The author explains the clinical presentation, pathophysiology, prevention, diagnostic work-up, and management of anthrax meningoencephalitis. Anthrax meningoencephalitis generally presents with fever, headache, vomiting, and confusion or agitation, but there may also be symptoms related to the source of infection (eg, cutaneous, gastrointestinal, or inhalational). Hemorrhagic meningitis should raise strong suspicion of anthrax infection. Anthrax meningoencephalitis is usually rapidly fatal, with roughly two thirds of affected patients dying within 24 hours of presentation; however, there are now at least 8 reported survivals following anthrax meningoencephalitis. Unfortunately, most physicians and hospitals are not adequately prepared to diagnose and manage potential bioterrorism agents, including anthrax, and not much has changed since the U.S. bioterrorism outbreak in 2001. Guidelines suggest that empiric treatment for anthrax in which anthrax meningitis is suspected, or cannot be ruled out, should include at least 3 antimicrobial drugs. The preferred regimen includes a fluoroquinolone (ciprofloxacin), a carbapenem (meropenem), and a protein-synthesis inhibitor (linezolid).
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• Anthrax has been developed as a biological warfare agent by at least 7 countries. It remains a significant bioweapons threat and is considered the most likely biological warfare agent.
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• Meningoencephalitis may develop with any clinical type of anthrax, including cutaneous, gastrointestinal, mixed gastrointestinal and cutaneous, inhalational, and injectional.
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• Injectional anthrax has emerged since 2009 among heroin users in Europe.
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• Anthrax meningoencephalitis generally presents with fever, headache, vomiting, and confusion or agitation, but there may also be symptoms related to the source of infection (eg, cutaneous, gastrointestinal, or inhalational).
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• Hemorrhagic meningitis should raise strong suspicion of anthrax infection.
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• Anthrax meningoencephalitis is usually rapidly fatal, with roughly two thirds of affected patients dying within 24 hours of presentation; however, there are at least 8 reported survivals following anthrax meningoencephalitis.
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• Guidelines suggest that empiric treatment for anthrax in which anthrax meningitis is suspected, or cannot be ruled out, should include at least 3 antimicrobial drugs. The preferred regimen includes a fluoroquinolone (ciprofloxacin), a carbapenem (meropenem), and a protein-synthesis inhibitor (linezolid).
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• Most physicians and hospitals are not adequately prepared to diagnose and manage potential bioterrorism agents including anthrax, and not much has changed since the U.S. bioterrorism outbreak in 2001.
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• Anthrax is now classified as a category A biological warfare agent, a category of microorganisms or toxins that can be easily spread, leading to intoxication with high death rates.
Historical note and terminology
Anthrax derives its name from the Greek word for coal (anthrakis) because the disease is commonly associated with black, coal-like, cutaneous eschars.
Anthrax has so far been used on a limited basis as either a biological warfare or bioterrorism agent. In World War I German agents reportedly tried to infect allied horses as they were being shipped to the European front (48; 173), although other accounts discount this claim (150). Japan reportedly first developed anthrax as a bioweapon in the 1930s and used anthrax against China during World War II (150; 48; 161; 75; 173). In 1993 the Japanese terrorist group Aum Shinrikyo dispersed aerosols of anthrax and botulism throughout Tokyo on at least 8 occasions (88), but these attacks failed to produce illness, apparently in part because the terrorists mistakenly used a harmless anthrax strain developed for vaccines (135). In 2001 anthrax was used as a bioterrorism agent in the United States, with several deaths, more than 20 cases, and over 32,000 individuals receiving postexposure prophylaxis because of anthrax delivered through the United States mail system (33).
The United States began research on offensive bioweapons in 1943 at Camp Detrick (now Fort Detrick) in Frederick, Maryland. To assess the risk of covert biological attacks in the 1960s, the army conducted large-scale covert tests at various civilian sites (eg, National Airport and Greyhound Terminal in Washington, D.C. and the New York City subway) using the anthrax simulant Bacillus globigii (150). The United States bioweapons program, which included development of weaponized anthrax, was terminated in 1969 following an Executive Order by President Richard Nixon. All stockpiles of biological agents were destroyed by May 1972 (161). There is no evidence that these U.S. weapons were ever deployed.
