The plague has caused more fear and terror than perhaps any other infectious disease in the history of humankind. It has laid claim to nearly 200 million lives and has brought about monumental changes such as the end of the Dark Ages and the advancement of clinical research in medicine. 
Although still debated by historians, the plague has been responsible for at least 3 great pandemics and multiple epidemics in history. The first spread occurred from the Middle East to the Mediterranean basin during the fifth and sixth centuries CE, killing approximately 50% of the population in these areas. The second pandemic afflicted Europe between the 8th and 14th centuries, destroying nearly 40% of the population. The third pandemic started in approximately 1855 in China, and, although it has been mostly controlled, it is still ongoing.
Alexandre Yersin isolated the plague bacillus, developed an antiserum to combat the disease, and postulated its connection with fleas and rats during the epidemic of 1894. The plague bacillus was named Yersinia pestis in his memory. [2, 3]
Pandemics have succeeded in entrenching the plague in every major continent, with the possible exception of Australia. Unlike smallpox, the plague never will be eradicated. It lives in millions of animals and on billions of fleas that reside on them. It is a disease of the desert, the steppes, the mountains, and the forest. 
Although plague has been considered a disease of the Middle Ages, multiple outbreaks in India and Africa during the last 20 years have stoked fears of another global pandemic. Since the number of human cases has been rising and outbreaks are reappearing in a variety of countries after years of quiescence, the plague is considered a reemerging disease. [5, 6, 2]
One reason for plague's reemergence may be global warming, which is ideal for increasing the prevalence of Ypestis in the host population. One study has estimated a more than 50% increase in the plague host prevalence with an increase of 1º C of the temperature in spring.  Another reason may be the human population explosion worldwide, which is bringing humans into ever-increasing contact with wildlife. Lastly, the dramatic population increase will contribute to conditions of overcrowding and poor sanitation—conditions ripe for plague hosts and vectors to flourish in.
Additionally, there has been significant concern over the return of plague as a potential biological weapon. [8, 9, 10, 11, 12] In 1347, the Tartars catapulted bodies of plague victims over the city walls during the siege of Kaffa, and, in World War II, the Japanese dropped bombs containing fleas inoculated with Y pestis to infect their enemies with the deadly illness.
During the Cold War, the Soviets succeeded in aerosolizing the bacteria and in creating strains of multidrug-resistant Yersinia. [13, 14] Aerosolized Y pestis, causing primary pneumonic plague, has been recognized by bioterrorism experts as having one of the highest potentials as a bioterrorism agent due to its extremely high mortality, its high uptake into enzootic and epizootic animals as well as humans, and its ability to be spread over a large area. It has been classified as a Category A, or high priority, bioterroism agent by the Centers for Disease Control and Prevention (CDC). Biosafety level 3 precautions must be observed for any cultured specimens. 
The etiologic agent of the plague is Y pestis, a facultative anaerobic, intracellular, gram-negative bacillus. Significant genomic similarity and conservation of DNA sequences suggest Y pestis evolved from the less virulent Yersinia pseudotuberculosis. 
The organism can be transmitted from a host to a human via the bite of a vector (usually a flea), via close contact with infected tissue or body fluids, and via direct inhalation of aerosolized bacteria. Currently, the most common form of transmission involves the bite of an infected flea. More than 200 different rodents and species can serve as hosts.
The vector is usually the rat flea, Xenopsylla cheopis. Thirty different flea species have been identified as able to carry the plague bacillus. Other carriers of plague include ticks and human lice. A flea is shown in the image below.
Rodents resistant to the infection, such as wood rats, kangaroo roots, deer mice, grasshopper mice, and voles, form an enzootic stage that ensures the long-term survival of the bacillus. Occasionally, fleas transfer the bacteria to animals that are susceptible to plague such as ground squirrels (an infected squirrel is shown in the image below), prairie dogs, and chipmunks. In the event of large numbers of host animals dying off, hungry fleas search out new food sources. This is known as an epizootic stage and ensures the spread of the organism to new territory. A sylvatic stage occurs when humans are infected from wild animals. Carnivores with the exception of cats  and black-footed ferrets have a fairly strong resistance profile, but they can be transfer vectors. Birds and hoofed animals are seldom infected, and reptiles and fish are resistant to plague. 
Three forms of the plague exist: bubonic plague, pneumonic plague, and septicemic plague. The bubonic form makes up approximately 80-95% of cases worldwide  and is caused by deposition of the bacillus in the skin by the bite of an infected vector. If the vector is a flea, bacillus proliferates in the flea's esophagus, preventing food entry into the stomach. To overcome starvation, the flea begins a blood-sucking rampage. Between its attempts to swallow, the distended bacillus-packed esophagus recoils, depositing the bacillus into the victim's skin.
The bacillus invades nearby lymphoid tissue, producing the famous bubo, an inflamed, necrotic, and hemorrhagic lymph node. Spread occurs along the lymphatic channels toward the thoracic duct, with eventual seeding of the vasculature. Bacteremia and septicemia ensue. The bacillus potentially seeds every organ, including the lungs, liver, spleen, kidneys, and rarely even the meninges.
The most virulent form, pneumonic plague, results from direct inhalation of the bacillus, which occurs from close contact of infected hosts or from aerosolized bacteria such as may occur if used as a biological weapon. A severe and rapidly progressive multilobar bronchopneumonia ensues with subsequent bacteremia and septicemia. Secondary pneumonic plague is caused when an infected patient seeds his or her lungs and airways.
The third type of plague is a primary septicemic plague. This is hypothesized to occur when the bacillus is deposited in the vasculature, bypassing the lymphatics. Early dissemination with sepsis occurs but without the formation of a bubo. This usually is observed in bites to the oral, tonsillar, and pharyngeal area and is believed to occur because of the vascularity of the tissue and short lymphatic distance to the thoracic duct.
An average of seven (range, 1-17) human plague cases have been reported each year in the United States in recent decades.  One of the largest animal foci of the plague worldwide is found west of the 100th parallel, in states such as New Mexico, Arizona, Colorado, Utah, and California. Only one case of imported plague has been reported since 1926. Most cases occur during the wet, warmer months of the year. 
Worldwide, plague occurs within a broad belt in tropical, subtropical, and warmer temperate climates (see the image below). Its geographical distribution coincides with that of the rodents it infects, which are found on all continents except Australia. Plague epidemics have occurred in Africa, Asia, and South America but since the 1990s, most human cases have occurred in Africa. The three most endemic countries are Madagascar, the Democratic Republic of Congo and Peru.
According to the World Health Organization (WHO), 3248 cases of plague with 584 deaths were reported worldwide from 2010 to 2015.  The actual number of cases is likely much higher, however. Almost all of the cases reported in the last 2 decades have been in inhabitants of small towns and villages or agricultural areas rather than in larger towns and cities. 
Mortality from plague varies by type and treatment, as follows:
Bubonic plague has a 1-15% mortality rate in treated cases and a 40-60% mortality rate in untreated cases.
Septicemic plague (primary or secondary) has a 40% mortality rate in treated cases and 100% mortality rate in untreated cases.
Pneumonic plague (primary or secondary) has 100% mortality rate if not treated within the first 24 hours of infection.
Sex- and Age-related Demographics
More than 50% of cases of plague occur in males, probably because of greater participation in outdoor activities. Approximately 50% of cases occur in persons younger than 20 years.
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