Special Feature: Treating and Preventing Anthrax
By Leslie A. Hoffman, RN, PhD
Historical Perspective
For centuries, anthrax has caused disease in animals and, in rare instances, humans throughout the world. The causative organism, Bacillus anthracis, can persist in the soil for many years. Grazing animals such as sheep, cattle, and goats are most commonly affected.1 Intensive animal vaccination programs have restricted the disease to sporadic outbreaks, with the exception of Africa and Asia where vaccination remains spotty.2 Under natural circumstances, human cases arise by 2 means: direct contact with an animal dying of anthrax (agricultural cases) or contact with spores that contaminate hides, hair, and bones used in manufacturing (industrial cases).1,2 There are no known cases of human-to-human transmission of anthrax.1
The current interest in anthrax stems from its use as a biological weapon. At least 17 nations are believed to have programs to produce offensive biological weapons, including Iraq, which has acknowledged producing and weaponizing anthrax.3 In 1995, a terrorist group in Japan dispersed aerosols of anthrax throughout Tokyo on at least 8 occasions. For unclear reasons, none of these events produced illness.3 In 1979, the accidental aerosolized release of anthrax spores from a military facility in the former Soviet Union resulted in at least 79 cases of anthrax and more than 60 deaths. Most significantly, this disaster demonstrated the lethal potential of anthrax in aerosolized form.3
Epidemiology
In humans, 3 types of anthrax occur: inhalational, cutaneous, and gastrointestinal. Inhalational anthrax results from exposure to dust or aerosols that contain spores 2-5 mm in size. Larger spores (> 5 mm) are deposited in the upper airways and cleared by the mucociliary system.1,3 The term "weapons-grade" anthrax refers to the presence of small spores capable of penetrating deeply into the lungs.1 It is believed that a relatively large number of spores (~ 8000-50,000) must be inhaled to cause a fatal infection.1,4 Consequently, naturally occurring cases of inhalational anthrax are rare, even in areas of high soil contamination.1 There were 18 cases reported in the United States between 1900 and 1978. Of these, 2 were laboratory-associated, and the remainder occurred in wool or tannery workers.3 There were no reports of inhalational anthrax in the United States between 1978 and October 4, 2001, when the Centers for Disease Control (CDC) reported a case in Florida.4 Since that time, additional individuals have been diagnosed with the disease. In the majority of cases, there has been a clear link to the deliberate spread of anthrax, as a weapon, through the mail system.4,5
The ability to use anthrax as a biological weapon requires small spores (2-5 mm) and treatment of the spore-containing vehicle with chemicals to remove static electricity.6 Without such treatment, fewer spores become airborne, reducing their lethal capability. It has been reported that the spores used in the recent bioterrorist attack were purified and small in size, but not treated to reduce static electricity. Consequently, they were less likely to disseminate in the air, but more likely to stick to envelopes and surfaces.6
Cutaneous anthrax accounts for 95% of anthrax cases worldwide.1 It is the most common naturally occurring form in the United States, with 224 cases reported in the United States between 1944 and 1994. Cutaneous anthrax begins after spores are introduced through a break in the skin; anthrax spores cannot penetrate intact skin.1 Gastrointestinal anthrax is uncommon and typically follows ingestion of insufficiently cooked contaminated meat. Most cases of the cutaneous and gastrointestinal forms of anthrax have occurred in Africa and Asia.3
Microbiology
B anthracis is a large, Gram-positive, nonmotile, spore-forming rod. The spores have a "jointed bamboo rod" cellular appearance, making identification by an experienced microbiologist relatively straightforward.1 However, prior to October 2001, few outside the veterinary community had seen anthrax colonies other than in textbooks.1,3 Consequently, both luck and astute diagnostic skill played a part in the outcomes of the earliest cases of intentional anthrax exposure.7,8
Clinical Manifestations
Inhalational Anthrax. The syndrome that results from inhalational anthrax follows a 2-stage pattern with an incubation period that is typically 1-7 days but may be as long as 60 days.4 After spores are inhaled, they are ingested by macrophages, some of which undergo lysis and destruction. However, a significant number of spores survive secondary to an antiphagocytic capsule surrounding the cell wall. Surviving spores are transported to the mediastinal lymph nodes, where germination occurs and virulent exotoxins are released.3 Once germination takes place, clinical disease quickly ensues. Initially, the patient develops a nonspecific influenza-like illness, characterized by mild fever, muscle aches, headache, nonproductive cough, and mild chest discomfort.1,5
