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The story of anthrax from antiquity to the present: a biological weapon of nature and humans
The Story of Anthrax from Antiquity to the Present: A Biological Weapon of Nature and Humans JOSEPH A. WITKOWSKI, MD LAWRENCE CHARLES PARISH, MD
A
nthrax is a disease of extraordinary interest. A condition affecting animals and humans identifiable clinically as anthrax occurred in both biblical times and during the classical period. The discovery of the etiologic agent parallels the history of modern bacteriology, whereas the control of anthrax previews the modern interest in occupational pulmonary medicine. The current wave of terrorism has brought renewed interest in this zoonosis, and anthrax has three presentations in humans.
Cutaneous Anthrax Cutaneous anthrax has also been known as “malignant pustule,” “malignant carbuncle,” and charbon. One to five days after inoculation, a small, slightly pruritic, red papule appears at the site.1. Intense, nonpitting edema then rims the base of the papule. By the second or third day, tense vesicles or even bullae filled with serosanguineous fluid arise on the edematous plaque (Fig 1). The central papule then becomes necrotic, ulcerates, and forms a brown to black eschar (Fig 2). The pathognomonic picture of anthrax, a black eschar ringed by vesicles or pustules on an edematous base, is seen after 5–7 days (Fig 3). The lesion continues to evolve for 12–14 days, at which time the eschar eventually separates, leaving a shallow ulcer that heals by secondary intention in 2–3 weeks. The so-called malignant pustule usually appears on exposed sites. For example, skin damaged by occupation, avocation, or grooming activities, such as the lips in carpet weavers and spinners, facial skin in shaving injuries, the nape of the neck and submandibular area where the collar rubs the skin, and the eyelids in persons wiping perspiration off their brow are predisFrom the Departments of Dermatology, University of Pennsylvania School of Medicine and Temple University School of Podiatric Medicine, Philadelphia, Pennsylvania; and the Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and the Jefferson Center for International Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania. Address correspondence to Jospeh A. Witkowski, MD, 3501 Ryan Ave, Philadelphia, PA 19103. E-mail: [email protected]. © 2002 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
posed.2 When the eyelids are involved, the edema is more pronounced. Cutaneous anthrax is characteristically painless, although it may be tender on palpation. The regional lymph nodes often become painful and tender after a few days. Most patients experience headache, develop malaise, and mount a fever of up to 102°F for several days. A few patients have no systemic manifestations. Rarely, inflammatory signs are progressive, with extensive edema, multiple necrotic areas, and bulbous formation. This occurs along with fever and signs of meningeal, pulmonary, or other organ involvement. Internal hemorrhage, characteristic shock, and death follow within days. The differential diagnosis varies with the location and stage of the disease. Angioneurotic edema, a carbuncle, or furuncle might be considered early stages. Cowpox, accidental vaccinia, a cutaneous infarct, a spider bite, and a factitious lesion might be considered later in the course of the disease.
Pulmonary Anthrax The classic clinical picture of inhalational anthrax, also called woolsorter’s disease, Bradford disease, and rag picker’s disease, is biphasic.3 The initial stage consists of the gradual onset of a mild fever, malaise, fatigue, myalgia, nonproductive cough, and at times, a sensation of precordial oppression. There are few objective findings aside from fever. Rhonchi may be heard on auscultation of the lungs. This initial phase typically lasts for several days, after which there may be some improvement in the clinical condition. Frequently, the clinical features suggest a cold, influenza, or bronchitis. The second stage develops suddenly, with the onset of acute dyspnea and subsequent cyanosis. The patient may appear moribund with a rapid pulse and respiratory rate. The temperature may be mildly elevated, or it may be subnormal because of shock. Stridor may occur, and profuse perspiration is frequently present. Physical examination of the chest reveals moist, crepitant rales and signs of pleural effusion. Typically, the patient remains conscious until death, but with meningeal in0738-081X/02/$–see front matter PII S0738-081X(02)00250-X
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Figure 3. Typical lesion of cutaneous anthrax. (Courtesy of W. Ho¨ fler, MD)
Gastrointestinal Anthrax Figure 1. Cutaneous anthrax at 3 days. (Courtesy of Bernard Appel, MD collection)
volvement, there may be disorientation, coma, and meningismus. A chest x-ray film (Fig 4) usually shows widening of the mediastinum. The average duration of this stage is ⬍24 hours, and it usually ends in death. The differential diagnosis includes cardiac failure, a cardiovascular accident, and conditions causing widening of the mediastinum, pulmonary edema with septicemia.
Figure 2. Cutaneous anthrax at 10 days. (Courtesy of Bernard Appel, MD collection)
Anthrax involving the gastrointestinal tract, also known as “splenic fever” and der milzbrand, is a rare occurrence in humans. Ingested organisms from contaminated meat multiply in the stomach and the intestinal submucosa. An ulcer results at the site of penetration.2 A necrotic ulcer in the ilium or cecum is usually associated with severe hemorrhagic mesenteric lymphadenitis. Diarrhea is severe. The abdomen greatly distends because of severe ascites and splenic enlargement. Shock and death usually follow. The differential diagnosis includes end-stage liver disease. Anthrax in animals is primarily a gastrointestinal affliction. It is known as murrain, charbon, “splenic fever,” or der milzbrand and occurs most commonly after ingestion of food contaminated with spores,4 occurring when the grass is so short that the animal grazes closer to the ground or must forage in the soil for food. The primary site appears along the gastrointestinal tract and rapidly leads to widespread systemic disease.
Figure 4. Marked widening of the mediastinum and early pulmonary edema. (Courtesy of W. Dutz, MD)
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Table 1.
Milestones in the identification of B. anthracis
1823 1842 1849 1850 1857 1860 1863 1875 1879 1879 1881
Eloy Barthe´ lemy Christain Joseph Fuchs Aloys Pollender Pierre Francois Rayer Frederich Brauell One´ sime Delafond Casimir Davaine Ferdinand Julius Cahn Robert Koch John H. Bell Louis Pasteur
The course may be either acute or subacute. The acute, fulminant form results in death after several hours without any prodromal signs. The subacute variety begins with chills and fever. Edema is a prominent feature. This often involves the neck. Death may result from respiratory obstruction when the tongue or pharynx is involved. The abdomen becomes greatly distended because of splenic enlargement and ascites. Bloody diarrhea is a common manifestation, along with hemorrhagic discharges from other body orifices. Central nervous system involvement results in tremors, spasms, and convulsions. Finally, coma and death ensue.
