Col. Byron Weeks, M.D., Ret.
Wednesday, Oct. 17, 2001

Like anthrax, plague is a highly lethal bacterium. Unlike anthrax, plague is contagious - and poses a significant threat to America's national security.

Plague is present in many areas of the world and is endemic in prairie dogs and squirrels in the southwestern United States.

American scientists found that plague bacteria quickly lose infectivity in an aerosol.

Weaponized plague was successfully developed after Pasechnik in the Soviet Union developed a powdered form covered with a polymer capsule.

The best delivery system, developed in Russia, is one that releases a canister that sprays a cloud of the dried and powdered bacterium from a low-flying and hard to detect object, the cruise missile.

Overview

Bubonic plague has been the most lethal disease pandemic (the term for an exceptionally widespread epidemic) in history. It killed one quarter of the European population in the 14th century. It is the most lethal, virulent and invasive disease known to man.

The plague bacterium, Yersinia pestis, is a rod-shaped bacillus that is non-motile (non-moving), doesn't form spores, stains red with Gram stain, and is of the family Enterobacteraceae.

It causes plague, a zoonotic disease (communicable from animals to humans) of rodents (e.g., rats, mice, ground squirrels and prairie dogs).

Various species of fleas that live on the rodents can transmit the bacteria to humans, who then suffer from the bubonic form of plague.

The bubonic form may progress to the septicemic (blood poisoning) and/or pneumonic forms.

Pneumonic plague is the most serious form of the disease and would be the predominant form after a purposeful aerosol dissemination.

Recovery from plague is followed by temporary immunity.

The organism remains viable in water, moist soil and grains for several weeks. At near freezing temperatures, it will remain alive from months to years but is killed by 15 minutes of exposure to 55°C.

It can live for some time in dry sputum, flea feces and buried bodies, but sunlight kills it within a few hours.

History and Significance

The United States worked with Y. Pestis as a potential biowarfare agent in the 1950s and 1960s before our offensive biowarfare program was terminated, and other countries are suspected of weaponizing this organism.

The former Soviet Union had more success than America and has tons of the dry powdered form for use as a bioweapon.

The Japanese army attempted to use infected fleas on the Chinese in World War II but met with little success. This method was cumbersome and unpredictable.

The Soviet Union developed the more reliable and effective method of aerosolizing the organism, and this method was later adopted in the U.S.

The contagious nature of pneumonic plague makes it particularly dangerous as a biological weapon.

Clinical Features

The three forms of plague in man are bubonic, septicemic and pneumonic.

Bubonic plague begins after an incubation period of two to 10 days, with high fever, malaise, headache, muscle aches and, usually, nausea, vomiting and diarrhea. Up to half of patients will have abdominal pain.

Simultaneous with or shortly after the onset of these nonspecific symptoms, the bubo develops - a swollen, tender lump or lymph node, usually noted in the groin, in the lymphatic drainage from the leg where a bite ordinarily occurs.

The liver and spleen are enlarged and tender. Twenty-five percent of victims will have a pustule, blister, dark scab, or pimple where the flea bite occurred.

Secondary septicemia (invasion of the bloodstream) is common, and 80 percent of patients will be positive for the bacteria on blood culture.

Occasionally the blood infection is primary, without buboes or skin lesions.

The symptoms are similar to other Gram-negative septicemias: high fever, chills, malaise, hypotension, nausea, vomiting and diarrhea.

The blood may clot in the small vessels of the fingers and toes, with necrosis and gangrene; clotting may even occur throughout the vascular system.

Blackened distal extremities (fingertips) and purplish patches under the skin are caused by a toxin and are signs of impending death. The bacteria can also spread to the central nervous system, lungs and elsewhere.

Plague meningitis occurs in about 6 percent of septicemic and pneumonic cases.

Pneumonic plague is an infection of the lungs due to either inhalation of the organisms (primary pneumonic plague) or spread to the lungs from septicemia (secondary pneumonic plague).

The pneumonic form is by far the most serious and usually comes on two to four days after either inhalation or via the infected bloodstream.

The first signs of illness include high fever, chills, headache, malaise and muscle pain, followed within 24 hours by a cough with bloody sputum, which may contain visible pus. Gastrointestinal symptoms, including nausea, vomiting, diarrhea and abdominal pain, may be present.

Rarely, a bubo might be seen in the neck area from an inhalational exposure. The chest X-ray commonly reveals patchy pneumonia, although at times it may be consolidated (lobar). The pneumonia progresses rapidly, resulting in shortness of breath, crowing breath sounds, and blueness of the skin. The disease terminates in about 18 hours with respiratory failure and shock.