After 1-3 days, some patients experience a brief period of apparent recovery prior to disease progression. Others progress directly to the fulminant stage of illness.3 The second stage begins when the regional lymph nodes are overwhelmed and anthrax toxins find their way into the systemic circulation. The patient develops a high fever, chest-wall edema, hemorrhage, dyspnea, stridor, cyanosis, tissue necrosis, and septic shock. In up to 50% of cases, there can be meningeal involvement. Chest radiographs show pleural effusions, and a widened mediastinum is evident on CT scan. Typically, no pneumonia is seen, unless there is pre-existing pathology. Mortality in untreated cases has been reported at nearly 100%. However, these data are based on observations in the early 1930s and, therefore, are dated. Mortality given today’s treatment options is unknown.1
Cutaneous Anthrax. This develops when spores gain entry through a scratch, abrasion, or cut, germinate and multiply into the bacillary form. Clinical manifestations usually develop an average of 1-7 days after exposure; however, the incubation period can be as long as 12 days.1,4 The first evidence is a nondescript papule that, during the next 24-48 hours, becomes vesicular and about 1-2 cm in diameter. At this stage, B anthracis is easily isolated from the vesicular fluid and visible on Gram stain.1,2 The lesion, which is usually pruritic but not painful, generally ruptures after 1 week, leaving an ulcer that progresses to the characteristic black eschar that gave the disease its name.1,2 The eschar then dries, loosens, and falls off 2-3 weeks later. Regional lymph nodes may be swollen during the initial period after infection, and most patients experience fever, headache, and malaise at this time.1,2 Lesions located in the neck or facial area may produce mediastinal edema and respiratory distress. About 5-30% of untreated cutaneous anthrax cases result in death. Mortality for treated cases is estimated to be less than 1%.1,2
Managing Exposures
The highest priority when dealing with anthrax exposure is to identify those at risk and to initiate effective antimicrobial therapy. Any individual directly exposed to or in an environment potentially contaminated with B anthracis should be given antibiotic prophylaxis.7,8 Up-to-date guidelines are available from the CDC at www.bt.cdc.gov.
Diagnosis
Health care providers should be alert to illness patterns and clues in the history. Early diagnosis of inhalational anthrax requires a high index of clinical suspicion as illustrated in the following case. On October 21, 2001, 1 day after the mayor of Washington, DC, announced that a Brentwood postal worker possibly had anthrax, 2 other Brentwood postal workers presented for treatment at hospitals 26 miles apart. Both complained of flu-like symptoms but were actually suffering from inhalational anthrax. By the end of the day, one of the men had been diagnosed with the flu and sent home—where he died the next day. The second patient was put on the antibiotic ciprofloxacin and is now recovering at home. The decision to start treatment followed a chance remark by the patient ("I work at Brentwood"), follow-up questions by the ED physician ("What is that?"), and the appropriate diagnostic test (chest CT) that revealed widening of the mediastinum.9
Inhalational anthrax presents with nonspecific symptoms that cannot be distinguished from common illnesses based on early clinical signs and symptoms and routine diagnostic tests.2 These nonspecific symptoms create a dilemma when attempting to rule out this diagnosis in patients who may also have influenza or other flu-like illnesses. The combination of a careful history and attention to eliciting potential environmental exposure should assist in diagnosis. If inhalational anthrax is a diagnostic consideration, a chest CT scan or chest x-ray needs to be included in the work-up.3,8 In advanced disease, patients have a characteristically widened mediastinum and pleural effusions, despite otherwise normal chest radiograph findings.1,3 The most useful microbiologic test is the standard blood culture, which should show growth in 6-24 hours. Sputum culture and Gram stain are unlikely to be diagnostic.3
Treatment
Current recommendations for treatment of inhalational anthrax with antibiotics are based on studies in nonhuman primates, other animals, and in vitro data (see Table 1).7 Because of the high associated mortality, 2 or more antimicrobial agents are recommended by the CDC (see Table 2). Penicillin is labeled for use to treat inhalational anthrax, but preliminary reports indicated resistance of B anthracis isolates from Florida, New York City, and Washington, DC. Therefore, treatment with penicillin is not recommended. Prompt treatment of inhalational anthrax is essential, as death may still occur if treatment is begun too late. The need for early treatment is the primary rationale for empiric treatment of those who may have been exposed to anthrax spores.7,8
|
Table 1 |
||
|
Inhalational Anthrax Treatment Protocol for Cases Associated with Bioterrorism Attack |
or
when clinically appropriate: doxycycline 100 mg q 12 h ciprofloxacin 500 mg p.o. b.i.d. or and doxycycline 100 mg p.o. b.i.d. 1-2 additional antibiotics continue 60 days (IV and po combined) Pregnant Women Same as above Same as above Immuno-Compromised
Patients Same as above Same as aboveAdapted from: MMWR Morb Mortal Wkly Rep. 2001;50(41):909-918.