Discovery of the Cause The history of the discovery of the etiologic agent of anthrax is almost as fascinating as the story of the disease itself. At the end of the 19th century and even into the 20th, German and French scholars were arguing over the question of priority for the discovery. From this dispute, the following facts emerge.5 In 1823, Eloy Barthe´ lemy, a Frenchman, proved the infectiousness of anthrax by inoculating healthy animals with the blood of animals that had died of the disease6 (Table 1). A German veterinarian, Christian Joseph Fuchs, discovered what he called “granulated threads” in the blood of animals that had died of anthrax in 1842. He did not publish his findings, however, until 1859 and renounced any claim to priority for discovering the cause. Aloys Pollender, who is credited with discovering the etiologic agent, had his first contact with the disease in 1841 when he unsuccessfully treated a flayer (one who strips off the skin) who had developed an anthrax carbuncle. After purchasing a modern microscope in 1849, he set out to investigate the cause of death of a large number of cows in his area. He saw the organisms, which he called “chyllus corpuscles” in the blood, spleen, and carbuncle fluid of cows, which had died of the disease. He wrote: “A countless number of extremely fine, apparently solid, and not fully transparent rodlike corpuscles of equal thickness throughout their length and neither coiled, nor wavy, nor constricted, but entirely straight and flat, with no branching along
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their course.” After subjecting the organisms to a variety of chemicals, he identified them as having a plantlike nature. He also observed that iodine solution stained them a pale yellow, thereby making them more visible. Pollender published his findings in 1855 and raised the question of whether the corpuscles he described could be the cause of anthrax. In 1859, the French dermatologist Pierre Francois Rayer detected the corpuscles he described as “little threadlike bodies” in the spleen and blood of sheep dying of anthrax. This finding was mentioned only briefly in a report on the transmission of the disease that he delivered to the Socie´ te´ de Biologie of Paris. He apparently attached so little significance to the discovery that his findings were not even included in a publication edited by himself.7 Frederick Brauell published an article on anthrax in 1857. He was the first to observe anthrax bacilli in the blood taken from a live animal. His discovery clouded the issue, however, as he identified the organism as a vibrio. Although One´ sime Delafond detected the organisms in the blood of sheep in 1856, he did not publish his findings until 1860. He was the first to note the diagnostic value of finding the organism, and he observed the growth of Bacillus anthracis. In 1863, Casimir Davaine, a collaborator of Rayer in Paris, claimed as his own the observations on the anthrax organisms made by Rayer 4 years prior. In so doing, he asserted priority over Pollender. He formally challenged Pollender’s priority in 1875. During 1863 and 1864, Davaine published a series of articles demonstrating that anthrax could be transmitted to sheep, horses, cattle, guinea pigs, and mice by subcutaneous inoculation with infected blood. The presence of “bacteridia,” as he called them, in the blood and other inocula was necessary for transmitting the disease. He also observed that after inoculation, the organism rapidly increased in number and then became filamentous. His findings led to the acceptance of the germ theory, a major turning point in the history of medicine. In 1876 and 1877, Robert Koch published his findings on the life cycle of B. anthracis.8 He grew the organisms in pure culture by using the aqueous humor of cattle eye. After inoculation, a single organism grew into long threads and into long, parallel, and twisting bundles. After this period of multiplication, which lasted 10 –15 hours, the organism began to sporulate. The vegetative, boxcarlike bacilli gave rise to refractile structures, or spores. He then demonstrated that these spore forms could revert to vegetative forms when placed in fresh medium and could cause anthrax when injected into mice. Koch was the first to produce anthrax in animals by inoculating them with pure cultures of the organism. Louis Pasteur produced the first attenuated anthrax vaccine in 1881.7 His discovery was based on the observations that an occasional animal would survive attacks
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Table 2.
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Anthrax firsts
Bacterial cause confirmed Single organism proven to be etiologic agent Natural history of organism discovered Fulfilled Koch’s postulates
of anthrax and that culturing the organism at higher temperatures of 42– 43°C destroyed its virulence. Table 2 shows some of the discoveries associated with anthrax. In 1960, with the cessation of bacteriologic warfare research and its declassification, a great source of information on the pathogenicity of anthrax spores became available.
Anthrax in Antiquity An early reference to anthrax is found in the Book of Exodus, wherein Moses describes a disease having the clinical features of anthrax in the Egyptian plagues9 (Table 3). According to some biblical scholars, the Egyptian plagues recorded in chapters 7 through 12 were a series of interdependent, extraordinary natural phenomena. Each plague modified the succeeding one until a climax was reached in the 10th and last plague, when a combination of disease, unsanitary conditions, and customs led to a catastrophic epidemic destructive to both humans and animals. After the plague of flies, grievous murrain was cast upon the animals of Egypt. This was an epidemic affecting cattle, horses, asses, camels, and sheep, which caused great mortality. Evidence supporting the concept that anthrax was the disease described by Moses is the following: only herbivores were affected, the apparent great communicability from animal to animal and then to humans, the high mortality among affected animals, the great number of stinging insects present at the time in Egypt that could have played a role as vectors, the housing of animals in close proximity to protect them from the annual flood of the Nile, and the prevailing soil conditions. Furthermore, animal anthrax had been known in Egypt for centuries. The sixth plague, the plague of boils and blains, immediately followed the murrain of cattle. This records the spread of the disease from cows to humans. The flies of the fourth plague and possibly also the gnats Table 3.
