This article is about the disease caused by Yersinia pestis. For the 14th-century pandemic commonly referred to as "The Plague", seeBlack Death. For other uses, seePlague (disambiguation).
The bubonic and septicemic forms are generally spread byflea bites or handling an infected animal,[1] whereas pneumonic plague is generally spread between peoplethrough the air via infectious droplets.[1] Diagnosis is typically made by finding the bacterium in fluid from a lymph node, blood orsputum.[2]
Vaccination is recommended only for people at high risk of exposure to plague. Those exposed to a case of pneumonic plague may be treated with preventive medication.[2] If infected, treatment is withantibiotics andsupportive care.[2] Typically antibiotics include a combination ofgentamicin and afluoroquinolone.[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 theDemocratic Republic of the Congo,Madagascar andPeru.[2] In the United States, infections occasionally occur in rural areas, where the bacteria are believed to circulate amongrodents.[5] It has historically occurred in largeoutbreaks, with the best known being theBlack Death in the 14th century, which resulted in more than 50 million deaths in Europe.[2]
There are several different clinical manifestations of plague. The most common form is bubonic plague, followed by septicemic and pneumonic plague.[6] Other clinical manifestations include plague meningitis, plague pharyngitis, and ocular plague.[6][7] General symptoms of plague include fever, chills, headaches, and nausea.[1] Many people experience swelling in their lymph nodes if they have bubonic plague.[1] For those with pneumonic plague, symptoms may (or may not) include a cough, pain in the chest, and haemoptysis.[1]
Swollen inguinal lymph glands on a person infected with the bubonic plague. The swollen lymph glands are termedbuboes from the Greek word for groin, swollen gland:bubo.
When a flea bites a human and contaminates the wound with regurgitated blood, the plague-causing bacteria are passed into the tissue.Y. pestis can reproduce inside cells, so even ifphagocytosed, they can still survive. Once in the body, the bacteria can enter thelymphatic system, which drainsinterstitial fluid. Plague bacteria secrete severaltoxins, one of which is known to causebeta-adrenergic blockade.[8]
Y. pestis spreads through thelymphatic vessels of the infected human until it reaches alymph node, where it causes acutelymphadenitis.[9] The swollen lymph nodes form the characteristicbuboes associated with the disease,[10] and autopsies of these buboes have revealed them to be mostlyhemorrhagic ornecrotic.[11]
If the lymph node is overwhelmed, the infection can pass into the bloodstream, causingsecondary septicemic plague and if the lungs are seeded, it can causesecondary pneumonic plague.[12]
Lymphatics ultimately drain into the bloodstream, so the plague bacteria may enter the blood and travel to almost any part of the body. Insepticemic plague, bacterial endotoxins causedisseminated intravascular coagulation (DIC), causing tiny clots throughout the body and possibly ischemic necrosis, in which tissues die due to a lack of blood circulation. 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 a red or black patchy rash, and coughing up and vomiting of blood. There are bumps on the skin that look somewhat like insect bites; these are usually red, and sometimes white in the centre. Untreated, the septicemic plague is usually fatal. Early treatment withantibiotics reduces the mortality rate to between 4 and 15 per cent.[13][14][15]
Thepneumonic form of plague arises frominfection of thelungs. It causes coughing and thereby producesairborne droplets that containbacterial cells and are likely to infect anyone inhaling them. Theincubation 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%.[16][17]
TheOriental rat flea (Xenopsylla cheopis) engorged with blood after a blood meal. This species of flea is the primaryvector for the transmission ofYersinia pestis, the organism responsible for bubonic plague in most plagueepidemics in Asia, Africa, and South America. Both male and female fleasfeed on blood and can transmit the infection.A child bitten by a fleainfected with the bacteriumYersinia pestis.Y. pestis, a member of the familyYersiniaceae, has caused the bite to becomeulcerated.
Transmission ofY. pestis to an uninfected individual is possible by any of the following means:[18]
droplet contact – coughing or sneezing on another person
direct physical contact – touching an infected person, including sexual contact
indirect contact – usually by touchingsoil 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
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° N and 40° S.[18]Contrary to popular belief, rats did not directly start the spread of the bubonic plague. It is mainly a disease in thefleas (Xenopsylla cheopis) that infested the rats, making the rats themselves the first victims of the plague. Rodent-borne 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.[19]
A 21st-century study of a 1665 outbreak ofplague in the village of Eyam in England's Derbyshire Dales – which isolated itself during the outbreak, facilitating modern study – found that three-quarters of cases are likely to have been due to human-to-human transmission, especially within families, a much larger proportion than previously thought.[20]
Symptoms of plague are usually non-specific and to definitively diagnose plague, laboratory testing is required.[21]Y. pestis can be identified through both a microscope and by culturing a sample and this is used as a reference standard to confirm that a person has a case of plague.[21] The sample can be obtained from the blood, mucus (sputum), or aspirate extracted from inflamed lymph nodes (buboes).[21] If a person is administered antibiotics before a sample is taken or if there is a delay in transporting the person's sample to a laboratory and/or a poorly stored sample, there is a possibility forfalse negative results.[21]
Polymerase chain reaction (PCR) may also be used to diagnose plague, by detecting the presence of bacterial genes such as thepla gene (plasmogen activator) andcaf1 gene, (F1 capsule antigen).[21] PCR testing requires a very small sample and is effective for both alive and dead bacteria.[21] For this reason, if a person receives antibiotics before a sample is collected for laboratory testing, they may have a false negative culture and a positive PCR result.[21]
Blood tests to detect antibodies againstY. pestis can also be used to diagnose plague, however, this requires taking blood samples at different periods to detect differences between the acute and convalescent phases of F1 antibody titres.[21]
