Naturally occurring anthrax has been known since antiquity and is found worldwide. It has also been used as a bioweapon: there were 22 anthrax cases and 5 deaths after the 2001 attacks in which anthrax spores were sent through the U.S. mail.6 Anthrax is caused by infection with the spore-forming, exotoxin-producing, gram-positive bacillus Bacillus anthracis. It is a disease of herbivores that ingest spores present in the soil that then germinate in the gut. In humans, three forms of anthrax are recognized: cutaneous (the most common), gastrointestinal, and inhalational (the most deadly).7 After the 2009–2010 European outbreak linked to heroin injection, a fourth type, injectional, was recognized.8 In all forms, the clinical manifestations are primarily caused by the toxins secreted by the vegetative bacterium.7,9

Cutaneous Anthrax

Figure 1. Figure 1. Characteristic Features of Diseases Caused by Category A Agents. Panel A shows a cutaneous anthrax lesion. Panel B is a chest radiograph of a patient with anthrax, showing mediastinal widening and pleural effusions. Panel C shows a smallpox rash. Panel D shows a patient with bubonic plague with axillary lymphadenopathy. Panel E shows paralysis in a patient with botulism. Panel F shows a tularemia skin ulcer. Images courtesy of the CDC Public Health Image Library.

The most common and least lethal form of anthrax, cutaneous anthrax occurs after spores penetrate breaks in the skin and germinate. After a 1-day to 12-day incubation period, a pruritic papule appears at the site of inoculation, progresses to become a vesicle or pustule, and finally becomes the characteristic painless, coal-black eschar from which the disease derives its name. Marked edema of the affected region is present, as well as lymphadenopathy and fever. When untreated, cutaneous anthrax carries a mortality rate of less than 1%, but in rare cases it can disseminate throughout the body and produce high lethality.9 Figure 1A shows the characteristic black eschar of cutaneous anthrax.

Gastrointestinal Anthrax

Gastrointestinal anthrax occurs after ingestion of vegetative B. anthracis bacteria from the meat of infected animals. The disease is divided into two phases: oropharyngeal and lower gastrointestinal. After an incubation period of 3 days, oral or esophageal ulcers, cervical lymphadenopathy, and dysphagia occur. Fever and constitutional symptoms are also present. Lower gastrointestinal involvement is signaled by the appearance of abdominal pain, nausea, vomiting, bloody diarrhea, and abdominal distention. Ascites and inflammatory changes in the bowel wall may be present and visible on imaging. Mortality can reach 60% if the disease is untreated.7,10

Injectional Anthrax

Injectional anthrax is characterized by skin lesions similar to those seen in “skin-popping” drug users. These lesions may progress rapidly and require surgical débridement. Dissemination with systemic symptoms, including meningitis and shock, may occur. Unlike cutaneous anthrax, injectional anthrax is not associated with eschar formation on the skin, and the mortality, even with treatment, is considerably higher, at 34%.11

Inhalational Anthrax

The most lethal form of anthrax, and the form that would follow an intentional aerosol release of spores, inhalational anthrax results from the inhalation of bacterial spores that later germinate in the lung. The incubation period of inhalational anthrax can be as short as 1 day; has been as long as 6 weeks, in the case of the Sverdlovsk outbreak12; and has also been as long as 9 weeks in experimentally exposed monkeys.13 Disease onset begins with nonspecific influenza-like symptoms, with the exception that rhinorrhea is absent.14 After the disease progresses through this stage, which lasts hours to days, a severe advanced phase occurs and includes high fever, shock, and respiratory distress. Inhalational anthrax does not cause pneumonia but nevertheless can progress to the acute respiratory distress syndrome. Hemorrhagic mediastinitis, as well as toxin-laden pleural and pericardial effusions, can be present.15 Spread of the disease to the meninges, with resultant hemorrhagic meningitis, is a frequent complication of systemic forms of anthrax, occurring in up to 50% of cases16; this complication confers a higher degree of mortality. In the 2001 attacks, all persons with meningitis died, a finding consistent with other cases.17 Traditionally, inhalational anthrax has carried a 90% case fatality rate; however, during the 2001 attacks, the case fatality rate was halved, to 45%.6 The reason for the decrement in mortality is probably multifactorial and includes the benefits of modern critical care, the drainage of toxin-laden pleural effusions, and the use of antimicrobial therapies.

Considerations for Anthrax in Special Populations

Children and pregnant women are populations that may require special consideration. In a recent systematic review of 20 natural cases — most of which were cutaneous — reported in pregnant women, high rates of maternal and fetal death were noted.18 It is unclear whether this represents a heightened proclivity for severe disease among pregnant women or a reporting bias. A systematic review of 73 pediatric cases, most of which were cutaneous or gastrointestinal, yielded no striking differences in the presentation of anthrax in children, as compared with adults.19

Diagnosis of Anthrax

Although clinical suspicion is of utmost importance, laboratory confirmation is required for diagnosis, because the clinical findings in anthrax may overlap with those of other infections. B. anthracis grows rapidly in culture, and patients with systemic disease can be identified with the use of routine blood cultures. Because other bacillus species are frequent contaminants, there is the potential for delayed diagnosis if results are disregarded. Cultures from skin, ascites, pleural fluid, cerebrospinal fluid, and pericardial fluid may be positive. Biopsy can also be used to identify cases of cutaneous anthrax. A serologic test that has been cleared by the Food and Drug Administration (FDA) is available, but it does not yield positive results until late in the disease course. Reference laboratories, such as a state health laboratory, can perform definitive testing, including polymerase-chain-reaction (PCR)–based assays.9

