Etiology

Smallpox was caused by the variola virus (family Poxviridae; genus Orthopoxvirus), a double-stranded DNA virus. There are two variants of the variola virus: variola major and variola minor (alastrim). Genome sequencing demonstrated that these were distinct, but closely related, viruses.[4] The variola minor variant was notable for being less virulent overall, but not to the extent that it was possible to reliably distinguish between infection with the two variants clinically without laboratory assistance.

The variola virus should not be confused with the vaccinia virus, an orthopoxvirus used in smallpox vaccines. It is unclear whether the vaccinia virus is a genetic variant of the variola virus (after innumerable passages in cultures), or a derivative of the original cowpox virus used for immunization in the 18th century.[5]

Smallpox was mainly spread by direct and prolonged face-to-face contact with an infected person. Transmission occurred mainly via the respiratory route (i.e., via saliva droplets from coughing or sneezing). Aerosol transmission did not occur until after the prodrome, and by then patients were usually prostrated, so transmission was slow and not very efficient. Transmission from direct contact with fomites (e.g., bedding) and infected bodily fluids (including from deceased patients) was also reported. Airborne transmission was reported rarely in laboratory and hospital settings. When circulating naturally, smallpox tended to occur during cool dry seasons when droplets remained in the environment for longer periods.[1][6][7] There is no evidence that smallpox can be spread by animals or that there are animal reservoirs.

The incubation period of variola virus was 12-14 days (range 7-17 days), with the rash typically appearing 2 to 3 days later. The patient was not infectious during this period. The most infectious period was during the first week of illness and until scabs developed. The secondary attack rate for variola major in unvaccinated people was estimated to be approximately 60% in households.[1]

Pathophysiology

Smallpox virus was transmitted via aerosol, primarily from upper respiratory tract secretions. The characteristic smallpox rash contained virus particles within vesicles, pustules, and subsequently scabs, but they were not the primary sources of transmission. Once smallpox virus had been inoculated into the respiratory tract it was engulfed by macrophages and then transported to regional lymph nodes, where it multiplied. The virus was distributed by hematogenous spread to the liver, spleen, and other lymphoid organs where there was a further cycle of amplification. Finally, there was a viremic phase where the virus seeds to small blood vessels in the skin and upper respiratory tract. Local viral amplification and infection of adjacent dermal and mucosal cells at these sites lead to the ulcerative and vesicular exanthem, with the potential for onward spread. Peak infectivity coincided with the onset of systemic symptoms and declined as the skin rash developed. Hemorrhagic smallpox was accompanied by a much more pronounced viremia than classical smallpox.

Studies on the immune response to smallpox are limited. Both humoral and cellular responses occur, but the former is slower than the initiation of T-cell responses that generate cytotoxic T cells and T cells that produce interferon gamma or other cytokines.[8]

Classification

Clinical classification

There are five main clinical forms of smallpox.[3]

  • Ordinary smallpox

    • Most common form, accounting for over 85% of cases.

  • Modified-type smallpox

    • Occurs in previously vaccinated people.

    • Once skin lesions appear, they are fewer and generally evolve more quickly than ordinary smallpox.

  • Malignant (flat-type) smallpox

    • Very rare.

    • Occurs more frequently in children.

    • Characterized by intense toxemia and skin lesions that develop slowly, remain flat and soft, merge together, and never progress to the pustular stage.

    • Prior vaccination appears protective.

    • Most cases are fatal.

  • Hemorrhagic smallpox

    • Occurs among all ages and both sexes, but is more common in adults, and pregnant women appear to be more susceptible.

    • Shorter incubation period and more severe prodromal symptoms.

    • Development of dusky erythema after onset of illness, followed by petechiae and skin/mucosal hemorrhages.

    • Prior vaccination is not protective.

    • Death usually occurs from profound toxemia leading to multi-organ failure by day 6 of the rash, often before characteristic lesions appear.

  • Variola sine eruptione

    • May rarely present with no rash at all, with a mild or even asymptomatic infection.

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