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BIOTERRORISM AND ANTHRAX James A. Wilkerson III, M.D. ABBREVIATED HISTORY OF BIOTERRORISM 6th Century BC: Assyrians poison the wells of their enemies with rye ergot.
6th Century BC: 0 Solon of Athens poisons the water supply with hellebore (skunk cabbage), an herb purgative, during the siege of Krissa.
184 BC: During the naval battle against King Eumenes of Pergamon, Hannibal's forces hurled earthen pots filled with serpents upon enemy decks. Hannibal won as the Pergamene were forced to fight against man and snake.
1346 AD: During the siege of Kaffa, the Tartar army hurls its plague-ridden dead over the walls of the city. The defenders are forced to surrender.
1422: At the battle of Carolstein, bodies of plague-stricken soldiers plus 2000 cartloads of excrement are hurled into the ranks of enemy troops.
15th Century: Reportedly, during Pizarro's conquest of South America, he improved his chances of victory by presenting to the natives, as gifts, clothing laden with smallpox virus.
1710: Russian troops hurl the corpses of plague victims over the city walls of Reval during Russia's war with Sweden.
1763: Captain Ecuyer of the Royal Americans, under the guise of friendship, presents to the native Americans two blankets and a handkerchief contaminated with smallpox.
1767: During the French and Indian War, the English general, Sir Jeffrey Amherst, gives blankets laced with smallpox to Indians loyal to the French. The epidemic decimates the tribes, arguably resulting in a successful British attack on Ft. Carillon.
1860-1865: W.T. Sherman's memoirs contain an account of Confederate soldiers poisoning ponds by dumping the carcasses of dead animals into them.
1925: The Geneva Protocol bans biological weapons on June 17. It is the first multilateral agreement that extends the prohibition of chemical agents to biological agents. Japan refuses to approve the ban.
1936: Unit 731, an actual bio-warfare unit masquerading as a water-purification unit, is formed. Shiro Ishii, a physician and army officer, constructs a 150 building complex just outside of Harbin, Manchuria for experimentation. Over 9000 test cases eventually die there. Another biological warfare site developed near Changchun is named Unit 100. Ishii field-tests biological warfare on Chinese soldiers and civilians. Tens of thousands die as a result of plague, cholera, and anthrax. One method was air dropping grain containing fleas infected with plague on Manchuria and China. The grain attracted rats, which became infected from the fleas (they can regurgitate up to 24,000 organisms in a single feeding) and brought the disease into the human population.
1941-1943: US launches its own studies of the use of and defense from biological agents. The Army Chemical Warfare Service develops Camp Detrick, Frederick, MD into a site for biological research and development.
1945: Unit 731 is blown up by the Japanese in the final days of WWII. Investigations by US officials begin. There is also speculation that over 3000 American, Korean, British, Australian, Soviet, and Mongolian POWs were used as guinea pigs.
1946: The initiation of an alleged deal between the US and Unit 731 leaders. Germ warfare data were to be exchanged for immunity from war crimes prosecution.
1966: A simulated covert biological warfare attack with a benign agent in the subway system of New York reveals that large numbers of individuals can be exposed with just one release.
1972: Members of the right-wing "Order of the Rising Sun" are arrested in Chicago. They possess 30 to 40kg of typhoid cultures that are to be used to poison the water supply in Chicago, St. Louis, and other mid-west cities. The two arrested are betrayed by recruits. It was felt that had the detailed plan succeeded it would have caused no problem due to chlorination of the water supplies.
1978: On September 7, Bulgarian exile Georgi Markov, in London, is injected in the leg with a steel ball impregnated with ricin via a specially constructed umbrella. He feels immediate pain at the injection site and within 5 hours becomes weak and dizzy. Fifteen to 24 hours later, Markov is febrile, nauseated and vomiting. He is admitted into a hospital 36 hours after the attack where he is found to be febrile, tachycardic, and with swollen lymph glands near the injection site. About 2 days after the attack, he becomes suddenly hypotensive. By the third day he is anuric and begins vomiting blood. He also is in complete heart block and eventually succumbs. The reason for the area of induration and redness on his leg is unknown to Markov or his doctors until the necropsy. This represents, in recent history, the first example of state-supported bioterrorism. The assassination is carried out by the communist Bulgarian government with technology supplied by the Soviet Union. The platinum-iridium pellet is the size of the head of a pin and cross-drilled with 0.016-inch holes to contain the toxin. A similar assassination attempt was made against Vladimir Kostov in Paris. Heavy clothing prevented the steel ball from entering any farther than Kostov's subcutaneous tissue. After he learned of his comrade's death, he went in for an examination and the pellet was found before any of the toxin was absorbed.