Chest imaging may reveal a widened mediastinum, pleural effusions, or both, as well as apparent infiltrates due to effusions, atelectasis, and changes consistent with the early phase of the acute respiratory distress syndrome (Figure 1B); in addition, many patients may have characteristic hyperdense (hemorrhagic) mediastinal lymphadenopathy on unenhanced computed tomography of the chest. An echocardiogram may reveal a pericardial effusion.9

Laboratory studies may reveal hemoconcentration, abnormal transaminases, anemia, thrombocytopenia, and coagulopathy, depending on disease severity. Lumbar puncture is required to rule out meningitis.9 There are decision support tools available to facilitate the diagnosis of anthrax after a known release of the bacillus.20

Treatment of Anthrax

Several antimicrobial agents have activity against B. anthracis, although concerns regarding engineered drug resistance influence the choice of treatment regimens.2 Because the disease is toxin-mediated, therapies that inhibit protein synthesis or disable toxins are preferred in the published CDC guidelines.21

The form of the disease and context of exposure (natural vs. intentional) determine the specifics of treatment. Treatment regimens can be divided into those for systemic disease and those for limited cutaneous disease.21

Uncomplicated cutaneous anthrax can be treated with an oral fluoroquinolone (ciprofloxacin, levofloxacin, or moxifloxacin) or doxycycline. Penicillin can be used if the isolate is known to be susceptible. The recommended duration of treatment is 7 to 10 days; however, a recent study suggests that shorter courses for naturally occurring cases are effective.22 In the setting of an intentional attack, in which inhalation of spores may also have occurred, the duration should be extended to 60 days to cover the full incubation period of inhalational anthrax.21

Ideally, systemic forms of anthrax should be treated in an intensive care unit, where interventions such as mechanical ventilation, hemodynamic monitoring, fluid resuscitation, vasopressor support, prophylaxis for deep-vein thrombosis, and prophylaxis for gastrointestinal bleeding can be provided, consistent with the current sepsis protocols.23 Anthrax-specific treatments include combination antimicrobial therapy. If meningitis has not been ruled out, the CDC recommends a regimen including a fluoroquinolone, such as ciprofloxacin; a drug that inhibits protein synthesis, such as linezolid; and a drug that penetrates the central nervous system, such as meropenem. If meningitis has been ruled out with the use of a lumbar puncture, a two-drug regimen that includes a fluoroquinolone plus linezolid or clindamycin is recommended. Glucocorticoid treatment could be initiated for anthrax meningitis in accordance with the protocols for bacterial meningitis. The treatment duration is 2 to 3 weeks.21

Because historical studies of anthrax showed benefit with the use of antiserum, modern antibody therapies directed against anthrax toxins have been developed as adjunctive treatment. Two antibody-based therapies are available: raxibacumab and anthrax immune globulin. Raxibacumab is an FDA-approved monoclonal antibody targeted at the protective antigen component of the toxins and is administered in a single dose. In studies in animals, the use of raxibacumab without the concomitant use of antimicrobials was highly protective against lethal disease.24 However, when raxibacumab was combined with antimicrobials, the protective effect was no longer significant, although a trend in favor of the effectiveness of the therapy was apparent.21 Similar findings were seen with anthrax immune globulin.21,25 The CDC recommends antitoxin treatments in cases of systemic anthrax.21 However, it is difficult to determine what added benefit they confer for patients who are effectively treated with antimicrobials.

Another recommended adjunctive therapy is drainage of pleural effusions, ascites, and pericardial effusions, all of which are toxin-laden. In a historical review, such treatment of pleural effusions was shown to be partly responsible for the diminished fatality rate in modern cases of anthrax.26 Surgical resection may be required in cases of gastrointestinal and injectional anthrax.21

Anthrax does not spread from person to person. Standard precautions are sufficient for infection control.9

Prevention of Anthrax

Anthrax vaccine adsorbed (AVA) is the FDA-licensed vaccine used for the prevention of anthrax. AVA was initially administered in a series of six subcutaneous injections followed by annual booster injections. A randomized clinical trial, however, showed noninferior immunogenicity results when five intramuscular injections were used.27 The intramuscular regimen is now the recommended method of vaccination. Evidence suggests that this schedule may be further simplified.28 Other anthrax vaccines are in development.

For postexposure prophylaxis, AVA would probably be recommended for off-label (or Emergency Use Authorization) use in a three-dose schedule21 on the basis of studies in animals.29 Antimicrobial therapy is coupled with vaccination for postexposure prophylaxis; ciprofloxacin and doxycycline are the preferred antimicrobials. The duration of prophylaxis, derived from the longest germination time of inhaled spores, is 60 days.21 After the 2001 anthrax attacks, approximately 10,000 persons received antimicrobial prophylaxis and had no resultant disease, despite compliance rates of less than 50%; this suggests that some modification of antibiotic recommendations is possible.30 On the basis of studies in animals, raxibacumab can also be used as single-agent postexposure prophylaxis when no other option is available,21,24 although the circumstances in which ordinary postexposure prophylaxis could not be used are limited.