Plague: a clinical perspective Speaker: Paul Mead, MD, PhD Centers for Disease Control and Prevention, Fort Collins, Colorado

Highlights

	The three main clinical forms of plague are bubonic, septicemic, and pneumonic; the latter is the most lethal.
	Plague is mainly transmitted to humans by bites of infected rodent fleas.
	Inhaling respiratory droplets from infected animals is another source of human disease; the inhalational route can also be exploited for bioterrorist purposes.
	Plague is a serious, but treatable, illness; however, delay in seeking care or misdiagnosis with delayed or incorrect treatment can be fatal.
	Guidelines for the medical and public health management of plague were developed in 2001 to address the availability of the required drugs and the feasibility of mass distribution for treatment.

Pandemics and weaponry

"Plague is a disease of considerable historical importance," said Paul Mead of the Centers for Disease Control and Prevention in Fort Collins, Colorado. The first known natural pandemic, called the "Justinian Plague," began in 451 AD in the Byzantine empire. It killed an estimated 100 million people and up to 40% of the population in some cities.

The second pandemic, known as the "Black Death," began in 1346 AD. Within a few years, it spread throughout Europe, killing an estimated 20-30 million people. The third, or "Modern" pandemic arose in China in 1894, and quickly spread, Mead noted, resulting in 12 million deaths in India alone. "Thanks to the advent of rapid transcontinental transportation in the form of steamships, the third pandemic spread to all inhabited continents, officially arriving in the United States in 1900, in San Francisco. Currently, plague occurs throughout the world, with infection of rodents on every populated continent except Australia," he explained. Today, nearly 80% of reported cases are from Africa, 15% from Asia, and the remaining from the Americas.

Plague occurs throughout the world.

"Much of the current interest in plague, at least in the United States, comes not from its historical importance or global distribution but rather from its potential for use as a biologic weapon either for warfare or for terrorism," Mead continued. During WWII, a unit of the Japanese army reportedly dropped plague-infected fleas over populated areas of China. During the Cold War, both the US and the USSR bioweapons programs included plague, and both tried to develop effective ways of delivering infectious aerosols. The US defensive program was reportedly dismantled in the 1970s, whereas the Soviet program reportedly continued until the 1990s. More recently, said Mead, a microbiologist in Ohio was arrested for fraudulently acquiring Yersinia pestis—the Gram-negative bacillus that causes plague—by mail, presumably for nefarious purposes.

Spreading infection

Plague can be transmitted to humans by several routes, most commonly through the bites of infected rodent fleas, which pose a "serious threat" in some residential areas, said Mead. Humans also can become infected through direct contact with infected animals, including pets. "Cats, in particular, are susceptible to plague and have been the source of several primary pneumonic infections in humans." Lagamorphs (rabbits and hares) are occasionally a source of infection for hunters and others who handle their carcasses.

Inhaling respiratory droplets from plague-infected animals can also cause human disease. But although the inhalational route can also be exploited for purposes of bioterrorism, Mead observed, "it is not clear, to me at least, whether man-made aerosols have the same properties or behave in the same way as naturally generated aerosols. For example, man-made aerosols might travel over greater distances or maintain virulence for longer periods of time than would be expected with natural aerosols."

Three types of plague

The three main types of plague are bubonic, septicemic, and pneumonic. The latter two occur most often as secondary complications of bubonic plague, but may also be primary forms of infection. In the United States, bubonic plague accounts for 80%-85% of primary cases, septicemic for approximately 15%, and pneumonic for 1%-2%. Among patients who present with primary bubonic plague, approximately 20% will develop secondary sepsis and about 10% will develop secondary pneumonia.

Untreated, plague is fatal in over 50% of bubonic cases, and in nearly all cases of septicemic or pneumonic plague. The overall plague case fatality rate in the United States is about 15%. Fatalities are most often due to delay in seeking care or misdiagnosis with delayed or incorrect treatment.

Bubonic plague: tender nodules

The incubation period for bubonic plague is two to six days, occasionally longer. As with other forms of plague, illness begins with fever, headache, chills, muscle weakness, and a feeling of fatigue. At the same time or within 24 hours of symptom onset, the affected individual notices tenderness and pain in inguinal, axillary, or other regional lymph nodes.

Plague patients typically have white blood cell counts of 12,000-25,000 cells per cubic millimeter, but counts may go as high as 50,000, especially in children. The buboes are "exquisitely tender," said Mead, and often remain large and tender for a week or more after treatment has begun. In about 5% of cases, the area around the flea bite may become infected, and the resulting lesion may be confused with those caused by tularemia or anthrax.

White blood cell counts may go as high as 50,000.

Mild forms of bubonic plague, referred to as pestis minor, have been reported in South America and elsewhere. In these cases, the affected individuals typically have milder illness and subacute buboes. "Although the classic description of plague includes profound fatigue and listlessness, we recently saw a man who walked more than 20 kilometers to a local clinic to get treatment," Mead noted.

The differential diagnosis for bubonic plague includes staphylococcal lymphadenitis (infection of the lymph nodes), tularemia, cat scratch disease, mycobacterial infection, chancroid and other sexually transmitted diseases that cause lymphadenitis, and strangulated inguinal hernias. The buboes in plague generally are distinguishable from lymphadenitis and most other causes by their rapid onset, extreme tenderness, and by the absence of cellulitis.