1979: In April, in the city of Sverdlovsk, USSR, an explosion from Military Compound 19 results in a toxic release. Over the next several days, citizens downwind are stricken with high fevers, difficulty breathing, and death. There are at least 79 infections with 68 fatalities. While local doctors announce an outbreak of inhalational anthrax, the government blames the situation on anthrax-contaminated beef. The military takes over a hospital to attend to these victims exclusively. The official cause is made known by President Boris Yeltsin in 1992 when he states that it was an accidental release of anthrax spores in a biological warfare program.
1984: In September, the Rajneeshee cult, an Indian religious cult, contaminates salad bars of The Dalles, OR, and Wasco County, OR, with Salmonella typhimurium. Over 750 are poisoned and 40 hospitalized. The purpose is to influence the outcome of a local election. It is only discovered a year later when members of the cult turned informants. Two were arrested eventually. Sheela, the chief of staff for Bhagwan Shree Rajneesh serves two and one-half years and is deported.
1995: With the defection of Iraqi General Hussein Kamal Hassan, evidence continues to grow that the Iraqi biological warfare program is more advanced than previously believed. The Iraqi authorities acknowledge that at the time of the war they had 100 botulinum toxin, 50 anthrax, and 16 aflatoxin bombs, 13 botulinum toxin, 10 anthrax, and 2 aflatoxin Scud missile warheads, and 122-mm rockets filled with anthrax, botulinum toxin, and aflatoxin.
1995: According to sources cited by the Office of Technology Assessment and at US Senate committee hearings, there are 17 countries suspected of manufacturing biological weapons (Iran, Iraq, Libya, Syria, North Korea, Taiwan, Israel, Egypt, Vietnam, Laos, Cuba, Bulgaria, India, South Korea, South Africa, China, Russia). 1999: On October 17, Russian soldiers discover plans to use biological weapons on the bodies of Chechans killed during fighting in Dagestan.
18 September 2001: A 38 year old assistant to NBC anchorman, Tom Brokaw, handles a letter containing powder which was postmarked on this date. On 9/25 she notices a raised skin lesion on her chest and over the next three days there is progressive erythema and edema. On 9/29, she develops malaise and a headache. By 10/1, the lesion has developed into a 5cm oval with raised borders and satellite vesicles. There is left cervical lymphadenopathy and a black eschar soon develops. This turns out to be the first case of cutaneous anthrax. The patient recovers with antibiotics.
26 September 2001: FBI arrives to investigate suspicious letter at NBC News. That letter is proven to be negative for anthrax.
28 September 2001: The seven-month-old son of a ABC producer is taken to his Mother's worksite at ABC in New York. On the 29th, a large, weeping skin lesion is noted on his left arm. Over the course of days, the lesion develops into an ulcer with a black eschar. The child is hospitalized and develops hemolytic anemia and thrombocytopenia. He is diagnosed as having cutaneous anthrax and recovers uneventfully with antibiotics. Subsequently, cases of cutaneous anthrax turns up at CBS, the NY Times, and the NY Post. All recover.
2 October 2001: Robert Stevens, 63, is admitted to a Lake Worth hospital gravely ill with the presumptive diagnosis of meningitis. The diagnosis of inhalational anthrax was made after further testing. Initial reports from HHS discount the possibility of terrorism. A co-worker, Ernest Blanco, is admitted to a Miami hospital with the diagnosis of pneumonia that over the course of time is diagnosed as inhalational anthrax. He eventually recovers.
5 October 2001: Robert Stevens dies from inhalational anthrax—the first bioterrorist casualty of this millenium. Anthrax was found at his workspace at American Media Inc.
8 October 2001: A letter postmarked Trenton, NJ, is mailed to Senate Majority leader, Tom Daschle. It contains a finely milled version of anthrax that has contaminated Capitol Hill and dozens of personnel. Twenty-eight are exposed.
14 October 2001: An aide to Majority Leader Senator Tom Daschle opens a letter with a return address from fictitious Greendale School in NJ. The letter is loaded with high-grade, light, fine-textured anthrax. Three days later, 28 others are positive when tested for exposure. This letter comes from the Brentwood postal facility where two workers later die from inhalational anthrax.