|
Table 2 |
Additional Considerations for Inhalational Anthrax Treatment
Initial TherapyCiprofloxacin or doxycycline should be considered an essential part of first-line therapy for inhalational anthrax. Based on the clinical course of the patient; 1 or 2 antimicrobial agents, eg, ciprofloxacin, doxycycline, may be adequate if the patient improves.
Additional Antibiotics
Other agents with in vitro activity include rifampin, vancomycin, penicillin,
ampicillin, chloramphenicol, imipenem,
clindamycin, and clarithromycin. Consultation with an infectious disease specialist is advised.
Because of concerns of constitutive and inducible beta-lactamase, penicillin and ampicillin should not be used alone.
SteroidsMay be considered as an adjunctive therapy for patients with severe edema and for meningitis based on experience with bacterial meningitis of other etiologies.
Meningitis If meningitis is suspected, doxycycline may be less optimal because of poor central nervous system penetration. Duration of TreatmentBecause of the potential persistence of spores after an aerosol exposure, antimicrobial therapy should be continued for 60 days.
Adapted from: MMWR Morb Mortal Wkly Rep. 2001;50(41):909-918.
For cutaneous anthrax, antimicrobial therapy with 1 of 2 agents is recommended (see Table 3). Intravenous therapy with a multidrug regimen is recommended if cases show signs of systemic involvement, such as extensive edema or lesions on the head and neck.7 Antimicrobial agents may cause cutaneous lesions to become culture-negative in 24 hours; however, progression to eschar formation still occurs.2 Usually, antibiotics are prescribed for 7-10 days. However, the CDC changed these guidelines to 60 days because of the high risk for simultaneous aerosol exposure.7 CDC guidelines for post-exposure prophylaxis to prevent inhalational anthrax in adults are the same as those for the treatment of cutaneous anthrax.4
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Table 3 |
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| Cutaneous Anthrax Treatment Protocol for Cases Associated with Bioterrorism Attack | ||
| Category | Initial Therapy (intravenous) | Duration |
| Adults | ciprofloxacin 500 mg p.o. b.i.d. | 60 days |
| or | ||
| doxycycline 100 mg p.o. b.i.d. | ||
| Pregnant women | Same as above | 60 days |
| Immuno- | ||
|
compromised |
Same as above | 60 days |
| Women | ||
|
Adapted from: MMWR Morb Mortal Wkly Rep. 2001;50(41):909-918. |
||
Conclusion
Recent incidents underscore the need for all health care personnel to become familiar with anthrax and its treatment. Early diagnosis requires attention to illness patterns and a high index of suspicion. Early treatment is particularly important because early recognition and rapid, aggressive initiation of appropriate treatment can transform anthrax into a serious, but treatable, disease.
References
1. Braun PC, Zoidis JD. Treating and preventing anthrax. RT: The Journal for Respiratory Care Practitioners. 2001;14(7):15-21.
2. Pile JC, et al. Anthrax as a potential biological warfare agent. Arch Intern Med. 1998;158:429-431.
3. Inglesby TV, et al. Anthrax as a biological weapon: Medical and public health management. JAMA. 1999; 281:1735-1745.
4. Update: Investigation of anthrax associated with intentional exposure and interim public health guidelines. MMWR Morb Mortal Wkly Rep. 2001;50(41): 889-892.
5. Recognition of illness associated with the intentional release of a biologic agent. MMWR Morb Mortal Wkly Rep. 2001;50(41):893-897.
6. Fialka J, Fields G. Static electricity present in anthrax letters made spores cling, may have saved lives. Wall Street Journal. December 3, 2001:A6.
7. Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy. MMWR Morb Mortal Wkly Rep. 2001;50(41):909-918.
8. Lane HC, Fauci AS. Bioterrorism on the home front. A new challenge for American medicine. JAMA. 2001;286(20):2595-2597.
9. Martinez B. Anthrax victims’ fate varied by what hospital, which doctor they saw. Wall Street Journal. November 27, 2001:B1, B6.
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