Info: Bacillus anthracis Spores Used as a Biologic Warfare Agent

Anthrax has been developed as a biologic warfare agent by Japan, the United Kingdom, the United States, Iraq, and the Soviet Union.

An epidemic of anthrax occurred during April 1979 among people who lived or worked within a distance of 4 km in a narrow zone downwind of a Soviet military microbiology facility in Sverdlovsk (now Ekaterinburg, Russia). In addition, livestock died of anthrax along the extended axis of the epidemic zone out to a distance of 50 km. Later, in 1992, Soviet authorities admitted that the facility had been part of an offensive biologic weapons system and that the epidemic was caused by accidental release of anthrax spores. At least 77 cases and 66 deaths occurred, constituting the largest documented epidemic of inhalation anthrax in history. Main autopsy features included hemorrhagic necrosis of the thoracic lymph nodes in the lymphatic drainage of the lungs and hemorrhagic mediastinitis. More recently, between 1985 and 1991, Iraq developed anthrax for biologic warfare. By the time the Persian Gulf War occurred, Iraq had deployed bombs and missiles laden with biologic agents, which fortunately were not used.

Anthrax spores have several characteristics suitable for a biologic weapon, such as low visibility, high potency, accessibility, and relatively easy delivery, and could be used not only in war but during terrorist activities. A millionth of a gram of anthrax spores constitutes a lethal inhalation dose; a kilogram, depending on meteorologic conditions and means of delivery, has the potential to kill hundreds of thousands of people in a metropolitan area. Concerns have been raised by recent reports from Russia that scientists were able to insert all the B. anthracis genes determining the pathogenicity of anthrax into other bacilli, such as Bacillus cereus, against which the present available vaccine is ineffective. In addition, the vaccine may not protect against some rare B. anthracis strains. It is also possible to produce B. anthracis strains that are resistant to antibiotics.

In response to the growing threat of terrorism with chemical and biologic weapons, the United States and several other governments have developed new antiterrorist legislation and concepts of operations of emergency health and medical services response. Because the incubation period of inhalation anthrax may last a few days, the impact of a bioterrorist anthrax exposure could be reduced by early diagnosis; therefore, this disease should be considered in the differential diagnosis for an unusual epidemic

Anthrax is usually a disease of herbivores and only incidentally infects humans who come into contact with infected animals or their products. Because anthrax remains a problem in developing countries, animal products imported from these areas continue to pose a risk.

Human cases may occur in an industrial or an agricultural environment. Industrial cases result from contact with anthrax spores that contaminate raw materials used in manufacturing processes. In the United States, occasional epidemics have occurred in industrial settings, probably related to the processing of batches of highly contaminated imported animal fibers, particularly goat hair. These epidemics were primarily of cutaneous anthrax.

One epidemic occurred in Switzerland. ^[3] ^[4] Within less than 3 years, 25 workers in one textile factory contracted the disease; 24 cases were of the cutaneous type, and one was inhalation anthrax. The infection was due to goat hair imported from Pakistan. Owing to the rarity of the illness, which contributed to a general lack of experience among medical personnel, recognition of the clinical symptoms was delayed. In addition, repeated attempts failed to identify the pathogenic agent conclusively.

Human cases of anthrax in an agricultural environment result from direct contact with animals that are sick or have died from anthrax. In African wildlife, which cannot easily be vaccinated and in which the other aspects of control are not relevant, the disease remains a major cause of uncontrolled mortality in herbivores. ^[5]

In Africa there have been multiple epidemics of human disease associated with epizootics of anthrax in cattle. The largest reported agricultural outbreak occurred in Zimbabwe, with more than 10,000 cases reported between 1979 and 1985. Endemic cases continue to occur in the involved area. The majority of patients had cutaneous infections located primarily on the exposed parts of the body; some gastrointestinal cases were also reported. Domestic cattle deaths were noted. A similar large outbreak of human and animal cases of anthrax occurred in Chad, from September to December 1988, infecting more than 50% of donkeys and horses. ^[6] There were 716 human cases reported, with 88 deaths.

In an epidemiologic study of a human anthrax outbreak in Zimbabwe, the following factors were significantly associated with the disease: skinning and cutting meat of an animal alleged to have shown symptoms of anthrax, eating contaminated meat, and handling contaminated meat in the process of selling it.

HISTORICAL BACKGROUND

The earliest known description of anthrax is found in the Book of Genesis, in which the fifth plague (1491 BC), which appears to have been anthrax, is described as killing the Egyptians' cattle. There are descriptions of anthrax involving both animals and humans in the early literature of Hindus, Greeks, and Romans. In the 17th century, a pandemic referred to as the "black bane" swept through Europe, causing many human and animal deaths. Later, the disease in humans was described as the "malignant pustule."

