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  • Updated 05.20.2024
  • Released 12.03.2001
  • Expires For CME 05.20.2027

Anthrax meningoencephalitis

Introduction

Overview

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 eight 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 three antimicrobial drugs. The preferred regimen includes a fluoroquinolone (ciprofloxacin), a carbapenem (meropenem), and a protein-synthesis inhibitor (linezolid).

Key points

• Anthrax has been developed as a biological warfare agent by at least seven countries. It remains a significant bioweapons threat and is considered the most likely biological warfare agent.

• Meningoencephalitis may develop with any clinical type of anthrax, including cutaneous, gastrointestinal, mixed gastrointestinal and cutaneous, inhalational, and injectional.

• Injectional anthrax has emerged since 2009 among heroin users in Europe.

• 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 at least eight reported survivals following anthrax meningoencephalitis.

• Guidelines suggest that empiric treatment for anthrax in which anthrax meningitis is suspected, or cannot be ruled out, should include at least three antimicrobial drugs. The preferred regimen includes a fluoroquinolone (ciprofloxacin), a carbapenem (meropenem), and a protein-synthesis inhibitor (linezolid).

• 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.

• 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.

Occupational anthrax (eg, woolsorters’ disease). In the 19th century and early 20th century, occupational anthrax was a common problem in the United States and Great Britain, affecting workers in agriculture and industries involving direct contact with animals or animal products (135; 06). Workers in industries processing wool, other animal hair and bristles, leather, and horn and bone were all at risk.

In the 19th and early 20th century, cutaneous anthrax was the most common form of occupational anthrax (as it is now).

Occupationally acquired cutaneous anthrax infection

Before infection (left) and during the "most acute stage of infection" (right). Note the black eschar and the marked edema of the neck extending to the face and chest. Treatment was limited to washing the wound and applying tin...

Treatment, though, was limited, and about one in four affected workers died. Even in the early 20th century, treatment was limited to washing the wound and applying tincture of iodine. Internal administration of iodine, tonics, and stimulants (quinine, alcohol, coffee), inhalation of oxygen, and experimental serotherapy were also advocated. The Italian physician Achille Sclavo (1861-1930) produced in 1895 a serum therapy for anthrax that he initially used for experiments on animals, but by 1897 was using this serum in human patients with unprecedented success (141; 194).

Italian physician Achille Sclavo (1861-1930), c1920

(Source: Archivio Università di Sassari. Public domain.)

It consisted of the injection, usually intravenously, of fluids from an immunized animal. After 6 years he had only 10 deaths among 164 cases (6.1%), a marked improvement over the case fatality rate of 24.1% in Italy at the time (06; 07). Sclavo's anti-anthrax serum was introduced to Britain in 1904 by the enterprising British physician and first medical inspector of factories Sir Thomas Morison Legge (1863–1932) (194). Within months, the serum became regarded by medical practitioners as an effective treatment of cutaneous anthrax, though access to “fresh” serum and the necessary speedy diagnosis remained problematic.

Sir Thomas Morison Legge (1863-1932)

Sir Thomas Morison Legge was a British physician and the first medical inspector of factories. (Source: Photograph by British professional photographer Graystone Bird [1862-1943]. Courtesy of the Wellcome Trust, London. Creativ...

In the early 20th century, another form of serotherapy was developed by Austrian pathologist and immunologist Rudolf Kraus, then working in Buenos Aires; Kraus and colleagues reported only one death among 140 cases using intravenous injection of normal ox serum heated for 30 minutes to 1324 °F (06; 07).

The U.S. government published the common appearance of anthrax on the skin at different stages as a guide to clinicians to facilitate recognition of the disease and similarly prepared diagrams of anthrax bacilli and spores.

Anthrax as an impetus to development of microbiology and immunology. Because the burden of occupational anthrax was costly and threatened multiple industries, there were strong incentives to identify the cause of the disorder and to find potential preventive measures and treatments. Among these was German physician Robert Koch (1843-1910), who had been working in a rural general medical practice (123; 124; 125; 126; 127; 128; 31; 132; 22).

German physician and pioneering microbiologist Robert Koch (1843-1910)

Halftone photomechanical print by German photographer Josef Albert (1825-1886). (Source: Bibliothèque interuniversitaire de Santé. https://www.biusante.parisdescartes.fr/histoire/images/index.php?refphot=CIPB0672. Licence Ouv...

Koch organized his own small microbiological laboratory, and with great discipline, he developed novel techniques and pursued innovative experiments.

