• Caused by the variola virus[1]
  • Passed through direct contact with the person, with body fluids, as well as with airborne droplets of an infected, symptomatic person
    • Can survive for 24-48 hours in the environment
  • Most infectious during the first week of symptoms, but will remain infectious until the last pox scab falls off
  • Humans are the only known host[2]
  • Declared eradicated in 1980 after a global immunization campaign from 1966-1980; last known natural case was in Somalia in 1977; last known cases were in England in 1978 after a laboratory accident[3]


  • There are stocks of the virus in 2 laboratories – one in Atlanta, Georgia, USA and one in Moscow, Russia
  • There are concerns some laboratories may illegally have the virus and could release it as a weapon of bioterrorism[4]
  • It is considered a potential bioterrorism threat as most people are now considered to be vulnerable to the virus because vaccination programs have stopped

Vaccination History

  • The vaccine “vaccinia variola” was made from a closely-related virus
  • Vaccination is considered successful if at least one pustule forms at the injection site
  • Does have serious side effects, especially in the immunocompromised, including death in rare cases
  • Due to the side effects and the current eradication, it is not used anywhere in the world currently
    • Only select groups of individuals will be vaccinated, including some members of the US military (depending on where they are deployed) [5]
  • Many governments have large stockpiles of the vaccinia vaccine and plans in place for rapid response and vaccination if an outbreak were to occur

Clinical Features

Child with Smallpox
Man with small pox displaying the characteristic rash.
  • Incubation period: 7-19 days
  • Initial phase begins as a fever, fatigue/weakness, dorsal-lumbar pain, myalgias, nausea/vomiting
  • 2-4 days later the characteristic rash appears
    • Worst on the face, arms, legs, and includes the palms and soles
    • Lesions will generally all be at same stage
    • Lesions begin as clear fluid-filled vesicles, progress to pustules, and then harden and form a crust, ultimately falling off in about 3-4 weeks

Clinical Forms

  • Variola major and minor (90% of cases)
    • Variola major
      • More severe, mortality rate 30%
    • Variola minor
      • Less severe, mortality rate 1%
      • Fewer pox
  • Other (10% of cases)
    • Hemorrhagic
      • Hemorrhages occur within the blisters as well as mucus membranes and internal organs, death usually within 5-6 days
    • Malignant
      • Soft, flattened lesions, does not progress to pustules
      • Resolve without forming scabs [6]

Differential Diagnosis

Pediatric Rash

Vesiculobullous rashes



Bioterrorism Agents[7]

Category A

Category B

  • Ricin
  • Brucellosis
  • Epsilon toxin
  • Psittacosis
  • Q Fever
  • Staph enterotoxin B
  • Typhus
  • Glanders
  • Melioidosis
  • Food safety threats
  • Water safety threats
  • Viral encephalitis

Category C


  • Clinical diagnosis based on symptoms and characteristic rash
  • PCR DNA test
  • When the disease was present, either electron microscopy of stained crusts of lesions or a slide precipitation method was used


  • Vaccine administered up to 3 days post-exposure was effective in preventing infection as well as lessening the severity of the disease if infection occurred [8]

Post-Exposure Prophylaxis

  • Vaccinia Vaccine (administer within 72hrs of exposure)

Active Disease

  • Supportive care and wound care for open lesions
  • Vaccinia Vaccine within the first 72hrs can decrease total disease severity and within 7 days may decrease symptoms
    • Vaccination is not efficacious once the patient has developed rash[9]

Vaccinia Vaccine Complications

Contraindications for administration include:

  • Pregnancy
  • Severe cardiac disease
  • Immunocompromise
  • Same living quarters as other person with above contraindications
    • due to viral shedding


  • Airborne and contact isolation with negative pressure
  • Personal protective wear level D with N95 respirator

See Also



  1. Rosen, Peter, John A. Marx, Robert S. Hockberger, and Ron M. Walls. "Smallpox." Rosen's Emergency Medicine Concepts and Clinical Practice. 8th ed. Vol. 2. Philadelphia, PA: Elsevier/Saunders, 2013. 1579-1580.
  2. Barquet, Nicolau, MD, and Pere Domingo, MD. "Smallpox: The Triumph over the Most Terrible of the Ministers of Death." Annals of Internal Medicine 127 (1997): 635-42.
  3. Ellner, P. D. "Smallpox: Gone but Not Forgotten." Infection 26.5 (1998): 263-69.
  4. Anderson PD. Bokor G. Bioterrorism: pathogens as weapons. J Pharm Pract. 2012 Oct;25(5):521-9.
  6. Schultz, C., & Koenig, K. Weapons of Mass Destruction. In Rosen's Emergency Medicine: Concepts and Clinical Practice (9th ed.). Philadephia, PA: Elsevier/Saunders.
  7. Accessed 02/26/16
  8. Kman NE, Nelson RN. Infectious agents of bioterrorism: a review for emergency physicians. Emerg Med Clin North Am. 2008 May;26(2):517-47
  9. 2020. Prevention and Treatment | Smallpox | CDC. [online] Available at: <> [Accessed 11 September 2021].