Several distinguished microbiologists in the 19th century characterized the pathologic basis of the disease and attempted to develop a vaccine because of serious problems with anthrax in the livestock industry. ^[2] Pasteur developed and field-tested in sheep his attenuated spore vaccine in 1881. In 1939, Sterne reported his development of an animal vaccine that is a spore suspension of an avirulent, nonencapsulated live strain. This is the animal vaccine currently recommended for use.

Outbreaks of occupational cutaneous and respiratory anthrax began to be reported in the mid-1800s in industrial European countries such as England and Germany. Cutaneous anthrax came from handling wool, hair, and hides. Respiratory anthrax came from processes that created an aerosol, such as carding wool (hence the appellation "woolsorter's disease") and handling contaminated sacks of imported dried bones, as occurred in an English bone meal factory. Ninety cases of cutaneous or inhalation anthrax occurred over 24 years in women employed in an Austrian paper factory to tear up rags imported from the Near East. Early in this century, in the United States, the disease occurred in persons who handled materials that had been woven from contaminated animal fibers.

From the beginning of this century the annual number of cases reported in developed countries has steadily decreased. This decrease is the result of use of a cell-free anthrax vaccine in persons employed in high-risk industrial groups, decreased use of imported potentially contaminated animal products, improved hygiene in industry, and improved animal husbandry.

PATHOGENESIS

Anthrax toxin, produced by the bacterium B. anthracis, is composed of three proteins: protective antigen (PA), edema factor (EF), and lethal factor (LF). PA binds to specific cell surface receptors and, upon proteolytic activation to a 63-kD fragment (PA63), forms a membrane channel that mediates entry of EF and LF into the cell. EF is an adenylate cyclase and together with PA forms a toxin referred to as edema toxin. LF and PA together form a toxin referred to as lethal toxin. Lethal toxin is the dominant virulence factor produced by B. anthracis and is the major cause of death in infected animals. Intravenous injection of lethal toxin into rats causes death in as little as 38 minutes. Production of the toxic factors is regulated by one plasmid and that of the capsular material by a second plasmid.

The effects of anthrax toxin components on human neutrophils have been studied in detail. Phagocytosis of opsonized and radiation-killed B. anthracis was not affected by the individual anthrax toxin components. However, a combination of lethal toxin and edema toxin inhibited bacterial phagocytosis and blocked the oxidative burst of polymorphonuclear neutrophils. The two-toxin combination also increased intracellular cyclic AMP levels.

In macrophages, lethal toxin, after internalization via cell surface receptors, induces influx of calcium and inhibition of macromolecular synthesis. Lethal toxin causes apoptosis and necrosis via protein phosphatases, leading to lysis within 2 hours. It has been shown recently that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and MAPKK2) and that this cleavage inactivates MAPKK1 and inhibits the MAPK signal transduction pathway.

These studies suggest that two of the protein components of anthrax toxin increase host susceptibility to infection by blocking signal transduction, suppressing polymorphonuclear or macrophage function, and inducing cytotoxic effects.

Experiments performed in animals suggest that spores deposited beneath the skin or in the respiratory or intestinal mucosa germinate, and that the resulting vegetative forms multiply and produce a toxin. The local lesion results from the action of the toxin on the surrounding tissue, which causes tissue necrosis. The toxin or organisms or both may disseminate by the vascular system, causing systemic symptoms and signs of toxicity or bacteremia. Organisms are also often picked up by the lymphatic system, resulting in lymphangitis and lymphadenopathy.

ANTICIPATION OF THREAT AGENTS

Under conventional military doctrine, a biological warfare agent should be highly reliable, able to be targeted precisely at an enemy, cheap to produce, enjoy long shelf life and aerosol durability, and show limited epidemic spread. These criteria have converged to form a fairly short list of tier 1 agents that can be artificially aerosolized to deadly effect, regardless of their natural mode of transmission.

Most of these diseases are expected to follow a clinical course after biological warfare inoculation similar to that of the natural infections and to have limited capacity for person-to-person spread. (This objective cannot be ensured for the very large group subsumed under viral hemorrhagic fevers.) Empirical data are limited, but every expectation is that early antibiotic treatment will be effective against any of the bacterial culprits.

Tier 1 Agents/Diseases

Anthrax
Plague
Tularemia
Brucellosis
Q fever
Alphaviruses
Venezuelan equine encephalitis
Western equine encephalitis
Eastern equine encephalitis
Viral hemorrhagic fevers
Smallpox--special category

Aerosolized anthrax induces a disease quite distinct from the more usual and often survivable cutaneous variety. With intense involvement of mediastinal lymph nodes, it has a mortality approaching 100% if untreated before overt symptoms develop. Studies with primates suggest that early treatment with penicillin or doxycycline may be effective but may have to be prolonged for weeks and supplemented with vaccination or boostering. With heavy inocula, it is thought that some inhaled spores may remain dormant for long periods before germinating and becoming exposed to administered antibiotic.

