Variola virus

• Cause of smallpox (i.e. variola)

Background

Microbiology

• Variola virus is a dsDNA virus in Orthopoxvirus genus
• Virus replicats in the cell cytoplasm rather than nucleus

Pathophysiology

• Virus enters through a respiratory route, a mucosal surface, or a break in the skin
• Replicates locally then spreads through local lymphatics, causing a primary viremia
• Then spreads to the reticuloendothelial system, where replication results in secondary viremia
• The virus then ultimately seeds skin, causing a characteristic “pock” rash

Epidemiology

• Human are only known hosts (no animal reservoir)
• Droplet transmission, can be transmitted on fomites (survives 6 to 24 hours on surfaces or cloth)
  • There have been outbreaks among hospital laundry staff
  • Virus in scabs can survive longer
• Period of communicability is about 3 weeks, from just before first lesions to disappearance of all scabs
  • Highest during first week of rash

Eradication

• Contagious during prodrome, but most highly infectious for the first 7 to 10 days following rash and continues until all the lesions have crusted over
• Eradicated worldwide with the last case in Somalia in 1977

Differential Diagnosis

• Varicella-zoster virus
• Enterovirus
• Monkeypox: generally more lymphadenopathy
• Other causes of a vesicular rash

Risk Classification Algorithm

• Applied to patients with an acute generalized vesicular or pustular rash (AGVPR)
• Source: Hutchins SS, et al. CID. 2008:46(Suppl 3):S195-S203

High risk

1. A febrile prodrome (a temperature 38.3C occurring 1–4 days before rash accompanied by prostration, headache, backache, chills, vomiting, or severe abdominal pain);
2. Characteristic lesions, described as deep-seated, firm, hard, well-circumscribed vesicles or pustules; and
3. Vesicles or pustules all at the same stage of development on any 1 body part (e.g., face, leg, or arm).

Moderate risk

1. A febrile prodrome, an AGVPR, and at least 1 other major criterion; or
2. Afebrile prodrome, an AGVPR, and ≥4 minor criteria

Low risk

1. An AGVPR with a febrile prodrome and <4 minor clinical criteria; or
2. Only an AGVPR

Minor clinical criteria

Use to distinguish ordinary-type variola from varicella in the prevaccine era:

• Centrifugal rash distribution
• First lesions on the oral mucosa, face, or forearms
• A toxic or moribund appearance
• A slow rash evolution from macules to papules to pustules (1–2 days for each stage)
• Lesions on palms and soles

Clinical Manifestations

Variola major

• Most common clinical form, with a mortality of about 30%
• Four presentations: ordinary (most common), modified (if vaccinated), flat, and hemorrhagic

Ordinary

• Most common (90%), with 3 phases (incubation, prodrome, and pox)
• Incubation period 12 to 14 days (range 7 to 17 days)
• Prodrome lasts 2 to 4 days, with fever, headache, backache, chills, and vomiting
• Followed by rash, starting as a small red spot in the mouth or on the face (called herald spots)
  • Rash spreads centrifugally from the face to arms and legs (more distal than trunk)
  • Includes palms and soles
  • Usually spread to entire body within about 24 hours
  • Lesions initially maculopapular, followed by firm, well-defined vesicles, often with a central depression
  • Vesicles develop into pustules during the second week, then they flatten and scab over by third or fourth week
  • Lesions may become confluent
  • Lesions progress synchronously, unlike chicken pox
• Mortality

Modified

• Modified form occurs in patients with previous immunization
• Milder illness
• Atypical rash, with fewer lesions that evolve more rapidly
• Mortalilty <10%

Flat/malignant

• Rare and severe, usually fatal (50%)
• Similarly severe prodrome
• However, rash is slower to develop, and remains soft and flat and velvety
  • Like fine-grained, reddish-coloured crepe rubber
  • Sometimes hemorrhages

Hemorrhagic

• Rare and severe, usually fatal (~100%)
• Pregnancy is a risk factor, but occurs in all age groups and sexes
• Shorter incubation period with severe, prostrating prodrome with high fever, headache, back pain, and abdominal pain
• Erythema follows, then petechiae and skin and mucosal hemorrhages
• Death within 5 to 6 days

Variola minor

• Lower mortality rate ~1%
• Fewer constitutional symptoms, fewer skin lesions

Bioterrorism

• Last case globally in 1977, with no routine vaccination in Canada since 1972, and in Canadian armed forces personel since 1988
• The majority of people living in the US (and likely Canada) have not been vaccinated
• Limited vaccine reserves still exist in the US; a new horsepox-derived vaccine was developed in Canada in the 2010s
• In case of an outbreak
  • Healthcare workers should be vaccinated and, ideally, a single hospital designated for smallpox patients
  • Patients should be in negative-pressure isolation with HEPA filter
  • Standard precautions using gloves, gowns, and masks
  • All laundry and waste should be placed in biohazard bags and autoclaved before being laundered or incinerated
  • Rooms should be decontaminated after they are vacated

Diagnosis

• Samples should be collected by unroofing a lesion and soaking a swab
• RG-4 infection, must be processed in a CL-4 lab (i.e. the national micro lab)
• Viral swab with viral transport medium (e.g. NPS swab)
  • PCR can be done for routine viruses as well as Orthopoxviridae
• Tissue
  • Tzanck smear for intracellular inclusion bodies for HSV/VZV
  • Direct immunofluorescence
  • Electron microscopy
    • Smallpox and monkeypox virions may be indistinguishable, naturally occurring monkeypox is found only in tropical rain forest areas of Africa
• Viral culture: technically the gold standard

Management

• No specific treatment; supportive care
  • May try cidofovir
• Patients should be maintained in negative-pressure isolation with HEPA filters (airborne/contact)

Post-exposure prophylaxis

• Contacts may be given vaccine within 4 days of exposure to lessen the severity of symptoms
• Canada has developed a new vaccine derived from horsepox (fewer adverse events)