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by Mary T. Caserta, MD

Smallpox is a highly contagious disease caused by the smallpox virus, an orthopoxvirus. It causes death in up to 30%. Indigenous infection has been eradicated. The main concern for outbreaks is from bioterrorism. Severe constitutional symptoms and a characteristic pustular rash develop. Treatment is supportive. Prevention involves vaccination, which, because of its risks, is done selectively.

No cases of smallpox have occurred in the world since 1977 because of worldwide vaccination. In 1980, the World Health Organization (WHO) recommended discontinuation of routine smallpox vaccination. Routine vaccination in the US ended in 1972. Because humans are the only natural host of the smallpox virus and because the virus cannot survive > 2 days in the environment, WHO has declared natural infection eradicated. Concerns about bioterrorism using smallpox virus from retained research stores or even from synthetically created virus raise the possibility of a recurrence (see Biological Agents as Weapons and CDC: Smallpox: Emergency Preparedness and Response ).


There are at least 2 strains of smallpox virus:

  • Variola major (classic smallpox), the more virulent strain

  • Variola minor (alastrim), the less virulent strain

Smallpox is transmitted from person to person by inhalation or, less efficiently, by direct contact. Contaminated clothing or bed linens can also transmit infection. The infection is most communicable for the first 7 to 10 days after the rash appears. Once crusts form on the skin lesions, infectivity declines.

The attack rate is as high as 85% in unvaccinated people, and infection may lead to as many as 4 to 10 secondary cases from each primary case. However, infection tends to spread slowly and mainly among close contacts.

The virus invades the oropharyngeal or respiratory mucosa and multiplies in regional lymph nodes, causing subsequent viremia. It eventually localizes in small blood vessels of the dermis and the oropharyngeal mucosa. Other organs are seldom clinically involved, except for occasionally the CNS, with encephalitis. Secondary bacterial infection of the skin, lungs, and bones may develop.

Symptoms and Signs

Variola major has a 10- to 12-day incubation period (range 7 to 17 days), followed by a 2- to 3-day prodrome of fever, headache, backache, and extreme malaise. Sometimes severe abdominal pain and vomiting occur. After the prodrome, maculopapular lesions develop on the oropharyngeal mucosa, face, and arms, spreading shortly thereafter to the trunk and legs. The oropharyngeal lesions quickly ulcerate. After 1 or 2 days, the cutaneous lesions become vesicular, then pustular. Pustules are denser on the face and extremities than on the trunk, and they may appear on the palms. The pustules are round and tense and appear deeply embedded. Skin lesions of smallpox, unlike those of chickenpox, are all at the same stage of development on a given body part. After 8 or 9 days, the pustules become crusted. Severe residual scarring is typical. Mortality rate is about 30%. Death results from a massive inflammatory response causing shock and multiple organ failure and usually occurs during the 2nd wk of illness.

About 5 to 10% of people with variola major develop either a hemorrhagic or a malignant (flat) variant. The hemorrhagic form is rarer and has a shorter, more intense prodrome, followed by generalized erythema and cutaneous and mucosal hemorrhage. It is uniformly fatal within 5 or 6 days. The malignant form has a similar, severe prodrome, followed by development of confluent, flat, nonpustular skin lesions. In survivors, the epidermis frequently desquamates.

Variola minor results in symptoms that are similar but much less severe, with a less extensive rash. Mortality rate is < 1%.


  • PCR

  • Electron microscopy

Unless laboratory exposure is documented or an outbreak (due to bioterrorism) is suspected, only patients that fit the clinical case definition for smallpox should be tested because of the risk that test results may be falsely positive. An algorithm for evaluating the risk of smallpox in patients with fever and rash is available on the CDC web site ( CDC Algorithm Poster for Evaluation of Suspected Smallpox ), as is a worksheet that can be printed and sent to the CDC to aid in evaluation.

Diagnosis is confirmed by documenting the presence of variola DNA by PCR of vesicular or pustular samples. Or the virus can be identified by electron microscopy or viral culture of material scraped from skin lesions and subsequently confirmed by PCR. Suspected smallpox must be reported immediately to local public health agencies or the Centers for Disease Control and Prevention (CDC) at 770-488-7100. These agencies then arrange for testing in a laboratory with high-level containment capability (biosafety level 4).