No ex post facto specific treatment is known for the viral disorders, and for many of them there remain lacunae in our understanding of their natural history.

In a military defense setting, physical protection (masks and suits) plays the largest role--the same defense as against chemical weapons. In addition, mass prophylactic vaccination (e.g., against anthrax and some viral agents) is feasible in principle and has been adopted as routine for the U.S. Armed Forces. Likewise, routine monitoring of suspected clouds in the theater of operations should be conducted to provide early warning of chemical and biological warfare threats.

The changing threat, with special apprehension about vengeful individuals, forces our attention to agents and media beyond those of tactical military consequence. We can hardly monitor every civil airspace, although special attention has been paid to spectacular sites and events such as the Olympics--recalling the attacks at Munich in 1972. Massive outbreaks of foodborne and waterborne disease remind us of these vehicles for intentional infection. Other consumer product tampering has occurred on a minor scale for homicidal purposes; such tampering might be escalated manyfold for harassment of a corporation or a nation. Toxic tampering of a few grapes led to great economic losses for Chile in 1989. Similar harassment against domestic products, farm animals, or crops might be motivated for crass gains in the futures markets. Some terrorist mentalities may be undeterred by the untold havoc that would ensue from the reintroduction of smallpox into a global herd, the younger half of which is by now unvaccinated. ^[1] Smallpox had been discounted as a "rational" weapon because its spread might be uncontrollable. Now, our policy dilemmas about the merits (and hazards) of reintroducing vaccination are compounded by the technical ones of rediscovering and authenticating reliable seed stock and reconstituting the capacity for production of vaccine.

All things considered, anthrax has long held pride of place as an agent fairly easily grown and whose spores have long-lasting durability. Efficient dissemination is another matter: to produce a cloud of 1- to 5-mum particles takes more than a garden sprayer, and its action is subject to many vagaries of wind, rain, sunshine, and atmospheric turbulence. The oft-quoted figures of a potential for 10,000 casualties per kilogram of spore suspension are within the envelope of possibility, but as an optimal case combining substantial technical expertise, including meteorologic insight. The requisite technology remains within the reach of any determined state and requires investments in the low millions of dollars. That the reliability of outcome probably remains low may be less consequential to a clandestine terrorist, who can always try again, than to a military planner in a moment of tactical crisis. State-sponsored terrorism remains the most strident threat, and we should be particularly alert in connection with military confrontations with the states (mainly in the Middle East) that have had a history of use of such instrumentalities. Even if the principal state actors remain influenced by our deterrence strategies, others are often eager to precipitate hostilities in furtherance of their domestic political conflicts. The looming nuclear arms race on the Indian subcontinent also raises new alarms that these and other parties will look to biological warfare as a means of influencing the strategic balance there.

TREATMENT AND CHEMOPROPHYLAXIS

It is estimated that approximately 20% of untreated cases of cutaneous anthrax will result in death, whereas respiratory anthrax is almost always fatal. Deaths are, however, rare after antimicrobial treatment for the cutaneous form.

Intravenous penicillin G is the drug of choice, in a dose of approximately 4 million units every 4 to 6 hours. Lesions become culture-negative in a few hours, but therapy should be continued for 7 to 10 days. Some animal experiments suggest that addition of streptomycin (or gentamicin) may have additional benefit. In the absence of antibiotic susceptibility data, or for the penicillin-allergic patient, ciprofloxacin, 400 mg IV every 8 to 12 hours, or doxycycline, 200 mg IV and then 100 mg IV every 8 to 12 hours, is a satisfactory alternative.

If there is indication that an anthrax outbreak is occurring or that anthrax spores may have been used in biologic warfare, prophylaxis with ciprofloxacin (500 mg by mouth twice a day), or doxycycline (100 mg by mouth twice a day) may be given to potential susceptible nonimmunized persons. The duration of treatment for postexposure prophylaxis is for at least 6 weeks (or 2 weeks after the third vaccine dose when vaccine-induced antibodies are detectable).

Antibiotic therapy ameliorates systemic symptoms, although progression to eschar is not prevented. Excision of the lesion is contraindicated. Topical therapy is not effective. Systemic corticosteroids have been used for patients with extensive or cervical edema and in those with meningitis but indications are not well established. Tracheotomy may be needed when cervical edema compromises the airway.

Dressings with drainage from the lesions should be incinerated, autoclaved, or otherwise disposed of as biohazardous waste. Patients with draining lesions should be placed in "contact isolation." Person-to-person transmission has not been documented, including from patients with inhalation anthrax.

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