Robert Koch in his laboratory

This represents work Koch did to understand cholera in South Africa, but it undoubtedly portrays a laboratory very close to what he earlier created for his studies of Bacillus anthracis. Photogravure of gouache paintin...

By 1876, Koch had proven the microbiological nature of anthrax and worked out much of the biology of the responsible organism, Bacillus anthracis.

Bacillus anthracis drawn by Robert Koch

Anthrax bacilli from a mouse spleen after 24 hours of culture in a drop of aqueous humor; (a) in the filaments elongated round spores have developed at regular intervals like a string of pearls; (b) some threads are in the proc...

Koch sent a letter announcing his discoveries to the preeminent German biologist and bacteriologist Ferdinand Cohn (1828-1898), who invited Koch to Breslau to demonstrate his findings.

German biologist and bacteriologist Ferdinand Cohn (1828-1898)

(Source: Portrait of Ferdinand Julius Cohn, vignetted head and shoulders, autographed Ferdinand Cohn. Bulletin of the Institute of History of Medicine, Johns Hopkins Press, Baltimore, Maryland, 1939;VII: Facing Page 49. Courtes...

Koch's 3-day-long series of demonstrations were a resounding success, and his work was published in Cohn's Beitrage zur Biologie der Pflanzen (“Contributions to the biology of plants”) in July 1876, an event later considered to represent "the birth of modem bacteriology" (123; 22). German-Jewish pathologist Julius Friedrich Cohnheim (1839-1884), who was present at Koch's demonstrations, said, "I consider this to be the greatest discovery in the field of microorganisms and I believe that Koch will surprise and shame us all once again with further discoveries” (130).

German-Jewish pathologist Julius Friedrich Cohnheim (1839-1884) heralded Koch's discoveries concerning Bacillus anthracis

(Source: Wagner E, editor. Gesammelte Abhandlungen von Julius Cohnheim [Collected essays by Julius Cohnheim]. Berlin: August Hirschwald, 1885.)

To support his conclusions, Koch began photographing his findings and published his first photographs of Bacillus anthracis from cultures in 1877 (124). By 1881, he was able to demonstrate Bacillus anthracis in diseased tissue (125).

In 1880, French veterinary surgeon Jean Joseph Henri Toussaint (1847-1890) developed an early anthrax vaccine, and because Toussaint was not member of the French Academy of Sciences, his paper describing his accomplishment was presented before the academy by French veterinarian and pathologist Henri Bouley (1814-1885) on July 12, 1880. Toussaint had tested his attenuated vaccine on eight dogs and 11 sheep, half of which died after inoculation, a result that was not particularly compelling.

French veterinary surgeon Jean Joseph Henri Toussaint (1847-1890)

(Source: Louis Georges Neumann, professeur à l'École vétérinaire de Toulouse. Courtesy of the Bibliothèque interuniversitaire de Santé. Public domain. Image edited by Dr. Douglas J Lanska.)

However, almost all of the credit for creation of an anthrax vaccine went to French microbiologist Louis Pasteur (1822-1895) (57).

French microbiologist Louis Pasteur (1822-1895)

Lithograph by Christian Schultz (1817-1882) after photograph by French photographer Pierre Petit (1832-1909). (Courtesy of the Bibliothèque interuniversitaire de Santé https://www.biusante.parisdescartes.fr/histoire/images/in...

Pasteur gave a celebrated demonstration of anthrax vaccination on sheep at Pouilly-le-Fort in May 1881, using a vaccine that he portrayed as having been developed like his prior vaccine for chicken cholera, ie, by attenuating the microbe with prolonged exposure to atmospheric oxygen. He also commanded that his assistants publish nothing about this during his lifetime.

In the demonstration, 24 sheep, one goat, and six cows were inoculated twice with an anthrax vaccine on May 5 and 17, 1881, whereas a control group of 24 sheep, one goat, and four cows remained unvaccinated.

Pasteur vaccinating a sheep at Pouilly-le-Fort in May 1881

(Source: Chamberland C. Le charbon et la vaccination charbonneuse: d'après les travaux récents de M. Pasteur [Anthrax and anthrax vaccination: according to the recent works of M. Pasteur]. Paris: Bernard Tignol, 1883. Courtes...

On May 31, all the animals were inoculated with anthrax bacilli, and the results were examined on June 2. All but one of the vaccinated animals remained healthy, whereas the unvaccinated sheep and goats had all died by the end of the day, and the unvaccinated cows were all manifesting symptoms of anthrax. Pasteur accepted the accolades he received and publicly attributed his success to his preparatory experiments.

