Clinical Overview

Plague is a zoonotic infection caused by the Gram-negative bacillus Yersinia pestis. Three great human plague pandemics have been responsible for more deaths than any other infectious agent in world history. Plague is maintained in nature, predominantly in urban and sylvatic rodents, by a flea vector. Humans are not necessary for persistence of the organism. As a secondary host, we acquire the disease from animal fleas, contact with infected animals or rarely, from other humans, via aerosol or direct contact with infected secretions.

Throughout history, the black rat, Rattus rattus, has been most responsible worldwide for the persistence and spread of plague in urban epidemics. All rodents, and even burrowing owls may mechanically transmit fleas. Mammals that are partially resistant to plague infection serve as continuous reservoirs of plague. In the United States, deer mice and ground squirrels are thought to serve as the main reservoirs. Some susceptible mammals are only occasionally infected: chipmunks, tree squirrels, cottontail rabbits and domestic cats. Highly susceptible animals amplify both fleas and bacilli. Such epizootics occur in chipmunks, ground squirrels and wood rats, but especially in prairie dogs, rock squirrels and California ground squirrels.

Plague has been endemic in the continental United States since at least 1900 and now is permanently established from the eastern slope of the Rocky Mountains. The U.S. has averaged 9 human cases of natural plague per year since 1990, primarily in the west. Ninety-three percent of cases have occurred between April and November, peaking in July. As few as 1 to 10 Y pestis organisms are a sufficient infectious dose via the oral, intradermal, subcutaneous and intravenous routes. It is thought that 100 to 20,000 organisms are required for infection via inhalation.

Clinical Presentation

In the United States, most patients (85-90 percent) with human plague present clinically with the bubonic form, 10-15 percent with the primary septicemic form, and 1 percent with the pneumonic form. Secondary septicemic plague occurs in 23 percent of patients who present with bubonic plague, and secondary pneumonic plague occurs in 9 percent. If Y pestis were used as a biological warfare agent, the clinical manifestations of plague would be (a) epidemic pneumonia with blood-tinged sputum if aerosolized bacteria were used or (b) bubonic or septicemic plague, or both, if fleas were used as carriers.

Bubonic Plague

Buboes manifest after a 1 - 8 day incubation period, with the regular onset of sudden fever, chills and headache often followed several hours later by nausea and vomiting. Presenting symptoms include prostration or severe malaise, headache, vomiting, chills, altered mentation, cough, abdominal pain and chest pain. Six to 8 hours after onset of symptoms, buboes, heralded by severe pain, occur in the groin, axillary, or cervical lymph nodes depending on the site of bacterial inoculation. Buboes become visible within 24 hours. Other manifestations of bubonic plague include bladder distention, apathy, confusion, fright, anxiety, oliguria and anuria. Tachycardia, hypotension, leukocytosis and fever are frequently encountered. Untreated, septicemia will develop in 2 - 6 days. Approximately 5 -15 percent of bubonic plague patients will develop secondary pneumonic plague and, as a result, the potential for airborne transmission will arise.

Septicemic Plague

Septicemic plague may occur primarily, or secondarily as a complication of hematogenous dissemination of bubonic plague. Presenting signs and symptoms of primary septicemic plague are essentially the same as those for any Gram-negative septicemia: fever, chills, nausea, vomiting and diarrhea. Later, disseminated intravascular coagulation (DIC), acral cyanosis and necrosis may be seen.

Pneumonic Plague

Pneumonic plague may occur primarily from inhalation of aerosols, or secondarily, from hematogenous dissemination. Patients typically have a productive cough with blood-tinged sputum within 24 hours after onset of symptoms. The findings on chest x-ray may be variable, but bilateral alveolar infiltrates appear to be the most common finding in pneumonic plague.

Diagnosis

To be able to differentiate endemic disease from plague used in biological warfare, understanding the natural vector is important. First, a die-off of animals in the mammalian reservoir that harbor bacteria-infected fleas will occur. Second, patients in close proximity to such infected mammals will become infected. By contrast, in the most likely biological warfare scenario, plague would be spread via aerosol. A rapid person-to-person spread of fulminant pneumonia, characterized by blood-tinged sputum, would then ensue.

A patient with a typical presentation of bubonic plague (e.g., with a painful bubo in the setting of fever, prostration and possible exposure to rodents or fleas in an endemic area) should readily suggest the diagnosis of plague. However, if the patient presents in a nonendemic area or without a bubo, then the diagnosis can be most difficult. Diagnosis is established by isolating the organism from blood or other tissues. Rapid diagnosis may be made with fluorescent antibody stains of sputum or tissue specimens. In patients with lymphadenopathy, a bubo aspirate should be obtained. Cultures of blood, bubo aspirate, sputum and cerebrospinal fluid (if indicated) should be performed; cultures will usually grow within 48 hours, but can be completely negative for the first 24 hours. Serologic assays measuring the immune response to plague infection are mainly of value retrospectively, since patients present clinically before they develop a significant antibody response. A polymerase chain reaction (PCR) test, can detect as few as 10 Y pestis organisms, even in the presence of flea tissue.

Treatment

Since 1948, streptomycin has remained the treatment of choice for bubonic, septicemic and pneumonic plague. It should be given intramuscularly in a dose of 30 mg/kg/d in two divided doses. In cases of suspected meningitis or in patients who are hemodynamically unstable, intravenous chloramphenicol (50-75 mg/kg/d in four divided doses) should be added. Treatment should be continued for a minimum of 10 days or 3 - 4 days after clinical recovery. Buboes typically recede with 10 -14 days of antibiotic treatment and do not require drainage. Patients are unlikely to survive primary pneumonic plague if antibiotic therapy is not initiated within 18 hours of the onset of symptoms. Without treatment, mortality is 60 percent for bubonic plague and 100 percent for the pneumonic and septicemic forms.

In the event of mass exposure and the need for post-exposure prophylaxis, the regiment for adults is: adults preferred choice: Doxycycline, 100 mg PO twice daily for 7 days or Ciprofloxacin, 500 mg PO twice daily for 7 days. Alternative choice: Chloramphenicol, 25 mg/kg PO 4 times daily for 7 days. For Children preferred choice: Doxycycline, if >45 kg, give adult dosage; if < 45 kg, give 2.2 mg/kg PO twice daily for 7 days or Ciprofloxacin, 20 mg/kg PO twice daily for 7 days (maximum daily dose, 1 gm). An alternative choice is Chloramphenicol, 25 mg/kg PO 4 times daily for 7 days (maximum daily dose, 4 gm).

Transmissibility and Infection Control

Plague may be spread through droplet contact. All patients with plague should be isolated for the first 48 hours after the initiation of treatment. Special care must be taken in handling blood and bubo discharge. If pneumonic plague is present, strict, rigidly enforced respiratory isolation procedures must be followed, including the use of gowns, gloves and eye protection. Patients with pneumonia must be isolated until they have completed at least 4 days of antibiotic therapy. If patients have no pneumonia or draining lesions at 48 hours, they may be taken out of strict isolation.

A licensed, killed, whole-cell vaccine is available to protect humans against bubonic, but not against primary pneumonic, plague. Only individuals at high risk for plague should be immunized. High risk groups include military troops and other field personnel that work in plague endemic areas in which exposure to rats and fleas cannot be controlled.

As with any bioterrorism agent, a case or suspected case of plague in someone living or working in the County should be immediately reported by phone call to the Anne Arundel County Department of Health at 410-222-7256. To report communicable diseases, click here for instructions.