Ten plagues of Egypt, according to the Book of Exodus
1 2 3 4 5 6 7 8 9 10
Discoloration of the Nile Plague of frogs Plague of insects Swarm of flies Plague of murrain Plague of boils and blains Plague of hail and thunder Plague of locusts Plague of darkness Plague of death
Ex., Ex., Ex., Ex., Ex., Ex., Ex., Ex., Ex., Ex.,
vii, 20, 21 viii, 6 viii, 17 viii, 24 ix, 3 ix, 9 ix, 25 x, 13 x, 22 xii, 29
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and mosquitoes of the third plague may have played a role in this transmission by acting as carriers or by causing wounds that could be contaminated by anthrax spores. In support of anthrax as the cause of the sixth Egyptian plague are the clinical manifestations—raised, inflammatory swelling and blains or blisters. The cutaneous disease was apparently mild, as death was not mentioned in the account. “The magicians could not stand before Pharaoh because of the boils.” All of these features are consistent with the modern concept of cutaneous anthrax. The seventh, eighth, and ninth plagues set the stage for the final plague. The plague of thunder and hail destroyed vegetables and cereals. “The hail smote every herb and broke every tree in the field.” Any remaining vegetation was then devoured by the following plague, the plague of locusts. The Egyptians were left with nothing to eat except the animal flesh, blood, and milk, which were probably contaminated. Three days of darkness followed. Historians have interpreted this plague as a sand storm. “There was a thick darkness in all the land of Egypt, even darkness which may be felt.” The hot wind stirred up soil and dust from decomposing animal carcasses contaminated with anthrax spores. In this setting of internal anthrax, the Egyptians contracted a far more serious disease than that of the sixth plague. The disease was sudden and fatal and attacked both humans and beasts, a characteristic of anthrax contracted by ingestion or inhalation. The anthrax described by Moses in the fifth, sixth, and Tenth Egyptian plagues and the anthrax studied by Robert Koch were probably the same disease. Another reference to anthrax is found in Virgil’s writing some 2000 years ago. In his third Georgic,10 which is devoted to animal husbandry, he gives a detailed account of an epizootic that occurred in an Alpine district of Rome. The murrain devastated the farms and meadows of Noricum. “A terrible plague once sprang up there and raged on through the warmer part of autumn, not only destroying one flock of sheep after another but killing animals of all kinds by polluting the water and contaminating the food supply with its poison. Nor did the victims die an early and uncomplicated death. After a burning fever had raged through the animal’s veins and shriveled its flesh, the fluids again became abundant and virtually desolved the bones.” Cattle, dogs, horses, oxen, wolves, deer, and birds succumbed. Virgil provides us with a remarkable description of the clinical manifestations of anthrax and how the disease could spread from diseased animals to healthy ones and to humans, either by direct contact or through exposure to contaminated soil, water, and wool. “If anyone wore a garment made from tainted wool, his limbs were soon attacked by inflamed papules and a foul exudate, and if he delayed too long to remove the material, a violent inflammation consumed
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the parts it had touched.” Finally, he noted that covering them with earth or throwing them into pits best disposed of the carcasses of dead animals. In addition to cremation, this method of disposal is still recommended today. Anthrax has been responsible for several devastating animal plagues during modern times. Around the middle of the 18th century, a panzootic of anthrax destroyed an estimated half of the sheep in Europe. A century later, the disease was still causing the same heavy death toll in parts of France. Some farms were called charbon farms; elsewhere, certain fields and hills were looked on as accursed, and an evil spell seemed to be thrown over flocks bold enough to forage in them. Moist soil in some valleys, swampy districts, and lake regions were known to be areas to avoid because of observations spanning many generations of European farmers and sheep herders.11 In 1864, 72,000 horses died in Russia alone from the disease. From 1867 to 1870, ⬎56,000 horses, cattle, and sheep and 528 men perished in the province of Novgorod in Russia.7 Although anthrax has not been a prevalent disease among animals in the United States, there have been a few upsurges in certain agricultural areas from 1894 to 1899.12 Epidemics have been reported in Louisiana, Mississippi, Illinois, Pennsylvania, and Delaware until 1962. In several of these, humans were affected, the disease ending fatally in a few.13 The most recent major epidemic occurred in Sverdlovsk, Soviet Union, in 19792 at a Soviet germ-warfare plant. Inhalational anthrax was caused by overwhelming contamination with toxic anthrax spores. To this date, anthrax remains a serious threat to livestock and occasionally humans in the semiarid regions of Asia, Africa, and South America.
History of Occupational Anthrax The first chapter in the history of anthrax as an occupational disease began in 1847 when the condition was recognized clinically and ends in 1880 when the specific microbial etiology was established.11 From 1827 to 1847 when mohair from Asia Minor and alpaca from Peru had been introduced as textile fibers, deaths began to occur among the woolsorters and carders of Bradford, England. Carders used two of these instruments to separate the fibers (Fig 5). Inhalational anthrax contracted by these workers became known as woolsorters’ or Bradford disease. Because of the great likelihood of contracting the disease, workers drew lots to see who would have to sort batches of mohair and alpaca. After proving that woolsorters’ disease was caused by anthrax in 1879, John H. Bell, a Bradford physician, focused his attention on preventive measures. The manufacturers finally accepted his suggestions concerning the handling of potentially dangerous material after a
Figure 5. fibers.
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Carders used two of these instruments to separate the
coroner’s inquiry and public outcry over the death of Samuel Firth in 1880. On the death certificate, Dr Bell wrote that Mr Firth died of woolsorters’ disease and added that the “death resulted from his employer’s neglect in not having the mohair he was sorting disinfected beforehand.” The Bradford rules became law in 1897. This was followed by creation of the Anthrax Investigation Board. Through the efforts of Dr F. W. Eurich, a bacteriologist, and Elmhurst Duckering, a factory inspector, methods for decontaminating fibers were discovered. The Anthrax Prevention Act, which included the creation of a wool-disinfecting station in Liverpool, became law in 1919. Woolsorters’ disease has since become a medical curiosity. Some of the occupations at risk for anthrax before 2001 are shown in (Table 4). Between 1900 and 200l, only 18 cases of inhalational anthrax have been reported in the American literature.3 This is the result of improvements in industrial hygiene and the use of human anthrax vaccine.
Anthrax in the Recent Past As many as 100,000 cases of human anthrax occur annually throughout the world. From 1955 to 1999, there were 236 reported cases of anthrax, most of them Table 4.
Occupations at risk for anthrax
Wool sorters Combers Carders Spinners Cloth weavers Carpet weavers Upholsterers Mattress makers Brush makers Longshoremen Warehouse workers
Slaughterhouse workers Butchers Bone meal processers Ranchers Herders Veterinarians Dairy workers Skinners Tanners Furriers Shoemakers
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cutaneous, in the United States. Before 2001, the last case of cutaneous anthrax occurred in North Dakota.14 Inhalational anthrax has become a medical curiosity in the United States. The last case of pulmonary anthrax in this country was reported in 1976.15
Anthrax 2001 Until recently, anthrax in humans had always been a work-related hazard, occurring sporadically in farmers, wool mill workers processing goat hair, and veterinarians. After the destruction of the World Trade Center in New York City and the damage to the Pentagon in Washington, DC, anthrax became a disease of journalists and postal employees. Anthrax spores have been found in news media offices, US Senate offices, and postal facilities in New Jersey and Washington, DC. The spores were delivered through the mail. They became aerosolized on opening the envelopes or by mail-sorting machines that disseminated spores through intact envelopes. By November 21, 200l, five people had died of pulmonary anthrax and 13 others were fighting either the pulmonary or cutaneous form of the disease.
