During natural infection, variola entered the lymph nodes, leading to an asymptomatic viremia about 3 to 4 days following infection. The virus replicated in the reticuloendothelial system before a second episode of viremia resulted in fever, headache, backache, and generalized malaise. This febrile prodrome was followed, after 2 to 3 days, by development of an enanthem and generalized rash. The disease was associated with an overall mortality rate of approximately 30%, with the highest rates noted among infected infants, elderly persons, and pregnant women. Death occurred most often during the second week of illness without apparent involvement of organ systems other than the skin and reticuloendothelial system. Electrolyte abnormalities, dehydration, and secondary bacterial infection were noted, but death was most often attributed to “toxemia.”

Neutralizing, hemagglutinin-inhibiting, and complement-fixing antibodies developed during the disease, beginning at the end of the first week. Neutralizing antibodies may persist for many years, but the relationship between persistence of these antibodies and protection from smallpox is not understood.

Historically, smallpox entered the body via the respiratory route via the oropharynx or nasopharynx in aerosolized or droplet secretions from an infected individual. Other means of spread, through direct contact with respiratory secretions or with contaminated bedding or clothing, also occurred. Infected individuals were not generally considered contagious until the onset of the rash, which occurred after an incubation period of 7 to 17 days (mean, 12 days). Infectivity persisted until all lesions scabbed over and the scabs separated from underlying skin. Scabs themselves contained infective virus, but they were not believed to be a frequent source of infection. Variola survives best in aerosolized form during periods of low temperature and humidity. Historically, therefore, outbreaks were more common during cold, winter months. Smallpox was not as easily spread from person to person as is measles, varicella, or influenza. Prolonged, close contact (face-to-face contact within 6 to 7 feet), usually in a household or hospital, was usually required for secondary spread. Immunity can be induced by vaccination or natural disease.

There are two known forms of variola virus, variola major and variola minor, or alastrim. The two types can now be distinguished virologically, but when smallpox was endemic only clinical distinction was possible. Variola major is historically more important because of its greater overall case fatality rate (ranging from 15% to 45%). Variola major was classified into five types based on the type of lesions produced and the progression of the disease. The disease type in an individual is thought to have been determined by host factors and virus virulence. Ordinary smallpox was the most common and was subdivided into three types according to the appearance of the skin lesions: ordinary-discrete (case fatality less than 10%), ordinary-semiconfluent (case fatality 25% to 50%), and ordinary-confluent (case fatality 50% to 75%). Flat smallpox, in which lesions evolved more slowly and finally coalesced, made up about 7% of cases and resulted in death in over 90%. Hemorrhagic smallpox accounted for approximately 3% of cases and resulted in near-100% mortality. This type was difficult to diagnose because of the absence of discrete vesiculopustular lesions. It was seen in all age groups but disproportionately affected pregnant women. Modified smallpox was a milder disease that evolved more rapidly than ordinary smallpox and was accompanied by fewer, smaller, and more superficial lesions. Mortality was rare; most affected individuals had been previously vaccinated. Variola sine eruptions occurred in infants who were young enough to retain maternal antibody against variola or in previously vaccinated contacts. As the name suggests, individuals with this type had no rash. They were asymptomatic or had brief periods of fever with associated flu-like symptoms, and they were not thought to be able to transmit infection to others.

Variola minor is a less severe form of smallpox. The mortality rate associated with this virus was about 1%. It was first recognized in the early twentieth century in South Africa and later appears to have spread to the Americas and to Europe.

High fever, malaise, headache, backache, and prostration were the symptoms of the preeruptive phase of typical smallpox. Vomiting, diarrhea, abdominal pain, and seizures sometimes occurred. After 2 to 3 days, the infected individual developed painful lesions in the mouth and throat, followed closely (within 24 hours) by a maculopapular rash predominantly on the face and extremities but gradually spreading to the entire body. The orpharyngeal lesions became ulcerated, releasing large numbers of virions into the saliva. It was at this stage that the individual was most contagious. The papules developed into vesicles 4 to 5 days after the rash appeared. The initially clear vesicular fluid became turbid and gave the lesions the appearance and texture of firm, tense pustules (Fig. 206.1). The lesions developed an umbilicated center and began to crust approximately 10 days to 2 weeks after the rash appeared. By the second week, the lesions had scabbed, and the crusts began to separate from the underlying skin. Scarring was seen in the majority of those who survived.