Smallpox (variola, variola major, variola minor, variola vera, alastrim, the pox, variole, viruela, pocken, blattern

Are You Confident of the Diagnosis?

Disclaimer: The opinions and assertions contained herein are the private views of the author, and are not to be construed as official or as reflecting the views of the US Department of the Army or the Department of Defense.

Smallpox is a contagious, sometimes fatal disease manifested most commonly by a severe febrile prodrome, followed by a characteristic vesicular-pustular rash.

Variola is a derivative of the Latin varius, meaning “spotted,” or varus, meaning “pimple.” There is no specific treatment for smallpox, but smallpox vaccination (vaccinia virus) is highly protective, even after exposure.

Smallpox was declared “eradicated” from nature in 1979, but remains a potential bioterrorism agent. The US Centers for Disease Control (US CDC) labels smallpox a Category A agent, a group of 13 highly lethal pathogens. Even a single case of smallpox would be considered an international health emergency.

What you should be alert for in the history

The incubation period of smallpox is typically about 12 days (range: 7 to 17 days), during which time there are no symptoms and the infection is not contagious.

The first stage of disease in smallpox is a severe febrile prodrome, which is a critical feature of the disease. Before skin lesions appear, the prodrome has an abrupt onset, lasting 2 to 4 days, with high fever (39ºC to 41ºC), headache, myalgias and prostration.

As the prodrome evolves, an evanescent enanthem develops on the tongue and palate, characterized by petechiae. On days 4 to 6, as the enanthem ulcerates, an exanthem begins, characterized by a centrifugal distribution, discussed below. The fever may lessen as skin lesions develop.

Relevant points in the history to form a differential diagnosis, discussed in more detail below:

  • - febrile prodrome (> 39ºC) for 2 to 4 days, followed by skin lesions

  • - chronic skin disease, such as atopic dermatitis

  • - medications

  • - exposure to ill persons, farm animals, wild animals

  • - recent first or re-vaccination for smallpox

  • - varicella vaccination

  • - international travel

In the United States, the last case of smallpox was in 1949. Smallpox vaccination of the American general population was stopped in 1972, but continued in military personnel until 1990.

More recently, because of bioterrorism concerns, first time or re-vaccination for smallpox is occurring in certain high-risk groups, such as health care workers and the US military. There are sufficient stockpiles of smallpox vaccine in the event larger numbers of people require vaccination. Smallpox vaccination is protective in more than 95% of people for at least 3 to 5 years. Partial protection lasts longer, which likely reduces disease severity.

Varicella vaccination prevents chickenpox and herpes zoster.

Characteristic findings on physical examination

A clinical diagnosis of smallpox involves the following:

  • - Prodrome: fever > 39°C, flu-like symptoms for 2 to 4 days

  • - Skin lesions (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5)

    • - deep seated, firm vesicles, evolving to pustules

    • - centrifugal: concentrated on face and distal extremities

    • - all in same stage of development

    • - usually on palms and soles (distinguishes smallpox from varicella)

  • - Fever may continue during the rash, but reduced in comparison with the prodrome

  • - No other apparent cause

Figure 1.

Ordinary smallpox, rash evolution

Figure 2.

Ordinary smallpox, centrifugal distribution

Figure 3.

Ordinary Smallpox (US CDC)

Figure 4.

Left, ordinary smallpox on palm; right, varicella

Figure 5.

Left, ordinary smallpox on sole; right, varicella

Smallpox is broadly classified into major smallpox (variola major) and minor smallpox (variola minor), reflecting clinical features and disease severity, with subcategories in each.


Clinical criteria:

Febrile prodrome

  • - Abrupt onset

  • - lasts 2 to 4 days, before rash

  • - temperature 39ºC to 41ºC

  • - at least one of the following: prostration, headache, myalgias, chills, vomiting, or severe abdominal pain

Characteristic skin lesions (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5)

- deep-seated, firm, round, well-circumscribed vesicles or pustules (often umbilicated; may be confluent)

Lesions in same stage of development (Figures 1-5), ie, all vesicles, all pustules; especially on any single body part (eg, face)

Major smallpox has five clinical forms, based on the features and evolution of skin lesions:

  1. Ordinary (classic)

  2. Modified (varioloid)

  3. Flat (malignant type)

  4. Hemorrhagic (black pox, sledge hammer pox, hemorrhagic death)

  5. Variola sine eruption

1. Ordinary smallpox (> 90% of cases) (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5)

Ordinary smallpox, by far the most common form, is what dermatologists and other health care providers would most likely encounter, and recognize. Among unvaccinated persons who acquire smallpox, greater than 90% develop ordinary type, presenting in the following proportions:

  • - 60%: discrete skin lesions in centrifugal distribution (concentrated on face and extremities), including palms and soles (Figure 2, Figure 3, Figure 4, Figure 5)

  • - 30%: semi-confluent to confluent skin lesions, often with desquamation. Patients often remain ill, even after lesions have crusted.