Therapy—Then and Now At the beginning of the 20th century, most experts recommended surgery for the early treatment of cutaneous anthrax, especially before general infection occurred.16,17 The pustule was widely excised, going well beyond the borders, utilizing antiseptic conditions to prevent reinfection. The resultant wound was treated with bichloride of mercury. Second lines of therapy were destruction by thermocautery or free excision followed by application of pure carbolic acid. Markedly edematous cases were treated by injection of either tincture of iodine or a 5% solution of carbolic acid. This was administered into the pustule and at five or six points around the border. Injections were repeated after several hours if the process continued to progress. Pasteur, Jourbert,18 and later Fortineau recommended antibiosis therapeutically. Certain bacteria, including B. pyocyaneus, antagonized the growth of B. anthracis.17 Sometimes, injection of these bacteria yielded favorable results. Constitutional therapy included administration of sodium sulfite or hyposulfite and large doses of quinine. Alcoholic stimulants and ammonium carbonate were given when symptoms of cardiac failure or collapse appeared. Antimicrobials are the mainstay of modern therapy.1 Incision and excision are contraindicated because of the possibility of inducing septicemia, and local treatment is not advocated. Therapy should begin as soon as anthrax is a serious diagnostic consideration. Were this 1982, penicillin would be the treatment of choice because of its bactericidal action. The drug is administered as penicillin G in a dose of l-6 million units
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intramuscularly QD for at least 2 weeks. In the event of penicillin allergy or penicillinase production, chlortetracycline 2 g QD, streptomycin l-2 g QD, or chloramphenicol 2 m QD might be used. When the organism is penicillin resistant, cloxacillin or dicloxacillin might also be used. For fulminating anthrax with widespread edema, disseminative anthrax, or pulmonary, intestinal, or meningeal anthrax, 2 million units of crystalline penicillin intravenously every 6 hours, intravenous fluids, and hydrocortisone are recommended. Inhalational anthrax still has a mortality of 80%, primarily because the diagnosis is seldom made before development of bacteremia and toxemia.
Therapeutic Recommendations in 2002 For cutaneous anthrax without systemic symptoms or extensive edema and not located on the head or neck, ciprofloxacin 500 mg twice daily or doxycycline l00 mg twice daily is recommended for adults. For children ⬎8 years old or weighing ⬎45 kg, ciprofloxacin 10 –15 mg per kg of body weight every 12 hours, not to exceed 1 g/day, or doxycycline 100 mg every 12 hours is recommended. For all other children, use doxycycline 2.2 mg/kg every 12 hours. Second-line therapy is amoxacillin 500 mg orally three times daily for adults and 80 mg/kg per day divided every 8 hours for children. Treatment should be continued for 60 days because of the possible simultaneous exposure to aerosolized B. anthracis. For cutaneous anthrax with systemic symptoms, extensive edema, or involving the head and neck or for inhalational anthrax exposure in adults and children, the same antimicrobials and doses listed previously should be given but given intravenously every 12 hours, and one or two additional antimicrobials with in vitro activity, such as rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, or clarithromycin are advised. Corticosteroids may be considered as adjunctive therapy for patients with severe edema and for meningitis. Intravenous treatment may be switched to oral therapy when clinically appropriate.19
Conclusions The fascinating story of anthrax has taken us from biblical times to the 21st century. Although it was a relatively unimportant disease in the recent past, in antiquity it was a major threat to the life of humans and animals. Its use as an instrument of biologic warfare reflects its historical past. Many of the great men of medicine played a role in solving the problems of etiology and control of anthrax.
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References 1. O’Quin S. In: Demis JD, McGuire J, et al, Editors. Anthrax in clinical dermatology. Philadelphia: Harper & Row, 1984;3:16 –3:35:1– 4. 2. Dutz W, Kouhout-Dutz E. Anthrax. Int J Dermatol 1981; 20:203– 6. 3. Brachman PS. Inhalation anthrax. Ann NY Acad Sci 1980; 353:83–93. 4. Van der Hoeden J. Zoonoses. Amsterdam: Elsevier Publishing Co, 1964:202–23. 5. Schadewaldt H. Aloys Pollender. In: Dictionary of scientific biography. New York: Scribner, 1971;11:68 –71. 6. Wilkinson L. Anthrax. In: Kiple KF, Editor. Cambridge world history of human disease. Cambridge: Cambridge University Press, 1993:584. 7. Vallery-Radot R. The life of Pasteur. Translated by A. L. Devonshire. New York: Dover Publications, Inc, 1949:257. 8. Koch R. The etiology of anthrax based on the ontogeny of the anthrax bacillus. Med Classics 1937;2:787– 82l. 9. Blanc HW. Anthrax: the disease of the Egyptian plagues. New Orleans Med Surg J 1890;18:1–25.
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10. Dirckx JH. Virgil on anthrax. Am J Dermatopathol 1981; 3:191–5. 11. Laforce MF. Woolsorters’ disease in England. Bull NY Acad Med 1978;54:956 – 63. 12. Jopson JH, Ghriskey AA. A CASE of anthrax. Proc Pathol Soc Phila 1899;NS3:47–52. 13. Van Ness GB. Ecology of anthrax. Science 1971;172:1303– 7. 14. Epidemiological notes and reports on anthrax in California. MMWR 1976;25:33– 4. 15. Human anthrax associated with epizootic among livestock in North Dakota. 2000;5:677. 16. Stelwagon HW. Diseases of the skin. Philadelphia: Saunders, 1914:418 –20. 17. Hartzell MB. Diseases of the skin. Philadelphia: Lippincott, 1917:338 – 40. 18. Selwyn S. Microbial interactions and antibiosis. In: Maibach H, Aly R, Editors. Skin Microbiology. New York: Springer-Verlag, 1981:63. 19. Update. Investigation of bioterrorism-related anthrax and interim guidelines for exposure, management, and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep 2001:50:909 –19.