In 2020, a study about rapid diagnostic tests that detect the F1 capsule antigen (F1RDT) by sampling sputum or bubo aspirate was released.[21] Results show rapid diagnostic F1RDT test can be used for people who have suspected pneumonic and bubonic plague but cannot be used in asymptomatic people. F1RDT may be useful in providing a fast result for prompt treatment and fast public health response as studies suggest that F1RDT is highly sensitive for both pneumonic and bubonic plague. However, when using the rapid test, both positive and negative results need to be confirmed to establish or reject the diagnosis of a confirmed case of plague and the test result needs to be interpreted within the epidemiological context as study findings indicate that although 40 out of 40 people who had the plague in a population of 1000 were correctly diagnosed, 317 people were diagnosed falsely as positive.[21][22][23]
BacteriologistWaldemar Haffkine developed the first plague vaccine in 1897.[24][25] He conducted a massive inoculation program inBritish India, and it is estimated that 26 million doses of Haffkine's anti-plague vaccine were sent out fromBombay between 1897 and 1925, reducing the plague mortality by 50–85%.[24][26]
Since human plague is rare in most parts of the world as of 2023, routine vaccination is not needed other than for those at particularly high risk of exposure, nor for people living in areas withenzootic 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 United StatesCDC thus only recommends vaccination for (1) all laboratory and field personnel who are working withY. pestis organisms resistant to antimicrobials: (2) people engaged in aerosol experiments withY. pestis; and (3) people engaged in field operations in areas with enzootic plague where preventing exposure is not possible (such as some disaster areas).[27] A systematic review by theCochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine.[28]
Pre-exposure prophylaxis for first responders and health care providers who will care for patients with pneumonic plague is not considered necessary as long as standard and droplet precautions can be maintained.[7] In cases of surgical mask shortages, patient overcrowding, poor ventilation in hospital wards, or other crises, pre-exposure prophylaxis might be warranted if sufficient supplies of antimicrobials are available.[7]
Postexposure prophylaxis should be considered for people who had close (<6 feet), sustained contact with a patient with pneumonic plague and were not wearing adequate personal protective equipment.[7] Antimicrobial postexposure prophylaxis also can be considered for laboratory workers accidentally exposed to infectious materials and people who had close (<6 feet) or direct contact with infected animals, such as veterinary staff, pet owners, and hunters.[7]
Specific recommendations on pre- and post-exposure prophylaxis are available in the clinical guidelines on treatment and prophylaxis of plague published in 2021.[7]
If diagnosed in time, the various forms of plague are usually highly responsive to antibiotic therapy.[6][21] The antibiotics often used arestreptomycin,chloramphenicol andtetracycline. Amongst the newer generation of antibiotics,gentamicin anddoxycycline have proven effective inmonotherapeutic treatment of plague.[6][29] Guidelines on treatment and prophylaxis of plague were published by the Centers for Disease Control and Prevention in 2021.[7]
The plague bacterium could developdrug resistance and again become a major health threat. One case of a drug-resistant form of the bacterium was found inMadagascar in 1995.[30] Further outbreaks in Madagascar were reported in November 2014[31] and October 2017.[32]
Globally about 600 cases are reported a year.[2] In 2017, the countries with the most cases include theDemocratic Republic of the Congo,Madagascar andPeru.[2] It has historically occurred in largeoutbreaks, with the best known being theBlack Death in the 14th century which resulted in more than 50 million dead.[2] In recent years, cases have been distributed between small seasonal outbreaks which occur primarily in Madagascar, and sporadic outbreaks or isolated cases in endemic areas.[2]
In 2022, the possible origin of all modern strands ofYersinia pestis DNA was found in human remains in three graves located inKyrgyzstan, dated to 1338 and 1339. Thesiege of Caffa in Crimea in 1346, is known to have been the first plague outbreak with following strands, later to spread over Europe. Sequencing DNA compared to other ancient and modern strands paints a family tree of the bacteria. Bacteria today affectingmarmots in Kyrgyzstan, are closest to the strand found in the graves, suggesting this is also the location where plague transferred from animals to humans.[33]
The plague has a long history as abiological weapon. Historical accounts fromancient China andmedieval Europe details the use of infected animal carcasses, such as cows or horses, and human carcasses, by theXiongnu/Huns,Mongols,Turks and other groups, to contaminate enemy water supplies.Han dynasty generalHuo Qubing is recorded to have died of such contamination while engaging in warfare against theXiongnu[citation needed]. Plague victims were also reported to have been tossed bycatapult into cities under siege.[34]
In 1347, theGenoese possession ofCaffa, a great trade emporium on theCrimean peninsula, came under siege by an army ofMongol warriors of theGolden Horde under the command ofJani Beg. 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 theBlack Death via their ships into the south ofEurope, possibly explaining its rapid spread.[35]
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.[37][38]
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 asdiphtheria), and genetic engineering. Scientists who worked inUSSR 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 and US projects is largely unavailable. Aerosolized pneumonic plague remains the most significant threat.[39][40][41]
The plague can be easily treated with antibiotics. Some countries, such as the United States, have large supplies on hand if such an attack should occur, making the threat less severe.[42]
^Ryan KJ, Ray CG, eds. (2004).Sherris Medical Microbiology: An Introduction to Infectious Diseases (4th ed.). New York: McGraw-Hill.ISBN978-0-8385-8529-0.
^Hawgood BJ (February 2007). "Waldemar Mordecai Haffkine, CIE (1860–1930): prophylactic vaccination against cholera and bubonic plague in British India".Journal of Medical Biography.15 (1):9–19.doi:10.1258/j.jmb.2007.05-59.ISSN0967-7720.PMID17356724.S2CID42075270.
.jpg)