However, 40 years after Pasteur's death, new facts emerged from Pasteur's nephew that Pasteur had instead used a method similar to that employed by Toussaint, killing the microbe with potassium bichromate. Pasteur's laboratory notebooks became available for study only in the 1970s, and careful analysis proved that Pasteur was guilty of scientific misconduct, and as some have alleged, fraud. As American historian Gerald L. Geison (1943-2001) concluded in his award-winning The Private Science of Louis Pasteur (1995), "Pasteur deliberately deceived the public and the scientific community about the nature of the vaccine actually used at Pouilly-le-Fort." Instead of an oxygen-attenuated live vaccine, Pasteur had in fact used a potassium dichromate-killed vaccine, employing a process very much like Toussaint's. Pasteur subsequently developed an oxygen-attenuated anthrax vaccine (that nevertheless lost potency over time) but at the time of the Pouilly-le-Fort demonstration Pasteur's own approach to vaccine development had not progressed to a satisfactory state. Pasteur never gave proper credit to Toussaint for his discovery, nor did he acknowledge having used Toussiant's method for the celebrated demonstration (183; 85; 192; 193; 58).

Use of anthrax as biological warfare agent. 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 (60; 221), although other accounts discount this claim (191). Japan reportedly first developed anthrax as a bioweapon in the 1930s and used anthrax against China during World War II (191; 60; 207; 92; 221). In 1993 the Japanese terrorist group Aum Shinrikyo dispersed aerosols of anthrax and botulism throughout Tokyo on at least eight occasions (107), but these attacks failed to produce illness, apparently in part because the terrorists mistakenly used a harmless anthrax strain developed for vaccines (175). 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 (43).

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 (191). 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 (207). 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") (207). 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 (207).

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; 144; 109; 60; 207; 217). 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 (144). 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 (66; 162; 02; 144; 109; 60; 207). In 1992 Russian President Boris Yeltsin confirmed that this outbreak was a result of "military developments" (144), and clinical and epidemiologic studies documented inhalational anthrax from a mixture of different Bacillus anthracis strains as the cause (02; 144; 109).

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 (207). 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 (207). 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 (207).

Anthrax has been developed as a biological warfare agent by at least seven countries. It remains a significant bioweapons threat and is considered the most likely biological warfare agent, as it is stable in spore form and can be stored for prolonged periods (65). It is easy and cheap to produce, and as there is no natural immunity in industrialized nations, it can be dispersed in air; the inhalational form is highly lethal, and the agent is difficult to detect (208). Nevertheless, aerosolized anthrax has not yet been used on the battlefield, possibly in part because of "moral repugnance" of biological weapons, potential retaliation in kind, delayed manifestations following use, and uncertain effects depending on weather conditions (176). Indeed, the uncertainties of such weapons are demonstrated by the Sverdlovsk incident in the U.S.S.R. in 1979, which involved the accidental release of an estimated 10 kilograms of weapons-grade anthrax spores: this accident produced a total of 66 fatalities among a potentially exposed population of 1.2 million people (176).

Offensive anthrax bioweapons were initially manufactured as slurries of highly concentrated bacteria. Although easy and safe to manufacture, such slurries had to be refrigerated for storage and were difficult to disseminate (60). Later, freeze-dried powder formulations of anthrax spores were developed as bioweapons that although technically difficult and dangerous to manufacture, were thermally stable without refrigeration and were easily disseminated (60). Bioweapon anthrax may also be modified to be multidrug resistant and may be stabilized with other substances (eg, silica) to decrease electrostatic charges imparted by the milling process and thereby keep the particles from clumping. The latter issue is critical because biowarfare agents are most effectively delivered as an aerosol of particles from 1 to 5 microns in size (60). Particulates in this size range behave similar to a gas and are taken into bronchioles and alveoli during respiration, whereas larger particles are much more difficult to disperse, rapidly fall to the ground, or become trapped in the upper airway (60). Anthrax aerosols are invisible, odorless, colorless, and tasteless.

Use of anthrax in bioterrorism. In late 2001 an anthrax outbreak attributed to bioterrorism occurred in the United States. Anthrax was spread through the mail (49; 39). Twenty-two cases were identified, 11 with inhalational anthrax and 11 with cutaneous anthrax (47; 45; 48; 49; 111; 108; 88). Five of the inhalational cases died. Only one of these cases had documented anthrax meningoencephalitis (111).

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 (146; 33). 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 four 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 (77). In only eight of the study’s samples were all four mutations identified, and all were directly related to spores Ivins had created in 1997 (77). 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 (33).

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 (12). Other biological warfare agents in this category include botulism, plague, smallpox, tularemia, and viral hemorrhagic fevers (12; 14).

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