II. Epidemiology

  1. No natural source of Smallpox remains as of 1977
  2. Biological Weapon potential
  3. Outbreaks historically occurred in winter
    1. Same time as Varicella Zoster Virus and Measles

III. History

  1. British first used Smallpox as Biological Weapon
    1. French and Indian Wars 1754-1767
    2. Distributed contaminated blankets to Native Americans
  2. Edward Jenner demonstrated efficacy of Vaccine 1796
    1. Found milkmaids who had Cowpox did not get Smallpox
    2. Initiated Cowpox inoculation which prevented Smallpox
  3. Eradication of Smallpox completed in 1977
    1. Smallpox Vaccination discontinued
      1. United States: 1972
      2. Worldwide: 1980
    2. Most labs destroyed Variola virus samples by 1999

IV. Pathophysiology

  1. Variola Virus is a brick-shaped 200 nm member of Orthopoxvirus genus
  2. Cowpox is also a member of Orthopoxviruses

V. Types

  1. Standard Smallpox (90% of cases)
    1. Variola major (much more severe, lethal form)
    2. Variola Minor
  2. Severe variants
    1. Hemorrhagic Smallpox (more common in pregnant women)
    2. Malignant Smallpox

VI. Transmission

  1. Contagious only after onset of rash
    1. Infectious for first 7 to 10 days after rash
    2. Infectivity wanes after scabs form
    3. Only very low dose (few virions) needed for infection (highly contagious)
      1. Pandemic can be caused by 100 active cases
  2. Direct contact with oropharyngeal droplets or aerosols
  3. Contaminated clothing or linen
  4. Person to person transmission
    1. No animal or Insect hosts

VII. Symptoms

  1. Incubation Period of 7 to 17 days (usually 12-14 days)
  2. Viral prodrome (2-3 days before rash)
    1. High fever
    2. Rigors
    3. Malaise
    4. Myalgia
    5. Headache
    6. Backache
    7. Abdominal Pain
    8. Vomiting

VIII. Signs: Rash

  1. Timing
    1. Onset of rash within 2-4 days of fever
  2. Location
    1. Initial: Oropharynx, face (centrifugal)
    2. Next: Arms (esp. Forearms)
    3. Next: Remainder of extremities including legs
    4. Next: Palms and soles
    5. Later: Trunk
  3. Typical Smallpox Characteristics
    1. Initial: Maculopapular
    2. Next: Vesicles or Oral Ulcers within 1-2 days
    3. Next: Round, tense and embedded Pustules
    4. Next: Crusts or scabs form by 8-9 days of rash
    5. Last: Scars form with Sebaceous Gland destruction
  4. Hemorrhagic Smallpox Characteristics
    1. Initial: Dusky erythema
    2. Next: Petechiae
    3. Next: Hemorrhaging from skin and mucus membranes
  5. Malignant Smallpox Characteristics
    1. Initial: Slow confluence of lesions
    2. Next: Soft, flattened, velvety Vesicles form
    3. Next: Reddish fine-grained Skin Coloration
    4. Contrasts: No formation of Pustules or scabs

IX. Differential Diagnosis

  1. Varicella Zoster Virus (features of VZV listed)
    1. No lesions on palms or soles in VZV
    2. VZV with minimal prodrome; fever onset with rash
    3. Stages of maturation much faster in VZV
      1. Rash develops rapidly
      2. Scab forms within 7 days of rash
      3. Scab separates within 14 days of rash
    4. Trunk more involved in VZV than face or extremities
  2. Meningococcemia
    1. Contrast with Hemorrhagic or Malignant Smallpox
  3. Severe Acute Leukemia
    1. Contrast with Hemorrhagic or Malignant Smallpox

X. Labs: Used to identify epidemic

  1. Throat swab for PCR (preferred) or ELISA
  2. Obtain samples from possible source
    1. Open Vesicle with scalpel and dab with cotton swab
    2. Obtain scab sample with forceps
  3. Send sample in sealed Vacutainer (tape top)
  4. Encase Vacutainer in second, water proof container
  5. Send samples to high-containment labs (BL-4)
  6. Smallpox rapidly identified under electron microscopy

