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  • Prodromal high fever.

  • Eruption progressing from papules to vesicles to pustules, then crusts.

  • All lesions in the same stage.

  • Face and distal extremities (including palms and soles) favored.


Concern for the use of smallpox virus as a bioterrorist weapon has led to the reintroduction of vaccination in some segments of the population (first responders and the military).


The incubation period for variola averages 12 days (7–17 days). The prodrome begins with abrupt onset of high fever, severe headaches, and backaches. At this stage, the infected person appears quite ill. The infectious phase begins with the appearance of an exanthem, followed in 1–2 days by a skin eruption. The lesions begin as macules, progressing to papules, then pustules, and finally crusts over 14–18 days. The face and distal extremities are favored. The face is affected first, followed by the upper extremities, then the lower extremities and trunk, completely evolving over 1 week. Lesions are relatively monomorphous, especially in each anatomic region.

Inoculation with vaccinia produces a papular lesion on day 2–3 that progresses to an umbilicated papule by day 4 and a pustular lesion by the end of the first week. The lesion then collapses centrally, and crusts. The crust eventually detaches up to a month after the inoculation. Persons with eczema should not be immunized because widespread vaccinia (eczema vaccinatum), which might resemble the lesions of smallpox, may develop. Vaccinia is moderately contagious, and patients with atopic dermatitis and Darier disease may acquire severe generalized disease by exposure to a recently vaccinated person. Generalized vaccinia may be fatal. Prior vaccination does not prevent generalized vaccinia, but previously vaccinated individuals have milder disease. Progressive vaccinia (vaccinia gangrenosum)—progression of the primary inoculation site to a large ulceration—occurs in persons with systemic immune deficiency. It can have a fatal outcome.


Smallpox and vaccinia are to be distinguished from generalized varicella zoster virus infection or generalized herpes simplex. The latter two viral infections are not associated with a severe febrile prodrome. Lesions are at various stages at each anatomic site. Varicella usually appears in waves or crops. Multiple palm and sole lesions are common in variola and uncommon in generalized varicella-zoster and herpes simplex infection.

Direct fluorescent antibody testing for HSV and varicella zoster virus are the first-line diagnostic tests to differentiate varicella zoster virus, HSV, vaccinia, and variola. Until the diagnosis is confirmed, strict isolation of the patient is indicated. Similar fluorescent testing for variola can be performed in special laboratories.


There is no specific and proven antiviral therapy for vaccinia or variola. Vaccinia immune globulin is used to treat eczema vaccinatum and progressive vaccinia. Cidofovir may have some activity against these poxviruses.


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