The overall fatality rate in unvaccinated people is 30%, varying by pock distribution:

  • - discrete, less than 10%

  • - semi-confluent, 25% to 50%

  • - confluent, 50% to 75%

Among recently vaccinated persons (not less than 3 to 5 years) who acquire smallpox, 70% develop the ordinary type, with a mortality rate of 3%.

Ordinary smallpox is characterized by a febrile prodrome, followed by a single crop of lesions, progressing relatively rapidly over 4 weeks as follows (Figure 1):

Day of rash

  • 1: macules to papules

  • 2: vesicles: deep seated, tense, containing opalescent fluid

  • 3-4: vesicular fluid becomes opaque and turbid (contains tissue debris, not pus)

  • 5-7: pustules – characteristically prominent, deep-seated, round, tense, firm

  • 9-13: lesions crust

  • 14-28: crusts separate; leaving depressed, sometimes depigmented scars

Important features of pustules

  • - Feel like “BB pellets” embedded in the skin

  • - Often umbilicated

  • - Usually on palms and soles – distinguishes smallpox from varicella

2. Modified smallpox (variable %) (Figure 6)

Figure 6.

Modified smallpox

Modified smallpox is similar to ordinary smallpox but milder. It occurs mostly in previously vaccinated, partially immune people, and is rarely fatal.

After 1 to 2 days of a mild to moderate febrile prodrome, an enanthem develops, with red macules on the mouth, tongue, and oropharnyx. The lesions progress into vesicles, which then erode, releasing large amounts of virus.

The rash appears after 2 to 4 days, often with little or no fever, coinciding with the enanthem ulceration. Like the ordinary type, skin lesions may be discrete, semi-confluent, or confluent.

In comparison with ordinary smallpox, modified smallpox skin lesions may:

  • - be fewer in number

  • - evolve more rapidly

  • - be more superficial

  • - not develop at same rate (less uniformity in morphology)

Modified smallpox may be confused with chickenpox (discussed below)

3. Flat smallpox (5% to 10% of cases) (Figure 7)

Figure 7.

Flat smallpox day 6, (US CDC)

A severe prodrome lasts 3 to 4 days, followed by prolonged high fever and severe symptoms of toxemia.

The enanthem on the tongue and palate is extensive. Skin lesions mature relatively slowly; by days 7 to 8, vesicles are flat, and nearly flush with the skin surface. Unlike ordinary-type smallpox, vesicles contain little fluid, are soft, and may contain hemorrhage. Death is often associated with pneumonia.

Historically, most patients with flat smallpox were children (approximately 70%) and unvaccinated persons lacking cellular immunity. Case-fatality rates are at least 95% in unvaccinated patients, and 66% in vaccinated patients.

4. Hemorrhagic smallpox (3% of cases)

This form is difficult to diagnose clinically unless there is an ongoing smallpox epidemic or known exposure. Diagnosis is typically by biopsy.

The prodrome is severe and prolonged, with toxemia and prostration. There is extensive bleeding into the skin, nasal and oral mucous membranes, and gastrointestinal tract. This form usually develops in adults, equally among the vaccinated and unvaccinated, and is usually fatal.

Hemorrhagic smallpox accounts for 3% to 25% of all fatal cases, depending on the virulence of the smallpox strain. Platelets and clotting factors are affected, denoting some similarity with disseminated intravascular coagulation. Hemorrhagic smallpox has two clinical forms, early and late.

Early: the prodrome is characterized by petechial hemorrhages in the skin or mucous membranes. Subconjunctival bleeding may cause the sclera to appear deep red. There may be hemorrhage in the retina, spleen, kidney, serosa, muscle, and other organs. The skin remains smooth, but bleeding causes a charred, black appearance, invoking the term “black pox.” Death occurs suddenly, typically within 8 days of illness onset.

Pregnant women are especially susceptible to the early form.

Late: hemorrhages appear in the early period of a typical smallpox exanthem, but the lesions remain relatively flat and do not progress beyond the vesicular stage. Death occurs by day 12. Men and women are equally susceptible.

