the Biological Weapons Convention of 1975, but several Middle Eastern states have not. Reliance will have to be put upon military and police intelligence, with firm links being developed with the medical community. Most hospitals have major incident plans designed for natural and man-made disasters. Adequate planning and preparation will help. NYC has completed an exercise of simulated anthrax attack and other US cities will follow. Officials released a harmless form into the subways in 1966 and within 10 minutes, the agent was detected at the furthest ends of the line. Surveillance systems are to be put into action to detect covert activities. Biosensor technology is available to the military but not to civilians. Resistance to antibiotics has not yet been described, but "altered" B. Anthracis strains could be created by adding foreign genes from other toxic organisms or for multiple-antibiotic resistance (or protease inhibitor resistance).

Hilary Cramner, MD
Emergency Medicine Program
Boston Medical Center
 

References

(1) Tigertt WD. Anthrax: William Smith Greenfield, MD, FRCP. Professor superintendant, the Brown Animal Sanatory Institution (1878-81)- concerning the priority due to him for the production of the first vaccine against anthrax. J Hyg (Lond). 1980;85:415-420.
(2) Pile JC: Arch Intern Med 158:429-434, 1998.
(3) Pile JC et al ibid, p430
(4) Brachman PS. Inhalation anthrax. Ann NY Acad Sci. 1980;353:83-93.
(5) Franz DR: JAMA, 278(5):399-411, 1997.
(6) Pile JC et al. Ibid, p432
(7) Pile JC et al. Ibid, p430
(8) Bail O. Cited by: Sterne M. Anthrax. In: Stableforth AW, Galloway IA, eds. Infectious diseases of Animals, Volume 1. London, England: Butterworth Scientific Publications;1959:22.
(9) Hanna P: Science 280:1671-4, 1998.
(10) Duesbery H: Science 74, 1998.
(11) Hanna P: Science 280;1671-4, 1998.
(12) Anthrax vaccine. Med Lett DrugsTher: Vol 40(1026):52-3, 1998.
(13) Franz DR: JAMA, 278(5):399-411, 1997.
(14) Duesbery H: Science May 1:734, 1998.
(15) Domestic Preparedness Course Document, p5.
(16) Health Aspects of Chemical and Biological Weapons:Report of a WHO Group of Consultants. Geneva, Switzerland:WHO;1970:72,99.
(17) Lancet editorial May 9, 1998.
(18) Chevrier MI: Washington Post Dec. 21, 1997, pC1.
(19) Kaufman AF: Emerging Infectious Dis 1997;3:83-94.
(20) Franz DR: JAMA, 278(5):399-411, 1997.
(21) Boyce N: New Scientist 158:2127. P4
(22) Woodall JP. Assessing the risk to civilians after biological attack:the need for international technology transfer. International Conference on Emerging Infectious Diseases. March 8-11, 1998, Atlanta. Abstr no p19.2.
(23) Hanna P, ibid.
 

• February 2000: Adventurous trip to the Aral Sea, Kazakhstan