21 October 2001: A DC postal worker, Thomas Morris Jr., 53, dies of inhalational anthrax.
22 October 2001: D.C. postal worker, Joseph Curseen Jr., 47, is brought back to the hospital and dies of inhalational anthrax. More than 2,200 D.C. postal workers are placed on a 10-day supply of ciprofloxacin. 24 October 2001: A 59 year old D.C. postal worker presents to an ER with a fever of 100.8F, sweats, myalgias, chest pain, cough, nausea, vomiting, diarrhea, and abdominal pain. A chest x-ray and CT scan reveal a widened mediastinum. The patient is placed on ciprofloxacin, rifampin, and penicillin. Blood cultures diagnose anthrax.
25 October 2001: Homeland Security Director Tom Ridge reports that the anthrax sent to Daschle's office was highly concentrated and designed to be disseminated and inhaled more easily. The US Postal Service to begin environmental testing at 200 postal facilities along the East Coast. Number of confirmed anthrax cases rises to 13- 7 inhalation and 6 cutaneous. Most of the cases are linked to mail passing through NJ, NY, or Washington, D.C. An estimated 10,000 people have been placed on prophylactic antibiotics.
25 October 2001: Kathy Nguyen, a 61 year old female who worked in the stockroom at Manhattan Eye, Ear, and Throat Hospital falls ill with myalgias and malaise. Over the course of the next few days she develops shortness of breath, chest discomfort, and a cough productive of blood-tinged sputum.
28 October 2001: Officials confirm a new case of inhalational anthrax in a NJ postal worker. He works at the same facility that processed three anthrax-laden letters going to NY and Washington, D.C.
29 October 2001: CDC reports two new cases of anthrax in NJ. One is inhalational in a postal worker and the other is a private citizen who may have contracted the cutaneous form the mail. This totals 15, the number of confirmed anthrax cases in NY, NJ, Washington D.C., and FL.
31 October 2001: Nguyen dies of inhalational anthrax. Health officials are puzzled that she had no direct ties with postal services or with the media.
2 November 2001: CDC reports 21 anthrax cases: 16 confirmed—10 inhalational and 6 cutaneous; 5 suspected. Complete history is available at http://bioterry.com/HistoryBioTerr.html . ANTHRAX
Anthrax is one of the great infectious diseases of history. The fifth and sixth plagues in the Bible's book of Exodus may have been outbreaks of anthrax in cattle and humans. In 1876 anthrax became the first infectious disease to fulfill Koch's postulates, and five years later it became the first bacterial infection for which a vaccine was available. It is a zoonosis to which most mammals, especially grazing herbivores, are susceptible. With the exception of bioterrorist acts, human infections result from contact with contaminated animals or animal products. No human-to-human transmission has been identified. Anthrax infections are produced by B. anthracis, a gram-positive organism found in soil worldwide. An estimated 20,000 to 100,000 infections occur worldwide annually. In Zimbabwe between 1979 and 1985 and estimated 10,000 infections occurred as the result of interruption of veterinary public health practices in association with war. In the United States the annual incidence was only 127 in the early part of the 20th century, and it subsequently declined to less than one infection a year. Only eighteen inhalation anthrax infections have been diagnosed in the U.S. in the 20th century. Before the induced infections in 2001 no inhalation anthrax had been encountered in twenty years. When anthrax organisms are exposed to air they form endospores. The endospores do not divide, have no measurable metabolism, and are resistant to drying, heat, ultraviolet light, gamma radiation, and many disinfectants. In some types of soil, anthrax spores can remain dormant for decades. Their hardiness and dormancy have allowed anthrax spores to be developed as biologic weapons by a number of nations, although their only known use in war was by the Japanese army in Manchuria in the 1940s. Contagiousness for anthrax is relatively low. The estimated LD 50 for humans based on primate data is 2,500 to 55,000 spores. Anthrax, in the minds of most military and counterterrorism planners, represents the single greatest biological warfare threat. WHO report estimated that three days after the release of 50kg of anthrax spores along a 2km line upwind of a city of 500,000, 125,000 infections would occur producing 95,000 deaths. The U.S. Congressional Office of Technology estimated that between 130,000 and 3 million deaths would follow the aerosolized release of 100kg of anthrax spores upwind of Washington, DC—lethality matching or exceeding a hydrogen bomb.
