Clinical Description


Smallpox was a systemic viral disease generally presenting with a characteristic skin eruption. Preceding the appearance of the rash was a prodrome of sudden onset, with high fever (40°C/104°F), malaise, headache, prostration, severe backache and occasional abdominal pain and vomiting—a clinical picture that resembled influenza. After 2–4 days, the fever began to fall, and a deep-seated rash developed in which individual lesions containing infectious virus progressed through successive stages of macules, papules, vesicles, pustules, then crusted scabs that fell off 3–4 weeks after the appearance of the rash. The lesions first appeared on the face and extremities, including the palms and soles, and subsequently on the trunk—the so-called centrifugal rash distribution. They were well-circumscribed, and at the same stage of development in a given area.

Two types of smallpox were recognized during the 20th century: variola minor (including a genetically and biologically distinct subgroup described as alastrim), which had a case fatality rate of less than 1%; and variola major, which had a fatality rate among unvaccinated populations of 20–50% or more (30% on average). Fatalities normally occurred between the fifth and seventh day, occasionally as late as the second week. Fewer than 3% of variola major cases experienced a fulminant hemorrhagic course, characterized by a severe prodrome, prostration, and bleeding into the skin and mucous membranes; such hemorrhagic cases were rapidly fatal. In hemorrhagic smallpox the usual vesicular rash did not appear, and the disease might have been confused with severe leukemia, meningococcemia, or idiopathic thrombocytopenic purpura. The rash of smallpox could also be significantly modified in previously vaccinated persons, to the extent that only a few highly atypical lesions might be seen. In such cases, prodromal illness was not modified, but the maturation of lesions was accelerated, with crusting by the tenth day.

Smallpox was most frequently confused with chickenpox, in which skin lesions commonly occur in successive crops with several stages of maturity visible at the same time. The chickenpox rash is more abundant on covered than on exposed parts of the body, and is centripetal rather than centrifugal. Smallpox was indicated by a clear-cut prodromal illness; the more or less simultaneous appearance of all lesions when the fever broke; the similarity of appearance of all lesions in a given area rather than successive crops; and the more deep-seated lesions, often involving sebaceous glands and scarring of the pitted lesions (whereas chickenpox lesions are superficial, not well circumscribed and manifested with irregular borders, and chickenpox rash is usually pruritic). Smallpox lesions were virtually never seen at the apex of the axilla; and chickenpox lesions were rarely, if ever, seen on the palms and soles of the feet—a distribution characteristic of smallpox in many cases.

Outbreaks of variola minor were recognized by low case-fatality rates in the late 19th century. Although the rash was like that in ordinary smallpox, patients generally experienced less severe systemic reactions, and hemorrhagic cases were virtually unknown.

Infectious Agent

Variola virus, a species of Orthopoxvirus.


Prior to eradication, laboratory confirmation of smallpox used isolation of the virus on chorioallantoic membranes or tissue culture from the scrapings of lesions, from vesicular or pustular fluid, from crusts, and sometimes from blood during the febrile prodrome. Electron microscopy or immunodiffusion technique often permitted a rapid provisional diagnosis—though eradication was made possible on the basis of clinical, not laboratory, diagnosis. Molecular methods, such as PCR, are now available for rapid diagnosis of smallpox and other orthopoxvirus infections. Should smallpox infection be suspected, immediate communication by national authorities to WHO is imperative, for advice on appropriate laboratories for diagnosis.


Mode of Transmission

Infection usually occurred via the respiratory tract (droplet spread) or skin inoculation. The conjunctivae or the placenta were occasional portals of entry.

Incubation Period

From 7–19 days; commonly 10–14 days to onset of illness and 2–4 days more to onset of rash.

Period of Communicability

From the time of development of the earliest rash lesions to disappearance of all scabs; about 3 weeks. Risk of transmission appears to have been highest in the first week after appearance of the earliest lesions, through droplet spread from the oropharyngeal enanthem and subsequent oropharyngeal excretion of virus.


As epidemiologically described in the 19th and 20th centuries, smallpox was exclusively a human disease, with no known animal or environmental reservoir. Currently, the virus is maintained only in two WHO-designated laboratories.


Susceptibility among the unvaccinated is universal.


Formerly a worldwide disease; no known human cases since 1978.

Prevention and Control

Control of smallpox was based on identification and isolation of cases, vaccination (vaccinia virus) of contacts and those living in the immediate vicinity (ring vaccination), surveillance of contacts (including daily monitoring of temperature), and isolation of those contacts in whom fever develops.

Because of the relatively long period of incubation for smallpox, vaccination within a 4-day period after exposure prevented or attenuated clinical illness.


Further information can be found at:

Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.

Common Disease Taxonomy: