Arthur M. Friedlander, MD
Inhalational anthrax begins after an incubation period of 1 to 6 days with nonspecific symptoms of malaise, fatigue, myalgia, and fever. There maybe an associated nonproductive cough and mild chest discomfort. These symptoms usually persist for 2 or 3 days, and in some cases there may be a short period of improvement. This is followed by the sudden onset of increasing respiratory distress with dyspnea, stridor, cyanosis, increased chest pain, and diaphoresis. There may be associated edema of the chest and neck. Chest X-ray examination usually shows the characteristic widening of the mediastinum and, often, pleural effusions). Pneumonia has not been a consistent finding but can occur in some patients.(1) While cases of inhalational anthrax have been rare in this century, several have occurred in patients with underlying pulmonary disease, suggesting that this condition may increase susceptibility to the disease.(2) Meningitis is present in up to 50 percent of cases, and some patients may present with seizures. The onset of respiratory distress is followed by the rapid onset of shock and death within 24 to 36 hours. Mortality has been essentially 100 percent despite appropriate treatment.
Oropharyngeal and Gastrointestinal Anthrax
Oropharyngeal and gastrointestinal anthrax result from the ingestion of infected meat that has not been sufficiently cooked. After an incubation period of 2 to 5 days, patients with oropharyngeal disease present with severe sore throat or a local oral or tonsillar ulcer, usually associated with fever, toxicity, and swelling of the neck due to cervical or submandibular lymphadenitis and edema. Dysphagia and respiratory distress may also be present.
Gastrointestinal anthrax begins with nonspecific symptoms of nausea, vomiting, and fever; these are followed in most cases by severe abdominal pain. The presenting sign may be an acute abdomen, which may be associated with hematemesis, massive ascites, and diarrhea. Mortality in both forms may be as high as 50 percent, especially in the gastrointestinal form.
Meningitis occurs following bacteremia complicating other clinical forms of the disease. Meningitis may also occur, very rarely, without a clinically apparent primary focus. It is very often hemorrhagic, which is important diagnostically, and almost invariably fatal.
The most critical aspect in making a diagnosis of anthrax is a high index of suspicion associated with a compatible history of exposure. Cutaneous anthrax should be considered following the development of a painless pruritic papule, vesicle, or ulcer --- often with surrounding edema --- that develops into a black eschar. With extensive or massive edema, such a lesion is almost pathognomonic. Gram's stain or culture of the lesion will usually confirm the diagnosis. The differential diagnosis should include tularemia, staphylococcal or streptococcal disease, and orf (a viral disease of sheep and goats, transmissible to humans).
The diagnosis of inhalational anthrax is extraordinarily difficult, but the disease should be suspected with a history of exposure to a B anthracis-containing aerosol. The early symptoms are entirely nonspecific. However, (1) the development of respiratory distress in association with radiographic evidence of a widened mediastinum due to hemorrhagic mediastinitis, and (2) the presence of hemorrhagic pleural effusion or hemorrhagic meningitis should suggest the diagnosis. Sputum examination is not helpful in making the diagnosis, since pneumonia is not usually a feature of inhalational anthrax.
Gastrointestinal anthrax is exceedingly difficult to diagnose because of the rarity of the disease and its nonspecific symptoms. Only with a history of ingesting contaminated meat in the setting of an outbreak is diagnosis usually considered. Microbiologic cultures are not helpful in confirming the diagnosis. The diagnosis of oropharyngeal anthrax can be made from the clinical and physical findings in a patient with the appropriate epidemiological history.
Meningitis due to anthrax is clinically indistinguishable from meningitis due to other etiologies. An important distinguishing feature is that the cerebral spinal fluid is hemorrhagic in as many as 50 percent of cases. The diagnosis can be confirmed by identifying the organism in cerebral spinal fluid by microscopy, culture, or both.
Serology is generally only of use in making a retrospective diagnosis. Antibody to protective antigen or the capsule develops in 68-93 percent(3-6) of reported cases of cutaneous anthrax and 67-94 percent(5,6) of reported cases of oropharyngeal anthrax. A positive skin test to anthraxin (an undefined antigen derived from acid hydrolysis of the bacillus that was developed and evaluated in the former Soviet Union) has also been reported(7) to be of value in the retrospective diagnosis of anthrax. Western countries have limited experience with this test.(8)
Penicillin is the drug of choice for anthrax. Cutaneous anthrax without toxicity or systemic symptoms may be treated with oral penicillin. If evidence of spreading infection or systemic symptoms is present, then intravenous therapy with high-dose penicillin (2 million units administered every 6 h) may be initiated until a clinical response is obtained. Effective therapy will reduce edema and systemic symptoms but will not change the evolution of the skin lesion itself. Treatment should be continued for 7 to 10 days.
