during the first week of rash. Scab material forms as the rash dries and usually consists of large fragments of cellular debris, with virions bound within a dense, fibrous mesh containing a large amount of the antiviral substance interferon. Infectious virus is difficult to release from scabs except by mechanical grinding.

Inoculation smallpox sometimes occurs when variola virus is introduced into the skin either intentionally or accidentally. A local skin lesion appears on the third or fourth day, with fever and constitutional symptoms beginning on the eighth day. The incubation period is typically 2 to 3 days shorter than in natural smallpox. The rash, which is usually less severe than in naturally acquired smallpox, appears on the tenth or eleventh day. The milder course of disease stemming from deliberate variola inoculation was the basis for variolation, which preceded Jenner's use of cowpox and the subsequent use of vaccinia inoculation as a preventive for smallpox (as discussed further below).

Very rarely, vaccinia vaccination produces dissemination vaccinia, a systemic infection characterized by malaise combined with a generalized rash similar to inoculation lesions. In another condition, called progressive vaccinia, the inoculation lesion fails to heal, and secondary lesions sometimes appear elsewhere. Both conditions are problematic predominantly for individuals with deficient immune mechanisms.

Variola major caused severe problems in pregnant women. Abortions and stillbirths were frequent, and a majority of the babies born to infected women in hospital died within 15 days, most within 3 days. About half of the babies acquired infection in utero or at the time of delivery.

Dissemination

The appearance of high fever and then lesions on the skin marks the end of the incubation period. Smallpox pathogenesis is a poorly understood series of events in which the virus first disseminates locally, then through the lymphatic system, and finally to the skin without affecting vital organs. In mousepox, the primary source of molecular studies of orthopoxvirus pathogenesis, the infection moves from the respiratory tract to the liver and spleen following breach of the macrophage barrier. The virus then replicates extensively in both organs, which produces semiconfiuent necrosis. About a day after infection of the liver and spleen, large numbers of virions are liberated into the bloodstream, leading to secondary infection of the skin, kidneys, lungs, intestines, and other organs. This phase is followed by an interval of 2 or 3 days during which the virus replicates and reaches a high titer before visible changes are apparent in the infected organs.

As noted earlier, mousepox is unusual among the generalized orthopoxvirus infections in that the spleen and liver are the major target organs for viral replication. There is inadequate evidence regarding exactly where the virus replicates during a smallpox infection. The likely sites for viral replication are the lymphoid organs (spleen, bone marrow, lymph nodes), but extensive necrosis does not occur in those sites. At this stage, the virus in the blood is largely cell-associated.



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