Anthrax: a clinical perspective Speaker: Mary E. Wright, MD, MPH Chief of the Biodefense Clinical Research Branch, Office of Clinical Research, Office of the Director, NIAID

Highlights

	The clinical presentation of anthrax has not changed over time; patients in 2001 had similar signs and symptoms to patients in 1876.
	The clinical tools have changed; imaging, PCR, immunofluorescence, and other relatively new techniques can aid in diagnosis.
	Potential new treatments in various stages of testing include a shortened course of the AVA (anthrax vaccine adsorbed) vaccine, a protective antigen vaccine, and an anthrax capsule vaccine.

Natural or intentional release?

“Like many of the people calling in to today's teleconference, I was drawn into anthrax during the 2001 letter attacks,” said Mary E. Wright, chief of the biodefense clinical research branch of the US National Institute of Allergy and Infectious Diseases, in her lecture on clinical aspects of anthrax. She focused on routes of infection, symptomatology, the clinical course of the disease, and treatments.

Wright began by describing the clinical, historical context within which the letter attacks occurred. Before 2001, if a patient came into a physician's office or emergency department with fever, cough, and weakness, the doctor was unlikely to suspect anthrax. Medical students were taught that in 1876, anthrax became the first disease to fulfill Koch's postulates (i.e., the first disease for which a microbial etiology was firmly established), and in 1881, the first bacterial disease for which immunization was available. In the 1970s, anthrax infected 6000 people in Zimbabwe, and in the 1990s, thousands of cases—primarily cutaneous anthrax—were reported worldwide each year.

During the first half of the 20th century, cutaneous infection with naturally-occurring anthrax was not uncommon in the United States in mill workers and was thus called “Wool Sorters Disease.” However, said Wright, “Only 18 cases of inhalational anthrax had been reported in the United States in 100 years, the last one in 1978. So, in 2001, as soon as it was known that there was a second case of inhalational anthrax in Florida, concern that this was an act of bioterrorism intensified.”

Before 2001, only 18 cases of inhalational anthrax had been reported in the US in 100 years.

Since inhalational anthrax had been so rare in the United States, US researchers and practitioners searched older medical literature for guidance regarding pathogenesis and clinical course. No formal clinical studies had ever been performed in the United States, so this consisted primarily of anecdotal case reports prior to 1960. In addition, review of the literature related to a 1979 anthrax outbreak in the city of Sverdlovsk revealed clinical findings consistent with those seen in US case reports. The Sverdlovsk outbreak was caused by an accidental release of anthrax spores from a suspected Soviet biological weapons facility. “The incident was originally reported as the naturally occurring gastrointestinal form, but later it was learned that it was part of a bioweapons program and that it was primarily inhalational anthrax,” Wright said.

Modes of transmission

Gastrointestinal anthrax, which comes from eating undercooked meat, is less common than cutaneous anthrax, but more dangerous in that it causes more systemic disease than the cutaneous form. The Zimbabwe outbreak in the 1970s was caused by gastrointestinal anthrax.

Cutaneous anthrax, which is transmitted through contact of the spore with the skin, causes a swollen, painless, itchy papule that initially looks like a bug bite. Over 8-10 days, a blister forms and ruptures, leaving an ulcer with a classic black eschar. Anthrax letters sent in 2001 to media outlets in New York City and to various postal facilities there and elsewhere resulted in 11 confirmed cutaneous anthrax infections.

“At that time, the National Academy of Dermatology issued a statement noting that although physicians evaluating patients with suspected cutaneous anthrax should avoid contact with exudate, blood, or body fluid, they should not considered at risk for contracting pulmonary [inhalational] anthrax because the disease requires contact with the spores of the active bacteria,” Wright emphasized. “This was an important reminder, because certainly the United States had not dealt with anthrax for a very long time, and we know that, technically, there is no person-to-person transmission, although there have been some anecdotal cases of cutaneous transmission in other parts of the world.”

Inhalational anthrax cannot be transmitted person-to-person.