A
nthrax is a disease of extraordinary interest. A condition affecting animals and humans identifiable clinically as anthrax occurred in both biblical times and during the classical period. The discovery of the etiologic agent parallels the history of modern bacteriology, whereas the control of anthrax previews the modern interest in occupational pulmonary medicine. The current wave of terrorism has brought renewed interest in this zoonosis, and anthrax has three presentations in humans.
Cutaneous Anthrax Cutaneous anthrax has also been known as “malignant pustule,” “malignant carbuncle,” and charbon. One to five days after inoculation, a small, slightly pruritic, red papule appears at the site.1. Intense, nonpitting edema then rims the base of the papule. By the second or third day, tense vesicles or even bullae filled with serosanguineous fluid arise on the edematous plaque (Fig 1). The central papule then becomes necrotic, ulcerates, and forms a brown to black eschar (Fig 2). The pathognomonic picture of anthrax, a black eschar ringed by vesicles or pustules on an edematous base, is seen after 5–7 days (Fig 3). The lesion continues to evolve for 12–14 days, at which time the eschar eventually separates, leaving a shallow ulcer that heals by secondary intention in 2–3 weeks. The so-called malignant pustule usually appears on exposed sites. For example, skin damaged by occupation, avocation, or grooming activities, such as the lips in carpet weavers and spinners, facial skin in shaving injuries, the nape of the neck and submandibular area where the collar rubs the skin, and the eyelids in persons wiping perspiration off their brow are predisFrom the Departments of Dermatology, University of Pennsylvania School of Medicine and Temple University School of Podiatric Medicine, Philadelphia, Pennsylvania; and the Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and the Jefferson Center for International Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania. Address correspondence to Jospeh A. Witkowski, MD, 3501 Ryan Ave, Philadelphia, PA 19103. E-mail: [email protected]. © 2002 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
posed.2 When the eyelids are involved, the edema is more pronounced. Cutaneous anthrax is characteristically painless, although it may be tender on palpation. The regional lymph nodes often become painful and tender after a few days. Most patients experience headache, develop malaise, and mount a fever of up to 102°F for several days. A few patients have no systemic manifestations. Rarely, inflammatory signs are progressive, with extensive edema, multiple necrotic areas, and bulbous formation. This occurs along with fever and signs of meningeal, pulmonary, or other organ involvement. Internal hemorrhage, characteristic shock, and death follow within days. The differential diagnosis varies with the location and stage of the disease. Angioneurotic edema, a carbuncle, or furuncle might be considered early stages. Cowpox, accidental vaccinia, a cutaneous infarct, a spider bite, and a factitious lesion might be considered later in the course of the disease.
Pulmonary Anthrax The classic clinical picture of inhalational anthrax, also called woolsorter’s disease, Bradford disease, and rag picker’s disease, is biphasic.3 The initial stage consists of the gradual onset of a mild fever, malaise, fatigue, myalgia, nonproductive cough, and at times, a sensation of precordial oppression. There are few objective findings aside from fever. Rhonchi may be heard on auscultation of the lungs. This initial phase typically lasts for several days, after which there may be some improvement in the clinical condition. Frequently, the clinical features suggest a cold, influenza, or bronchitis. The second stage develops suddenly, with the onset of acute dyspnea and subsequent cyanosis. The patient may appear moribund with a rapid pulse and respiratory rate. The temperature may be mildly elevated, or it may be subnormal because of shock. Stridor may occur, and profuse perspiration is frequently present. Physical examination of the chest reveals moist, crepitant rales and signs of pleural effusion. Typically, the patient remains conscious until death, but with meningeal in0738-081X/02/$–see front matter PII S0738-081X(02)00250-X
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Figure 3. Typical lesion of cutaneous anthrax. (Courtesy of W. Ho¨ fler, MD)
Gastrointestinal Anthrax Figure 1. Cutaneous anthrax at 3 days. (Courtesy of Bernard Appel, MD collection)
volvement, there may be disorientation, coma, and meningismus. A chest x-ray film (Fig 4) usually shows widening of the mediastinum. The average duration of this stage is ⬍24 hours, and it usually ends in death. The differential diagnosis includes cardiac failure, a cardiovascular accident, and conditions causing widening of the mediastinum, pulmonary edema with septicemia.
Figure 2. Cutaneous anthrax at 10 days. (Courtesy of Bernard Appel, MD collection)
Anthrax involving the gastrointestinal tract, also known as “splenic fever” and der milzbrand, is a rare occurrence in humans. Ingested organisms from contaminated meat multiply in the stomach and the intestinal submucosa. An ulcer results at the site of penetration.2 A necrotic ulcer in the ilium or cecum is usually associated with severe hemorrhagic mesenteric lymphadenitis. Diarrhea is severe. The abdomen greatly distends because of severe ascites and splenic enlargement. Shock and death usually follow. The differential diagnosis includes end-stage liver disease. Anthrax in animals is primarily a gastrointestinal affliction. It is known as murrain, charbon, “splenic fever,” or der milzbrand and occurs most commonly after ingestion of food contaminated with spores,4 occurring when the grass is so short that the animal grazes closer to the ground or must forage in the soil for food. The primary site appears along the gastrointestinal tract and rapidly leads to widespread systemic disease.
Figure 4. Marked widening of the mediastinum and early pulmonary edema. (Courtesy of W. Dutz, MD)
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Table 1.
Milestones in the identification of B. anthracis
1823 1842 1849 1850 1857 1860 1863 1875 1879 1879 1881
Eloy Barthe´ lemy Christain Joseph Fuchs Aloys Pollender Pierre Francois Rayer Frederich Brauell One´ sime Delafond Casimir Davaine Ferdinand Julius Cahn Robert Koch John H. Bell Louis Pasteur
The course may be either acute or subacute. The acute, fulminant form results in death after several hours without any prodromal signs. The subacute variety begins with chills and fever. Edema is a prominent feature. This often involves the neck. Death may result from respiratory obstruction when the tongue or pharynx is involved. The abdomen becomes greatly distended because of splenic enlargement and ascites. Bloody diarrhea is a common manifestation, along with hemorrhagic discharges from other body orifices. Central nervous system involvement results in tremors, spasms, and convulsions. Finally, coma and death ensue.
