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 1998 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.

Fleas carry the bacterium Yersinia pestis, formerly known as Pasteurella pestis. The plague bacillus can be stained with Giemsa stain and typically looks like a safety pin under the microscope. When a flea bites an infected rodent, it swallows the plague bacteria. The bacteria are passed on when the fleas, in turn, bite a human. Interestingly, the plague bacterium grows in the gullet of the flea, obstructing it and not allowing the flea to eat. Transmission occurs during abortive feeding with regurgitation of bacteria into the feeding site. Humans also may become infected if they have a break or cut in the skin and come in direct contact with body fluids or tissues of infected animals.

More than 100 species of fleas have been reported to be naturally infected with plague; in the western United States, the most common source of plague is the golden-manteled ground squirrel flea. Chipmunks and prairie dogs have also been identified as hosts of infected fleas.

Since 1924, there have been no documented cases in the United States of human-to-human spread of plague from droplets. All but one of the few pneumonic cases have been associated with handling infected cats. While dogs and cats can become infected, dogs rarely show signs of illness and are not believed to spread disease to humans. However, plague has been spread from infected coyotes (wild dogs) to humans. In parts of central Asia, gerbils have been identified as the source of cases of bubonic plague in humans.

Two to five days after infection, patients experience a sudden fever, chills, seizures, and severe headaches, followed by the appearance of swellings or "buboes" in armpits, groin, and neck. The most commonly affected sites are the lymph glands near the site of the first infection. As the bacteria multiply in the glands, the lymph node becomes swollen. As the nodes collect fluid, they become extremely tender. Occasionally, the bacteria will cause an ulcer at the point of the first infection.

Bacteria that invade the bloodstream directly (without involving the lymph nodes) cause septicemic plague. (Bubonic plague also can progress to septicemic plague if not treated appropriately.) Septicemic plague that does not involve the lymph glands is particularly dangerous because it can be hard to diagnose the disease. The bacteria usually spread to other sites, including the liver, kidneys, spleen, lungs, and sometimes the eyes, or the lining of the brain. Symptoms include fever, chills, prostration, abdominal pain, shock, and bleeding into the skin and organs.

Pneumonic plague may occur as a direct infection (primary) or as a result of untreated bubonic or septicemic plague (secondary). Primary pneumonic plague is caused by inhaling infective drops from another person or animal with pneumonic plague. Symptoms, which appear within one to three days after infection, include a severe, overwhelming pneumonia, with shortness of breath, high fever, and blood in the phlegm. If untreated, half the patients will die; if blood poisoning occurs as an early complication, patients may die even before the buboes appear.

Life-threatening complications of plague include shock, high fever, problems with blood clotting, and convulsions.

Plague should be suspected if there are painful buboes, fever, exhaustion, and a history of possible exposure to rodents, rabbits, or fleas in the West or Southwest. The patient should be isolated. Chest x rays are taken, as well as blood cultures, antigen testing, and examination of lymph node specimens. Blood cultures should be taken 30 minutes apart, before treatment.

A group of German researchers reported in 2004 on a standardized enzyme-linked immunosorbent assay (ELISA) kit for the rapid diagnosis of plague. The test kit was developed by the German military and has a high degree of accuracy as well as speed in identifying the plague bacillus. The kit could be useful in the event of a bioterrorist attack as well as in countries without advanced microbiology laboratories.

As soon as plague is suspected, the patient should be isolated, and local and state departments notified. Drug treatment reduces the risk of death to less than 5%. The preferred treatment is streptomycin administered as soon as possible. Alternatives include gentamicin, chloramphenicol, tetracycline, or trimethoprim/sulfamethoxazole.

Plague can be treated successfully if it is caught early; the mortality rate for treated disease is 1–15% but 40–60% in untreated cases. Untreated pneumonic plague is almost always fatal, however, and the chances of survival are very low unless specific antibiotic treatment is started within 15–18 hours after symptoms appear. The presence of plague bacteria in a blood smear is a grave sign and indicates septicemic plague. Septicemic plague has a mortality rate of 40% in treated cases and 100% in untreated cases.

Anyone who has come in contact with a plague pneumonia victim should be given antibiotics, since untreated pneumonic plague patients can pass on their illness to close contacts throughout the course of the illness. All plague patients should be isolated for 48 hours after antibiotic treatment begins. Pneumonic plague patients should be completely isolated until sputum cultures show no sign of infection.

Residents of areas where plague is found should keep rodents out of their homes. Anyone working in a rodent-infested area should wear insect repellent on skin and clothing. Pets can be treated with insecticidal dust and kept indoors. Handling sick or dead animals (especially rodents and cats) should be avoided.

Plague vaccines have been used with varying effectiveness since the late nineteenth century. Experts believe that vaccination lowers the chance of infection and the severity of the disease. However, the effectiveness of the vaccine against pneumonic plague is not clearly known.

Vaccinations against plague are not required to enter any country. Because immunization requires multiple doses over a 6–10 month period, plague vaccine is not recommended for quick protection during outbreaks. Moreover, its unpleasant side effects make it a poor choice unless there is a substantial long-term risk of infection. The safety of the vaccine for those under age 18 has not been established. Pregnant women should not be vaccinated unless the need for protection is greater than the risk to the unborn child. Even those who receive the vaccine may not be completely protected. The inadequacy of the vaccines available as of the early 2000s explains why it is important to protect against rodents, fleas, and people with plague. A team of researchers in the United Kingdom reported in the summer of 2004 that an injected subunit vaccine is likely to offer the best protection against both bubonic and pneumonic forms of plague.