Nonspecific laboratory findings include a total WBC count up of to 20,000 cells with increased band cells, a sign of infection, and greater than 80 percent polymorphonuclear cells.

One also often finds increased fibrin split products in the blood, indicative of a low-grade onset of coagulation disorder. Signs of kidney and liver failure are usually evident in blood chemistry.

In the bubonic type, the death rate is about 60 percent, and close to 100 percent in the pneumonic type when treatment is begun beyond 18 hours after infection.

In the absence of biowarfare the pneumonic type is rare. In the U.S. over the past 50 years, four out of seven pneumonic plague patients (57 percent) died.

Diagnosis

Diagnosis is based primarily on clinical suspicion.

The sudden appearance of large numbers of previously healthy patients with sudden onset of severe, rapidly progressive pneumonia with spitting up of blood strongly suggests plague. A blood smear, or examination of a bubo aspirate or spinal fluid, may demonstrate the organism. Blood culture is reliable and readily available, although studies of antibodies are specific when available.

The organism grows slowly at normal incubation temperatures, and may be misidentified by automated systems because of delayed biochemical reactions.

It may be cultured on blood agar, MacConkey agar or infusion broth. In immunoassay, a fourfold rise in antibody titer in patient serum is diagnostic, but the results tend to be available only after the patient is dead or has survived as a result of empiric treatment. Most clinical assays can be performed in Biosafety Level 2 labs, whereas procedures producing aerosols or yielding significant quantities of organisms require Level 3 containment.

Medical Management

Suspected pneumonic plague cases require strict isolation with masking and gowning to avoid droplets coughed by the patient.

Suspended droplets in the air around the patient are highly contagious. Isolation and quarantine must continue for at least the first 48 hours of antibiotic therapy, or until sputum cultures are negative in confirmed cases.

If competent vectors (fleas) and reservoirs (rodents) are present, flea insecticide sprays must be used, along with attempts at eradication of rodents near patient care areas.

In the areas of native infection, streptomycin, gentamicin, doxycycline, and chloramphenicol are highly effective, if begun early. The bioweaponized form from Russia is resistant to 16 different antibiotics and plague pneumonia is almost always fatal if treatment is not initiated with an effective antibiotic such as ciprofloxacin within 24 hours of the onset of symptoms.

Dosage regimens are as follows: gentamicin, 5mg/kg IM or IV once daily, or 2mg/kg loading dose followed by 1.75 mg/kg IM or IV every eight hours; doxycycline 200 mg initially, followed by 100 mg every 12 hours. Duration of therapy is 10 to 14 days. While the patient is typically afebrile after three days, the extra week of therapy prevents relapses. These may not be efficacious in resistant strains.. Recommended dosage of ciprofloxacin is 400mg IV twice daily. Chloramphenicol, 25 mg/kg IV loading dose followed by 15 mg/kg IV four times daily x 10-14 days, is required for the treatment of plague meningitis.

Usual supportive therapy includes IV saline and potassium if laboratory studies indicate. Monitoring of vital signs is important. Although low-grade coagulation disorders may occur, clinically significant hemorrhage is uncommon, as is the need to treat with heparin. Shock is common from the release of the bacterial endotoxin, but pressor agents such as dopamine are rarely needed. Buboes should not be drained, since they nearly always recede with antibiotic therapy and incision may tend to spread the infection to attendants. Aspiration with a needle and syringe is recommended for diagnostic purposes and may provide symptomatic relief.

Prophylaxis

Vaccine: No vaccine is available for prophylaxis of plague. A licensed, killed whole cell vaccine was available in the U.S. from 1946 until November 1998. It offered protection against bubonic plague, but was not effective against aerosolized Y. Pestis. A (fusion protein) antigen vaccine is in development at USAMRIID (U.S. Army Medical Research Institute of Infectious Diseases). It protected mice for a year against an inhalational challenge and is being tested in primates.

Antibiotics: For face-to-face contacts (within 2 meters), patients with pneumonic plague or persons possibly exposed to a plague aerosol in a plague biowarfare attack should be given antibiotic prophylaxis using a quinolone such as ciprofloxacin for seven days or the duration of risk of exposure plus seven days. If fever or cough occurs in these individuals, treatment with IV antibiotics should be started.

Ciprofloxacin, 500 mg orally twice daily, has also shown to be effective in preventing disease if the patient does not have any symptoms of infection, and it may be more available in a wartime setting, as it is also distributed in blister packs for anthrax post-exposure prophylaxis.

Tetracycline, 500 mg orally four times daily, and chloramphenicol, 25 mg/kg orally four times daily, are acceptable alternatives if the strain is native and not genetically modified. Contacts of bubonic plague patients need only be observed for symptoms for a week. If symptoms occur, start treatment with antibiotics.

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