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Smallpox is a disease caused by the variola virus. The last naturally occurring cases of smallpox were identified in 1977, and in 1980 the World Health Organization declared smallpox officially eradicated from the planet. However, there remain two sources of smallpox virus in storage and for research purposes, one in the United States and one in Russia. Any new cases of smallpox will be a medical and public health emergency. Strict respiratory and contact isolation of confirmed or suspected smallpox cases are essential to prevent spread of this virus.

There are four main clinical forms of smallpox: ordinary smallpox (variola major), modified‐type smallpox, malignant smallpox, and hemorrhagic smallpox [51, 52]. All forms of smallpox infection begin with an incubation period usually lasting between 10 and 14 days. During this time, the infected person does not have symptoms, is not contagious, and may feel fine. Symptoms begin with a prodrome that typically lasts 2‐4 days, starting abruptly with fever, headache, abdominal pain, nausea, vomiting, muscle pain, headache, and malaise. In patients with pale‐skins, an erythematous or petechial rash may be visible.

Ordinary smallpox is the most common and severe form of disease, accounting for over 85% of cases during the smallpox era. After the prodrome, mucous membrane lesions called enanthem begin in the mouth. This consists of red spots on the tongue and mucosa that enlarge and ulcerate quickly, followed by a rash on the face. The rash then progresses from the proximal extremities to the distal extremities and trunk within 24 hours. The macules progress to papules, vesicles, pustules, and crusts. Crusts later separate leaving depigmented skin and pitted scars. The case‐fatality rate for ordinary smallpox is about 30%.

Transmission of smallpox is via virus inhalation from airborne droplets or fine particle aerosols from the oral, pharyngeal, or nasal mucosa of an infected person, physical contact with an infected person, or with contaminated articles through skin inoculation.

Medical personnel in contact with suspected or confirmed smallpox cases should be wearing N95 respirators and should take other standard precautions. All bedding and clothing should be autoclaved or laundered in hot water with bleach.

Treatment of smallpox patients generally involves supportive care. Smallpox vaccines can prevent or lessen the severity of disease if given within 2‐3 days of the initial exposure. They may decrease symptoms if given within the first week of exposure. There are antiviral therapies shown to be effective against poxviruses, including variola. However, no treatment has been tested and proven effective for people who are sick from smallpox.

Given that smallpox no longer exists as a naturally occurring disease, even a single suspected or known case should be considered an outbreak and public health authorities must be alerted immediately.