Plague
Infectious Diseases


 

Xenopsylla cheopis, the Oriental rat flea that carries the plague.

Clinical Aspects of the Plague

Plague is primarily a disease of rodents, particularly marmots (in which the most virulent strains of plague are primarily found), but also black rats, prairie dogs, chipmunks, squirrels and other similar large rodents.

Plague normally appears in three forms in man:

  • bubonic,
  • primary septicemic,
  • pneumonic.

The buboes in the bubonic form are normally seen in the inguinal lymph nodes as the legs are the most commonly "flea-bitten" part of the human body. Septicemia is common, as greater than 80 percent of blood cultures are positive for the organism in bubonic plague, although primary septicemia may occur without lymphadenopathy. The pneumonic form is an infection of the lungs due either to inhalation of the organisms (primary pneumonic plague), or spread to the lungs from septicemia (secondary pneumonic plague). In man, the mortality of untreated bubonic plague is approximately 50 percent, whereas in pneumonic plague the mortality rate is 100 percent.

Fleas, humans, and rats served as hosts for the plague. The infection was transmitted to humans in two ways:

  1. Septicemic and bubonic plague - via a direct bite from an infected flea.

Human infection most often occurs when a person is bitten by the Oriental rat flea (Xenopsylla cheopsis) that has fed on an infected rodent. The bacteria multiplied in the stomach of the flea, blocking the feeding tube to the stomach and causing the flea to become very hungry. The flea would then start voraciously biting a host but unable to satisfy its hunger. During the frenzied feeding process, the blood consumed by the flea is regurgitated along with the bacillus which then flowed into the human's wound and was carried into the bloodstream. The plague bacteria now had a new host and the flea soon starved to death.
  1. Pneumonic plague - through airborne droplets of saliva from the mouth and lungs that were coughed up by bubonic or septicemic infected humans. In the droplets were the bacteria that caused the plague. The bacteria entered the lungs through the windpipe and started attacking the lungs and throat.

Bubonic Plague Bacterium

In 1894, bacteriologists Alexandre Yersin and Shibasaburo Kitasato independently isolated the responsible bacterium and Yersin further determined that rodents were the likely common mode of transmission. The disease is caused by the bacterium Yersinia pestis.

Yersinia pestis
(Lehmann & Neumann, 1896)

Yersinia pestis under fluorescent staining, 2000x. Source: CDC
Yersinia pestis under fluorescent staining, 2000x. Source: CDC

Scientific classification

Kingdom: Bacteria
Phylum: Proteobacteria
Class: Gamma Proteobacteria
Order: Enterobacteriales
Family: Enterobacteriaceae
Genus: Yersinia
Species: Y. pestis

Yersinia pestis, a rod-shaped, non-motile, non-sporulating, gram-negative, bipolar staining, facultative anaerobic bacterium belonging to the family Enterobacteriaceae and which has a fermentative metabolism. It is the infectious agent of Bubonic plague, normally a zoonotic disease of rodents (e.g., rats, mice, ground squirrels, and can also cause Pneumonic plague and Septicemic plague. Yersinia pestis produces a antiphagocytic slime. The organism is motile when isolated, but becomes nonmotile in the mammalian host.

Fleas which live on the rodents can sometimes pass the bacteria to human beings, who then suffer from the bubonic form of plague. The pneumonic form of the disease would be seen as the primary form after purposeful aerosol dissemination of the organisms. The bubonic form would be seen after purposeful dissemination through the release of infected fleas. All human populations are susceptible. Recovery from the disease may be followed by temporary immunity. The organism will probably remain viable in water and moist meals and grains for several weeks. At near freezing temperatures, it will remain alive from months to years but is killed by 15 minutes exposure to 72 ° C. It also remains viable for some time in dry sputum, flea feces, and buried bodies but is killed within several hours of exposure to sunlight.

All forms have been responsible for enormous mortality in many fearsome epidemics throughout the history of mankind (without treatment, 75% of all infected patients with the bubonic form die, and almost 100% with the pneumonic form), such as the Great Plague and the Black Death

History and Significance

The United States worked with Y. pestis as a potential biowarfare agent in the 1950's and 1960's before the old offensive biowarfare program was terminated, and other countries are suspected of weaponizing this organism. During World War II, there is reported evidence that Japan investigated the use of Y. pestis as a biological weapon. It was reported that they worked on a plan for attacking enemy troops with the organism by releasing plague-infected fleas. This bacterium could be delivered theoretically as an aerosol.

