Anthrax: What Every Clinician Should Know, Part 1
(October 18, 2001)
(View the webcast on the University of North Carolina School of Public Health site.)
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Dr. Baker (moderator):
Welcome back. You have just heard about issues that relate to this broadcast in general terms. But now we are going to turn to Dr. David Stephens, who is in the Meningitis and Special Pathogens branch here at CDC, and is a professor of medicine and director of the Division of Infectious Diseases at Emory University School of Medicine. David has clinical appointments at Emory University Hospital, the VA Medical Center, and Crawford Long Hospital, as well as Grady Memorial Hospital here in Atlanta. David, thank you for being with us today. David will talk to us today about clinical anthrax.
Dr. David Stephens:
Thank you very much, Ed. I think we have all learned a lot the last several weeks about anthrax. Let me present to you the basics. Anthrax is caused by the spore-forming bacterium Bacillus anthracis. It has historically been a zoonotic disease seen in sheep, goats, cattle, and follows the ingestion of spores in the soil. It is often seen now in developing countries. Anthrax has been rare in the United States. Infections are acquired through contact with anthrax-infected animals or animal products, or through (as in the case in Florida) intentional exposure. There are 3 clinical forms: cutaneous, inhalational, and gastrointestinal. This slide shows the etiology of anthrax, Bacillus anthracis. It is a gram-positive, spore-forming, nonmotile bacillus. It is seen on your left with the characteristic spores, and on your right, in a Gram stain of clinical material, the vegetative form of the organism is shown. Again, a gram-positive, spore-forming, nonmotile bacillus.
Anthrax comes in several clinical forms. First is the cutaneous form, which begins as a papule, progresses through a vesicular stage to a depressed black necrotic ulcer or eschar. Edema, redness and a necrosis without ulceration may occur. It’s the form most commonly encountered in naturally occurring cases. These lesions are often painless. They may be pussy. They often develop in exposed sites on the hands, fingers and face.
The next form is inhalational anthrax. This is a clinical syndrome characterized by a brief prodrome resembling a viral-like illness occurring over a 2-3 day period, but sometimes longer. It is characterized by myalgias, fatigue, fever, with or without respiratory symptoms. This is followed by the development of hypoxia and dyspnea often with radiographic evidence of mediastinal widening. Meningitis occurs in 50% of patients. Inhalational anthrax has been extremely rare in the United States. There were only 20 or so reported cases in the last century.
The third form of anthrax is gastrointestinal anthrax. This is associated with abdominal distress, often followed by bloody vomiting or diarrhea and fever and signs of septicemia. It can present as oropharyngeal ulcerations with cervical adenopathy and fever. It develops after the ingestion of contaminated and poorly cooked meat.
This slide shows the virulence factors associated with Bacillus anthracis. Three important virulence factors are encoded by a plasmid, the pX01 plasmid, edema factor, protective antigen, and lethal factor. A second plasmid, pX02, encodes a capsule which inhibits phagocytosis.
The pathogenesis of anthrax is illustrated in this drawing. This illustration is by Drs. Dixon and colleagues and was published in the New England Journal of Medicine in 1999 and is a good source and good reference for information about anthrax. Spores may enter the skin, may enter the gastrointestinal tract, may enter the pulmonary alveoli. They are taken up by macrophages. These spores vegetate into bacilli. Bacilli then are spread either by lymphatic spread or hematogenous spread to multiple sites. This organism through its toxins produces edema. It also produces a proinflammatory cytokine release characterized by the release of TNF Alpha and other cytokines leading to shock and ultimately, in some instances, to death. And as we mentioned earlier, meningitis is also a prominent feature of—may be a feature of inhalational anthrax.
Now I want to illustrate some of the manifestations of cutaneous anthrax. The vesicle may develop as early as Day 2. This progresses to a blackened eschar between Days 4-10 of cutaneous anthrax.
Again, another illustration of cutaneous anthrax from the Armed Forces Institute of Pathology’s collection showing a vesicle on your left and ultimately the ulcer and eschar formation on your right.
