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Brenda L. Tesini

, MD, University of Rochester School of Medicine and Dentistry

Last full review/revision Dec 2020| Content last modified Dec 2020
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Smallpox is a highly contagious disease caused by the smallpox virus, an orthopoxvirus. It causes death in up to 30%. Natural infection has been eradicated. The main concern for outbreaks is from bioterrorism. Severe constitutional symptoms and a characteristic pustular rash develop. Treatment is generally supportive and potentially with antiviral drugs. 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 Centers for Disease Control and Prevention [CDC]: Smallpox/Bioterrorism).

Pathophysiology of Smallpox

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 of respiratory droplets 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 central nervous system, with encephalitis. Secondary bacterial infection of the skin, lungs, and bones may develop.

Symptoms and Signs of Smallpox

Variola major

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.

Case fatality rate is about 30%. Death results from a massive inflammatory response causing shock and multiple organ failure and usually occurs during the 2nd week 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

Variola minor results in symptoms that are similar but much less severe, with a less extensive rash.

Case fatality rate is < 1%.

Diagnosis of Smallpox

  • Polymerase chain reaction (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).

Diagnosis of smallpox 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 CDC at 770-488-7100. These agencies then arrange for testing in a laboratory with high-level containment capability (biosafety level 4).

Point-of-care antigen detection assays are being developed.

Treatment of Smallpox

  • Supportive care

  • Isolation

  • Possibly tecovirimat, consider cidofovir or brincidofovir (CMX 001)

Treatment of smallpox is generally supportive, with antibiotics for secondary bacterial infections. However, the antiviral drug tecovirimat was approved by the US Food and Drug Administration (FDA) in 2018 based on experimental studies and is the first drug to be licensed for the treatment of smallpox (1). Although its effectiveness against smallpox in humans is unknown, tecorvirimat would likely be the drug of choice for attempted treatment and is available in the US Department of Health and Human Services Strategic National Stockpile. Cidofovir and the investigational drug brincidofovir (CMX001) also may be considered (2).

Isolation of people with smallpox is essential. In limited outbreaks, patients may be isolated in a hospital under airborne transmission precautions in an airborne-infection isolation room. 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.

Treatment references

Prevention of Smallpox

Licensed smallpox vaccines in the US consist of live replication-competent vaccinia virus (ACAM2000) and JYNNEOS, a live attenuated (replication-deficient) modified vaccinia Ankara (MVA) vaccine (1). Vaccinia is related to smallpox and provides cross-immunity. ACAM2000 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.

JYNNEOS is administered as 2 subcutaneous injections 4 weeks apart. It is licensed by the FDA for people 18 years of age and older and may have a particular role in vaccinating people for whom ACAM2000 may be contraindicated, such as those with immunocompromised states or atopic dermatitis.

Another live virus investigational vaccine Aventis Pasteur smallpox vaccine (APSV) is also available from the Strategic National Stockpile in the event of an emergency.

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

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 [2]).


Live vaccinia virus 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 with a replication-competent vaccine 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 7 days postexposure.

Prevention references

  • 1. Pittman PR, Hahn M, Lee HS, et al: Phase 3 efficacy trial of modified vaccinia ankara as a vaccine against smallpox. N Engl J Med 381(20):1897-1908, 2019. doi: 10.1056/NEJMoa1817307

  • 2. Petersen BW, Harms TJ, Reynolds MG, et al: Use of vaccinia virus smallpox vaccine in laboratory and health care personnel at risk for occupational exposure to orthopoxviruses: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2015. MMWR Morb Mortal Wkly Rep 65 (10):257–262, 2016. doi: 10.15585/mmwr.mm6510a2

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 tecorivimat has been approved for use; cidofovir and the investigational drug brincidofovir (CMX001) may be considered.

  • Vaccination is highly protective, but rare complications from replication-competent virus vaccine (about 1:10,000) can be serious.

  • Immunity fades over decades.

More Information

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

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