Bioterrorism Update: Anthrax

Suddenly, with little experience and few resources to guide them, primary care and emergency physicians in the United States find themselves on the front lines in the defense of public health against terrorism. The author addresses key questions about anthrax in the first of a series of articles on agents of biological and chemical warfare.

By Mark Graber, MD

 
What is anthrax and what do we know about its effectiveness as a biological weapon?

Bacillus anthracis, the pathogen that causes anthrax, is a ubiquitous, spore-forming gram-positive bacillus that is found in soil. The spores are very resistant to drying, heat, and ultraviolet radiation and can survive for decades. When a host is infected, this lethal toxin causes the release of tumor necrosis factor alpha and interleukin 1-beta, rapidly leading to shock and death. A second toxin, edema toxin, causes edema by disrupting water homeostasis. When both of these toxins appear together, they block bacterial phagocytosis and the oxidative killing of bacteria.

During the last century, workers employed in trades involving the processing of livestock or animal products were routinely exposed to aerosolized B. anthracis spores in the course of their work, but cases of anthrax were rare.

Perhaps the earliest mention of anthrax is in the Old Testament's story of Moses. In the Book of Exodus, it appears as the fifth plague suffered by Egypt, an event notable, ironically enough, as also the first documented use of anthrax—or any lethal disease—as a biological weapon.

Two sentinel events have helped shape our understanding of anthrax as a potential weapon. The first occurred during World War II, when the Japanese attempted to use anthrax in their war against Manchuria. A second and better documented event occurred in 1979, when aerosolized B. anthracis spores were inadvertently released near Sverdlovsk (now Yekaterinburg), in the Ural Mountains region of Soviet Russia. In this event, 77 persons were infected, of whom 66 died.
 

Cutaneous anthrax. Naturally occurring anthrax in its cutaneous form is primarily a disease of workers who handle animal products. In the United States, the most common cause is imported animal hair and raw wool contaminated with anthrax spores. Images courtesy of the centers for Disease Control and Prevention; available at www.cdc.gov/niosh/ocderm.html (left) and http://phil.cdc.gov/phil (right).

How is anthrax acquired and what are the symptoms?

The bacillus is acquired mainly through cutaneous contact, inhalation, and the ingestion of infected, undercooked meat. In 95% of cases in the U.S., anthrax is acquired cutaneously. Human-to-human transmission of the disease has not been documented. Among those who are infected with inhalational anthrax, the fatality rate is close to 100%. The rate is 10% to 25% among those with the untreated cutaneous form and is approximately 60% among those with gastrointestinal anthrax, which has not been seen in the United States.

Cutaneous anthrax. Cutaneous anthrax appears as a nonpainful, pruritic papule that develops three to five days after a person is infected with the spores. This papule then develops into a vesicle with a central black eschar surrounded by purplish vesicles. (The black eschar is what gives the disease its name: anthrax is a Greek word meaning coal.) Edema, frequently severe, may be present. Purulent drainage, if it appears, suggests secondary infection, usually staphylococcal. The mortality rate associated with cutaneous anthrax can be as high as 20% if the disease is not treated, but among persons who receive treatment, the rate is as low as 1%. Healing occurs without scarring in 80% to 90% of patients who receive treatment.

Inhalational anthrax. The symptoms of inhalational anthrax, the most serious form of the disease, usually develop within 10 days of exposure, but onset may be delayed for up to 6 weeks. The symptoms begin as a nonspecific, flulike illness accompanied by fever, malaise, cough, and myalgia. The cough may be light and occasionally produce blood-tinged sputum. Pleuritic pain is common, as is nausea, abdominal pain, and a feeling of chest heaviness. In most cases, dyspnea is a prominent feature, which can help to differentiate anthrax from influenza.

Leukocytosis has been documented in some recent cases. A chest radiograph may show a widened mediastinum, which is the result of adenopathy, hemorrhage, and effusion. Such a finding is an almost pathognomonic feature of anthrax. Hemorrhagic pleural effusion may also be present and tends to reaccumulate. Pulmonary infiltrates are present in about half of patients who have inhalational anthrax. Symptoms progress rapidly from increased fever, chills, dyspnea, and cough to shock and death. During the outbreak in Sverdlovsk, no patient under the age of 24 died; host factors may therefore play a role in survival.

