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.
Treatment regiments are as follows:
Adults
Preferred choices:
Streptomycin, 1 gm IM twice daily for 10 days or
Gentamicin, 5 mg/kg IM or IV once daily or 2 mg/kg loading dose followed by 1.7 mg/kg IM or IV 3 times daily for 10 days.
Alternative choices include:
Doxycycline, 100 mg IV twice daily or 200 mg IV once daily for 10 days,
Ciprofloxacin, 400 mg IV twice daily for 10 days,
Chloramphenicol, 25 mg/kg IV 4 times daily for 10 days.
Children
Preferred choices include:
Streptomycin, 15 mg/kg IM twice daily (maximum daily dose, 2 gm) or
Gentamicin 2.5 mg/kg IM or IV 3 times daily for 10 days.
Alternative choices include:
Doxycycline >45 kg, give adult dosage, < 45 kg, give 2.2 mg/kg IV twice daily for 10 days (maximum, 200 mg/day),
Ciprofloxacin, 15 mg/kg IV twice daily for 10 days (maximum daily dose, 1 gm), or
Chloramphenicol, 25 mg/kg IV 4 times daily for 10 days (maximum daily dos3 4 gm.
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.
Patient Handouts
What is plague?
Plague is a disease caused by Yersinia pestis (Y. pestis), a bacterium found in rodents (e.g., squirrels, prairie dogs or mice) and their fleas in many areas around the world.
How do people become infected with plague?
There are two ways:
- Pneumonic plague occurs when Yersinia pestis infects the lungs. Transmission can take place if someone breathes in Y. pestis particles, which could happen in an aerosol release during a bioterrorism attack, or by breathing in Y. pestis suspended in respiratory droplets from a person (or animal) with pneumonic plague. Becoming infected in this way usually requires direct and close (within 6 feet) contact with the ill person or animal. It can be spread by sneezing or coughing.
- Bubonic plague is transmitted primarily by the bite from infected fleas; however, transmission can occur by bites or scratches from infected wild rodents and cats, or through contact with tissue from infected animals.
Can plague be spread from person to person?
Yes. The bacteria can spread from person to person by exposure to droplets in those who have close contact with a person with plague in his or her lungs.
What are the symptoms of plague?
Initial symptoms include fever, chills, muscle aches, headache, nausea, vomiting, diarrhea, abdominal pain and extreme exhaustion. Swollen and tender lymph nodes near where the infected flea bit the person are typical of bubonic plague. Pneumonic plague usually presents with a cough, bloody sputum and difficulty breathing.
How soon after infection do symptoms appear?
The incubation period for both types of plague is 2 to 7 days after exposure to the bacteria.
How is plague diagnosed?
Plague is diagnosed by isolating the bacteria from sputum, blood, spinal fluid or infected lymph nodes.
Can plague be treated?
Yes, plague can be treated with certain widely available antibiotics. If untreated, bubonic plague is fatal in approximately 50-60% of infected persons. Pneumonic plague is almost always fatal if not treated quickly after the onset of symptoms.
Can a person exposed to pneumonic plague avoid becoming sick?
Yes. People who have had close contact with an infected person can greatly reduce the chance of becoming sick if they begin treatment within 7 days of their exposure. Preventive treatment consists of taking antibiotics for at least 7 days.
Would medication be available in the event of a bioterrorism attack involving pneumonic plague?
Local jurisdictions, including Anne Arundel County, have plans for distributing medicines quickly in such an emergency. Large supplies of drugs would be needed in the event of a plague bioterrorism attack. These supplies are maintained in special stockpiles by the federal government and can be sent anywhere in the United States within 12 hours for distribution in local specifically arranged clinics.
Is a vaccine available to prevent pneumonic plague?
Currently, no pneumonic plague vaccine is available in the United States. Research is in progress, but we are not likely to have vaccines for several years or more. There is a vaccine for bubonic plague that is given to those who work in high-risk professions.
How can plague be prevented?
When traveling in areas such as the U.S. Southwest where plague is common, it is important to avoid being bitten by infected fleas, or having contact with plague-infected animals or persons infected with pneumonic plague. Patients with pneumonic plague should be quarantined until 3 full days of antibiotic treatment have been administered. Buildings should be rat-proofed, with appropriate storage and disposal of food, garbage and refuse. Dogs and cats in areas where plague is common should be treated with insecticides to prevent flea infestation.
Could plague be used for bioterrorism?
Yes. Plague is considered to be one of the agents that could be used for bioterrorism because the disease can be spread from person to person and would cause increased illness and death in the population if used as a weapon. If plague were used for bioterrorism, it probably would be aerosolized (made airborne).
Why are we concerned about pneumonic plague as a bioweapon?
Yersinia pestis used in an aerosol attack could cause cases of the pneumonic form of plague. One to six days after becoming infected with the bacteria, people would develop pneumonic plague. Once people have the disease, the bacteria can spread to others who have close contact with them. Because of the delay between being exposed to the bacteria and becoming sick, people could travel over a large area before becoming contagious and possibly infecting others. Controlling the disease would be a challenge to public health. A bioweapon carrying Y. pestis is possible because the bacterium occurs in nature and could be isolated and grown in quantity in a laboratory. Even so, manufacturing an effective weapon using Y. pestis would require advanced knowledge and technology.
Additional information may be obtained from the Centers for Disease Control and Prevention at www.cdc.gov
Trainings/Powerpoint Presentations
The Plague Presentation (2003) is available as a PowerPoint or as a PDF.
The BW Agents Presentation (2003) is available as a PowerPoint or as a PDF.
Additional Resources
Essential Reading
Dennis DT, Henderson DA, Inglesby TV, et al. Plague as a Biological Weapon: Medical and Public Health Management. JAMA 200;283:2281-90.
Additional Readings
Centers for Disease Control and Prevention. Imported Plague — New York City, 2002. Morbidity and Mortality Weekly Report. 2001;52(31):725-28.
Centers for Disease Control and Prevention. Recognition of Illness Associated with the Intentional Release of a Biologic Agent. Morbidity and Mortality Weekly Report. 2001;50(41);893-7.
Internet Resources
Centers for Disease Control and Prevention, Information for Health Professionals
Center for Infectious Disease Research and Policy of University of Minnesota