5. Variola “sine eruption”

  • » Occurs in up to 30% to 50% of vaccinated contacts

  • » Prodrome occurs, but lasts only 48 hours

  • » No rash

  • » Not considered contagious


V. minor is an attenuated strain that causes minor smallpox, a milder form of disease. Synonyms include alastrim, cottonpox, milkpox, whitepox, and Cuban itch. Minor smallpox occurs in less than 10% of all smallpox infections. Fatality rates are less than 1% in unvaccinated persons.

Clinical criteria:

  1. Prodrome, but milder than major smallpox

  2. First lesions on the oral mucosa, palate, face and forearms

  3. Lesions in a centrifugal distribution (most on the face, distal extremities)

  4. Patient is moribund

  5. Lesion progression is relatively slow: macules to papules to pustules, 1 to 2 days/stage

  6. Lesions present on the palms, soles

Minor smallpox is similar to two forms of major smallpox: modified, and ordinary with discrete lesions.

Risk classification for smallpox, per US CDC guidelines:

Smallpox is presumptively diagnosed on clinical features and then confirmed by laboratory tests conducted at the US CDC or other high-containment laboratories. Confirmation of diagnosis is by US CDC specified laboratory tests. The US CDC provides a simple-to-use protocol, including case-workup checklists and algorithms, for addressing an acute, generalized vesicular or pustular rash, to include three categories of risk for smallpox: LOW, MODERATE and HIGH. The algorithm is especially helpful in differentiating smallpox from varicella (Figure 8).

Figure 8.

US CDC protocol for acute, generalized vesicular or pustular rash (2007)


  • Chart 1: symptoms of acute generalized vesiculo-pustular rash, and categories of risk for smallpox

  • Chart 2: flowchart for laboratory testing of patient specimens

  • Chart 3: algorithm for smallpox vaccine complications, or if monkeypox is suspected

  • Chart 4: orthopox testing algorithm for environmental samples

Key points of the smallpox risk categories are summarized here:


Criteria: febrile prodrome AND classic smallpox lesions AND lesions in the same stage of development

Action: immediate reporting

  • - Activate infection control measures (contact, airborne)

  • - Isolate the suspected case

  • - Infectious disease consult

  • - Report immediately: Local government health office; local health office contacts US CDC (1-800-CDC-INFO or 1-800-232-4636), 24 hours/day, 365 days/year

  • - Access US CDC smallpox website page, for updated information:

  • - Consider two common laboratory tests, as feasible: 1) Direct fluorescent antibody assay (DFA) for varicella-zoster, herpes viruses; 2) Tzanck smear for features of varicella-zoster, herpes viruses


Criteria: 1) febrile prodrome AND 1 other major smallpox criteria (classic lesions or lesions all in the same stage, or 2) febrile prodrome AND > 4 minor smallpox criteria

Minor smallpox criteria:

  1. Prodrome, but milder than major smallpox

  2. First lesions on oral mucosa, palate, face and forearms

  3. Lesions in centrifugal distribution (most on the face, distal extremities)

  4. Patient is moribund

  5. Lesion progression slow: macules to papules to pustules, 1 to 2 days/stage

  6. Lesions present on palms, soles

Action: urgent evaluation, including DFA and Tzanck smear, as feasible


Criteria: 1) No febrile prodrome, or 2) febrile prodrome and fewer than 4 minor smallpox criteria

  • Action: manage as clinically indicated

  • US Centers for Disease Control and Prevention (CDC)

  • 1600 Clifton Rd, Atlanta, GA 30333

  • Website:

  • TEL: 1-800-CDC-INFO (1-800-232-4636); 24 hours/day, 365 days/year

  • E-mail:

Expected results of diagnostic studies

Confirmatory molecular diagnostic tests

In accordance with US CDC guidelines, a definitive diagnosis of smallpox requires polymerase chain reaction (PCR) amplification of variola DNA. PCR can be done directly on a clinical specimen or on virus isolated from a clinical specimen, by the US CDC or a US World Health Organization designated smallpox reference laboratory.

Smallpox can be isolated from clinical specimens when placed into culture with any one of several common cultured cell lines. Variola inoculated onto chick chorioallantoic membrane produces characteristic “hemorrhagic” pocks (Figure 9).

Figure 9.

Smallpox virus grown on chick chorioallantoic membrane shows characteristic pocks (DC/Dr David Kirsh)

For a HIGH risk case, clinical specimens, which may include pustule contents (optimal); tonsillar swab, urine, skin biopsy or blood should be collected, if possible, by someone recently vaccinated for smallpox (within the past 5 years). Sampling, handling and transport guidelines vary. For a HIGH risk case, instructions should be obtained by the local government health office or US CDC (TEL: 1-800-CDC-INFO [800-232-4636]; 24 hours/day, 365 days/year). The receiving laboratory must have advanced bio-containment facilities.

