ToxCard: Smallpox

Authors: Whitney Ficker, MD (Pediatric Emergency Medicine Fellow, Atrium Health’s Carolinas Medical Center); Christine Murphy, MD (Emergency Medicine Attending, Medical Toxicologist, Atrium Health’s Carolinas Medical Center) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)


A 13-month-old male presents to the Emergency Department (ED) with his mother due to concern for a 3-day history of fever up to 101°F, decreased PO intake, and fussiness, as well as a 2-day history of rash. Mother states that the rash started as flat spots but then became raised bumps. The patient has been itching at the rash. He is otherwise normally healthy and was born at term with an uncomplicated birth history. He is up-to-date through his 6-month immunizations. Vital signs are temperature 100.6°F, heart rate 144, blood pressure 82/48, respiratory rate 32, and SpO2 99%. On exam, he is non-toxic appearing and active. He has erythematous macules, papules, and vesicles with some lesions appearing crusted. There are more lesions on the trunk than the extremities, and palms and soles are spared. The patient’s mother was recently reading a historically based novel about events that took place in the 1900’s, and there were some characters in the story who had smallpox. She is concerned that the patient may have smallpox given his rash and asks you if you think this could be the reason for his illness. How would you respond?


  • Smallpox was an endemic illness for many centuries.
    • Egyptian mummies had skin lesions that resemble smallpox, and the disease was first described clinically in China in the 4th1
  • Characterized by fever, rash (Figure), and a high mortality rate, smallpox is caused by the variola virus, a large DNA orthopoxvirus within the Poxviridae1-3 Highly contagious – on average 4-5 people are infected from a single primary case of smallpox, and the only host is humans.3-4
  • In the late 18th century, it was observed that milkmaids who contracted cowpox typically didn’t die from smallpox.
    • Edward Jenner injected a young boy with material from one of these cowpox lesions, and the child did not develop smallpox after being exposed, marking the beginning of the vaccination era.1,5
  • Global eradication of smallpox was announced in 1980 after an aggressive vaccination campaign.2
  • In 1996, the World Health Organization (WHO) called for the remaining stocks of variola virus to be destroyed or transferred to one of two designated biosafety level 4 facilities: the Center for Disease Control (CDC) in Atlanta, Georgia or the State Research Center of Virology and Biotechnology in Koltsovo, Russia.1 In 1999, however, due to fears that smallpox could be released in the future, the WHO delayed the destruction of the known stocks of variola virus.6 This followed an Institute of Medicine report recommending that added research and the development of antiviral agents and novel vaccines required maintaining the live virus.6,7 The use of smallpox a bioweapon remains a concern.
    • The former Soviet Union weaponized smallpox in the 1980s.1,8 Russian scientists may have bioengineered the virus during the Cold War to make it more virulent.8
    • Clandestine stocks of variola virus may exist today. Iraq, Iran, and North Korea, for example, have been accused of having the virus, but these accusations have not been substantiated.3
  • In addition, research has shown that the feasibility of recreating the virus de novo using synthetic biology.1,4


  • The variola virus is transmitted through inhalation of droplets or aerosols, contaminated fomites, or fluid from an infected patient’s sores.1,4,6 Inhaled secretions containing variola virus replicate in the respiratory epithelium.
    • The virus is taken up by macrophages and transported to regional lymph nodes where multiplication results in a primary viremia.
  • The virus then disseminates to lymphoid organs, and viral amplification within lymphoid organs results in a secondary viremia, which heralds the onset of symptoms.3 Incubation period is about 12 days (range 7-19 days). 3-4
  • There are no asymptomatic carriers.3 The contagious period starts when oral lesions appear and ends when the last scabs fall off; infectivity seems to be highest at the beginning of the rash, 2-3 days after the onset of fever.3

Clinical Presentation:

  • Occurs in 2 forms:3,5
    • Variola major: more serious, mortality rate about 30% in unvaccinated individuals
    • Variola minor: less serious, mortality rate < 1%
  • Classified into 4 clinical categories:
    • Ordinary type2
      • Most common form, and during the smallpox era, accounted for > 85% of cases
      • Symptoms of prodrome occur over 4 days and include the following symptoms: fever (101-105°F or 38.3-40.5°C), chills, malaise, pharyngitis, weakness, headache, vomiting, severe abdominal pain, anorexia
      • As the fever improves, characteristic rash begins to develop
        • Lesions typically erupt in the oropharynx first, followed by the face and extremities, and then the trunk, soles, and palms in a centrifugal manner
        • Lesions progress from macules to papules to vesicles over 4-5 days; then the vesicles become umbilicated and transition into pustules within another 1-2 days
        • Crusting and scab formation occurs by day 9 of rash, and crusts slough off approximately 14 days after onset of rash
      • Mortality rate: ranged from 10% for patients with discrete lesions to 60% for patients with confluent lesions3
    • Modified type2
      • Occurs in previously vaccinated individuals
      • Prodrome consists of severe headache, backache, and fever
      • There may be fewer skin lesions that are more superficial
      • Skin lesions progress more quickly, and crusting typically is complete within 10 days
    • Flat type2,9
      • Very rare and occurs more frequently in children
      • Vaccination may impart some protection
      • Skin lesions evolve slowly, become confluent, and never progress to pustules
      • Appearance of lesions suggests a deficient cellular immune response to the virus, and the majority of cases are fatal (95-100%)
    • Hemorrhagic type2-3
      • More common in adults but can occur in all ages
      • Pregnant women are more susceptible
      • Vaccination is not protective
      • Difficult to recognize
      • Different from ordinary smallpox due to a shorter incubation period, more severe prodromal symptoms, and development of a dusky erythema followed by lesions and mucous membranes that become hemorrhagic
      • Death, secondary to multi-organ failure, typically occurs by the 5th or 6th day of the rash; case-fatality rate is 93-100%


  • Primarily a clinical diagnosis
  • Use the CDC guidelines to determine risk of smallpox using major and minor criteria:2
    • Criteria:
      • 3 major criteria:
        1. Febrile prodrome: fever ³ 101°F (38.3°C) 1-4 days prior to rash onset with at least prostration, headache, backache, chills, vomiting, OR severe abdominal pain
        2. Classic smallpox lesions: deep-seated, firm/hard, round, well-circumscribed vesicles or pustules; lesions may umbilicate or become confluent
        3. Lesions in same stage of development: on any one part of the body, all lesions in same stage of development
      • 5 minor criteria:
        1. Centrifugal distribution of lesions
        2. First lesions on the oral mucosal/palate, face, or forearms
        3. Patient appears toxic or moribund
        4. Slow evolution of lesions from macules to papules to pustules (1-2 days for each stage)
        5. Lesions on the palms and/or soles
      • If the patient has no febrile prodrome OR has febrile prodrome AND < 4 minor criteria, the patient’s risk of smallpox is LOW
      • If the patient has a febrile prodrome AND one other major smallpox criterion OR if the patient has a febrile prodrome AND ³ 4 minor criteria, the patient’s risk of smallpox is MODERATE
      • If the patient has a febrile prodrome AND classic smallpox lesions AND lesions in the same stage of development (all 3 major criteria), the patient’s risk of smallpox is HIGH
    • If a presumptive diagnosis of smallpox is being considered, appropriate infection control precautions must be implemented.2
      • Patients should be placed in an airborne infection isolation room (AIIR)
      • Use standard, airborne, and contact precautions, such as N95 respirators, gloves, and gowns
      • During transport, place a sheet over the patient’s rash and cover the patient’s mouth and nose with an N95 respiratory or surgical mask
    • Testing:
      • Testing for smallpox is not indicated for patients at low or moderate risk since the positive predictive value is very low; testing for other etiologies should be carried out, such as varicella, HSV-1, and HSV-2.2-3
      • Definitive diagnosis is established with specific molecular testing after consultation with the CDC.1-2
      • Differential diagnosis:1-3
        • Chickenpox
        • Contact dermatitis
        • Disseminated herpes simplex virus
        • Disseminated varicella-zoster
        • Drug reactions
        • Eczema vaccinatum
        • Enteroviral infections
        • Erythema multiforme
        • Generalized vaccinia
        • Impetigo
        • Insect bites
        • Measles
        • Molluscum contagiosum
        • Monkeypox
        • Rubella
        • Rickettsialpox rash
        • Scabies
        • Scarlet fever
        • Secondary syphilis
        • Stevens-Johnson syndrome