Signs and Symptoms

  • bubonic plague - the incubation period ranges from two to ten days with the onset also being acute and often fulminant. Malaise, high fever, and tender lymph nodes (buboes); may progress spontaneously to the septicemic form, with spread to the central nervous system, lungs, and elsewhere (pneumonic form). The liver and spleen are often tender and palpable. One quarter of patients will have various types of skin lesions - black necrotic and purpuric - that are caused by the endotoxemia. Occasionally a pustule, vesicle, eschar or papule containing leukocytes and bacteria will be apparent in the bubo distribution and presumably represents the site of the inoculating flea bite.

  • Septicemic plague - bleeding into the skin and other organs which creates black patches on the skin, hence the name Black Death. Untreated septicemic plague is universally fatal, but early treatment with antibiotics (usually streptomycin or gentamicin) is effective, reducing the mortality rate to around 15% (USA 1980s). People who die from this form of plague often die on the same day symptoms first appear.
  • Pneumonic plague - with infecting lungs comes the possibility of person-to-person transmission through respiratory droplets. The incubation period for pneumonic plague is usually between two and four days, but can be in as little as a few hours. The initial symptoms of headache, weakness, and coughing with hemoptysis (bloody sputum) are indistinguishable from other respiratory illnesses. The chest X-ray reveals a patchy or consolidated bronchopneumonia. The pneumonia progresses rapidly, resulting in dyspnea, stridor, and cyanosis. The terminal event is one of respiratory failure, circulatory collapse, and a bleeding diathesis. Without diagnosis and treatment, the infection can be fatal in one to six days; mortality in untreated cases may be as high as 95%. The disease can be effectively treated with antibiotics.

Laboratory diagnosis

Laboratory findings include a leukocytosis, with a total WBC count up to 20,000 cells with increased bands, and greater than 80 percent polymorphonuclear cells. One also often finds increased fibrin split products in the blood indicative of a low-grade DIC, and the ALT, AST, and bilirubin are also elevated.

A presumptive diagnosis can be made microscopically by identification of the gram-negative coccobacillus with safety-pin bipolar staining in Gram or Wayson's stained smears from a lymph node needle aspirate, sputum, or cerebrospinal fluid sample. When available, immunofluorescent staining is very useful. A definitive diagnosis can be readily made by culturing the organism from blood, sputum, and bubo aspirates. 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. Most naturally occurring strains of Y. pestis produce an F1-antigen in vivo, which can be detected in serum samples by immunoassay. A four-fold rise in antibody titer in patient serum is also diagnostic.

Related conditions:

  • infection is an inflammatory response to a microorganism, or the invasion of normally sterile host tissues by the organism.
  • bacteraemia is the presence of bacteria in the blood. Bacteraemia can occur in sepsis and other serious diseases such as infective endocarditis, but it may also be a harmless and transient condition.
  • diffuse intravascular coagulation (DIC)
  • multiple organ dysfunction syndrome including sepsis induced acute lung injury
  • meningitis, infection of the mesh that supports the brain, can be a complication of sepsis
  • endocarditis, infection of the inner layer of the heart, can also be a complication

Treatment

Early administration of antibiotics is very effective. Supportive therapy is required.

Isolation and Decontamination

Standard Precautions for healthcare workers exposed to bubonic plague. Droplet Precautions for healthcare workers exposed to pneumonic plague. Heat, disinfectants (2-5% hypochlorite) and exposure to sunlight renders bacteria harmless.

Medical Management

Use Standard Precautions for healthcare workers exposed to bubonic plague and Droplet Precautions for healthcare workers exposed to pneumonic plague until the patient has been on antibiotic therapy for at least 48 hours and there has been a favorable clinical response to treatment. Streptomycin, tetracycline, chloramphenicol, and gentamicin are highly effective, especially if begun early (within 24 hours of onset of symptoms). Plague pneumonia is almost always fatal if treatment is not initiated within 24 hours of the onset of symptoms. Streptomycin remains the drug of choice and is given 30 mg/kg/day (IM) in two divided doses for ten days. Gentamicin is acceptable if streptomycin is unavailable. While the patient is typically afebrile after 3 days, the extra week of therapy prevents relapses. Intravenous doxycycline 200 mg initially, followed by 100 mg every 12 hours for 10-14 days is also effective. Results obtained from laboratory animal, but not human, experience, indicate that quinolone antibiotics, such as ofloxacin and ciprofloxacin, may also be effective. The addition of chloramphenicol is required for the treatment of plague meningitis.

