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Plague has been responsible for three great world pandemics, which caused millions of deaths and significantly altered the course of history. A pandemic is a disease occurring in epidemic form throughout the entire population of a country, a people, or the world. Although the cause of the plague was not identified until the third pandemic in 1894, scientists are virtually certain that the first two pandemics were plague because a number of the survivors wrote about their experiences and described the symptoms.

The first great pandemic appeared in AD 542 and lasted for 60 years. It killed millions of citizens, particularly people living along the Mediterranean Sea. This sea was the busiest, coastal trade route at that time and connected what is now southern Europe, northern Africa, and parts of coastal Asia. This pandemic is sometimes referred to as the Plague of Justinian, named for the great emperor of Byzantium who was ruling at the beginning of the outbreak. According to the historian Procopius, this outbreak of plague killed 10,000 people per day at its height just within the city of Constantinople.

The second pandemic occurred during the fourteenth century, and was called the Black Death because its main symptom was the appearance of black patches (caused by bleeding) on the skin. It was also a subject found in many European paintings, drawings, plays, and writings of that time. The connections between large active trading ports, rats coming off the ships, and the severe outbreaks of the plague were understood by people at the time. This was the most severe of the three, beginning in the mid-1300s with an origin in central Asia and lasting for 400 years. Between a fourth and a third of the entire European population died within a few years after plague was first introduced. Some smaller villages and towns were completely wiped out.

The final pandemic began in northern China, reaching Canton and Hong Kong by 1894. From there, it spread to all continents, killing millions.

The great pandemics of the past occurred when wild rodents spread the disease to rats in cities, and then to humans when the rats died. Another route for infection came from rats coming off ships that had traveled from heavily infected areas. Generally, these were busy coastal or inland trade routes. Plague was introduced into the United States during this pandemic and it spread from the West towards the Midwest and became endemic in the Southwest of the United States.

About 10-15 Americans living in the southwestern United States contract plague each year during the spring and summer. The last rat-borne epidemic in the United States occurred in Los Angeles in 1924–25. Since then, all plague cases in this country have been sporadic, acquired from wild rodents or their fleas. Plague can also be acquired from ground squirrels and prairie dogs in parts of Arizona, New Mexico, California, Colorado, and Nevada. Around the world, there are between 1,000 and 2,000 cases of plague each year. Recent outbreaks in humans occurred in Africa, South America, and Southeast Asia.

Some people and/or animals with bubonic plague go on to develop pneumonia (pneumonic plague). This can spread to others via infected droplets during coughing or sneezing.

Plague is one of three diseases still subject to international health regulations. These rules require that all confirmed cases be reported to the World Health Organization (WHO) within 24 hours of diagnosis. According to the regulations, passengers on an international voyage who have been to an area where there is an epidemic of pneumonic plague must be placed in isolation for six days before being allowed to leave.

While plague is found in several countries, there is little risk to United States travelers within endemic areas (limited locales where a disease is known to be present) if they restrict their travel to urban areas with modern hotel accommodations.

Over the past few years, this infection primarily of antiquity has become a modern issue. This change has occurred because of the concerns about the use of plague as a weapon of biological warfare or terrorism (bioterrorism). Along with anthrax and smallpox, plague is considered to be a significant risk. In this scenario, the primary manifestation is likely to be pneumonic plague transmitted by clandestine aerosols. It has been reported that during World War II the Japanese dropped bombs containing plague-infected fleas in China as a form of biowarfare.

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