Gastrointestinal anthrax. Gastrointestinal anthrax develops three to five days after the ingestion of undercooked, tainted meat. The symptoms include mucosal ulcerations; constipation or diarrhea, often bloody; coffee-ground emesis; ascites with abdominal pain; and possibly intestinal perforation. Meningitis may complicate any form of anthrax and is found in 5% of all cases and up to 50% of inhalational cases.
 

How is the diagnosis of anthrax made?

Because the symptoms and signs of the disease are nonspecific, clinicians must be highly suspicious. Culture results are usually not available in time to be of any use to a clinician. An enzyme-linked immunosorbent assay test is available that measures antibody response to the toxins that cause edema and death, but again, an infected patient may die before the results are available. A polymerase chain reaction test for anthrax is also available, and several laboratories are devising rapid tests that will allow the diagnosis of anthrax.

The differential diagnosis of inhalational anthrax includes infection with Mycoplasma or Legionella pathogens, psittacosis, tularemia, Q-fever, viral pneumonia, histoplasmosis, and coccidioidomycosis. The differential diagnosis of cutaneous anthrax includes ecthyma gangrenosum, orf, brown recluse spider bite, plague, leprosy, brucellosis ulcer, glanders, rickettsial pox, ulceroglandular tularemia, and cutaneous tuberculosis. In gastrointestinal anthrax, the differential diagnosis includes acute abdomen, ascites accompanied by peritonitis, and perforated viscus.
 

What cultures should be obtained from persons who may have been exposed to anthrax and how should specimens be plated and handled?

As most suspected exposures turn out to be hoaxes, the physician's first step should be to contact his or her state health department to determine whether cultures are even necessary. The Centers for Disease Control and Prevention (CDC) have devised laboratory guidelines, the Biosafety in Microbiological and Biomedical Laboratories [BMBL], 4th edition (accessible at http://bmbl.od.nih.gov/sect3bsl1.htm), that outline in four categories the necessary precautions that clinicians must follow when testing specimens obtained from persons who have been or may have been exposed to toxic pathogens.

According to these guidelines, any cultures and other specimens obtained from persons who have been exposed to a suspicious powder or substance should be handled in accordance with biosafety level 2 precautions. These criteria specify that laboratory personnel should have specific training in handling pathogenic agents and should be directed by competent scientists. They also require that access to the laboratory be limited when work is being conducted; that extreme precautions be taken with contaminated sharp items; and that certain procedures in which infectious aerosols may be released or splashes created be conducted in biological safety cabinets or other physical containment equipment, the details of which are described in the guidelines.

Specimens and cultures known to contain toxins that may aerosolize and are potentially lethal should be handled in accordance with biosafety level 3 precautions, which further require that all involved personnel be properly protected and trained in the handling of lethal toxins and that the laboratory and all equipment in it be designed for the testing of such pathogens.

The recommended sites for obtaining specimens for culturing include the nasopharynx, face, and hands. A saline-moistened swab should be used to collect specimens, which can then be plated on 5% sheep blood agar or MacConkey agar plates. The significance of the connection between positive culture results and infection rate is not known, however. Again, the local state health department should be contacted first to determine whether such cultures are even necessary.

If disease, rather than exposure, is suspected, cerebrospinal fluid and pleural smears and cultures should be obtained along with blood cultures. If gastrointestinal infection is suspected, stool cultures will also be necessary. Blood should be saved for titer determinations, if necessary. Wounds may be aspirated and cultured.

In addition to the BMBL guidelines, the CDC have formulated the Basic Laboratory Protocols for the Presumptive Identification of Bacillus anthracis (available at www.bt.cdc.gov/Agent/Anthrax/LevelAProtocol/Anthracis20010417.pdf), which explains in detail the procedure necessary to isolate and identify the pathogen.
 

What steps should be taken to protect the safety of health care personnel and other persons who have been exposed to a patient with anthrax?