Anthrax spores lend themselves well to aerosolization. Their size, 1 to 2 microns in diameter, is ideal for lodging in human lower respiratory mucosa. Fortunately, the manufacture and delivery of anthrax spores in this size range (avoiding clumping into larger particles) presents a substantial challenge and is beyond the capacity of individuals or groups without access to advanced biotechnology.
HUMAN CLIINICAL INFECTIONS
Human infections take three forms: cutaneous, intestinal and oropharyngeal, and pulmonary or inhalational.
Cutaneous Anthrax
Cutaneous anthrax accounts for 95 percent of all anthrax infections in the United States. In the fifty-six years between 1944 and 2000 only 224 cutaneous anthrax infections were diagnosed in the United States—only five between 1984 and 2000. Infected individuals often have a history of occupational contact with animals or animal products, particularly hides. The most common areas of exposure are the head, neck, and extremities, although any area can be involved.
Pathogenic endospores are introduced subcutaneously through a cut or abrasion, although a few infections have been transmitted by insect bites, presumably after the insect fed on an infected carcass. The primary skin lesion is usually a nondescript, painless, pruritic papule that appears three to five days after the introduction of endospores. In 24 to 36 hours, the lesion forms one or more vesicles that undergo central necrosis and drying, leaving a characteristic black eschar surrounded by severe, nonpitting edema and a number of purplish vesicles. The edema is usually more extensive on the head or neck than on the trunk or extremities. The name anthrax (from the Greek for coal) refers to the typical black eschar. Regional lymphadenopathy also is usually present. Lesions resolve without complications or scarring in 80 to 90 percent of cases.
Anthrax cutaneous lesions have been mistakenly diagnosed an Loxosceles recluse (brown or violin spider) bites. However, such spider biter typically are quite painful, whereas cutaneous anthrax usually is not.
Although cutaneous anthrax can be self-limiting, antibiotic treatment is recommended to avoid systemic infections, which can be overwhelming. Untreated cutaneous anthrax is associated with a mortality of 10 to 20 percent, but the mortality is less than 1 percent for antibiotic treated infections. Antibiotics can sterilize the cutaneous lesion in twenty-four hours, but it still progresses to form an eschar, presumably because toxins remain in the tissues. Malignant edema is a rare complication characterized by severe edema, induration, multiple bullae, and symptoms of shock. Malignant edema involving the neck and thoracic region often leads to breathing difficulties that require corticosteroid therapy or intubation.
In a few individuals temporal arteritis has been associated with cutaneous anthrax infection, and corneal scarring has resulted from palpebral cutaneous anthrax .
Histologic examination of anthrax skin lesions shows necrosis and massive edema with lymphocytic infiltrates. No liquefaction or abscess formation is present, indicating that the lesions are not suppurative. Focal points of hemorrhage are evident, with some thrombosis. Gram's staining reveals bacilli in the subcutaneous tissue.
Anthrax can be diagnosed by culture or smears of aspirated fluid from the vesicle. Squeezing the vesicle must be avoided to prevent forcing organisms deeper into the tissues. Anthrax also can be diagnosed, particularly by immunocytochemistry, in biopsies of skin lesions. However, biopsies are not recommended because they also can introduce organisms into deeper tissues. Gastrointestinal And Oropharyngeal Anthrax Gastrointestinal and oropharyngeal anthrax results from ingestion of inadequately cooked meat from an animal infected with anthrax. Such infections have never been identified in the United States, and are most common in Africa and Asia. The symptoms appear two to five days after the ingestion of endospore-contaminated meat. As a result, multiple cases can occur within individual households. An unusually prolonged outbreak was attributed to the consumption of stored meat products. Presumably bacterial inoculation takes place at a breach in the mucosal lining, but exactly where the endospores germinate is unknown. Bacilli can be seen microscopically in the mucosal and submucosal lymphatic tissue, and mesenteric lymphadenitis is grossly evident. Ulceration always occurs, most commonly in the terminal ileum and cecum. Whether ulceration occurs only at sites of bacterial infection or is distributed more diffusely as a result of the action of anthrax toxin is not known. The symptoms of gastrointestinal anthrax consist of nausea, vomiting, fever, and abdominal pain with rebound tenderness. The manifestations progress rapidly to severe, bloody diarrhea and