  • Mainstay is supportive care
    • Giving the smallpox vaccine can prevent and decrease severity of symptoms if given within 2-3 days after exposure6,8 Vaccine uses a live vaccinia virus (derived from cowpox vaccine)
    • Adverse reactions may occur, including encephalitis and progressive vaccinia
    • Two antivirals are approved by the FDA for treatment of smallpox:2,4 Tecovirimat
      • Approved in July 2018
      • Taken orally
      • Approved in adults and pediatric patients weighing ³ 13 kg
      • Weight-based dosing with duration of treatment 14 days10 Available through the U.S. Government’s Strategic National Stockpile
    • Brincidofovir
      • Approved in June 2021
      • Taken orally
      • Approved in adults and all pediatric patients
      • Weight-based dosing with a total of two weekly doses (day 1 and day 8)11
    • Smallpox complications and sequelae: secondary bacterial infections, sepsis, corneal ulcers, blindness, arthritis, limb deformities, and encephalitis3 The majority of survivors (65-80%) will have facial pockmarks

Clinical Pearls:

  • Was eradicated in 1980, but there is concern that it could be used as a biological weapon
  • Transmitted via droplets or aerosols, as well as contaminated fomites
  • Contagious period starts when oral lesions appear and ends when the last scabs fall off
  • Classified into 4 clinical categories: ordinary type, modified type, flat type, and hemorrhagic type
  • A symptomatic patient’s risk of smallpox is determined using the CDC’s major and minor criteria
  • Must consider extensive differential diagnosis before testing for smallpox
  • Treatment is made up of supportive care, smallpox vaccination, and two FDA-approved antivirals

Case Follow-up:

You provide reassurance to the patient’s mother that the patient’s rash is not consistent with smallpox given the following factors: there was a minimal prodrome of symptoms; patient is not significantly ill-appearing; the lesions appear in different stages with rapid evolution; the lesions are concentrated on the trunk rather than the extremities; and palms and soles are not involved. You also provide reassurance that smallpox was eradicated in 1980, and a case hasn’t been seen in over 40 years. In addition, upon further questioning, a recent chickenpox exposure occurred at the patient’s daycare and given the appearance of the rash and the fact that the patient has not yet been immunized against varicella, chickenpox is the most likely diagnosis. The patient’s mother is relieved to hear that she doesn’t have to worry about smallpox, and the patient is discharged with instructions for continued supportive care at home.


  1. Meyer H, Ehmann R, Smith GL. Smallpox in the Post-Eradication Era. Viruses. 2020;12(2):138. doi:10.3390/v12020138
  2. Smallpox – For Clinicians. Updated October 8, 2019. Accessed March 19, 2022.
  3. Moore ZS, Seward JF, Lane JM. Smallpox. Lancet. 2006;367(9508):425-435. doi:10.1016/S0140-6736(06)68143-9
  4. Delaune D, Iseni F. Drug Development against Smallpox: Present and Future. Antimicrob Agents Chemother. 2020;64(4):e01683-19. doi:10.1128/AAC.01683-19
  5. Breman JG. Smallpox. J Infect Dis. 2021;224(12 Suppl 2):S379-S386. doi:10.1093/infdis/jiaa588
  6. Suchard JR. Biological Weapons. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e. McGraw-Hill; 2019. Accessed March 19, 2022.
  7. Shalala DE. Smallpox: setting the research agenda. Science. 1999;285(5430):1011. doi:10.1126/science.285.5430.1011
  8. Wittek R. Vaccinia immune globulin: current policies, preparedness, and product safety and efficacy. Int J Infect Dis. 2006;10(3):193-201. doi:10.1016/j.ijid.2005.12.001
  9. Rao AR. Smallpox. Bombay: Kothari Book Depot; 1972. Accessed April 30, 2022.
  10. Tecovirimat (TPOXX) FDA Package Insert. Accessed April 30, 2022.
  11. Brincidofovir (Tembexa) FDA Package Insert. Accessed April 30, 2022.,214461s000lbl.pdf

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