Tests which may support an orthopoxvirus as an etiology (genus level), include the following:

  1. Electron microscopy: orthopoxviruses, including smallpox, produce oval or brick-shaped virions (Figure 10).

  2. Serologic tests: enzyme-linked immunosorbent assays (ELISA), others.

  3. Histology: poxviruses, including smallpox, show multilocular intraepidermal vesicles with ballooning degeneration, cell necrosis and serous exudate. Characteristic cytoplasmic eosinophilic inclusion bodies, the most important being Guarnieri bodies (B type inclusions), represent sites of virus replication. Guarnieri bodies are readily seen in skin biopsies stained with hematoxylin and eosin, and appear as pink “blobs.” All poxviruses produce Guarnieri bodies, yet their absence cannot be used to rule out smallpox. Guarnieri bodies are not produced by herpesviruses.

Figure 10.

Electron micrograph of smallpox virus showing brick-like shapes

Common laboratory tests useful in formulating a differential diagnosis for an acute, generalized vesiculopustular rash: DFA test for varicella-zoster and herpes viruses; if (+), argues against smallpox. Tzanck smear for varicella-zoster or herpes virus-associated cellular features, such as multinucleated giant cells (Figure 11), or ballooning degeneration; if (+), argues against smallpox.

Figure 11.

Tzanck smear showing multinucleated giant cell

Diagnosis confirmation

Conditions most likely to be confused with smallpox include those with acute onset of fever and disseminated vesicular or pustular rash (Figure 12—Tables 1 and 2).

Figure 12.

Tables 1 and 2

Varicella is most commonly confused with smallpox (Figure 12—Tables 1 and 2, attached as PDF; Figure 13, Figure 14).

Figure 13.

Smallpox versus chickenpox lesion distribution

Figure 14.

Varicella, lesions characteristically concentrated on torso

Monkeypox, described as a human disease in 1970 in the Congo, is endemic in West Africa (Figure 15). It was first reported in the United States in 2003, when imported Ghana giant rats transmitted the disease to prairie dogs and humans. Reservoirs include rodents (African squirrels) and possibly monkeys. Monkeypox is transmitted by aerosol droplets or direct skin-to-skin contact and is less infectious and less lethal than smallpox. Smallpox vaccination may prevent monkeypox.

Figure 15.


Monkeypox is characterized by prominent lymphadenopathy, a distinguishing feature.

Who is at Risk for Developing this Disease?

Smallpox virus is highly contagious, but less so than measles and influenza. The most common form of transmission is inhalation of airborne virus droplets shed from the nasopharyngeal mucosa of an infected person. Smallpox can also be transmitted by direct contact with infected body fluids or contaminated objects such as bedding or clothing. Rarely, smallpox has been spread by virus carried in the air in enclosed settings such as buildings, buses, and trains.

Transmission from one person to another generally requires direct (within 6 feet) and prolonged (estimated 1 to 3 hours) face-to-face contact. Attack rates for unvaccinated close contacts range from 30% to 88%. Family members and other close household contacts of symptomatic (rash) smallpox patients, and health care workers are most at risk.

Among family members, the very young, pregnant women and elderly are most susceptible. Overall mortality rates for children younger than 1 year of age is 40% to 50%. Variola can cross the placenta, but congenital smallpox occurs infrequently.

The severity of a smallpox index case (first case in household or community) is not predictive of transmissibility or severity of secondary cases. However, rash severity is predictive of clinical outcome.

Smallpox generally spreads more slowly and less widely than many other viral diseases spread by nasal droplet to include measles, varicella and influenza, in part because transmission requires close contact and primarily occurs when the rash is apparent. Smallpox is not transmitted by insects or animals.

Smallpox is not considered highly infectious during the prodrome. However, some virus is found in the saliva during prodromal fever and enanthema, before the rash appears, suggesting mild contagiousness. Patients are most contagious in the first week, when the rash appears and most lesions are intact, associated with viral shedding. Infectivity diminishes at days 7 to 10 when lesions are crusting, but the disease remains contagious until the last crusted lesion detaches.

There is no asymptomatic carrier state, akin to typhoid fever (“Typhoid Mary”).

Age distribution of smallpox infections largely depends on acquired immunity. Vaccine protective immunity lasts at least 3 to 5 years, and continues to modulate disease severity for longer periods.

The last recorded case of smallpox in nature was in 1977, in Somalia. Eradication of smallpox was possible because of relatively slow spread, short duration of the infectious stage, an effective vaccine, the lack of a carrier state or animal reservoir, that only symptomatic patients are infectious to others, lifelong immunity after infection, and worldwide cooperation.

