Be aware before biowarfare strikes

An expert offers an overview of anthrax, tularemia, and plague.

It's challenging to be completely prepared for a biowarfare attack, according to Ryan Maves, MD, FACP.

To aid in preparation, he offered attendees at CHEST 2019, held in New Orleans in October, an overview of clinical manifestations and management of three naturally occurring infections that are also potential agents of biowarfare: anthrax, tularemia, and plague.

Photo by Getty Images
Photo by Getty Images

All three can manifest in the soft tissue, lungs, or both. These overlaps can affect the differential diagnosis, said Dr. Maves, who is staff physician on the critical care medicine and infectious diseases services at the Naval Medical Center in San Diego and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md. For example, plague and tularemia can have multiple features in common. “I think about this probably more than the average guy,” he said, “and I think the odds of me clinically distinguishing between them at the bedside is somewhere between zero and whatever's less than zero.”

He also reminded attendees that these diseases do occur naturally. “I'll admit that it's a little bit odd to think about dying of the Black Death in 2019, but it happens,” he said. “So one case is not an outbreak. One case can be sporadic.”

To help determine whether you have an outbreak on your hands, close coordination with public health authorities is essential, Dr. Maves said. Many of the necessary diagnostic assays are not readily available to practicing clinicians but are accessible through state and county public health departments. The CDC also offers diagnostic support through its Laboratory Response Network, he noted.


Anthrax is caused by Bacillus anthracis, a gram-positive, spore-forming rod that occurs naturally in the soil, Dr. Maves said. Its reservoir is herbivores such as sheep, cattle, and goats that become infected while grazing. About 100,000 human anthrax cases occur naturally worldwide each year, he said. Anthrax does not spread from human to human.

The incubation period of anthrax depends on the form of the disease, Dr. Maves said. The cutaneous form takes one to seven days, while the inhalational form can take up to 60 days, with incubation periods of over 100 days reported with weaponized forms. “If you have spores, and you inhale them, they can make it all the way down into the alveoli,” he said. “They can also kind of set up shop in your nasopharynx and be present for up to two months.”

The vast majority of human anthrax cases, 95%, are cutaneous, Dr. Maves said, and occur due to a break in the skin. A black ulcer with a gelatinous halo and nonpitting edema forms one to seven days after exposure. “This is culturable [from blood and biopsy specimens] on conventional media,” Dr. Maves said. “Sputum culture in inhalational anthrax is basically worthless. I wouldn't waste a lot of psychic energy on obtaining that.”

Painful regional lymphadenopathy is common with cutaneous anthrax, as are fever, headache, and malaise. The mortality rate for cutaneous anthrax is less than 1% with appropriate antibacterial therapy and surgical debridement, Dr. Maves said.

Inhalational anthrax, Dr. Maves said, “is the bugaboo. That's the thing we're all scared of.” Infected patients exhibit bimodal distribution of syndromes: “People get acutely ill, have a transient improvement, and then get dramatically worse,” with respiratory failure and cardiovascular collapse, he said.

Although people may refer to “pulmonary anthrax” or “respiratory anthrax,” Dr. Maves noted that lung involvement is actually fairly limited. “You might see some degree of pneumonitis on CT imaging, but mainly this is a hemorrhagic mediastinitis.” Patients typically have fever, pleurisy, and headache, Dr. Maves said. Large effusions are not unusual and pleural drainage appears to improve outcomes, he noted. Airspace opacities and pneumonitis may be absent, and bilateral bloody pleural effusions are common.

Hematogenous dissemination to the central nervous system with secondary meningitis is one of the initial things that needs to be evaluated in a suspected anthrax case. “Get lumbar puncture done early to exclude or rule in meningitis,” he said.

Naturally occurring cases of anthrax are broadly susceptible to penicillin, Dr. Maves said. For severe inhalational anthrax, the CDC recommends empiric therapy with meropenem, 2 g IV every 8 hours; ciprofloxacin, 400 mg IV every 8 to 12 hours; and clindamycin, 900 mg IV every 8 hours.

Once susceptibilities have been determined, meropenem can be withdrawn (after meningitis has been excluded) and penicillin can be substituted for a quinolone, Dr. Maves said. People who have been exposed to anthrax require 60 days of postexposure prophylaxis with oral ciprofloxacin, levofloxacin, or doxycycline, regimens that Dr. Maves called a “challenge” to implement. He recommended working with public health officials to determine who has been exposed and who needs to be on these drugs.

Nondrug therapy includes surgical debridement of skin lesions, hemodynamic and respiratory support, and drainage of serosal fluid collections, Dr. Maves said. Immunotherapy includes raxibacumab and obiltoxaximab, which are monoclonal antibodies directed against the protective antigen, and IV anthrax immune globulin, which is derived from vaccinated donors. All are approved or have orphan-drug status in the United States and the European Union, he noted, and are available through the CDC's Strategic National Stockpile.