Usual supportive therapy required includes IV crystalloids and hemodynamic monitoring. Although low-grade DIC may occur, clinically significant hemorrhage is uncommon as is the need to treat with heparin. Finally, buboes rarely require incision and drainage or any form of local care, but instead recede with systemic antibiotic therapy. In fact, incision and drainage may pose a risk to others in contact with the patient.

Prevention

Vaccine

A licensed, killed whole cell vaccine is available for use in those considered to be at risk of exposure. The primary series consists of three doses. The initial dose of 1.0 ml IM followed by 0.2 ml IM at 1 and 6 months. Three booster doses of 0.2 ml IM are given at 6 month intervals following the third dose of the primary series and then every 1-2 years thereafter. The current vaccine offers protection against bubonic plague, but is probably not effective against aerosolized Y. pestis. Presently, 8-10 percent of inoculations result in local reactions which include erythema, induration, tenderness and edema at the site of injection. These typically resolve within 48 hours. Approximately 7-10 percent of inoculations will result in systemic symptoms including malaise, lymphadenopathy, fever and very rarely anaphylaxis, tachycardia, urticaria, or hypotension.

Antibiotics

Because of oral administration and relative lack of toxicity, the choice of antibiotic for prophylaxis or for use in face-to-face contacts of patients with pneumonic plague or after a confirmed or suspected plague BW attack is doxycycline 100 mg orally twice daily, for seven days or the duration of risk of exposure, whichever is longer. Ciprofloxacin has also shown to be effective in preventing disease in exposed mice, and may be more available in a wartime setting as it is also distributed in blister-packs for anthrax post-exposure prophylaxis.

References:

  • Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group (2001). Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine 344 (10): 699-709. PMID 11236773
  • Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM; Surviving Sepsis Campaign Management Guidelines Committee (2004). Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Critical Care Medicine 32 (3): 858-73. PMID 15090974
  • Martin GS, Mannino DM, Eaton S, Moss M (2003). The epidemiology of sepsis in the United States from 1979 through 2000. New England Journal of Medicine 348 (16): 1546-54. PMID 12700374

Plague as a Biological weapon

Plague has a long history as a biological weapon. Historical accounts from medieval Europe detail the use of infected animal carcasses, by Mongols, Turks and other groups, to contaminate enemy water supplies. Plague victims were also reported to have been tossed by catapult into cities under siege.

During World War II, the Japanese Army developed weaponized plague based on the breeding and release of large numbers of fleas. During the Japanese occupation of Manchuria, Unit 731 deliberately infected civilians and prisoners of war with the plague bacillus. These subjects, called "logs", were then studied by dissection, some while still living and conscious. After World War II, both the United States and the Soviet Union developed means of weaponizing pneumonic plague. Experiments included various delivery methods, vacuum drying, sizing the bacillus, developing strains resistant to antibiotics, combining the bacillus with other diseases, such as diphtheria, and genetic engineering. Scientists who worked in USSR bio-weapons programs have stated that the Soviet effort was formidable and that large stocks of weaponized plague bacillus were produced. Information on many of the Soviet projects is largely unavailable. Aerosolized pneumonic plague remains the most significant threat.

Sources:

  • http://en.wikipedia.org/wiki/Bubonic_plague
  • http://en.wikipedia.org/wiki/Yersinia_pestis
  • http://www.nbc-med.org/SiteContent/MedRef/OnlineRef/FieldManuals/medman/Plague.htm
  • http://en.wikipedia.org/wiki/Third_Pandemic
  • http://en.wikipedia.org/wiki/Climate_changes_of_535-536
  • http://www.insecta-inspecta.com/fleas/bdeath/Flea.html

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Created: Sunday, February 05, 2007; Last Updated: Sunday, December 16, 2012
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