The last known naturally acquired case of smallpox occurred in Somalia in 1977; the disease was officially declared eradicated in 1980, the culmination of a 12-year intensive campaign undertaken by the WHO (Fenner et al., 1988). At that time all laboratories involved in the global eradication effort were asked to voluntarily destroy or relocate their variola virus stocks to the CDC and the State Research Center of Virology and Biotechnology in Russia (Rotz et al., 2005). However, because of concerns that variola virus stocks may have either been removed from, or sequestered outside of, their officially designated repositories, smallpox is today considered to be a potential bioterror threat. It is a cruel irony of the modern world that perhaps mankind's greatest triumph over nature - the eradication of smallpox - could be undone, volitionally and maliciously, by man.

Multiple features make smallpox an attractive biologic weapon and ensure that its reintroduction into human populations would be a global public health catastrophe: it is stable in aerosol form with a low infective dose; case fatality rates are historically high, approaching 30 percent; secondary attack rates among unvaccinated close contacts are 37 percent to 88 percent and are amplified; and much of the world's population is susceptible, as routine civilian vaccination was terminated more than three decades ago, vaccine-induced immunity wanes over time, and there is no virus circulating in the environment to provide low-level booster exposures (Breman and Henderson, 2002). Additionally, vaccine supplies are currently limited, although this problem has begun to be addressed, and there are currently no antiviral therapies of proven effectiveness against this pathogen.

After an incubation period of 7-17 days (average 10-12 days), the patient experiences the acute onset of a prostrating prodrome of fever, rigors, headache, and backache that may last 2-3 days. This is followed by a centrifugally distributed eruption that generalizes as it evolves through macular, papular, vesicular, and pustular stages in synchronous fashion over approximately eight days, with umbilication in the latter stages (Fenner et al., 1988). Enanthema in the oropharynx typically precedes the exanthem by a day or two. The rash typically involves the palms and soles early in the course of the disease. The pustules begin crusting during the second week of the eruption; separation of scabs is usually complete by the end of the third week. The differential diagnosis of smallpox is delineated in Table 12.5. Historically, varicella and drug reactions have posed the most problematic differential diagnostic dilemmas (Breman and Henderson, 2002).

Smallpox is transmitted person-to-person by respiratory droplet nuclei and, less commonly, by contact with lesions or contaminated fomites. Historically, therefore, most transmission has resulted from prolonged face-to-face contact, such as within families or health-care settings. Air-borne transmission by fine-particle aerosols has, under certain conditions, been documented (Wehrle et al., 1970). The virus is communicable from the onset of the enanthema until all of the scabs have separated, although transmissibility is thought to peak during the first week of the rash due to high titers of replicating virus in the oropharynx (Henderson et al., 1999). Thus, hospitalized cases are placed in negative-pressure rooms with contact and air-borne precautions; cases that do not require hospitallevel care should remain isolated at home to avoid infecting others.

The suspicion of a single smallpox case should prompt immediate notification of local public health authorities and infection-control specialists. Containment of smallpox is predicated on the "ring vaccination" strategy, which was successfully deployed in the WHO global eradication campaign and mandates the identification and vaccination of all directly exposed persons, including close contacts, health-care workers, and laboratory personnel. Vaccination, if deployed within four days of infection during the early incubation period, can significantly attenuate or prevent disease and may reduce secondary transmission (Henderson et al., 1999). Because variola virus does not exist in nature, and legitimate stocks were confined to the two sites in the US and Russia, the occurrence of even a single case of smallpox outside of an accidental laboratory exposure would be tantamount to bioterrorism. An epidemiologic investigation would be necessary to ascertain the perimeter of the initial release, so that tracing of initially exposed persons could be accomplished.

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