Tularemia is acquired by direct or indirect contact with rabbits, hares, rodents, and deer; the bites of ticks or deer flies; consumption of contaminated water; or inhalation. Its incubation period is one to 21 days. It is found worldwide but only in the Northern Hemisphere, with periodic, localized outbreaks in the U.S. of about 100 to 300 cases per year, usually during the summer. “It has this interesting age distribution, where it's a little more common in little kids and in men in their 40s and 50s,” Dr. Maves said.

A bacteremic phase occurs after initial inoculation, with dissemination throughout the reticuloendothelial system, Dr. Maves said. Tularemia replicates intracellularly and produces endotoxin, but this is only weakly antigenic and doesn't appear to have a large role in human disease, he noted. Clinical manifestations vary based on site of infection, he said, and pulmonary tularemia caused by inhalation is the more life-threatening, severe form. Tularemia does not spread from humans to humans.

Patients with pulmonary tularemia may have minimal symptoms similar to those of upper respiratory infection, a dry cough, or fulminant pneumonia with unilateral or bilateral airspace opacities, Dr. Maves said. The incubation period is followed by rapid and acute illness, with nonspecific initial symptoms and high fever, diaphoresis, myalgia, and headache.

The gold standard for diagnosis of tularemia is a blood culture of Francisella tularensis from cysteine-enriched media. Cultivation is slow and difficult, however, and laboratory staff should be notified that there is a substantial risk of cultures spreading infection, Dr. Maves stressed. The serology of tularemia is not well standardized and often cross-reacts with Brucella, so “it's not super-reliable,” he said. “We can get [polymerase chain reaction] from respiratory specimens in whole blood and tissue through reference laboratories.”

Historically, the preferred treatment for tularemia has been streptomycin, 500 mg intramuscularly every 12 hours for 7 to 14 days, Dr. Maves said. However, since the drug is not readily available in the United States, alternate regimens include IV gentamicin, 5 mg/kg every 24 hours, and IV doxycycline, 200 mg every 12 hours for 72 hours, then 100 mg IV or orally every 12 hours for 7 to 14 days. Chloramphenicol and ciprofloxacin can be effective also but are not considered the therapy of choice if the other regimens are available, Dr. Maves stressed.

A live attenuated vaccine is available as an investigational new drug for high-risk groups, for example, lab workers, he said. Doxycycline or ciprofloxacin is recommended as postexposure prophylaxis for 14 days after high-risk exposure.


The bacteria that causes plague, Yersinia pestis, lives in rodents and is usually transmitted to humans by flea bite. It's a typical enteric gram-negative rod with bipolar staining, Dr. Maves said: “If I look at plague under a microscope, I can't tell this apart from E. coli.” It grows on conventional media within 24 to 48 hours and can be diagnosed serologically, with polymerase chain reaction, and with immunohistochemistry on formalin-fixed tissue. Bubonic plague is the localized form, while septicemic and pneumonic plague are systemic and have higher mortality rates. Pneumonic plague is often acquired by inhaling aerosolized particles from an index patient with bubonic plague, Dr. Maves said.

Bubonic plague has an incubation period of one to seven days, followed by aching in the limbs and malaise. Patients have a high fever and intense thirst and develop painful, draining lymphadenopathy, called a bubo, at the site of the bite. Prostration is common, Dr. Maves said: “People are laid out flat. They are profoundly unwell.” The mortality rate is 14%. Bubonic plague may progress to septicemic plague if left untreated, with a mortality rate of 30% to 50%.

Pneumonic plague presents as lobar pneumonia with typical gram-negative rods on sputum Gram stain. It is highly contagious, so both droplet and contact precautions are required, Dr. Maves stressed: “They need to be in both, and they need to be in both generally until they're clinically improving.” Patients typically have intense headache, myalgias, and watery blood-tinged sputum. There can also be marked encephalopathy, as well as hemorrhagic necrosis of most organ parenchyma.

In patients with pneumonic or septicemic plague, rapid antibacterial therapy is critical to survival, Dr. Maves said. The mortality rate is 57% overall, 100% if diagnosis is delayed. He noted that the CDC guidelines for plague treatment are currently under revision but offered thoughts on optimum therapy, pending the release of the formal guidelines.

“Right now, the thought is combination therapy with gentamicin and a fluoroquinolone [for pneumonic or septicemic plague]. This is more due to concerns for resistance in the organism rather than synergy between them,” he said. IV gentamicin, 5 mg/kg, can be given every 24 hours, plus IV ciprofloxacin, 400 mg every 12 hours, for 10 days. For bubonic plague, Dr. Maves recommends IV doxycycline, 200 mg every 12 hours for two doses, then 100 mg IV or orally every 12 hours for 10 days. Beta-lactams are not recommended, he said.

Antibiotics are also in order for anyone exposed to the plague. “For people who are exposed, a week of fluoroquinolone- or tetracycline-based postexposure prophylaxis is what we recommend,” Dr. Maves said.