Discovery of the Cause The history of the discovery of the etiologic agent of anthrax is almost as fascinating as the story of the disease itself. At the end of the 19th century and even into the 20th, German and French scholars were arguing over the question of priority for the discovery. From this dispute, the following facts emerge.5 In 1823, Eloy Barthe´ lemy, a Frenchman, proved the infectiousness of anthrax by inoculating healthy animals with the blood of animals that had died of the disease6 (Table 1). A German veterinarian, Christian Joseph Fuchs, discovered what he called “granulated threads” in the blood of animals that had died of anthrax in 1842. He did not publish his findings, however, until 1859 and renounced any claim to priority for discovering the cause. Aloys Pollender, who is credited with discovering the etiologic agent, had his first contact with the disease in 1841 when he unsuccessfully treated a flayer (one who strips off the skin) who had developed an anthrax carbuncle. After purchasing a modern microscope in 1849, he set out to investigate the cause of death of a large number of cows in his area. He saw the organisms, which he called “chyllus corpuscles” in the blood, spleen, and carbuncle fluid of cows, which had died of the disease. He wrote: “A countless number of extremely fine, apparently solid, and not fully transparent rodlike corpuscles of equal thickness throughout their length and neither coiled, nor wavy, nor constricted, but entirely straight and flat, with no branching along
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their course.” After subjecting the organisms to a variety of chemicals, he identified them as having a plantlike nature. He also observed that iodine solution stained them a pale yellow, thereby making them more visible. Pollender published his findings in 1855 and raised the question of whether the corpuscles he described could be the cause of anthrax. In 1859, the French dermatologist Pierre Francois Rayer detected the corpuscles he described as “little threadlike bodies” in the spleen and blood of sheep dying of anthrax. This finding was mentioned only briefly in a report on the transmission of the disease that he delivered to the Socie´ te´ de Biologie of Paris. He apparently attached so little significance to the discovery that his findings were not even included in a publication edited by himself.7 Frederick Brauell published an article on anthrax in 1857. He was the first to observe anthrax bacilli in the blood taken from a live animal. His discovery clouded the issue, however, as he identified the organism as a vibrio. Although One´ sime Delafond detected the organisms in the blood of sheep in 1856, he did not publish his findings until 1860. He was the first to note the diagnostic value of finding the organism, and he observed the growth of Bacillus anthracis. In 1863, Casimir Davaine, a collaborator of Rayer in Paris, claimed as his own the observations on the anthrax organisms made by Rayer 4 years prior. In so doing, he asserted priority over Pollender. He formally challenged Pollender’s priority in 1875. During 1863 and 1864, Davaine published a series of articles demonstrating that anthrax could be transmitted to sheep, horses, cattle, guinea pigs, and mice by subcutaneous inoculation with infected blood. The presence of “bacteridia,” as he called them, in the blood and other inocula was necessary for transmitting the disease. He also observed that after inoculation, the organism rapidly increased in number and then became filamentous. His findings led to the acceptance of the germ theory, a major turning point in the history of medicine. In 1876 and 1877, Robert Koch published his findings on the life cycle of B. anthracis.8 He grew the organisms in pure culture by using the aqueous humor of cattle eye. After inoculation, a single organism grew into long threads and into long, parallel, and twisting bundles. After this period of multiplication, which lasted 10 –15 hours, the organism began to sporulate. The vegetative, boxcarlike bacilli gave rise to refractile structures, or spores. He then demonstrated that these spore forms could revert to vegetative forms when placed in fresh medium and could cause anthrax when injected into mice. Koch was the first to produce anthrax in animals by inoculating them with pure cultures of the organism. Louis Pasteur produced the first attenuated anthrax vaccine in 1881.7 His discovery was based on the observations that an occasional animal would survive attacks
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Table 2.
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Anthrax firsts
Bacterial cause confirmed Single organism proven to be etiologic agent Natural history of organism discovered Fulfilled Koch’s postulates
of anthrax and that culturing the organism at higher temperatures of 42– 43°C destroyed its virulence. Table 2 shows some of the discoveries associated with anthrax. In 1960, with the cessation of bacteriologic warfare research and its declassification, a great source of information on the pathogenicity of anthrax spores became available.
Anthrax in Antiquity An early reference to anthrax is found in the Book of Exodus, wherein Moses describes a disease having the clinical features of anthrax in the Egyptian plagues9 (Table 3). According to some biblical scholars, the Egyptian plagues recorded in chapters 7 through 12 were a series of interdependent, extraordinary natural phenomena. Each plague modified the succeeding one until a climax was reached in the 10th and last plague, when a combination of disease, unsanitary conditions, and customs led to a catastrophic epidemic destructive to both humans and animals. After the plague of flies, grievous murrain was cast upon the animals of Egypt. This was an epidemic affecting cattle, horses, asses, camels, and sheep, which caused great mortality. Evidence supporting the concept that anthrax was the disease described by Moses is the following: only herbivores were affected, the apparent great communicability from animal to animal and then to humans, the high mortality among affected animals, the great number of stinging insects present at the time in Egypt that could have played a role as vectors, the housing of animals in close proximity to protect them from the annual flood of the Nile, and the prevailing soil conditions. Furthermore, animal anthrax had been known in Egypt for centuries. The sixth plague, the plague of boils and blains, immediately followed the murrain of cattle. This records the spread of the disease from cows to humans. The flies of the fourth plague and possibly also the gnats Table 3.