XI. Management: Emergently reduce transmission risk

  1. Patient Isolation at facility (home is preferred)
    1. Negative pressure room
    2. High-efficiency particulate air filtration
    3. Deceased patients should be cremated
      1. Vaccinate mortuary workers
  2. Protect all medical facility personnel
    1. Medical care by recently vaccinated persons only
    2. Immunize all hospital employees
    3. Furlough non-immunized employees
    4. Infectious precautions (Gloves and Mask)
    5. Contact public health immediately
    6. Decontamination
      1. Laundry in biohazard bags, autoclave, then launder
      2. Waste in biohazard bags and incinerate
      3. Room Decontamination per protocol
  3. Identify and immunize contacts of infection source
    1. Household or face-to-face contact with febrile source
    2. Isolate if fever >101 within 17 days of exposure
    3. Forced quarantine may be necessary

XII. Management: Medical

  1. See Prevention below (include Postexposure Prophylaxis)
  2. Symptomatic and supportive care
  3. Tecovirimat (TPOXX)
    1. Indicated in severe Vaccinia
    2. Dose: 600 mg orally twice daily for 14 days
    3. Interrupts virus transmission between cells
  4. Other agents with benefit
    1. Cidofovir (Vistide)
    2. Brincidofovir

XIII. Prognosis

  1. Variola major: 30% to 50% mortality rate in unvaccinated patients
  2. Variola Minor: 1-2% mortality rate
  3. Hemorrhagic Smallpox: Uniformly fatal by day 6 of rash
  4. Malignant Smallpox: Frequently fatal

XIV. Prevention

  1. Pre-exposure Smallpox Vaccination
    1. Immunity wanes after 5-10 years
    2. Those vaccinated 30 years ago are likely susceptible
    3. Routine Smallpox Vaccination stopped in U.S. 1972
  2. Post-exposure Prophylaxis
    1. Vaccinia Immune Globulin 0.6 ml/kg IM
      1. Must be given within 3 days (ideally within 24 hours)
    2. Smallpox Vaccination
      1. Must be given within 4 days of exposure (before symptoms) to be effective
      2. Contraindicated in pregnancy (risk of fetal Vaccinia) unless benefits outweight risks
  3. Variola Immunoglobulin (Vaccinia immune globulin)
    1. High risk patients, given within first 7 days
    2. Give in combination with post-exposure Vaccination
    3. Dose: 100 mg/kg IM
  4. Cidofovir
    1. May be efficacious if used within 2 days of exposure
    2. Indicated in significant exposure during pregnancy

XV. References

  1. Seeyave (2015) Crit Dec Emerg Med 29(5): 13-21
  2. Wilson (1991) Harrison's IM, McGraw-Hill, p. 709-11
  3. Breman (1998) N Engl J Med 339:556-9 [PubMed]
  4. Henderson (1999) JAMA 281:2127-37 [PubMed]
  5. Rathjen (2021) Am Fam Physician 104(4): 376-85 [PubMed]

Images: Related links to external sites (from Bing)

Related Studies

Ontology: Cowpox (C0010232)

Definition (MSHFRE) Maladie virale bénigne survenant chez les vaches laitières due au cowpox virus, se manifestant par des éruptions cutanées localisées principalement au niveau de la mamelle et des trayons. L'homme peut se contaminer lors de la traite d'un animal infecté.
Definition (MSH) A mild, eruptive skin disease of milk cows caused by COWPOX VIRUS, with lesions occurring principally on the udder and teats. Human infection may occur while milking an infected animal.
Concepts Disease or Syndrome (T047)
MSH D015605
ICD9 051.01
ICD10 B08.010
SnomedCT 154344005, 266193008, 70090004
English Cow Pox, Pox, Cow, yaba, cowpox, cowpox (diagnosis), Cow pox, Cowpox [Disease/Finding], cow pox, Cowpox (disorder), Cowpox
French Cow-pox, Vaccine, Cowpox
Italian Malattia vaccinica, Vaiolo bovino
Spanish Vacuna, Viruela Bovina, Cowpox, viruela vacuna (trastorno), viruela vacuna, Vaccinia, Viruela Vacuna
Swedish Kokoppor
Japanese ギュウトウ, 牛痘
Czech kravské neštovice, Kravské neštovice, Nepravé neštovice
Finnish Lehmärokko
Polish Ospa krowia
Hungarian Tehénhimlő, tehén himlő
Norwegian Kukopper
Portuguese Cowpox, Vacínia, Varíola Bovina
Dutch koepokken, Koepokken, Pokken, koe-
German Kuhpocken