signs suggestive of an acute abdomen. The primary intestinal lesions are ulcerative and occur mainly in the terminal ileum or cecum. Gastric ulcers may be associated with hematemesis. Hemorrhagic mesenteric lymphadenitis is also a feature of gastrointestinal anthrax. Ascites develops and may be severe with concomitant reduction in abdominal pain two to four days after the onset of symptoms. The ascites fluid ranges from clear to purulent, and it often yields colonies of B. anthracis . Morbidity is due to blood loss, fluid and electrolyte imbalances, and subsequent shock. Death results from intestinal perforation or anthrax toxemia. If the patient survives, most of the symptoms subside in 10 to 14 days. Although mediastinal widening is considered pathognomonic of inhalational anthrax , it has also been reported in a case of gastrointestinal anthrax . Symptoms include fever and diffuse abdominal pain. Both constipation and diarrhea have been reported; the stools are either melenic or blood-tinged. Because the gastrointestinal mucosa is ulcerated, patients often vomit material that is blood-tinged or has a coffee-ground appearance. Oropharyngeal anthrax is less common than the gastrointestinal form, but is also associated with the ingestion of contaminated meat. Initial symptoms include cervical edema and local lymphadenopathy, which cause dysphagia and respiratory difficulties. Lesions can be seen in the oropharynx and usually have the appearance of pseudomembranous ulcerations. This form is milder than the classic gastrointestinal disease and has a more favorable prognosis. Pulmonary Or Inhalation Antrax Inhalation anthrax is rare, and usually occurs after the inhalation of pathogenic endospores from contaminated animal hides or products. Only 18 such infections occurred in the United States from 1900 to 2001, and two of those were in laboratory workers. Before the 1960's introduction of hygienic measures, including vaccination, workers in goat-hair mills, for example, were regularly exposed to high concentrations of viable anthrax spores. Nevertheless, for reasons that are not understood, few cases of inhalational anthrax occurred. When dispersed in the atmosphere as an aerosol, anthrax spores can present a respiratory hazard even far downwind from the point of release. Inhalation anthrax is usually fatal, even with aggressive antimicrobial therapy. Although the lung is the initial site of contact, inhalational anthrax does not produce a true pneumonia. In most individuals, no infection is present in the lungs. About one-fourth of the Sverdlovsk anthrax victims (See 1979 in the above history of bioterrorism.) had small hemorrhagic foci suggestive of a Gohn complex. The endospores are engulfed by alveolar macrophages and transported by them to the mediastinal and peribronchial lymph nodes. The spores germinate en route, and anthrax bacilli multiply in the lymph nodes, causing hemorrhagic mediastinitis. Subsequently they invade the blood stream and spread massively throughout the body. Typically inhalation anthrax is a biphasic illness. In the initial phase that follows an incubation period of one to six days, it appears as a nonspecific illness characterized by mild fever, malaise, myalgia, nonproductive cough, and some chest or abdominal pain. Generally no objective findings are present. Within two or three days the illness progresses to the second phase, which begins abruptly and is characterized by further fever, acute dyspnea, diaphoresis, and cyanosis. Stridor is present in some patients due to extrinsic obstruction of the trachea by enlarged lymph nodes, and subcutaneous edema of the chest and neck. Chest radiographs disclose a widened mediastinum—evidence of hemorrhagic mediastinitis and a grave prognostic sign—and marked pleural effusions. In up to half of patients, obtundation and nuchal rigidity have developed as a result of complicating anthrax meningitis. The second stage of illness is rapidly progressive, with shock, associated hypothermia, and death occurring within 24 to 36 hours; 16 of the 18 cases reported in the United States between 1900 and 1978 were fatal. Anthrax Meningitis Involvement of the meninges is a rare complication of anthrax . The most common portal of entry is the skin, from which the organisms can spread to the central nervous system by hematogenous or lymphatic routes. M eningitis also occurs in cases of pulmonary and gastrointestinal anthrax . Anthrax meningitis is almost always fatal; death occurs one to six days after the onset of illness, despite intensive antibiotic therapy. In the few cases in which patients have survived, antibiotic therapy was combined with the administration of antitoxin, prednisone, or both. In addition to common meningeal symptoms and nuchal rigidity, individuals with meningitis have fever, fatigue, myalgia, headache, nausea, vomiting, and