This is also a series of pictures from the New England Journal of Medicine article I mentioned earlier showing cutaneous anthrax on the face and on the hand in different presentations. Again, for the purposes of recognition, this is another illustration of cutaneous anthrax to remind us—to remind you that this often occurs on exposed areas of the skin. The ulcer often has a heaped-up border or vesicular ring and progresses to this black eschar during its clinical course. Sometimes the lesions can be multiple, as seen here, with a considerable amount of edema.
Now let me turn to inhalational anthrax. This is due to inhalation of spores. It is felt that the number of spores required to produce inhalational anthrax (and this is supported by animal data) is between 8,000 and 40,000 spores. The incubation period is 2-3 days with a range of possibly up to 60 days. Spores are engulfed by macrophages and transported to mediastinal and peribronchial lymph nodes. The onset is insidious, with malaise, low-grade fever, non-productive cough. There is an abrupt development after this prodrome period of respiratory distress often accompanied by hemorrhagic mediastinitis. Bacilli are hematogenously spread, and as we mentioned earlier, in 50% of patients meningitis develops, which is often fatal.
This slide illustrates from an article in the Journal of the American Medical Association by Inglesby and D.A. Henderson, et al., looking at mediastinal widening associated with inhalational anthrax. This is a second illustration of a chest X-ray of mediastinal widening with pleural effusions.
Now, the differential diagnosis of cutaneous anthrax is long, as was mentioned earlier—spider bites or insect bites are often mentioned in the differential diagnosis. There are a number of other conditions, including ecthyma gangrenosum, ulceroglandular tularemia, plague, and even staphylococcal or streptococcal cellulitis.
Now, the differential diagnosis of inhalational anthrax is also long. It includes a variety of agents that cause pneumonia: Mycoplasma, Legionella, psittacosis, Q fever, viral pneumonias. Histoplasmosis with mediastinitis is sometimes mentioned in the differential diagnosis, as is coccidioidomycosis. For patients who present with acute sepsis or acute meningitis, we should be thinking about anthrax in the differential as with down in the Florida case. There are a number of other causes of pneumonia which probably should be included in this list as shown.
Now the diagnosis of cutaneous anthrax is made by the characteristic eschar, in addition culture and Gram stain of vesicular fluid or exudates, blood cultures, biopsy. PCR is available, as is immunofluorescence and immunohistochemistry, which have been used in the diagnosis of the current cases.
Inhalational anthrax is associated with widened mediastinum, but not in all cases. Pleural effusions and blood or CSF cultures may be positive and Gram stains can be an important early clue. Again, PCR, immunofluorescence, and immunohistochemistry are important in establishing the diagnosis.
I have listed the current MMWR guidelines regarding postexposure prophylaxis to prevent inhalational anthrax. In adults these are ciprofloxacin or doxycycline, 500 mg po b.i.d. of ciprofloxacin, 100 mg po b.i.d. of doxycycline. The current recommended duration is 60 days. In children, again, the current recommendations are ciprofloxacin 10-15 mg/kg po q. 12 hours or doxycycline in the doses listed. I will comment that this dosing schedule is available on the CDC Web site.
I want to emphasize that cephalosporins should not be used in the treatment of Bacillus anthracis infection as Bacillus anthracis is resistant to cephalosporins. Additional recommendations concerning prophylaxis to prevent inhalational anthrax will be forthcoming as additional data is developed.
Now, the recommendations for initial anthrax treatment regarding inhalational or cutaneous exposure are listed on this slide. Again, they include ciprofloxacin or doxycycline; ciprofloxacin, 500 mg. po b.i.d. in adults, or doxycycline, 100 mg. po b.i.d. for 14 days. Inhalational anthrax is again intravenous ciprofloxacin or doxycycline. Ciprofloxacin and doxycycline are also currently recommended as initial therapy for children in appropriate doses. As more information becomes available on antimicrobial susceptibility these recommendations may be modified.
I want to end by emphasizing these points. I think it is very important that we do not panic. We must remain vigilant. Individuals must be—to develop anthrax—must be exposed to B. anthracis spores. To cause disease the spores must enter the skin, they must be swallowed, or they must be inhaled. Disease can be prevented after exposure to anthrax spores by early treatment with appropriate antibiotics. And lastly, anthrax is not spread from person to person.
Dr. Baker (moderator):
David, thank you very much for that very comprehensive and very useful discussion.
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