Septicemic plague: overwhelming infection

Septicemic plague is characterized by rapidly progressive, overwhelming bacterial infection, said Mead. Symptoms include fever, chills, physical exhaustion, and abdominal symptoms such as nausea, vomiting, and diarrhea. The course of illness is very rapid; patients develop signs of shock with low blood pressure and small red dots caused by bleeding into the skin.

Septicemic plague is a rapidly progressive, overwhelming bacterial infection.

Difficult-to-treat acute respiratory distress syndrome (ARDS) can occur in septic plague. Thrombi (clots) in the microvasculature, especially in areas such as the tips of the ears and fingers, may cause gangrene of the affected tissues, requiring amputation. The differential diagnosis for septicemic plague includes many other overwhelming systemic infections, including gram-negative sepsis and bacterial endocarditis. In some countries, the disease in its early stages may be confused with typhoid fever or with malaria.

Pneumonic plague: highly virulent

Pneumonic plague is a highly virulent form of plague. Primary pneumonic plague is caused by direct inhalation of infected respiratory droplets or aerosolized bacteria. The incubation period for this form of pneumonic plague is one to seven days, although most cases arise three to five days after exposure. Onset is usually sudden, with chills, fever, headache, body pain, weakness, dizziness, chest discomfort, and gastrointestinal symptoms. Cough, sputum production, increasing chest pain, and difficulty breathing typically predominate on the second day of illness, and may be accompanied by increasing respiratory distress. This is followed by cardiopulmonary insufficiency, cyanosis, and ultimately, circulatory collapse.

A patient with pneumonic plague requires intensive medical and nursing support.

Secondary pneumonic plague is caused by the spread of infection to the lungs from another part of the body, such as a bubo. Secondary pneumonic plague begins as an inflammation of the lungs with little sputum production. However, left untreated, it may progress to severe bronchial pneumonia with bloody sputum. Affected individuals occasionally develop pulmonary abscesses.

A patient with pneumonic plague requires intensive medical and nursing support, Mead emphasized. Death can occur quickly unless the person receives prompt treatment with antimicrobials. Health care providers who have close contact with pneumonic plague patients may be advised to take antibiotics prophylactically, usually doxycycline. Those who have less contact may watch for fever, taking their temperature several times a day for a week and getting immediate antibiotic treatment if they develop a fever.

The differential for pneumonic plague includes other bacterial pneumonias, Legionnaire's disease, streptococcal pneumonia, tularemia pneumonia, hantavirus pulmonary syndrome (particularly in the southwest United States) and acute respiratory syndrome of coronavirus.

Diagnosis and treatment

As with many diseases, a high index of clinical suspicion and careful history and physical exam are required to make a timely diagnosis of plague. As noted earlier, delayed or misdiagnosis is associated with a high case fatality rate. When plague is suspected, specimens should be obtained promptly for microbiologic study, Mead stressed. Appropriate diagnostic assessments include blood, lymph node aspirates in individuals with suspected buboes, sputum samples or tracheal bronchial aspirates in those suspected pneumonic plague, and cerebrospinal fluid in those with signs of meningitis.

Because of recent concerns about bioterrorism, CDC has worked with state and local health departments to develop the Laboratory Response Network, or LRN, a national network with the capability to identify plague, as well as other bioterrorism agents. Laboratory confirmation of plague depends on the isolation of Y. pestis from body fluids or tissues. When the organism can't be recovered, plague cases can still be confirmed by demonstrating a four-fold or greater change in antibodies to Y. pestis F1 antigen.

Recently, antigen capture, polymerase chain reaction assays, and hand-held dip sticks have been developed for rapid and early diagnoses. These are being further evaluated. The hand-held devices, in particular, allow for diagnosis at the bedside even in fairly primitive conditions. Mead's colleagues are currently studying the use of such devices in Madagascar and Uganda.

Treatment of plague is complicated because some drugs are not widely available or FDA-approved.

"The antimicrobial treatment of plague is complicated by the fact that some of the drugs are not widely available and other ones are not FDA-approved," Mead noted. Because of its availability and ease of administration, gentamicin is replacing streptomycin as the treatment of choice for plague patients in the United States. Trials comparing the safety and efficacy of streptomycin with gentamicin in plague have not been completed. However, case reports indicate that gentamicin is an acceptable substitute, although it is not FDA-approved for this indication.

Chloramphenicol is indicated for conditions in which high tissue penetration is important, such as plague meningitis. The drug can be used on its own or in combination with aminoglycosides. Ciprofloxacin has also shown promise in vitro and in laboratory animal studies, but studies demonstrating its utility in human plague have not been widely reported.

Penicillin, cephalosporins, and macrolides have poor efficacy and should not be used, Mead cautioned. Although trimethoprim-sulfamethoxazol has been used successfully to treat bubonic plague, it is not considered a first-line choice, nor is it recommended for severe forms of the disease.

Y. pestis strains showing some degree of antimicrobial resistance have been occasionally isolated from humans, Mead said. However, in most instances they have not been associated with treatment failure.

Mead noted that guidelines for the medical and public health management of a potential bioterrorist attack involving plague have been developed and published in the Journal of the American Medical Association in 2000. The guidelines recommend streptomycin and gentamicin as first-line therapy in contained casualty settings, and oral doxycycline or ciprofloxacin as the preferred agent in mass casualty situations. "The guidelines were driven in part by the belief that pneumonic plague would be the most likely form of plague following an intentional release, and by the need to address the availability of effective drugs and the feasibility of mass distribution for treatment," he concluded.