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Plague is a highly virulent zoonosis that has claimed hundreds of millions of lives over recorded history.1–3 The etiologic agent, Yersinia pestis, persists in complex enzootic cycles of rodents and fleas in discrete geographic foci in Asia, Africa, and the Americas. Humans are incidental hosts, most often infected by flea bites, but also by direct contact with infected animal tissues or inhalation of infectious respiratory droplets. The clinical syndrome varies with route of inoculation of the bacterium, resulting in three primary clinical forms, bubonic, septicemic, and pneumonic plague. Although most cases of plague are sporadic and effective therapy exists, periodic outbreaks can generate fear among the public, driven by misinformation. Plague remains a persistent public health concern due to its rapid clinical course, high mortality, and potential for epidemic spread. Y. pestis is currently classified as a Tier 1 select agent, subject to high-level regulation and oversight, due to both its past and potential use as a bioweapon.4


During the course of recorded history, plague caused three deadly pandemics, collectively giving rise to a notorious reputation in modern society.1–3 Although possible epidemics occurring before 1000 BC have been described, the first well-recorded plague pandemic began in AD 542. The associated cumulative death toll is highly debatable, but most historians agree that roughly half of the population was lost during the series of epidemics that occurred over the ensuing 150 years.1 This event is often referred to as the Justinian Plague, named after the Byzantine emperor under whose rule the most consequential effects of the pandemic were felt. The pandemic affected the entire “known” world at the time—primarily the Mediterranean basin, but also central and southern Asia.

Plague retreated at the close of the first pandemic only to emerge several centuries later, spreading along trade routes from central Asia.1 After reaching Europe in AD 1347, plague decimated one-third to one-half of Europe’s population in a few short years in what is now referred to as the “Black Death.”2,5 Ongoing epidemics continued for the next three centuries, not only in Europe but also in the Mediterranean basin and central Asia. The second pandemic has earned an important place in human history due to its consequential effect on the economics, labor markets, culture, art, religion, and politics in medieval Europe.1,5 The origin of public health practice dates from this time, when administrative functions of governments expanded to institute quarantines and barriers to trade to limit the spread of disease.5

The third pandemic began in China during the mid-to-late 1800s, and spread to the port of Hong Kong in 1894, presumably accelerated by troop movement. Soon thereafter, plague rapidly spread worldwide by way of new steamships, and was introduced into 77 different port cities on five continents, ultimately becoming entrenched on all continents except Australia.1–3 Shipborne spread of plague ceased ...

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