Plague, a zoonotic disease caused by the gram-negative bacterium Yersinia pestis, is transmitted to humans by the bites of infected fleas (eg, Xenopsylla cheopis), scratches from infected animals, inhalation of aerosols, or consumption of food contaminated with Y pestis. [1, 2] No disease has impacted civilization as deeply as the plague. As many as 200 million people have died from this disease.
The first pandemic, known as the Justinian plague (AD 541-544), began in Egypt and spread throughout the Middle East and Mediterranean areas. Eventually, the entire known world was affected. By the 8th century, plague receded into scattered endemic areas.
The second pandemic began in 1347, when traders from central Asia introduced plague into ports of Sicily. This became the first epidemic, known as the Black Death, which killed over one third of the population of Europe. Later, following the Great Plague of London (1665), the disease subsided.
The third pandemic began in Hong Kong in 1894 and continues to the present. Alexandre Yersin discovered the plague bacillus, Y pestis, and effective antibiotics were introduced in the early 1940s; however, plague remains endemic in much of the world. [3, 4]
Examples of findings are shown in the images below.
The classic mode of transmission to humans is a flea bite (see the image below).
Alternately, broken skin serves as a portal when tissue or blood of an infected animal is handled (skinning or evisceration of infected animals). Competency of the flea to serve as vector for transmission of plague to humans depends on its willingness to feed on a human host and its tendency to regurgitate intestinal contents during a blood meal. Fleas from sylvatic rodents feed on humans only reluctantly. However, the Oriental rat flea (Xenopsylla cheopis) is an effective vector because of its tendency to regurgitate and to feed on nonrodent hosts (see the image below).
When the flea takes a blood meal from an infected rodent, stomach enzymes cause a clot to form, blocking the flea's proventricularis. At its next attempt to feed, unable to swallow due to the blockage, the flea regurgitates plague bacilli into the bite wound.
The organisms invade the lymphatics and travel to regional lymph nodes, causing inflammation (see the image below).
Large, tender lymph nodes are termed buboes and give the bubonic form of plague its name. If the infection is not contained at this site, the organisms may be further spread via the bloodstream to organs such as lungs, spleen, liver, kidneys, and meninges. Bacteremia without the appearance of buboes is considered septicemic plague. Pneumonic plague occurs when pneumonia results from either hematogenous spread (secondary pneumonic plague) or inhalation (primary pneumonic plague) of organisms transmitted from animals or other humans.
Plague is considered endemic in all western and southwestern states.  Most human cases in the United States occur in two regions:
· Northern New Mexico, northern Arizona, and southern Colorado
· California, southern Oregon, and far western Nevada
Most cases of plague are acquired in rural areas. Native Americans who reside on reservations are at increased risk for acquisition of the disease. Ground squirrels and prairie dogs serve as major enzootic foci (see the image below). 
Dogs and cats are susceptible to plague. Domestic animals, cats in particular, have been responsible for human cases.
Between 1900 and 2012, 1006 confirmed or probable human plague cases occurred in the United States. Over 80% of United States plague cases have been the bubonic form. During 2001–2012, the annual number of human plague cases reported in the United States ranged from one to 17 (median = three cases). [7, 8]
However, plague activity increased during 2015. In a CDC report published on August 25, 2015, a total of 11 cases of human plague had been reported since April 1, 2015.  Affected patients were residents of six states: Arizona (two), California (one), Colorado (four), Georgia (one), New Mexico (two), and Oregon (one). The two cases in Georgia and California residents were linked to exposures at or near Yosemite National Park in the southern Sierra Nevada Mountains of California. It is unclear why the number of cases in 2015 is higher than usual.
Plague reached a worldwide maximum of 5419 cases (274 fatal) in 1997, and the incidence has declined since that time.  In 2003, 9 countries reported 2118 cases (182 fatal) to the World Health Organization (WHO).  Algeria reported cases of human plague for the first time in 50 years. India and Indonesia also recently reported cases after a 30-year to 50-year quiescent period. Almost all of the cases reported in the last 20 years have occurred among people living in small towns and villages or agricultural areas rather than in larger towns and cities. Between 1,000 and 2,000 cases each year are reported to the World Health Organization (WHO), though the true number is likely much higher. Occurrence is thought to be underreported. [12, 13] Currently, about 95% of the world’s human plague cases now occur in the African region, including Madagascar.  World distribution of plague is shown below.
Mortality is approximately 16%, which increases to 40-70% in untreated cases.  Practitioners must maintain a high index of suspicion for plague, especially with patients exposed to animals or fleas in endemic areas. The most common complications are secondary septicemia, pneumonia, and meningitis. Polyarthritis, lung abscesses, and superinfection of lymph nodes also rarely occur.
Mortality ranges from 30-50% for patients with septicemic plague and increases to nearly 100% in untreated cases. This high mortality rate reflects the difficulty in diagnosis, given the disease's similarity to gram-negative bacterial sepsis. Diagnosis is often made postmortem.
The fatality rate of untreated pneumonic plague approaches 100%. The last reported case of person-to-person transmission occurred during a plague epidemic in Los Angeles in 1924. Since then, cases of primary pneumonic plague have been acquired chiefly from infected cats.
Plague occurs in both men and women. It is slightly more common among men.
Plague has occurred in people of all ages, although, 50% of cases occur in people ages 12–45.
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