During 2013, cutaneous lesions developed in two men in the country of Georgia after they were exposed to ill cows. The men had never received vaccination against smallpox. Tests of lesion material with the use of a quantitative real-time polymerase-chain-reaction assay for non-variola virus orthopoxviruses were positive, and DNA sequence analysis implicated a novel orthopoxvirus species. During the ensuing epidemiologic investigation, no additional human cases were identified. However, serologic evidence of exposure to an orthopoxvirus was detected in cows in the patients' herd and in captured rodents and shrews. A third case of human infection that occurred in 2010 was diagnosed retrospectively during testing of archived specimens that were originally submitted for tests to detect anthrax. Orthopoxvirus infection should be considered in persons in whom cutaneous lesions develop after contact with animals. W ith the exception of the variola virus (the agent of smallpox), members of the orthopoxvirus genus are zoonotic. 3] Unlike patients with variola virus infection, patients with cowpox virus infection typically present with self-limited skin lesions. This infection is now most often acquired through contact with domestic animals such as cats. Results of serologic testing and a general non-variola virus orthopoxvirus molecular assay suggested that both patients had orthopoxvirus infection, but follow-up molecular assays did not show that the virus belonged to a known orthopoxvirus species. Whole-genome sequencing followed by phylogenetic analysis led to the discovery of a novel orthopoxvirus species. We describe
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