sometimes agitation, seizures, and delirium. The initial signs are followed by rapid neurologic degeneration and death. The pathological findings are hemorrhagic meningitis with extensive edema, inflammatory infiltrates, and numerous gram-positive bacilli in the leptomeninges. The cerebrospinal fluid is often bloody and contains many gram-positive bacilli. Gross examination at autopsy finds extensive hemorrhage of the leptomeninges, which gives them a dark red appearance described as "cardinal's cap." PATHOGENESIS Endospores introduced into the body by abrasion, inhalation, or ingestion are phagocytosed by macrophages and carried to regional lymph nodes. The spores germinate inside the macrophages and become vegetative bacteria, which are released from the macrophages, multiply in the lymphatic system, and enter the bloodstream. As many as 10 7 to 10 8 organisms per milliliter of blood may be present, a massive septicemia. Once they have been released from the macrophages, no evidence that an immune response is initiated against vegetative bacilli can be found. Anthrax bacilli express virulence factors, including toxins and a capsule. The resulting toxemia has systemic effects that lead to the death of the host. All known anthrax virulence genes are expressed by the vegetative form of B. anthracis that results from the germination of spores within the body. The major virulence factors of B. anthracis are encoded on two virulence plasmids, pXO1 and pXO2. The toxin-bearing plasmid, pXO1, codes for the genes that produce exotoxins. The toxin-gene complex is composed of protective antigen, lethal factor, and edema factor, which combine to form two binary toxins. Edema toxin consists of edema factor and protective antigen, the binding moiety that permits entry of the toxin into the host cell. Increased cellular levels of cyclic AMP upset water homeostasis and are believed to be responsible for the massive edema seen in cutaneous anthrax . Edema toxin inhibits neutrophil function in vitro, and neutrophil function is impaired in patients with cutaneous anthrax infection
Lethal
toxin consists of lethal factor and protective antigen. Lethal toxin
stimulates the macrophages to release tumor necrosis factor The smaller capsule-bearing plasmid, pXO2, codes for three genes involved in the synthesis of the polyglutamyl capsule. The exotoxins are thought to inhibit the immune response mounted against infection, whereas the capsule inhibits phagocytosis of vegetative anthrax bacilli. Both plasmids are required for full virulence; the loss of either one results in an attenuated strain. Historically, bacterial strains for anthrax vaccine were made by rendering virulent strains free of one or both plasmids. Pasteur, an avirulent pXO2-carrying strain, is encapsulated but does not express exotoxin components. Sterne, an attenuated strain that carries pXO1, can synthesize exotoxin components but does not have a capsule. LABORATORY DIAGNOSIS Rapid diagnostic procedures such as ELISA for protective antigen and PCA are available on at national reference laboratories. In view of the limited availability of these procedures and the time required to dispatch the specimens, rapid testing should be used only to confirm the diagnosis. The bacterial burden in advanced infection may be so great that bacilli are visible on Gram stained smears of unspun peripheral blood, although the use of automated cell counters makes identification of bacteria by this method unlikely. Standard blood culture is the most useful diagnostic procedure. It should produce growth in 6 to 24 hours, and a preliminary diagnosis 12 to 24 hours later, still too late for effective antibiotic therapy to be initiated. (The laboratory must be informed that anthrax is being considered. Bacillus species are common contaminants of cultures—usually B cereus —and are not further identified unless a specific request is made.) During autopsy the finding of thoracic hemorrhagic, necrotizing lymphadenitis and hemorrhagic, necrotizing mediastinitis are essentially pathognomonic of inhalation anthrax. However, anthrax is so uncommon that many pathologists in developed nations would not be familiar with these lesions. PREVENTION The standard anthrax vaccine in the United States is routinely administered to persons at risk for exposure to anthrax spores. The existing supplies are currently being used to immunize all military personnel. Designated " anthrax vaccine adsorbed" (AVA), it is an aluminum hydroxide–precipitated preparation of protective antigen from attenuated, nonencapsulated B. anthracis cultures of the Sterne strain. (The Sterne strain is the same organism used by Pasteur to develop a vaccine.) Two inoculations with AVA afforded substantial protection against inhalational anthrax in rhesus monkeys, and a limited trial of a similar vaccine in humans