In 1972 the United States, the United Kingdom, and the U.S.S.R. signed the Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction ("The Biological Weapons Convention") (161). This treaty prohibits research, development, and stockpiling of biological agents for offensive military purposes. Although this biological weapons treaty has since been ratified by more than 140 countries, biological warfare research and the development of biological weapons continued in many countries (161).
The Soviet bioweapons program began before World War II under the auspices of Biopreparat, their bioweapons agency. This program continued until the 1990s, despite the Biological Weapons Convention. By the 1980s Biopreparat could produce thousands of tons of weaponized anthrax annually. Biopreparat also developed antibiotic-resistant anthrax using recombinant DNA techniques.
In April 1979 accidental release of anthrax spores occurred at a military bioweapons factory (Military Compound 19) in Sverdlovsk in the former Soviet Union (now Yekaterinburg, Russia) (02; 112; 90; 48; 161; 170). This incident resulted in at least 66 human deaths (among the 77 patients identified) in a narrow zone up to 4 kilometers downwind from the facility, as well as outbreaks of anthrax in livestock up to 50 kilometers downwind (112). Although the Soviet Ministry of Health initially blamed the deaths on cutaneous and gastrointestinal anthrax occurring from consumption of contaminated meat, this scenario was doubted by military sources in the West (53; 125; 02; 112; 90; 48; 161). In 1992 Russian President Boris Yeltsin confirmed that this outbreak was a result of "military developments" (112), and clinical and epidemiologic studies documented inhalational anthrax from a mixture of different Bacillus anthracis strains as the cause (02; 112; 90).
In the aftermath of the Gulf War, Iraq acknowledged to the United Nations Special Commission Team 7 that it had conducted biological weapons research on a number of agents, including Bacillus anthracis (161). Further details were uncovered in 1995. Iraq had extensive research facilities at multiple sites, including Salman Park on the Tigris River. Iraq conducted field trials with Bacillus subtilis (an anthrax simulant) and various biowarfare agents using various delivery systems, including rockets, aerial bombs, sprayers attached to helicopters, and possibly unmanned drones (161). To reduce particle size in order to maximize the delivered dose of anthrax, Iraq used sequential filters in an arrangement reportedly similar to that used at Camp Detrick in the 1950s. Iraq produced 8500 liters of concentrated anthrax, of which 6500 liters were placed into R400 bombs, Al Hussein warheads, and other devices (161).
In late 2001 an anthrax outbreak attributed to bioterrorism occurred in the United States. Anthrax was spread through the mail (39; 29). Twenty-two cases were identified, 11 with inhalational anthrax and 11 with cutaneous anthrax (37; 35; 38; 39; 92; 89). Five of the inhalational cases died. Only one of these cases had documented anthrax meningoencephalitis (92).
The FBI alleges that the 2001 anthrax bioterrorism outbreak in the United States was conducted by U.S. Army biodefense scientist Bruce Ivins, who worked at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Dettrick, Maryland (114; 24). In 2008, shortly before these allegations were made public, Ivins committed suicide. The FBI employed a complex strategy to identify the source of the anthrax: (1) spores from the mailed envelopes were cultured, yielding thousands of colonies, one from each spore; (2) a small number of colonies with unusual features (“minority phenotypes”) were identified, and the genomes of these colonies were completely sequenced to identify the corresponding mutations; (3) tests were developed to screen anthrax samples for 4 of these mutations, using a polymerase chain reaction-based strategy; these molecular tests were applied to more than 1000 isolates from labs in the United States and other countries (64). In only 8 of the study’s samples were all 4 mutations identified, and all were directly related to spores Ivins had created in 1997 (64). However, in February 2011, a scientific panel of the U.S. National Academy of Sciences independently evaluated the genetic evidence and concluded that it was insufficient to prove that Ivins was responsible. In addition, Ivins's laboratory did not contain the equipment needed to manufacture the refined powder of spores that were implicated in the 2001 bioterrorism attacks (24).
Anthrax is now classified as a category A biological warfare agent, a category of microorganisms or toxins that can be easily spread, leading to intoxication with high death rates (09). Other biological warfare agents in this category include botulism, plague, smallpox, tularemia, and viral hemorrhagic fevers (09; 11).