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Prior to 2003, most monkeypox cases were diagnosed in remote areas of central and west Africa. Between February 1996 and October 1997, however, there were 511 suspected cases of monkeypox in the Democratic Republic of the Congo (DRC, formerly Zaire). This outbreak, the largest ever, raised fears that the virus had mutated and become more infectious.

In late 1997, the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) announced that this relatively large outbreak was likely due to human behavior, rather than virus mutation. During the outbreak, the DRC was embroiled in civil war. Food shortages increased reliance on hunting and raised chances that people would come into contact with infected animals.

The 2003 outbreak in the United States, which was the first confirmed instance of community-acquired monkeypox in North America, came to the attention of the CDC in early June, when a laboratory in Wisconsin identified the monkeypox virus in samples taken from the skin of an infected patient and lymph node tissue from the patient's pet prairie dog. By the end of June, cases of monkeypox in humans had been identified in six Midwestern states (Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin). The patients acquired the virus from infected prairie dogs purchased as pets, which in turn were infected through contact with animals imported from Africa that were sold in the same pet stores.

Monkeypox is less severe than smallpox and can sometimes be confused with chickenpox. It seems partly preventable with smallpox vaccination, but vaccination programs were discontinued in the late 1970s. (Barring samples stored in laboratories, smallpox has been eradicated.) People under the age of 16'those born after smallpox vaccination ended'seem the most susceptible to monkeypox. During the 1996–97 outbreak, approximately 85% of the cases were in this age group.

Although the monkeypox virus is related to the smallpox virus, experts do not think (as of late 2003) that it is likely to be cultivated as an agent of bioterrorism. Monkeypox is much less easily transmitted person-to-person than smallpox and has a much lower fatality rate.

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