Tetracycline, erythromycin, and chloramphenicol have also been used successfully. These drugs may be used for treatment of the rare case caused by naturally occurring penicillin-resistant organisms. Additional antibiotics shown to be active in vitro include ciprofloxacin, gentamicin, cefazolin, cephalothin, vancomycin, clindamycin, and imipenem.(9-11) These drugs should be effective in vivo, but there is no reported clinical experience.
Inhalational, oropharyngeal, and gastrointestinal anthrax should be treated with large doses of intravenous penicillin (2 million units administered every 2 h) with appropriate vasopressors, oxygen, and other supportive therapy.
Prophylactic Treatment After Exposure
Experimental evidence(12) has demonstrated that treatment with antibiotics beginning I day after exposure to a lethal aerosol challenge with anthrax spores can provide significant protection against death. All three drugs used in this study --- ciprofloxacin, doxycycline, and penicillin --- were effective. The optimal protection was afforded by combining antibiotics with active immunization.
The only licensed human vaccine against anthrax is produced by the Michigan Department of Public Health. This vaccine is made from sterile filtrates of microaerophilic cultures of an attenuated, unencapsulated, nonproteolytic strain (V770-NPl-R) of B anthracis.(13-17) The recommended schedule for vaccination is 0.5 mL given subcutaneously at 0, 2, and 4 weeks, followed by boosters of 0.5 mL at 6, 12, and 18 months. Annual boosters are recommended if the potential for exposure continues.
The vaccine should be given to industrial workers exposed to potentially contaminated animal products imported from countries in which animal anthrax remains uncontrolled. These products include wool, goat hair, hides, and bones. People in direct contact with potentially infected animals as well as laboratory workers should also be immunized. Vaccination is also indicated for protection against the use of anthrax in biological warfare. Approximately 150,000 service members received this licensed MDPH vaccine between January 11 and February 28, 1991 (25-30 percent of the total U.S. forces deployed during the Persian Gulf War).
A live, attenuated, unencapsulated, spore vaccine is used for humans in the former USSR. The vaccine is given by scarification or subcutaneously. Its developers claim it to be reasonably well tolerated and to show some degree of protective efficacy against cutaneous anthrax in clinical field trials.(7)
In the United States, immunization with the licensed vaccine induced an immune response, measured by indirect hemagglutination, to protective antigen in 83 percent of vaccinees 2 weeks after the first three doses,(18) and in 91 percent of those tested after receiving two or more doses.(4) One hundred percent of the vaccinees develop a rise in titer in response to the yearly booster dose. When tested by an enzyme-linked immunosorbent assay, the current serological test of choice, more than 95 percent of vaccinees seroconvert after the initial three doses.(16,19)
A rough correlation between antibody titer to protective antigen and protection of experimental animals from infection exists after vaccination with the human vaccine. However, the exact relationship between antibody to protective antigen as measured in these assays, and immunity to infection remains obscure because the live, attenuated Sterne veterinary vaccine (made from an unencapsulated, toxin-producing strain) protects animalsbetter than the human vaccine, yet it induces lower levels of antibody to protective antigen.(14-16)
The protective efficacy of experimental protective antigen-based vaccines produced from sterile culture filtrates of B anthracis was clearly demonstrated using various animal models and routes of challenge.(20,21) A placebo-controlled clinical trial was conducted with a vaccine similar to the currently licensed U.S. vaccine.(22) This field-tested vaccine was composed of the sterile, cell-free culture supernatant from an attenuated, unencapsulated strain of B anthracis --- different from that used to produce the licensed vaccine and grown under aerobic, rather than micro-aerophilic, conditions.(23) It was precipitated with alum rather than adsorbed to aluminum hydroxide. The study population worked in four mills in the northeastern United States where B anthracis --- contaminated imported goat hair was used. The vaccinated group, compared to a placebo inoculated control group, was afforded 92.5 percent protection against cutaneous anthrax, with a lower 95 percent confidence limit of 65 percent effectiveness. There were insufficient cases of inhalational anthrax to determine whether the vaccine was effective against this form of the disease. This same vaccine was previously shown to protect rhesus monkeys against an aerosol exposure to anthrax spores.(23)
There have been no controlled clinical trials in humans of the efficacy of the currently licensed U.S. vaccine. This vaccine has been extensively tested in animals and has protected guinea pigs against both an intramuscular(15,16) and an aerosol challenge.(14) The licensed vaccine has also been shown to protect rhesus monkeys against an aerosol challenge.(12,24)
In two different studies, the incidence of significant local and systemic reactions to the vaccine used in the placebo-controlled field trial was 2.4-2.8 percent(22) and 0.2-1.3 percent.(23) The vaccine currently licensed in the United States is reported to have a similar incidence of reactions.(19,25) Local reactions considered significant consist of induration, erythema in an area larger than 5 cm in diameter, edema, pruritus, warmth, and tenderness. These reactions peak at 1 to 2 days and usually disappear within 2 to 3 days. Very rare reactions include edema extending from the local site to the elbow or forearm, and a small, painless nodule that may persist for weeks. People who have recovered from a cutaneous infection with anthrax may have very severe local reactions.(22) Systemic reactions are characterized by mild myalgia, headache, and mild-to-moderate malaise that lasts for 1 to 2 days. There are no long-term sequelae of local or systemic reactions.
