Smallpox, a disease unique to humans, is one of the oldest recorded infections affecting humankind. In endemic forms and in epidemic waves, smallpox killed and disfigured millions of people throughout history. This viral infection, spread by respiratory droplets, continued to have worldwide distribution at the beginning of the 20th century.

Because smallpox confers immunity in the survivors of an attack, its persistence depends on contact of nonimmune persons with infected persons in the initial 2 weeks of acquiring the infection.

Centuries ago, physicians realized that inoculating smallpox matter into nonimmune persons conferred partial or total immunity against smallpox. This practice was known in India and China as variolation.

Variolation was introduced in England in 1721 by the wife of Ambassador Montagu, Lady Montagu, who herself was disfigured by smallpox. The practice spread rapidly in England despite skepticism from the scientific community and resistance from the Church.

Variolation was risky and sometimes fatal. In 1783 Octavius, the son of King George III, died as a result of complications from variolation. Benjamin Franklin was an ardent supporter of variolation in the American colonies.

In 1778, Edward Jenner, an English physician, reported that milkmaids infected with cowpox were immune to smallpox during epidemics. In 1796 he decided to test his hypothesis by injecting cowpox material into James Phipps. Phipps developed no signs or symptoms of smallpox 2 months after the inoculation, when he had variolation. This experiment was the birth of vaccination (Latin vacca, “cow”) against smallpox. With the support of King George IV, vaccination was implemented in England, and variolation was slowly abandoned and finally declared illegal in 1840. Vaccination was introduced in the United States in 1800 by Dr. Benjamin Waterhouse, a Harvard physician, and supported by President Thomas Jefferson, who immunized members of his household. The last-documented natural case of smallpox in the United States was documented in 1947.

The World Health Organization (WHO) designed an Intensified Eradication Program based on a ring vaccination strategy that began in 1966 and eradicated smallpox from humans in an unprecedented effort in less than 10 years. The last natural case was documented in Somalia in 1977. Routine immunization against smallpox ceased in the United States in 1972 and worldwide in 1980. It was thought that without a human reservoir, reemergence of this infection would not occur.

Smallpox virus stocks are still available in the United States at the CDC in Atlanta, Georgia, and in Russia at the State Center for Virology and Biotechnology in Novosibirk, Siberia. These stocks are maintained under strict bio-containment measures. In the aftermath of the terrorist attacks on September 11, 2001 and the deliberate distribution of Bacillus anthracis afterwards, President Bush announced plans to immunize health care workers and first responders against smallpox by 2003. Although the plan fell short of it goals, 40,000 first responders and health care workers were vaccinated by the end of 2003.

The Agent

Smallpox is a single, linear double-stranded DNA virus that belongs to the Orthopoxvirus genus, family Poxviridae. The poxviruses replicate in cell cytoplasm. They are brick-shaped and measure about 300 by 250 by 200 nm.


The natural reservoir of smallpox is the patient suffering from the disease. Smallpox spreads from person to person through droplet nuclei or fine-particle aerosols released from the pharynx of infected persons. Smallpox can also be transmitted by fomites such as clothing and bedding. Smallpox patients are not infectious until the third day of the clinical disease, typically 1 day before the skin eruption. The secondary attack rate of smallpox is 37% to 88% among unvaccinated contacts, depending on many variables.

Clinical Presentation

Smallpox occurs as either variola major or variola minor (Alastrim). Variola major had a mortality rate of 30% compared with 1% for variola minor.

After an incubation period of 10 to 14 days, the illness begins with intense prostration and high fever lasting 4 to 6 days (Figure 1).

Headache, photophobia, and vomiting are noted. During the prodrome phase most patients are bedridden. Around the fourth day the fever breaks and the patient feels better.

FIGURE 1    Clinical manifestations and pathogenesis of smallpox  and the immune response. A, The initial phases of infection and the clinical manifestations include temperature spikes and progressive skin lesions (photographs of lesions courtesy of Dr. David Heymann, World Health Organization). B, The pathogenesis of the infection. The photographs on the right show the characteristic features of the vesicles caused by smallpox (H&E, × 90). C, The immune response to smallpox and the period of infectiousness.Abbreviations: CF = complement fixation; HI = hemagglutination inhibition. (Reprinted with permission from Breman JG, Henderson DA. Diagnosis and management of smallpox. N Eng J Med 2002;346:1300–1308.)

The eruptive phase is signaled by an enanthem involving the buccal mucosa and pharynx and a centrifugal exanthem that begins on the face and forearms. The initial rash is macular and turns pustular in 1 to 2 days. Within 2 days the papules evolve into vesicles that become cloudy and pustular. Most patients exhibit lesions on their soles and palms. A typical feature of variola is that the exanthem everywhere is in the same state of evolution, unlike the exanthem of chickenpox, in which lesions exhibit all stages of evolution. At the end of day 8 to 10 the skin rash crusts and dries; it takes 3 to 4 weeks from the onset of the disease for all the scabs to fall off. The period of contagiousness ends when the last scab falls off. Scarring and pitting of the skin are common sequelae.

Patients with hemorrhagic disease develop severe prostration, high fever, abdominal pain, petechiae, and extensive cutaneous ecchymoses. In the malignant or flat form, the lesions fail to progress to the pustular stage. In the hemorrhagic and the malignant forms, death invariably occurs within 1 week.

History of smallpox vaccination modifies the course of the disease.

Vaccinated persons who contract smallpox have fewer skin lesions and an accelerated clinical course.


Bacterial infections of the skin and other organs are common. Ocular involvement may result in blindness. Encephalitis (one in 500 cases of variola major) is a devastating complication.