Although no cases of human-to-human transmission of anthrax have been documented, medical personnel should still exercise caution. Persons who may have been exposed to anthrax should shower with soap, water, and shampoo before presenting to the ED or office. Standard barrier isolation is a reasonable precaution in the ED or office, but high-efficiency filter masks and more elaborate equipment are not necessary.

Unless they were exposed to the primary source of infection, friends, acquaintances, health care personnel, and household members who have been in contact with a person known to have anthrax do not require any special prophylaxis.
 

What is the procedure for isolating a potential source of the disease in the field?

The state health department or local hazmat team should be contacted first. Only they are equipped to handle suspicious packages or items. Clinicians who suspect anthrax or anthrax exposure should contact the Public Health Practice Program Office (www.cdc.gov/phppo) of the CDC or statepublichealth.org (www.statepublichealth.org/index.php), which lists all state health agencies and other databases, including contacts for public hotlines.
 

How is the presence of B. anthracis spores in a specific location confirmed?

Unfortunately, it is not easy. Handheld assay devices are available that are designed to allow local emergency personnel to evaluate potentially contaminated sites. However, the exact sensitivity and specificity of these units are unknown. To yield a positive result they must be able to detect at least 10,000 spores, which means that lower levels of contamination will not be detected by the devices. In addition, currently used rapid tests for detecting B. anthracis are susceptible to producing false-positive results in response to the presence of other Bacillus species, such as Bacillus cereus, which is a common contaminant of food, especially rice. The best course is to allow state investigators to determine the risk of significant exposure in a suspected area.

The Public Health Emergency Preparedness & Response unit of the CDC also has a Web site (www.bt.cdc.gov/index.asp) that lists the latest alerts, advisories, updates, and other information regarding the recognition of and emergency response to current threats to public health.
 

Is the sterilization of surfaces in an affected area necessary? How is it done?

Surfaces can be sterilized with a sodium or calcium hypochlorite solution, but it is important to note that once airborne spores have settled, they are not likely to become airborne again, which is probably why no cases of secondary aerosolization of B. anthracis spores have been reported. Spores usually remain airborne for 24 hours or less, depending on weather conditions. After they have settled, they should present no further inhalational risk (they still pose a cutaneous threat, however), but that determination should be made only by state epidemiologists who have investigated the affected area.
 

Should persons exposed to an unknown powder receive prophylactic therapy? What is the recommended therapy?

Most exposures to date have been hoaxes. The state health department or CDC will have the latest news regarding a significant exposure as well as information to help guide treatment.

In most cases, anthrax is responsive to multiple antibiotics, including chloramphenicol, erythromycin, clindamycin, and rifampin, but not to cephalosporins or trimethoprim/sulfamethoxazole. Penicillin should not be used as the sole drug for prophylactic treatment, because isolates from recent cases have been found to contain beta-lactamase.

Prophylactic ciprofloxacin therapy is recommended for two reasons. First, it is FDA approved for this purpose, and second, multidrug-resistant strains of anthrax can be prevented by administering a single drug nationwide. The recommended prophylactic dosage is 500 mg taken orally twice daily for 60 days. The adjusted dosage for children is 20 to 30 mg/kg/day in divided doses every 12 hours. Although ciprofloxacin is usually not recommended for children, the risk/benefit ratio in this instance favors the drug for this group. However, if cultures yield a strain that will respond to other antibiotics, such as penicillin, those options should be tried first. As an alternative to ciprofloxacin, doxycycline can be given in an oral dosage of 100 mg twice daily for 60 days.

An anthrax vaccine has been developed and is still used in some parts of Russia. Supplies in the United States are limited, however, and are currently reserved for military use. Experimental antitoxin therapy has been useful, but it is not available in the United States. Other therapies are currently under investigation, including antitumor necrosis factor, but none is ready for clinical use.

The treatment of anthrax should involve a team of physicians that includes infectious disease and critical care specialists as well as primary care physicians. A full review of treatment is beyond the scope of this discussion but Dixon and colleagues address the topic in detail, as does the October 26, 2001 edition of the Morbidity and Mortality Weekly Report (see Suggested Reading).

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Emerg Med 33(12):41, 2001

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