In inhalational or pulmonary anthrax, spores are inhaled and taken up by macrophages in the lungs that migrate to mediastinal lymph nodes where they germinate into the bacteria. From the lymph nodes, bacteria easily enter the bloodstream, multiply, and produce anthrax toxins. Once in the bloodstream, bacteria and toxins travel to the meninges and other organ sites. Eleven people developed inhalational anthrax during the 2001 attacks, five of whom died.

Pathogenesis and presentation

B. anthracis has two virulence factors—the anthrax toxin protein and the capsule—that are encoded by separate large plasmids called pXO1 and pXO2. The anthrax toxin is made up of three proteins that combine to form two toxins—edema toxin and lethal toxin, Wright explained. (For more information on the structure of B. anthracis, click here.)

“From a clinical standpoint, the take-home message is that the disease mechanism in anthrax is very different from that of community-acquired pneumonia,” she said. “In Streptococcus pneumoniae, for example, basically we're colonized within and something happens when we become susceptible, causing bacteria to multiply inside the alveoli and basal epithelium. Then you get alveolar consolidation and infection. In anthrax, we know that the mediastinal lymph nodes are very important for the germination of the spores into the bacteria, and that something happens at the toxin-mediated level to cause this response. Even in field animal studies, when bacteremia was eradicated, animals could still go on to die, presumably due to the toxin.”

The disease mechanism in anthrax is different from that of community-acquired pneumonia.

Wright showed chest x-rays and CT scans comparing normal lungs with lungs of individuals with inhalational anthrax. The images were among those published in an article by John Jernigan and colleagues, who documented the clinical findings in the first 10 inhalational anthrax cases in 2001. Scans of infected individuals showed a widened mediastina and, in most cases, pleural effusions. Patients' symptoms included fever, chills, fatigue, cough, shortness of breath, nausea, drenching sweat, chest pain, and fever. In some patients, heart rate was greater than 100 beats per minute, systolic blood pressure less than 110 mmHg, and at least half of patients had a low saturation of oxygen.

The findings prompted the Centers for Disease Control and Prevention to develop a case definition for anthrax with the following criteria: 1) a clinically compatible case of cutaneous, inhalational, or gastrointestinal illness that is laboratory confirmed by isolation of B. anthracis from an affected tissue or site; or 2) other laboratory evidence of B. anthracis infection based on at least two supportive laboratory tests. The lab tests, noted Wright, “could include immunohistochemical staining, PCR, detecting DNA, or the old fashioned standby of the presence of antibodies.”

She went on to describe various models for screening patients for anthrax when they present to the emergency department, given that many of the symptoms are nonspecific. She cited one retrospective hospital study suggesting that at least five symptoms and two signs of the disease, plus an abnormal white cell count, could confer a high index of suspicion.

Future treatment and prevention

Wright wrapped up her talk with a summary of anthrax treatment, post-exposure prophylaxis, and prevention. All of the 2001 inhalational anthrax survivors received multi-drug treatment, she noted, which usually included ciprofloxacin or doxycycline, an antimicrobial for central nervous system penetration such as rifampin and clindamycin. Researchers are looking at new treatment modalities, including globulins, monoclonal antibodies, and protease inhibitors.

From a prevention standpoint, AVA (anthrax vaccine adsorbed) has been in use for years and remains the only anthrax vaccine that is currently available. In October 2004, the US District Court mandated that AVA needed additional evaluation by the Food and Drug Administration and called for the Department of Defense to halt AVA vaccination of its troops. In January 2005, the Food and Drug Administration issued an order authorizing its temporary use under Project BioShield's Emergency Use Authority but giving individuals in the military the right to refuse vaccination without penalty. The schedule is somewhat “arduous,” she said, in that it requires six doses; however, research is underway to shorten the course to three doses with a booster at periodic intervals.

Research is underway to lower the required number of anthrax vaccine doses.

Treatments on the horizon include a shortened course of AVA vaccine with an alternate route of administration (e.g., intramuscular instead of subcutaneous); the recombinant or RPA protective antigen vaccine, now in phase-II trials; and the capsule vaccine.

As for diagnosis and evaluation, “it's a matter of using our relatively new tools to learn about this old pathogen,” said Wright. When inhalational anthrax cases occurred in the 1970s, “we didn't have magnetic resonance imaging (MRI), we didn't have PCR, and many of the other tools that are now available to us.”