Smallpox is primarily a clinical diagnosis and must be differentiated from other eruptive illnesses, particularly chickenpox. A suspected case of smallpox is a public health emergency and requires immediate contact with local public health authorities.
Microbiological diagnosis can be achieved by PCR or growth of the virus in cell culture. Both of these techniques must be performed in specialized containment (Biosafety Level 4) laboratories available only at the CDC or United States Army Medical Research Institute for Infectious Diseases.

Treatment and Postexposure Prophylaxis
There is no treatment approved by the FDA for smallpox infection. Supportive care is the primary intervention. Any individual exposed to a patient with smallpox should be immunized immediately and placed on a fever watch for a period of 17 days. If performed within 3 to 4 days of exposure, vaccination with vaccinia virus can attenuate or possibly prevent the clinical manifestations of smallpox. Vaccine is administered with the use of a bifurcated needle, which is inserted into a bottle of reconstituted vaccine. The needle is held at right angles to the skin, and 15 perpendicular strokes into the dermis of the upper deltoid are given in an area of about 0.5 cm in diameter. A trace amount of blood should appear at the vaccination site after 15 to 30 seconds. After vaccination, excess vaccine should be removed from the site, and a loose bandage placed to prevent inadvertent spread of the virus to other parts of the body. Adverse reactions to the vaccine have included urticarial rash, postvaccinial encephalitis, eczema vaccinatum, generalized vaccinia, and autoinoculation. Vaccinia immunoglobulin (0.6 ml/kg intramuscularly in divided doses over 24 hours) can be used to treat the complications and adverse effects of vaccinia immunization, but its availability is severely limited.

Infection Control
All patients with suspected cases of smallpox should be isolated in negative-pressure rooms. Airborne and contact precautions should remain in effect until all lesions have scabbed and separated.