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For further information, see CMDT Part 6-21: Variola (Smallpox) & Vaccinia

Key Features

Essentials of Diagnosis

  • 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

General Considerations

  • Recent reintroduction of vaccination for first-responder and military population because of bioterrorist threat

  • The incubation period for smallpox averages 12 days (7–17 days)

  • Immunization with vaccinia is not recommended for persons with eczema, in whom widespread vaccinia (eczema vaccinatum) may result, with lesions resembling those of smallpox

  • Exposure to a recently vaccinated person may lead to generalized disease in persons with certain skin diseases

  • Prior vaccination does not prevent generalized vaccinia, but previously vaccinated individuals have milder disease

  • Progression of the primary inoculation site to a large ulceration occurs in persons with systemic immune deficiency, with a possible fatal outcome

Clinical Findings

Symptoms and Signs


  • Prodrome

    • Abrupt onset of high fever

    • Severe headaches, and backaches

    • Infected person appears quite ill

  • Infectious phase

    • Appearance of an enanthem, followed in 1–2 days by a skin eruption

    • Lesions begin as macules, progressing to papules, then pustules, and finally crusts over 14–18 days

    • The face is affected first, followed by the upper extremities, the lower extremities, and trunk, completely evolving over 1 week

    • Lesions are relatively monomorphous, especially in each anatomic region

  • All lesions in same stage of development differentiates rash from varicella


  • 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 collapses centrally, and crusts, with the crust eventually detaching up to a month after the inoculation

Differential Diagnosis

  • Generalized varicella zoster virus (VZV) infection

  • Generalized herpes simplex virus (HSV)


Laboratory Tests

  • Direct fluorescent antibody testing for HSV and VZV are first-line diagnostic tests to differentiate VZV, HSV, vaccinia, and smallpox

  • Smallpox is a clinical diagnosis but viral infection can be confirmed by electron microscopy, antigen detection, and polymerase chain reaction



  • No specific and proven antiviral therapy for vaccinia or smallpox

  • Vaccinia immune globulin is used to treat eczema vaccinatum and progressive vaccinia

  • Cidofovir may have some activity against these poxviruses

Therapeutic Procedures

  • Strict respiratory and contact isolation crucial

  • Patient should be immunized if in early stage of disease

  • No antiviral therapy clearly effective

  • Supportive care critical

  • Centers for Disease Control and Prevention should be contacted immediately ...

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