Ten plagues of Egypt, according to the Book of Exodus
1 2 3 4 5 6 7 8 9 10
Discoloration of the Nile Plague of frogs Plague of insects Swarm of flies Plague of murrain Plague of boils and blains Plague of hail and thunder Plague of locusts Plague of darkness Plague of death
Ex., Ex., Ex., Ex., Ex., Ex., Ex., Ex., Ex., Ex.,
vii, 20, 21 viii, 6 viii, 17 viii, 24 ix, 3 ix, 9 ix, 25 x, 13 x, 22 xii, 29
339
and mosquitoes of the third plague may have played a role in this transmission by acting as carriers or by causing wounds that could be contaminated by anthrax spores. In support of anthrax as the cause of the sixth Egyptian plague are the clinical manifestations—raised, inflammatory swelling and blains or blisters. The cutaneous disease was apparently mild, as death was not mentioned in the account. “The magicians could not stand before Pharaoh because of the boils.” All of these features are consistent with the modern concept of cutaneous anthrax. The seventh, eighth, and ninth plagues set the stage for the final plague. The plague of thunder and hail destroyed vegetables and cereals. “The hail smote every herb and broke every tree in the field.” Any remaining vegetation was then devoured by the following plague, the plague of locusts. The Egyptians were left with nothing to eat except the animal flesh, blood, and milk, which were probably contaminated. Three days of darkness followed. Historians have interpreted this plague as a sand storm. “There was a thick darkness in all the land of Egypt, even darkness which may be felt.” The hot wind stirred up soil and dust from decomposing animal carcasses contaminated with anthrax spores. In this setting of internal anthrax, the Egyptians contracted a far more serious disease than that of the sixth plague. The disease was sudden and fatal and attacked both humans and beasts, a characteristic of anthrax contracted by ingestion or inhalation. The anthrax described by Moses in the fifth, sixth, and Tenth Egyptian plagues and the anthrax studied by Robert Koch were probably the same disease. Another reference to anthrax is found in Virgil’s writing some 2000 years ago. In his third Georgic,10 which is devoted to animal husbandry, he gives a detailed account of an epizootic that occurred in an Alpine district of Rome. The murrain devastated the farms and meadows of Noricum. “A terrible plague once sprang up there and raged on through the warmer part of autumn, not only destroying one flock of sheep after another but killing animals of all kinds by polluting the water and contaminating the food supply with its poison. Nor did the victims die an early and uncomplicated death. After a burning fever had raged through the animal’s veins and shriveled its flesh, the fluids again became abundant and virtually desolved the bones.” Cattle, dogs, horses, oxen, wolves, deer, and birds succumbed. Virgil provides us with a remarkable description of the clinical manifestations of anthrax and how the disease could spread from diseased animals to healthy ones and to humans, either by direct contact or through exposure to contaminated soil, water, and wool. “If anyone wore a garment made from tainted wool, his limbs were soon attacked by inflamed papules and a foul exudate, and if he delayed too long to remove the material, a violent inflammation consumed
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the parts it had touched.” Finally, he noted that covering them with earth or throwing them into pits best disposed of the carcasses of dead animals. In addition to cremation, this method of disposal is still recommended today. Anthrax has been responsible for several devastating animal plagues during modern times. Around the middle of the 18th century, a panzootic of anthrax destroyed an estimated half of the sheep in Europe. A century later, the disease was still causing the same heavy death toll in parts of France. Some farms were called charbon farms; elsewhere, certain fields and hills were looked on as accursed, and an evil spell seemed to be thrown over flocks bold enough to forage in them. Moist soil in some valleys, swampy districts, and lake regions were known to be areas to avoid because of observations spanning many generations of European farmers and sheep herders.11 In 1864, 72,000 horses died in Russia alone from the disease. From 1867 to 1870, ⬎56,000 horses, cattle, and sheep and 528 men perished in the province of Novgorod in Russia.7 Although anthrax has not been a prevalent disease among animals in the United States, there have been a few upsurges in certain agricultural areas from 1894 to 1899.12 Epidemics have been reported in Louisiana, Mississippi, Illinois, Pennsylvania, and Delaware until 1962. In several of these, humans were affected, the disease ending fatally in a few.13 The most recent major epidemic occurred in Sverdlovsk, Soviet Union, in 19792 at a Soviet germ-warfare plant. Inhalational anthrax was caused by overwhelming contamination with toxic anthrax spores. To this date, anthrax remains a serious threat to livestock and occasionally humans in the semiarid regions of Asia, Africa, and South America.
History of Occupational Anthrax The first chapter in the history of anthrax as an occupational disease began in 1847 when the condition was recognized clinically and ends in 1880 when the specific microbial etiology was established.11 From 1827 to 1847 when mohair from Asia Minor and alpaca from Peru had been introduced as textile fibers, deaths began to occur among the woolsorters and carders of Bradford, England. Carders used two of these instruments to separate the fibers (Fig 5). Inhalational anthrax contracted by these workers became known as woolsorters’ or Bradford disease. Because of the great likelihood of contracting the disease, workers drew lots to see who would have to sort batches of mohair and alpaca. After proving that woolsorters’ disease was caused by anthrax in 1879, John H. Bell, a Bradford physician, focused his attention on preventive measures. The manufacturers finally accepted his suggestions concerning the handling of potentially dangerous material after a
Figure 5. fibers.
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Carders used two of these instruments to separate the
coroner’s inquiry and public outcry over the death of Samuel Firth in 1880. On the death certificate, Dr Bell wrote that Mr Firth died of woolsorters’ disease and added that the “death resulted from his employer’s neglect in not having the mohair he was sorting disinfected beforehand.” The Bradford rules became law in 1897. This was followed by creation of the Anthrax Investigation Board. Through the efforts of Dr F. W. Eurich, a bacteriologist, and Elmhurst Duckering, a factory inspector, methods for decontaminating fibers were discovered. The Anthrax Prevention Act, which included the creation of a wool-disinfecting station in Liverpool, became law in 1919. Woolsorters’ disease has since become a medical curiosity. Some of the occupations at risk for anthrax before 2001 are shown in (Table 4). Between 1900 and 200l, only 18 cases of inhalational anthrax have been reported in the American literature.3 This is the result of improvements in industrial hygiene and the use of human anthrax vaccine.
Anthrax in the Recent Past As many as 100,000 cases of human anthrax occur annually throughout the world. From 1955 to 1999, there were 236 reported cases of anthrax, most of them Table 4.
Occupations at risk for anthrax
Wool sorters Combers Carders Spinners Cloth weavers Carpet weavers Upholsterers Mattress makers Brush makers Longshoremen Warehouse workers
Slaughterhouse workers Butchers Bone meal processers Ranchers Herders Veterinarians Dairy workers Skinners Tanners Furriers Shoemakers
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cutaneous, in the United States. Before 2001, the last case of cutaneous anthrax occurred in North Dakota.14 Inhalational anthrax has become a medical curiosity in the United States. The last case of pulmonary anthrax in this country was reported in 1976.15
Anthrax 2001 Until recently, anthrax in humans had always been a work-related hazard, occurring sporadically in farmers, wool mill workers processing goat hair, and veterinarians. After the destruction of the World Trade Center in New York City and the damage to the Pentagon in Washington, DC, anthrax became a disease of journalists and postal employees. Anthrax spores have been found in news media offices, US Senate offices, and postal facilities in New Jersey and Washington, DC. The spores were delivered through the mail. They became aerosolized on opening the envelopes or by mail-sorting machines that disseminated spores through intact envelopes. By November 21, 200l, five people had died of pulmonary anthrax and 13 others were fighting either the pulmonary or cutaneous form of the disease.