Ontology: Poxviridae (C0032868)

Definition (NCI) A family of double-stranded DNA viruses infecting mammals, birds and insects. Contains two subfamilies: chordopoxvirinae, poxviruses of vertebrates, and entopoxvirinae, poxviruses of insects.
Definition (MSH) A family of double-stranded DNA viruses infecting mammals (including humans), birds and insects. There are two subfamilies: CHORDOPOXVIRINAE, poxviruses of vertebrates, and ENTOMOPOXVIRINAE, poxviruses of insects.
Definition (CSP) family of dsDNA viruses; replication occurs in the cytoplasm with inclusion bodies; natural host range is narrow; transmission is by several routes including airborne, fomites, direct contact and mechanically by arthropods.
Concepts Virus (T005)
MSH D011212
SnomedCT 424976006, 243567005
English Poxviruses, Family: Poxvirus group, Family Poxviridae, Poxvirus group, Family Poxviridae (organism), pox virus, poxviruses, poxvirus, virus pox, pox viruses, poxviridae, Poxvirus group (organism), Poxviridae, Poxvirus
Swedish Poxviridae
Spanish grupo Poxvirus, familia Poxviridae (organismo), familia: grupo Poxvirus, familia Poxviridae, Poxviridae, grupo Poxvirus (organismo)
Czech Poxviridae
Finnish Rokkovirukset
Japanese ポックスウイルス科
Italian Poxvirus, Poxviridae
Croatian Not Translated[Poxviridae]
Polish Poxviridae
French Poxvirus, Poxviridae
Norwegian Not Translated[Poxviridae]
German Pockenviren
Dutch Pokkenvirussen, Poxviridae
Portuguese Poxviridae

Ontology: Smallpox (C0037354)

Definition (MSHFRE) Maladie infectieuse hautement contagieuse, souvent mortelle, due à un orthopoxvirus. Elle est caractérisée par une fièvre bi-phasique, une éruption caractéristique au niveau de la peau. La vaccination a réussi à éradiquer la variole dans le monde. (Dorland, 28ème éd.)
Definition (MEDLINEPLUS)

Smallpox is a disease caused by the Variola major virus. Some experts say that over the centuries it has killed more people than all other infectious diseases combined. Worldwide immunization stopped the spread of smallpox three decades ago. The last case was reported in 1977. Two research labs still keep small amounts of the virus. Experts fear bioterrorists could use the virus to spread disease.

Smallpox spreads very easily from person to person. Symptoms are flu-like. They include

  • High fever
  • Fatigue
  • Headache
  • Backache
  • A rash with flat red sores

There is no treatment. Fluids and medicines for pain or fever can help control symptoms. Most people recover, but some can die. Those who do recover may have severe scars.

The U.S. stopped routine smallpox vaccinations in 1972. Military and other high-risk groups continue to get the vaccine. The U.S. has increased its supply of the vaccine in recent years. The vaccine makes some people sick, so doctors save it for those at highest risk of disease.

NIH: National Institute of Allergy and Infectious Diseases

Definition (MSH) An acute, highly contagious, often fatal infectious disease caused by an orthopoxvirus characterized by a biphasic febrile course and distinctive progressive skin eruptions. Vaccination has succeeded in eradicating smallpox worldwide. (Dorland, 28th ed)
Concepts Disease or Syndrome (T047)
MSH D012899
ICD9 050.9, 050
ICD10 B03
SnomedCT 186505008, 266193008, 154344005, 67924001, 47452006
English Variola, Variolas, Smallpox, unspecified, smallpox (variola), variola, smallpox, smallpox (diagnosis), Smallpox NOS, Smallpox [Disease/Finding], variola major, Small pox, smallpox disease, Smallpox NOS (disorder), Smallpox, Classical smallpox, Smallpox (disorder), Smallpox, NOS, Variola, NOS, Ordinary smallpox, small pox
Dutch pokken, niet-gespecificeerd, Pokken1, pokken, Pokken, Variola
French Variole, non précisée, Variole
German Pocken, unspezifisch, Blattern, Pocken, Variola
Italian Vaiolo non specificato, Variola, Vaiolo
Portuguese Varíola NE, Varíola
Spanish Viruela no especificada, viruela, SAI (trastorno), viruela, SAI, variola, viruela (trastorno), viruela, viruela clásica, viruela clásica (trastorno), Viruela, Variola
Japanese 痘瘡、詳細不明, トウソウショウサイフメイ, トウソウ, 小痘瘡, 天然痘, 疱瘡, 乳痘, アラストリム, 痘瘡
Swedish Smittkoppor
Czech variola, Variola, Pravé neštovice, blíže neurčené, neštovice pravé, pravé neštovice
Finnish Isorokko
Korean 마마
Croatian VARIOLA
Polish Ospa prawdziwa, Alastrim
Hungarian Variola vera, nem meghatározott, variola vera
Norwegian Variola, Kopper