Differential Diagnosis (Figure 2)

Many rashes can be confused with smallpox, especially at the outset of the eruption, when the rash is maculopapular. Herpes zoster, chickenpox, herpes simplex, impetigo, scabies, erythema multiforme, and syphilis are some of the conditions that can be confused with smallpox (Box 1). When smallpox was endemic, chickenpox was the most common condition confused with smallpox. The most useful clinical points of smallpox are the following:

Box 1
Conditions that Might Be Confused with Smallpox
Maculopapular Stage

Measles Rubella

Drug eruptions

Secondary syphilis Erythema multiforme

Scabies, insect bites


Scarlet fever

Vesicular/Pustular Stage


Disseminated herpes zoster

Disseminated herpes simplex virus

Drug eruptions

Contact dermatitis

Erythema multiforme (including Stevens-Johnson syndrome)

Enteroviral infections

Secondary syphilis


Generalized vaccinia



Scabies, insect bites

Disseminated molluscum contagiosum

FIGURE 2    Algorithm for assessing patients for smallpox. (Reprinted  with permission from Moore ZS, Seward JF, Lane JM: Smallpox. Lancet 2006;367:425–435.)

  • Centrifugal distribution of the lesions
  • All the lesions in the same stage of development
  • Progression of the rash from the face to the arms, trunk and legs
  • A severe prodrome phase that lasts 4 days
  • In an epidemic, known contact with an active case


The identification of a suspected case of smallpox should be treated as an international health emergency. Clinical samples may be collected from vesicular or pustular fluid, blood, tonsillar swabs, and skin biopsy and must be transported to a Biosafety level 4 facility for processing and testing with real-time polymerase chain reaction (PCR) assays to detect virus DNA.

Lesions of varicella zoster virus (chickenpox, herpes zoster) demonstrate multinucleated giant cells on Tzanck smears; lesions of smallpox do not. Serology or electronic microscopy are not recommended for the diagnosis of smallpox because these modalities cannot distinguish among different Orthopoxviruses.


A suspected case of smallpox should be placed in a negative-pressure room with strict respiratory and contact isolation precautions. Ideally to minimize the risk of contagion in health care personnel, patient with smallpox should be assisted by providers documented to have been immunized against this condition. Patients with smallpox require careful care of their eyes to avoid complications and this is accomplished with daily eye rinsing. Patients must receive adequate nutrition and hydration. Skin and soft issue infections must be treated with an antistaphylococcal β-lactams, and initially pending results of cultures, with an antimicrobial with activity against methicillin- resistant Staphylococcus aureus. There is no antiviral drug with demonstrated activity against smallpox.

Vaccines and Vaccination

Sanofi’s U.S.-licensed ACAM2000, a second-generation vaccine, was made from cell culture-derived vaccinia virus found in Dryvax, a first- generation vaccine that is no longer produced. ACAM2000 is indicated for active immunization of people who are determined to be at high risk for smallpox. A two-pronged stainless steel (or bifurcated) needle is dipped into the vaccine solution and the skin is pricked several times in the upper arm with a droplet of the vaccine. The virus begins growing at the injection site causing a localized infection or “pock” to form. A red, itchy sore spot at the site of the vaccination within 3-4 days is an indicator that the vaccination was successful; that is, there is “a take.” A blister develops at the vaccination site and then dries up forming a scab that falls off in the third week, leaving a small scar. If no evidence of vaccine take is apparent after 7 days, the person can be vaccinated again.

The vaccine causes local and systemic symptoms. There is an eruption at the injection site with redness and pain, systemic symptoms such as fever, and headaches. Swelling and tenderness of regional lymph nodes begin 3 to 10 days after vaccination and can last up to a month.


Adverse events of vaccinia have been reviewed extensively and include postvaccinial encephalitis, progressive vaccinia, eczema vaccinatum, and generalized vaccinia (Table 1). The most common complication is inadvertent autoinoculation causing self-limited satellite lesions. Generalized vaccinia results from viremia and may be life threatening in immunocompromised patients. Progressive vaccinia is characterized by necrosis at the inoculation site and distal sites such as bones and internal organs. Progressive vaccinia is often a fatal complication. Myopericarditis was observed with the use of adult vaccines in the United States in 2002 (Table 1).

Table 1

Rates of Complications from Vaccinia, According to Vaccination Status and Age*

Reprinted with permission from Breman JG, Henderson DA: Diagnosis and management of smallpox. N Engl J Med  2002;346:1300–1308.

*  Data are from a 1968 survey of 10 states. No deaths  occurred.

†  No children younger than 1 year were  revaccinated.

Contraindications to Vaccination

Persons who are immune compromised or who have severe eczema or who are pregnant should not receive Post-exposure vaccination against smallpox. However, in the event of exposure to a patient with smallpox, no absolute contraindication is applicable.

Control of Outbreaks

As soon as a diagnosis of smallpox is considered, suspected persons should be isolated and close contacts should be immunized. Post- exposure vaccination within the first 4 days can greatly mitigate subsequent illness. Contact isolation and ring vaccination are the strategies of choice to contain an outbreak of smallpox.

Use in Warfare

During the 15th century, variola-laden clothing and blankets were distributed by Europeans among Native Americans to spread smallpox in the local population. British soldiers used variola- contaminated blankets among the natives supporting the French during the French and Indian wars. The use of infectious agents in warfare is not new, and the potential use of smallpox as a weapon increased when routine immunization against smallpox ceased and worldwide immunity waned.

Because natural smallpox has been eradicated, the only possibility of a smallpox outbreak is the deliberate release of smallpox in a population by a nation or a terrorist group to inflict casualties in a civilian population. Preemptive vaccination of first responders and ring immunization of those exposed are the means available to avoid massive propagation of smallpox.


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