Therapy—Then and Now At the beginning of the 20th century, most experts recommended surgery for the early treatment of cutaneous anthrax, especially before general infection occurred.16,17 The pustule was widely excised, going well beyond the borders, utilizing antiseptic conditions to prevent reinfection. The resultant wound was treated with bichloride of mercury. Second lines of therapy were destruction by thermocautery or free excision followed by application of pure carbolic acid. Markedly edematous cases were treated by injection of either tincture of iodine or a 5% solution of carbolic acid. This was administered into the pustule and at five or six points around the border. Injections were repeated after several hours if the process continued to progress. Pasteur, Jourbert,18 and later Fortineau recommended antibiosis therapeutically. Certain bacteria, including B. pyocyaneus, antagonized the growth of B. anthracis.17 Sometimes, injection of these bacteria yielded favorable results. Constitutional therapy included administration of sodium sulfite or hyposulfite and large doses of quinine. Alcoholic stimulants and ammonium carbonate were given when symptoms of cardiac failure or collapse appeared. Antimicrobials are the mainstay of modern therapy.1 Incision and excision are contraindicated because of the possibility of inducing septicemia, and local treatment is not advocated. Therapy should begin as soon as anthrax is a serious diagnostic consideration. Were this 1982, penicillin would be the treatment of choice because of its bactericidal action. The drug is administered as penicillin G in a dose of l-6 million units
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intramuscularly QD for at least 2 weeks. In the event of penicillin allergy or penicillinase production, chlortetracycline 2 g QD, streptomycin l-2 g QD, or chloramphenicol 2 m QD might be used. When the organism is penicillin resistant, cloxacillin or dicloxacillin might also be used. For fulminating anthrax with widespread edema, disseminative anthrax, or pulmonary, intestinal, or meningeal anthrax, 2 million units of crystalline penicillin intravenously every 6 hours, intravenous fluids, and hydrocortisone are recommended. Inhalational anthrax still has a mortality of 80%, primarily because the diagnosis is seldom made before development of bacteremia and toxemia.
Therapeutic Recommendations in 2002 For cutaneous anthrax without systemic symptoms or extensive edema and not located on the head or neck, ciprofloxacin 500 mg twice daily or doxycycline l00 mg twice daily is recommended for adults. For children ⬎8 years old or weighing ⬎45 kg, ciprofloxacin 10 –15 mg per kg of body weight every 12 hours, not to exceed 1 g/day, or doxycycline 100 mg every 12 hours is recommended. For all other children, use doxycycline 2.2 mg/kg every 12 hours. Second-line therapy is amoxacillin 500 mg orally three times daily for adults and 80 mg/kg per day divided every 8 hours for children. Treatment should be continued for 60 days because of the possible simultaneous exposure to aerosolized B. anthracis. For cutaneous anthrax with systemic symptoms, extensive edema, or involving the head and neck or for inhalational anthrax exposure in adults and children, the same antimicrobials and doses listed previously should be given but given intravenously every 12 hours, and one or two additional antimicrobials with in vitro activity, such as rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, or clarithromycin are advised. Corticosteroids may be considered as adjunctive therapy for patients with severe edema and for meningitis. Intravenous treatment may be switched to oral therapy when clinically appropriate.19
Conclusions The fascinating story of anthrax has taken us from biblical times to the 21st century. Although it was a relatively unimportant disease in the recent past, in antiquity it was a major threat to the life of humans and animals. Its use as an instrument of biologic warfare reflects its historical past. Many of the great men of medicine played a role in solving the problems of etiology and control of anthrax.
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References 1. O’Quin S. In: Demis JD, McGuire J, et al, Editors. Anthrax in clinical dermatology. Philadelphia: Harper & Row, 1984;3:16 –3:35:1– 4. 2. Dutz W, Kouhout-Dutz E. Anthrax. Int J Dermatol 1981; 20:203– 6. 3. Brachman PS. Inhalation anthrax. Ann NY Acad Sci 1980; 353:83–93. 4. Van der Hoeden J. Zoonoses. Amsterdam: Elsevier Publishing Co, 1964:202–23. 5. Schadewaldt H. Aloys Pollender. In: Dictionary of scientific biography. New York: Scribner, 1971;11:68 –71. 6. Wilkinson L. Anthrax. In: Kiple KF, Editor. Cambridge world history of human disease. Cambridge: Cambridge University Press, 1993:584. 7. Vallery-Radot R. The life of Pasteur. Translated by A. L. Devonshire. New York: Dover Publications, Inc, 1949:257. 8. Koch R. The etiology of anthrax based on the ontogeny of the anthrax bacillus. Med Classics 1937;2:787– 82l. 9. Blanc HW. Anthrax: the disease of the Egyptian plagues. New Orleans Med Surg J 1890;18:1–25.
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10. Dirckx JH. Virgil on anthrax. Am J Dermatopathol 1981; 3:191–5. 11. Laforce MF. Woolsorters’ disease in England. Bull NY Acad Med 1978;54:956 – 63. 12. Jopson JH, Ghriskey AA. A CASE of anthrax. Proc Pathol Soc Phila 1899;NS3:47–52. 13. Van Ness GB. Ecology of anthrax. Science 1971;172:1303– 7. 14. Epidemiological notes and reports on anthrax in California. MMWR 1976;25:33– 4. 15. Human anthrax associated with epizootic among livestock in North Dakota. 2000;5:677. 16. Stelwagon HW. Diseases of the skin. Philadelphia: Saunders, 1914:418 –20. 17. Hartzell MB. Diseases of the skin. Philadelphia: Lippincott, 1917:338 – 40. 18. Selwyn S. Microbial interactions and antibiosis. In: Maibach H, Aly R, Editors. Skin Microbiology. New York: Springer-Verlag, 1981:63. 19. Update. Investigation of bioterrorism-related anthrax and interim guidelines for exposure, management, and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep 2001:50:909 –19.