cessation of universal vaccination within the United States in 1972, vaccine had been out of production until the 2007 licensing of a new product (ACAM2000, Acambis Corporation); although the CDC now controls enough ACAM2000 to vaccinate every American, susceptibility to the disease is nearly universal Also, effective therapy is lacking and healthcare providers are unfamiliar with the disease Finally, the potential for rapid spread potentially permits a terrorist to cause widespread disease and panic with a minimum of infectious material Pathophysiology Although infectivity is highest when the smallpox rash first appears, the disease may be spread by exposed persons about 24 hours before the exanthem manifests During the 7- to 17-day long incubation period, the virus replicates in upper respiratory tract mucosa, giving rise to a primary viremia The liver and spleen are then seeded, further amplification of the virus occurs, and a secondary viremia ultimately develops The skin is seeded with this secondary viremia, and the classic exanthem of smallpox develops Clinical Manifestations Clinical illness has an abrupt onset during the phase of secondary viremia and is characterized by fever, malaise, rigors, vomiting, headache, and backache The classic exanthem typically begins to days later as macules on the face and extremities These lesions progress in synchronous fashion to papules, vesicles, and then to pustules, which finally form scabs As scabs separate, survivors are left with disfiguring depigmented scars The rash spreads centrally to the trunk but remains more abundant at the periphery This centrifugal distribution and synchrony distinguish smallpox from chickenpox, which has a centripetal distribution of lesions in varying stages of development An enanthem usually accompanies the characteristic exanthem, and internal organs become viral targets as well Death historically occurred in approximately 30% of variola major (the predominant form of smallpox in the past) patients and typically resulted from hypotension and immune complex–associated toxemia Eye involvement led to blindness in a small number of victims Uncommon variants with lesser (variola minor) or greater (hemorrhagic and flat-type variants) mortality also existed Ominously, a 1971 smallpox outbreak in Aralsk, in the former Kazakh Soviet Republic, is thought by some to have originated from a bioweapons accident All three fatalities in this small outbreak involved unvaccinated individuals who contracted rare and universally fatal hemorrhagic disease, raising the specter of genomic manipulation for increased virulence Management The diagnosis of smallpox should be suspected on clinical grounds Laboratory confirmation (e.g., electron microscopy, PCR) is best