  • Supportive care

  • Isolation

  • Possibly cidofovir, brincidofovir (CMX 001), or tecovirimat (ST-246)

Treatment is generally supportive, with antibiotics for secondary bacterial infections. The antiviral drug cidofovir may be considered. Brincidofovir (CMX001), and tecovirimat (ST-246) are investigational drugs but have been used to treat severe vaccine-related complications (vaccinia) and may also be useful for treatment. Currently, there is no licensed drug for the treatment of smallpox.

Isolation of people with smallpox is essential. In limited outbreaks, patients may be isolated in a hospital in a negative-pressure room equipped with high-efficiency particulate (HEPA) filters. In mass outbreaks, home isolation may be required. Contacts should be placed under surveillance, typically with daily temperature measurement; if they develop a temperature of > 38° C or other sign of illness, they should be isolated at home.


Licensed smallpox vaccine in the US consists of live vaccinia virus (ACAM2000), which is related to smallpox and provides cross-immunity. Vaccine is administered with a bifurcated needle dipped in reconstituted vaccine. The needle is rapidly jabbed 15 times in an area about 5 mm in diameter and with sufficient force to draw a trace of blood. The vaccine site is covered with a dressing to prevent spread of the vaccine virus to other body sites or to close contacts. Fever, malaise, and myalgias are common the week after vaccination. Successful vaccination is indicated by development of a pustule by about the 7th day. Revaccination may cause only a papule surrounded by erythema, which peaks between 3 and 7 days. People without such signs of successful vaccination should be given another dose of vaccine. Two live-attenuated vaccines (modified vaccinia Ankara [MVA] and LC16m8) have been developed; MVA is licensed in Europe, and LC16m8 is licensed in Japan.

After a single vaccination, immunity begins to fade after 5 yr and is probably negligible after 20 yr. If people have been successfully revaccinated one or more times, some residual immunity may persist for ≥ 30 yr.

Until an outbreak in the population occurs, preexposure vaccination remains recommended only for people at high risk of exposure to the virus (eg, laboratory technicians).

Vaccine complications

Risk factors for complications include extensive skin disorders (particularly eczema), immunosuppressive diseases or therapies, ocular inflammation, and pregnancy. Widespread vaccination is not recommended because of the risk.

Serious complications occur in about 1 of 10,000 patients after their first (primary) vaccination and include

  • Postvaccinial encephalitis

  • Progressive vaccinia

  • Eczema vaccinatum

  • Generalized vaccinia

  • Myocarditis and/or pericarditis

  • Vaccinia virus keratitis

  • Noninfectious rashes

Postvaccinial encephalitis occurs in about 1 of 300,000 recipients of primary vaccination, typically 8 to 15 days postvaccination.

Progressive vaccinia (vaccinia necrosum) results in a nonhealing vaccinial (vesicular) skin lesion that spreads to adjacent skin and ultimately other skin areas, bones, and viscera. Progressive vaccinia may occur after primary vaccination or revaccination but occurs almost exclusively in patients with an underlying defect in cell-mediated immunity; it can be fatal.

Eczema vaccinatum results in vaccinial skin lesions appearing on areas of active or even healed eczema.

Generalized vaccinia results from hematogenous dissemination of the vaccinia virus and causes vaccinia lesions at multiple body locations; it is usually benign.

Vaccinia virus keratitis occurs rarely, when vaccinia virus is inadvertently implanted in the eye.

Some serious vaccine complications are treated with vaccinia immune globulin (VIG); one case of eczema vaccinatum apparently treated successfully with VIG, cidofovir, and tecovirimat has been reported. In the past, high-risk patients who required vaccination because of viral exposure were simultaneously given VIG to try to prevent complications. The efficacy of this practice is unknown, and it is not recommended by the CDC. VIG is available only from the CDC.

Postexposure prophylaxis

Postexposure vaccination can prevent or significantly limit the severity of illness and is indicated for family members and close personal contacts of smallpox patients. Early administration is most effective, but some benefit is realized up to 4 days postexposure.

Key Points

  • No cases of smallpox have occurred since 1977, but concerns about possible use for bioterrorism remain.

  • Diagnosis is made by PCR.

  • Treatment is mainly supportive, but cidofovir may be considered; brincidofovir (CMX001) and tecovirimat (ST-246) are investigational drugs but may also be useful.

  • Vaccination is highly protective, but rare complications (about 1:10,000) can be serious.

  • Immunity fades over decades.

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