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Plague
Yersinia pestis seen at 200× magnification with a fluorescent label.
Specialty	Infectious disease
Symptoms	Fever, weakness, headache[1]
Usual onset	1-7 days after exposure[2]
Types	Bubonic plague, septicemic plague, pneumonic plague[1]
Causes	Yersinia pestis[2]
Diagnostic method	Finding the bacterium in a lymph node, blood, sputum[2]
Prevention	Plague vaccine[2]
Treatment	Antibiotics and supportive care[2]
Medication	Gentamicin and a fluoroquinolone[3]
Prognosis	~10% risk of death (with treatment)[4]
Frequency	~600 cases a year[2]

Plague is an infectious disease caused by the bacterium Yersinia pestis.^[2] Symptoms include fever, weakness and headache.^[1] Usually this begins one to seven days after exposure.^[2] In the bubonic form there is also swelling of lymph nodes, while in the septicemic form tissues may turn black and die, and in the pneumonic form shortness of breath, cough and chest pain may occur.^[1]

Bubonic and septicemic plague is generally spread by flea bites or handling an infected animal.^[1] The pneumonitic form is generally spread between people through the air via infectious droplets.^[1] Diagnosis is typically by finding the bacterium in fluid from a lymph node, blood or sputum.^[2]

Those at high risk may be vaccinated.^[2] Those exposed to a case of pneumonic plague may be treated with preventative medication.^[2] If infected, treatment is with antibiotics and supportive care.^[2] Typically antibiotics include a combination of gentamicin and a fluoroquinolone.^[3] The risk of death with treatment is about 10% while without it is about 70%.^[4]

Globally about 600 cases are reported a year.^[2] In 2017 the countries with the most cases include the Democratic Republic of the Congo, Madagascar and Peru.^[2] In the United States infections occasionally occur in rural areas and the bacteria is believed to circulate among rodents.^[5] It has historically occurred in large outbreaks, with the most well known being the Black Death in the 14th century, which resulted in greater than 50 million dead.^[2]

Signs and symptoms

Bubonic plague

Swollen inguinal lymph glands on a person infected with the bubonic plague. The swollen lymph glands are termed buboes from the Greek word for groin, swollen gland: bubo.

When a flea bites a human and contaminates the wound with regurgitated blood, the plague carrying bacteria are passed into the tissue. Y. pestis can reproduce inside cells, so even if phagocytosed, they can still survive. Once in the body, the bacteria can enter the lymphatic system, which drains interstitial fluid. Plague bacteria secrete several toxins, one of which is known to cause beta-adrenergic blockade.^[6]

Y. pestis spreads through the lymphatic vessels of the infected human until it reaches a lymph node, where it causes acute lymphadenitis.^[7] The swollen lymph nodes form the characteristic buboes associated with the disease,^[8] and autopsies of these buboes have revealed them to be mostly hemorrhagic or necrotic.^[9]

If the lymph node is overwhelmed, the infection can pass into the bloodstream, causing secondary septicemic plague and if the lungs are seeded, it can cause secondary pneumonic plague.^[10]

Septicemic plague

Septicemic plague resulting in necrosis

Lymphatics ultimately drain into the bloodstream, so the plague bacteria may enter the blood and travel to almost any part of the body. In septicemic plague, bacterial endotoxins cause disseminated intravascular coagulation (DIC), causing tiny clots throughout the body and possibly ischemic necrosis (tissue death due to lack of circulation/perfusion to that tissue) from the clots. DIC results in depletion of the body's clotting resources, so that it can no longer control bleeding. Consequently, there is bleeding into the skin and other organs, which can cause red and/or black patchy rash and hemoptysis/hematemesis (coughing up/ vomiting of blood). There are bumps on the skin that look somewhat like insect bites; these are usually red, and sometimes white in the center. Untreated, septicemic plague is usually fatal. Early treatment with antibiotics reduces the mortality rate to between 4 and 15 percent.^[11][12][13] People who die from this form of plague often die on the same day symptoms first appear.^{[citation needed]}

Pneumonic plague

The pneumonic form of plague arises from infection of the lungs. It causes coughing and sneezing and thereby produces airborne droplets that contain bacterial cells and are likely to infect anyone inhaling them. The incubation period for pneumonic plague is short, usually two to four days, but sometimes just a few hours. The initial signs are indistinguishable from several other respiratory illnesses; they include headache, weakness and spitting or vomiting of blood. The course of the disease is rapid; unless diagnosed and treated soon enough, typically within a few hours, death may follow in one to six days; in untreated cases mortality is nearly 100%.^[14][15]

Cause

The Oriental rat flea (Xenopsylla cheopsis) engorged with blood after a blood meal. This species of flea is the primary vector for the transmission of Yersinia pestis, the organism responsible for bubonic plague in most plague epidemics in Asia, Africa and South America. Both male and female fleas feed on blood and can transmit the infection.

A child bitten by a flea infected with the bacterium Yersinia pestis. Y. pestis, a member of the family Enterobacteriaceae, has caused the bite to become ulcerated.

Transmission of Y. pestis to an uninfected individual is possible by any of the following means.^[16]

• droplet contact – coughing or sneezing on another person


• direct physical contact – touching an infected person, including sexual contact


• indirect contact – usually by touching soil contamination or a contaminated surface


• airborne transmission – if the microorganism can remain in the air for long periods


• fecal-oral transmission – usually from contaminated food or water sources


• vector borne transmission – carried by insects or other animals.