indicated that it afforded considerable protection against cutaneous anthrax . AVA is administered subcutaneously in a 0.5-ml dose that is repeated at 2 and 4 weeks and at 6, 12, and 18 months. Boosters are then given annually. For those receiving antibiotic prophylaxis for suspected exposure, AVA may be given concurrently. Vaccines with better protection and a simpler schedule are needed. A textile mill contaminated with anthrax spores was decontaminated with vaporized formaldehyde, and soil decontamination at Gruinard Island was achieved with formaldehyde in seawater. Although decontamination is desirable, the risk that resuspension of a deposited aerosol will lead to inhalational anthrax is much less than the risk due to a primary aerosol. Autoclaving and incineration are acceptable procedures for the decontamination of laboratory materials. ANTIMICROBIAL THERAPY Penicillin has been the drug of choice for anthrax for many decades, and only very rarely has penicillin resistance been found in naturally occurring isolates. In vitro, B. anthracis is also susceptible to most other commonly used antimicrobial drugs, such as ciprofloxacin, ofloxacin, levofloxacin, tetracyclines, chloramphenicol, macrolides, aminoglycosides, clindamycin, imipenem, rifampin, vancomycin, cefazolin, and other first-generation cephalosporins. It is resistant to cefuroxime, extended-spectrum cephalosporins such as cefotaxime and ceftazidime, aztreonam, trimethoprim, and sulfamethoxazole. Because a strain of B. anthracis has been produced in Russia that is resistant to multiple antibiotics (penicillin, doxycycline, chloramphenicol, macrolides, and rifampin), ciprofloxacin is now the drug of choice for initial therapy. If bioterrorism is suspected, treatment should continue for four weeks if vaccine is available or for 60 days if it is not. If the infection is thought to have been naturally acquired, therapy only needs to be continued for 10 to 14 days. The recommended initial therapy for adults with clinically evident inhalational anthrax is 400 mg of ciprofloxacin given intravenously every 12 hours. Ciprofloxacin and penicillin may be considered, in view of the frequent and rapid development of complicating meningitis and the clinical experience of cerebrospinal-fluid penetration with high-dose intravenous penicillin. For mild cases of cutaneous anthrax in adults, oral treatment with ciprofloxacin (500 mg every 12 hours) is recommended. If the strain is susceptible, oral doxycycline (100 mg every 12 hours) or amoxicillin (500 mg every 8 hours) is a suitable alternative. Severe cutaneous anthrax is treated with the same drugs and dosages as inhalational anthrax . Doxycycline, tetracycline, and ciprofloxacin are not recommended for pregnant women or young children, but anthrax can be such a devastating infection that the anthrax Working Group on Civilian Biodefense considers the need for these antibiotics to outweigh their risks to those two groups. Despite early and vigorous treatment, the prognosis for persons with inhalational, gastrointestinal, or meningeal anthrax remains poor. If individuals with inhalation anthrax have mediastinal widening, their infection usually has progressed too far to benefit from antibiotics. ANTHRAX IN ANIMALS One or more sudden deaths in a herd of livestock is usually the first sign of an anthrax outbreak. Clinical signs such as fever, disorientation, muscle tremors, respiratory distress, and convulsions often go unnoticed. In some animals, swelling of the face, jaw, neck, and shoulders may be observed. Lymph nodes around the neck may also become enlarged. The toxins from anthrax bacteria cause internal bleeding. After death, the characteristic signs of anthrax infection are bloody discharge from the nostrils and other orifices, rapid bloating, and a lack of rigor mortis. The following control measures are implemented when a case of anthrax is found:
A major outbreak of anthrax in buffalo occurred in Canada in the 1960's. Over a thousand animals died over a period of seven years. More detailed information about this outbreak can be found at http://www.findarticles.com/p/articles/mi_qa3712/is_200103/ai_n8933842
ADDITIONAL READING Dixon, TC, Meselson M, Guillemin J, Hanna, PC: Anthrax. New Eng J Med 1999; 341 :815-826. Jernigan JA, Stephens DS, Ashford DA, et al: Bioterroris-Related Inhalational Anthrax: The First 10 Cases Reported in the United States. Emerg Infect Dis 2001; 7 :933-944. Inglesby TV, Henderson DA, Bartlett JG, et al: Anthrax as a Biological Weapon: Medical and Public Health Management. JAMA 1999; 281 :1735-1746. Swartz MN: Recognition and Management of Anthrax—an Update. New Eng J Med 2001; 345 :1621-1626.
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interleukin-1ß, which are partly responsible for sudden death
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