Smallpox

See Also

Epidemiology

No natural source of Smallpox remains as of 1977
1. Smallpox infects only humans (no other animal reservoirs)
Biological Weapon potential
1. Two remaining virus stocks for research (Russia and U.S. CDC)
Outbreaks historically occurred in winter
1. Same time as Varicella Zoster Virus and Measles

History

British first used Smallpox as Biological Weapon
1. French and Indian Wars 1754-1767
2. Distributed contaminated blankets to Native Americans
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. Vaccinia virus later replaced Cowpox as the source of Smallpox Vaccine
Eradication of Smallpox completed in 1977
1. Most labs destroyed Variola virus samples by 1999
2. Smallpox Vaccination discontinued
  1. United States: 1972
  2. Worldwide: 1980
3. Smallpox was a perfect target for eradication by Vaccination (and among WHOs greatest triumphs)
  1. Infected only humans (no other animal reservoirs)
  2. Cases were easily identified (infections are always symptomatic)
  3. Vaccination was highly effective with long-lasting Immunity
  4. Smallpox was associated with high morbidity and mortality

Pathophysiology

Variola Virus (Smallpox)
1. Brick-shaped 200 nm, dsDNA virus member of Orthopoxvirus genus within the Poxviridae family
2. Smallpox infected only humans (no other animal reservoirs)
3. Smallpox always caused symptoms (no latent or asymptomatic carriers)
Poxviridae (Poxvirus)
1. Family of linear, double-stranded DNA (dsDNA) viruses
2. Poxviridae infect mammals, birds and Insects
3. Poxviridae are the most complex of viruses
  1. Virus is contained in a box-like membrane
  2. Virus has a large genome (coding for 100s of Proteins) enclosed in a dumbbell-like structure
4. Poxviridae replicate in the host cell cytoplasm with inclusion bodies
  1. Differs from other DNA Viruses, which replicate in the host cell nucleus
  2. Poxviridae carries most of its own enzymes for replication
5. Poxviridae contains 8 genera, of which 3 are important to human disease
  1. Orthopoxvirus (Smallpox, Cowpox and Monkeypox)
  2. Molluscipoxvirus ( Molluscum Contagiosum)
  3. Yatapoxvirus (Tanapox virus, Yaba Monkey Tumor Virus)
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. Person to person transmission
  1. No animal or Insect hosts
3. Direct contact with oropharyngeal droplets or aerosols (droplet transmission)
  1. Particles large enough to be expelled by cough or sneeze
  2. Particles small enough to remain airborne for transmission (<5 microns)
  3. Droplet transmission within 3-6 feet of contagious person
  4. May also be transmitted on contaminated clothing or linen

Types

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

Symptoms

Incubation Period of 7 to 17 days (usually 12-14 days)
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

Signs
Rash

Timing
1. Onset of rash within 2-4 days of fever
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
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
Hemorrhagic Smallpox Characteristics
1. Initial: Dusky erythema
2. Next: Petechiae
3. Next: Hemorrhaging from skin and mucus membranes
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

Differential Diagnosis

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
Measles
1. Measles is associated with a flat red rash that does not typically scab or scar
2. Measles is associated with Koplik's spots on the Buccal mucosa
3. Measles has a far lower mortality rate than Smallpox
Meningococcemia
1. Contrast with Hemorrhagic or Malignant Smallpox
Severe Acute Leukemia
1. Contrast with Hemorrhagic or Malignant Smallpox

Labs
Used to identify epidemic

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

Management
Emergently reduce transmission risk

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
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
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

Management
Medical

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

Prognosis

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

Prevention

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
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
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
Cidofovir
1. May be efficacious if used within 2 days of exposure
2. Indicated in significant exposure during pregnancy

References

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