Yersinia pestis circulates in animal reservoirs, particularly in rodents, in the natural foci of infection found on all continents except Australia. The natural foci of plague are situated in a broad belt in the tropical and sub-tropical latitudes and the warmer parts of the temperate latitudes around the globe, between the parallels 55 degrees North and 40 degrees South.^[16]
Contrary to popular belief, rats did not directly start the spread of the bubonic plague. It is mainly a disease in the fleas (Xenopsylla cheopis) that infested the rats, making the rats themselves the first victims of the plague. Infection in a human occurs when a person is bitten by a flea that has been infected by biting a rodent that itself has been infected by the bite of a flea carrying the disease. The bacteria multiply inside the flea, sticking together to form a plug that blocks its stomach and causes it to starve. The flea then bites a host and continues to feed, even though it cannot quell its hunger, and consequently the flea vomits blood tainted with the bacteria back into the bite wound. The bubonic plague bacterium then infects a new person and the flea eventually dies from starvation. Serious outbreaks of plague are usually started by other disease outbreaks in rodents, or a rise in the rodent population.^[17]

Prevention

Since human plague is rare in most parts of the world, routine vaccination is not needed other than for those at particularly high risk of exposure, nor for people living in areas with enzootic plague, meaning it occurs at regular, predictable rates in populations and specific areas, such as the western United States. It is not even indicated for most travellers to countries with known recent reported cases, particularly if their travel is limited to urban areas with modern hotels. The CDC thus only recommends vaccination for: (1) all laboratory and field personnel who are working with Y. pestis organisms resistant to antimicrobials: (2) people engaged in aerosol experiments with Y. pestis; and (3) people engaged in field operations in areas with enzootic plague where preventing exposure is not possible (such as some disaster areas).^[18]

A systematic review by the Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine.^[19]

Treatments

If diagnosed in time, the various forms of plague are usually highly responsive to antibiotic therapy. The antibiotics often used are streptomycin, chloramphenicol and tetracycline. Amongst the newer generation of antibiotics, gentamicin and doxycycline have proven effective in monotherapeutic treatment of plague.^[20]

The plague bacterium could develop drug-resistance and again become a major health threat. One case of a drug-resistant form of the bacterium was found in Madagascar in 1995.^[21] Further outbreaks in Madagascar were reported in November 2014^[22] and October 2017^[23].

Epidemiology

Distribution of plague infected animals 1998

Globally about 600 cases are reported a year.^[2] In 2017 the countries with the most cases include the Democratic Republic of the Congo, Madagascar and Peru.^[2] It has historically occurred in large outbreaks, with the most well known being the Black Death in the 14th century which resulted in greater than 50 million dead.^[2]

Biological weapon

Plague has a long history as a biological weapon. Historical accounts from ancient China and medieval Europe detail the use of infected animal carcasses, such as cows or horses, and human carcasses, by the Xiongnu/Huns, Mongols, Turks and other groups, to contaminate enemy water supplies. Han Dynasty General Huo Qubing is recorded to have died of such a contamination while engaging in warfare against the Xiongnu. Plague victims were also reported to have been tossed by catapult into cities under siege.

In 1347, the Genoese possession of Caffa, a great trade emporium on the Crimean peninsula, came under siege by an army of Mongol warriors of the Golden Horde under the command of Janibeg. After a protracted siege during which the Mongol army was reportedly withering from the disease, they decided to use the infected corpses as a biological weapon. The corpses were catapulted over the city walls, infecting the inhabitants. This event might have led to the transfer of the plague (Black Death) via their ships into the south of Europe, possibly explaining its rapid spread.^[24]

During World War II, the Japanese Army developed weaponised plague, based on the breeding and release of large numbers of fleas. During the Japanese occupation of Manchuria, Unit 731 deliberately infected Chinese, Korean and Manchurian civilians and prisoners of war with the plague bacterium. These subjects, termed "maruta" or "logs", were then studied by dissection, others by vivisection while still conscious. Members of the unit such as Shiro Ishii were exonerated from the Tokyo tribunal by Douglas MacArthur but 12 of them were prosecuted in the Khabarovsk War Crime Trials in 1949 during which some admitted having spread bubonic plague within a 36-km radius around the city of Changde.^[25]

Ishii innovated bombs containing live mice and fleas, with very small explosive loads, to deliver the weaponized microbes, overcoming the problem of the explosive killing the infected animal and insect by the use of a ceramic, rather than metal, casing for the warhead. While no records survive of the actual usage of the ceramic shells, prototypes exist and are believed to have been used in experiments during WWII.

After World War II, both the United States and the Soviet Union developed means of weaponising pneumonic plague. Experiments included various delivery methods, vacuum drying, sizing the bacterium, developing strains resistant to antibiotics, combining the bacterium 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 weaponised plague bacteria were produced. Information on many of the Soviet projects is largely unavailable. Aerosolized pneumonic plague remains the most significant threat.^{[citation needed]}

The plague can be easily treated with antibiotics, which some countries, such as the United States, have large supplies on hand if such an attack should occur, thus making the threat less severe.^[26]

See also

• Timeline of plague

References

External links

• WHO Health topic


• 
  CDC Plague map world distribution, publications, information on bioterrorism preparedness and response regarding plague


• Symptoms, causes, pictures of bubonic plague