Anthrax is a zoonotic disease that occurs in domesticated and wild animals. Humans become infected by contact with infected animals or contaminated products. Under natural circumstances, infection occurs by the cutaneous route and only extremely rarely by the inhalational or gastrointestinal routes.
An aerosol exposure to spores causes inhalational anthrax. This form of the disease, which is of military concern because of its potential for use as a biological warfare agent, begins with nonspecific symptoms followed in 2 to 3 days by the sudden onset of respiratory distress with dyspnea, cyanosis, and stridor. It is rapidly fatal. Radiographic examination of the chest often reveals the characteristic mediastinal widening, indicative of hemorrhagic mediastinitis. Hemorrhagic meningitis frequently coexists. Given the rarity of the disease and its rapid progression, the diagnosis of inhalational anthrax is difficult to make. Treatment consists of massive doses of antibiotics and supportive care. Postexposure antibiotic prophylaxis is effective in experimental animals and should be instituted as soon as possible after exposure. A licensed nonliving vaccine is available for human use.
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7. Shlyakhov EN, Rubinstein E. Human live anthrax vaccine in the former USSR. Vaccine. 1994;12:727-730.
8. Pfisterer RM. Retrospective verification of the diagnosis of anthrax by means of the intracutaneous skin test with the Russian allergen "anthraxin" in a recent epidemic in Switzerland. Salisbury Med Bull Suppl. 1990;68:80.
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11. Mikesell P. Major, Medical Service, US Army. Investigator, Bacteriology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md. Personal communication, January 1991.
12. Friedlander AM, Welkos SL, Pitt MLM, et al. Postexposure prophylaxis against experimental inhalation anthrax. J Infect Dis. 1993;167(5):1239-1243.
13. Ivins BE, Ezzell JW Jr, Jemski J, Hedlund KW, Ristroph JD, Leppla SH. Immunization studies with attenuated strains of Bacillus anthracis. Infect Immun. 1986;52:454-458.
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16. Turnbull PCB, Broster MG, Carman JA, Manchee RJ, Melling J. Development of antibodies to protective antigen and lethal factor components of anthrax toxin in humans and guinea pigs and their relevance to protective immunity. Infect Immun. 1986;52:356-363.
17. Ivins BE, Welkos SL. Cloning and expression of the Bacillus anthracis protective antigen gene in Bacillus subtilis. Infect Immun. 1986;54:537-542.
18. Johnson-Winegar A. Comparison of enzyme-linked immunosorbent and hemagglutination assays for determining anthrax antibodies. i Clin Microbiol. 1984;20:357-361.
19. Pittman PRE. Lieutenant Colonel, Medical Corps, US Army. Chief, Clinical Investigation, Medical Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md. Personal communication, January 1994.
20. Lincoln RE, Fish DC. Anthrax toxin. In: Montie TC, Kadis S, Aj1 SJ, eds. Microbial Toxins. Vol 3. New York, NY: Academic Press; 1970: 361-414.
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22. Brachman PS, Gold H, Plotkin SA, Fekety FR, Werrin M, Ingraham NR. Field evaluation of a human anthrax vaccine. Am J Public Health. 1962;52:632-645.
23. Wright GG, Green TW, Kanode RG Jr. Studies on immunity in anthrax, V: Immunizing activity of alum-precipitated protective antigen. J Immunol. 1954;73:387-391.
24. Ivins BE, Fellows PF, Pitt MLM, et al. Efficacy of a standard human anthrax vaccine against Bacillus anthracis aerosol challenge in rhesus monkeys. Salisbury Med Bull Suppl. 1996;87(suppl):125-126.
25. Puziss M, Wright GG. Studies on immunity in anthrax, X: Gel-adsorbed protective antigen for immunization of man. J Bacteriol. 1963;85:230-236.
Dr. Friedlander is a Colonel in the Medical Corps, U.S. Army; Chief, Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland; and Clinical Associate Professor of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Reprinted/Adapted with permission from Textbook of Military Medicine (TMM). Friedlander AM. Anthrax. In Sidell FR, Takafuji ET, Franz DR, eds. Medical Aspects of Chemical and Biological Warfare. Washington, DC: Dept of the Army, Office of The Surgeon General, Borden Institute; 1997:472-475.
Originally published in the Medical Sentinel 2001;6(4):126-128. Copyright © 2001 Association of American Physicians and Surgeons (AAPS).