Bioterrorism Update: Plague

Plague may be rare today in the United States, but health care professionals should be aware of its potential as a weapon, because its pathogens are easily aerosolized and the symptoms are not likely to arouse suspicion until an epidemic is evident.

By Gregory J. Moran, MD

What is plague and what do we know about its effectiveness as a biological weapon?

Plague is caused by the organism Yersinia pestis, a nonmotile, gram-negative bacillus. Plague is well known from history as the cause of the Black Death that occurred during the Middle Ages and killed about one third of the population of Europe. Several other pandemics have occurred throughout history, during which tens of millions have fallen victim. As living conditions and public health practices have improved over the years and antibiotic therapy has been introduced and developed, the threat of naturally occurring plague has been curtailed significantly, but the disease continues to be a problem in some developing countries and has been known to occur even in the United States.

History reveals many examples of plague used as a biological weapon. In the Middle Ages, for example, armies laying siege to a fortified city would catapult plague-infected corpses over the city walls. In World War II, the Japanese army reportedly dropped plague-infected fleas over populated areas of China. Biological weapons programs in the United States and the Soviet Union have developed methods to aerosolize plague directly, without having to rely on a vector for dissemination. According to a 1970 World Health Organization report, if 50 kg of Y. pestis were released as an aerosol over a city of 5 million people, as many as 150,000 persons would become infected with pneumonic plague and 36,000 of those would be expected to die. Although Y. pestis is sensitive to sunlight and heat and would not be as stable as anthrax spores when released in the environment, the organism could remain viable in the air for about one hour for a distance up to 10 kilometers.

How is plague acquired and what are the symptoms?

Like anthrax, plague can occur in various manifestations, depending on how the pathogens are spread. Naturally occurring plague is spread by the bite of infected fleas. Bacteria move through the lymphatic system to the regional lymph nodes and multiply. This progression leads to the bubonic form of plague, characterized by fever and lymphadenopathy. If plague were to be used as a biological weapon, the pathogens would likely be spread via aerosol and inhaled, leading to the pneumonic form.

Bubonic plague. Symptoms usually begin within a week of a person's exposure to the bacteria. The typical presentation involves fever of sudden onset, chills, and acutely swollen and extremely tender lymph nodes, or buboes, usually in the groin or axilla. As the disease progresses, sepsis may develop along with disseminated intravascular coagulation (DIC) and purpuric skin lesions, eventually producing necrosis of the digits or nose (hence the name Black Death). In a small percentage of patients, a septicemic form of plague will develop, in which the buboes are not noticeable. Some patients may also have secondary pneumonia caused by hematogenous spreading of bacteria to the lungs.

Pneumonic plague. Pneumonic plague usually begins two to four days after a person is exposed to the pathogen. Infected persons will have fever, cough, and dyspnea, sometimes with bloody sputum. The clinical course basically follows that of a very severe and rapidly progressive pneumonia. Symptoms may progress rapidly to respiratory failure and full-blown sepsis with DIC. Chest films commonly show bilateral infiltrates or consolidation. The results of laboratory studies of seriously ill patients usually reveal what would be expected to accompany sepsis and end organ failure–leukocytosis, coagulation abnormalities, elevated transaminase levels, and azotemia.

How is the diagnosis of plague made?

Because the symptoms and signs of pneumonic plague are very similar to those of any severe pneumonia, the first clues of a biological attack will probably be epidemiologic. A cluster of patients presenting with severe pneumonia or sepsis should prompt suspicion of plague or some other type of outbreak, whether intentional or naturally occurring.

Plague would probably be detected through the usual microbiologic investigations performed for patients with severe pneumonia or sepsis. A Gram's stain of blood, sputum, or node aspirate may reveal gram-negative coccobacilli. A Wright, Giemsa, or Wayson stain may show a characteristic bipolar pattern. Cultures of sputum, blood, or node aspirate will show growth in about 24 to 48 hours. Because some automated culturing systems may misidentify Y. pestis, the testing laboratory should be notified when this organism is suspected. Eventually, Y. pestis may be identified more accurately through special techniques. No rapid tests are widely available. Some state public health laboratories may be able to perform tests such as antigen detection, ELISA for IgM, fluorescent antibody staining of sputum or blood specimens, or polymerase chain reaction.

What steps should be taken to protect the safety of health care personnel and other persons who have been exposed to a patient who has plague?

Pneumonic plague can be spread through respiratory droplets. Such transmission necessitates close contact (within two meters) with an infected person. To prevent the spread of infection through respiratory droplets in health care facilities, medical staff should isolate infected persons in designated rooms and wear surgical masks when in close contact with those patients. Because plague does not appear to spread very effectively via aerosol, a negative pressure room is probably not necessary, although some experts do recommend isolating infected patients in such rooms as a prudent precaution against the spread of pneumonic plague. If patients must share a room, they should be placed at least three meters apart to prevent droplet transmission among the group. These precautions should be followed for each patient until he or she has undergone appropriate antimicrobial therapy for at least 48 hours and shows clinical improvement.

The testing laboratory should be notified whenever plague is suspected. Cultures of Y. pestis may pose a moderate risk to laboratory personnel. These cultures and other specimens should be handled in accordance with biosafety level 2 precautions. The Centers for Disease Control and Prevention (CDC) have devised laboratory guidelines, the Biosafety in Microbiological and Biomedical Laboratories [BMBL], 4th edition (accessible at http://bmbl.od.nih.gov/sect3bsl1.htm), that outline in four categories the necessary precautions that clinicians must follow when testing specimens obtained from persons who may have been exposed to dangerous pathogens.

Because the bacilli that cause plague do not persist in the environment for long periods, environmental decontamination should not be necessary.

What is the recommended therapy for plague?

Although study data are very limited regarding the success of treatment targeted against plague, Y. pestis is susceptible to a number of antibiotics. Historically, streptomycin has been the preferred treatment, although it is not commonly used now and its availability is limited. Other options include gentamicin, doxycycline, ciprofloxacin, levofloxacin, and chloramphenicol. The same antibiotics are administered to adults and children alike. Intravenous therapy is usually recommended for seriously ill patients. In the case of an epidemic, during which resources may be limited, oral therapy with doxycycline or a quinolone could be effective.

Once a population's exposure to plague has been established, prompt antibiotic therapy should be administered to any patient who presents with fever or cough, because to delay such treatment before confirmatory test results are obtained would threaten a patient's chance for survival.

Should asymptomatic persons who may have been exposed to plague receive prophylactic therapy?

Asymptomatic persons who are believed to have been exposed to the primary source or who have been close contacts of persons with pneumonic plague should undergo prophylactic antibiotic therapy. Although no studies have addressed this approach, oral therapy with doxycycline or a quinolone would likely be effective, as would a sulfonamide agent or chloramphenicol. The recommended duration for prophylaxis is seven days. Any patients who show symptoms should be evaluated promptly.

Is a vaccine available for plague?

No vaccine is currently available for plague. A killed whole-bacilli vaccine was previously licensed in the United States but is no longer available. It was intended for preventing or ameliorating bubonic plague in laboratory workers or military personnel in endemic areas, but it did not appear to be effective against pneumonic plague. Research for a vaccine effective against pneumonic plague is ongoing.