Smallpox Differential Diagnoses

Updated: Jul 28, 2020
  • Author: Aneela Naureen Hussain, MD, MBBS, FAAFM; Chief Editor: John L Brusch, MD, FACP  more...
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Diagnostic Considerations

The rash of chickenpox was frequently mistaken for that of smallpox during the days of natural infection. Both conditions can result in pustular scarring lesions that involve the face. Varicella typically does not have a prodromal phase, and the evolution of the rash from its appearance to scab separation takes approximately 7 days in varicella. Often, individuals who were previously vaccinated had only a mild prodrome without any rash.

The fever and vesicular rash of herpes zoster and erythema multiforme also were often confused with those of variola major.

Hemorrhagic smallpox, seen in the image below, develops fulminantly and was most often confused with meningococcemia or severe acute leukemia.

Hemorrhagic-type variola major lesions. Death usua Hemorrhagic-type variola major lesions. Death usually ensued before typical pustules developed. Reprinted with permission from the World Health Organization (WHO). 1988; 10-14, 35-36.

Contact dermatitis, although often vesicular, is distinguishable from smallpox lesions because contact dermatitis is pruritic and is not accompanied by fever or constitutional symptoms.

Conditions to consider in the differential diagnosis of smallpox include the following:

  • Rocky Mountain spotted fever

  • Syphilis

  • Varicella-zoster virus

  • Drug eruptions

  • Insect bites

  • Kawasaki disease

  • Measles, rubeola

  • Monkeypox

  • Rubella

  • Generalized vaccinia and eczema vaccinatum

  • Insect bites

  • Viral hemorrhagic fevers (may be confused with hemorrhagic smallpox)

  • Varicella virus

  • Acne

  • Atypical measles

  • Coxsackievirus

  • Acute leukemia

  • Secondary syphilis

  • Rat-bite fever

  • Infectious mononucleosis

  • Toxic erythemas

  • Parvovirus B19

  • Cytomegalovirus

  • Erythema multiforme (Stevens-Johnson syndrome)

  • Molluscum contagiosum

  • Scarlet fever

Differential Diagnoses