Ontology: Vaccinia (C0042214)

Definition (MSHFRE) Réactions cutanées et parfois généralisées, secondaires à une vaccination contre la variole
Definition (MSH) The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine.
Concepts Disease or Syndrome (T047)
MSH D014615
SnomedCT 111852003
English Vaccinias, vaccinia, vaccinia (diagnosis), Vaccinia [Disease/Finding], Vaccinia (disorder), Vaccinia, NOS, Vaccinia
Swedish Vaccinia
Czech vakcínie, Vakcínie
Finnish Vaccinia
Spanish Infección por el virus vaccinia, vaccina, vaccinia (trastorno), vaccinia, variola vaccina, Vaccinia
French Virus de la vaccine, Vaccine
Italian Vaccinia, Pustola vaccinica
Dutch vaccinia, Vaccinia
Japanese ワクシニア, ワクシニア
Portuguese Vaccinia, Vacínia
Polish Ospa poszczepienna, Krowianka
Hungarian vaccinia
Norwegian Vaccinia
German Vaccinia

Ontology: Orthopoxvirus (C0206580)

Definition (NCI_CDISC) Any viral organism that can be assigned to the genus Orthopoxvirus.
Definition (NCI) A genus of poxviruses that cause generalized infections with a rash in mammals. Orthopoxviruses are enveloped, double standed DNA viruses.
Definition (MSH) A genus of the family POXVIRIDAE, subfamily CHORDOPOXVIRINAE, comprising many species infecting mammals. Viruses of this genus cause generalized infections and a rash in some hosts. The type species is VACCINIA VIRUS.
Concepts Virus (T005)
MSH D018155
SnomedCT 29724001
LNC LP14832-7, MTHU002049
English Orthopoxvirus, Genus Orthopoxvirus (organism), Orthopoxvirus (organism), Genus Orthopoxvirus, orthopoxvirus, orthopoxviruses, Orthopoxviruses, ORTHOPOXVIRUS, Genus: Vaccinia subgroup, Vaccinia subgroup virus, Vaccinia subgroup, Orthopoxvirus, NOS, Vaccinia subgroup, NOS
Swedish Ortopoxvirus
Spanish género Orthopoxvirus (organismo), género Orthopoxvirus, ortopoxvirus (organismo), Orthopoxvirus, ortopoxvirus, subgrupo del virus de la vaccinia, subgrupo del virus vacunal
Czech Orthopoxvirus
Finnish Ortopoxvirus
Croatian Not Translated[Orthopoxvirus]
Polish Orthopoxvirus
Japanese オルソポックスウイルス, オルトポックスウイルス, オルトポックスウイルス属
French Orthopoxvirus
German Orthopoxvirus
Italian Orthopoxvirus
Dutch Orthopoxvirus, Virus, Orthopox-
Portuguese Orthopoxvirus

Ontology: Variola major (C1812609)

Concepts Disease or Syndrome (T047)
ICD9 050.0
SnomedCT 266193008, 154344005, 47452006
Dutch variola major
French Variole majeure
German Variola major
Italian Variola major
Portuguese Varíola major
Spanish Viruela mayor, variola mayor (trastorno), variola mayor
Japanese 大痘瘡, ダイトウソウ
English variola major, variola major (diagnosis), Variola major, Variola major (disorder)
Czech Variola major
Hungarian Variola major