What is the Cause of the Disease?


Smallpox, an infectious disease unique to humans, is caused by poxvirus variolae (family Poxviradae; genus Orthopox). Among 4 orthopoxviruses causing human disease, smallpox virus infects only humans in nature, whereas cowpox, monkeypox and vaccinia viruses infect both humans and animals.

Two variants include variola major and variola minor.

Variola virus contains a single linear double-stranded DNA genome composed of 186 kilobase pairs. Virions are brick-shaped and measure approximately 300 x 250 x 200 nm, the largest of the poxviruses that infect humans. The lifecycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry.

Poxviruses, unique among DNA viruses, replicate in the cytoplasm of the cell, rather than the nucleus. To replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses, the most important being viral-associated DNA-dependent RNA polymerase. These proteins may serve as targets for anti-viral drugs.

Both enveloped and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin.

The genomes of variola major and variola minor are approximately 98% homologous, yet differ markedly in mortality with rates at 30% and 1%, respectively. Infection with either variola major or variola minor confers lifelong immunity against the other.


For variola major and variola minor, disease severity depends upon virus strain virulence and host immunity.

Disease progression occurs in three phases:

Latent: Smallpox infection begins when virus contacts the respiratory mucosa, attaches to epithelial cells, and is transported by macrophages to regional lymph nodes. By approximately day 3, and continuing through days 10 through 14, a primary viremia leads to invasion of mononuclear phagocytes in distal lymph nodes, spleen and liver (reticuloendothelial system), where replication continues. This is the incubation period, and the disease is not infectious at this point.

Prodromal: Between days 10 and 14, a massive secondary viremia occurs, triggering the clinical prodrome. An enanthem appears, then erodes as the skin rash begins, releasing large numbers of virions into the saliva.

Overt: Infected mononuclear cells invade the mucosa and capillary epithelium of the dermis and trigger inflammatory mediator release, causing lesion formation. Secondary viremia causes a systemic inflammatory response syndrome (SIRS), largely by formation of immune complexes, often resulting in multiple organ failure.

Systemic Implications and Complications

The most common complications of smallpox are sepsis and toxemia, mediated by circulating immune complexes, and hypotension, which together are usually considered the cause of death in most cases. Treatment is supportive. Respiratory complications range from bronchitis to fatal pneumonia, tending to develop about the eighth day of illness. The etiology can be viral, sometimes bacterial. Treatment is supportive, antibiotics if bacterial.

Other complications include encephalitis which occurs in approximately 1 in 500 patients, often adults; symptoms range from headache and hallucinations to psychosis. Treatment is supportive.

Ocular complications occur in 2% of all cases. Pustules may form on the eyelid, conjunctiva or cornea, causing conjunctivitis, keratitis, corneal ulcer, iritis, iridocyclitis, or optic atrophy. Treatment is supportive in addition sometimes utilizing idoxuridine (topical antiviral for ophthalmic herpes infections) drops or ointment. Ointment is applied in small amounts to both eyes every 4 hours; or 2 to 3 eyedrops/eye, every 1 to 2 hours; apply until lesion improvement is observed.

Blindness occurs in up to 40% of eyes that develop keratitis or a corneal ulcer.

Bone invasion occurs in approximately 2% of young children. Smallpox virions invade joints or bone, causing arthritis and ostemyeolitis, respectively. Arthritis limits movement and may lead to limb deformities, malformed bones, flail joints, and stubby fingers. In osteomyelitis variolosa, lesions may be symmetrical and are most common in the elbows, tibia and fibula. Treatment is supportive, with physical therapy, if the patient survives.

Secondary bacterial infection of the skin is relatively uncommon. If it occurs, the fever usually remains high during rash evolution. Treatment is supportive in addition to prescribing appropriate antibiotics.

The cause of death in smallpox may vary in the different foms of the disease:

  • - Ordinary smallpox: a combination of massive viremia, systemic inflammatory response syndrome (SIRS), circulating immune complexes, and septic organ failure

  • - Flat smallpox: similar to burns, with loss of fluid, protein and electrolytes, and fulminating sepsis

  • - Hemorrhagic smallpox: Early, same as ordinary form—heart failure and pulmonary edema; late, same as ordinary form with severe thrombocytopenia and a poor immune response

Treatment Options

There is no specific medical or surgical treatment for smallpox, only supportive medical management. The main determinants of outcome in major smallpox are virus strain virulence, the form of disease, the rash severity, and patient immunity.

Supportive medical management, for all forms of smallpox, includes

  1. Hospitalization

  2. Isolation in a negative-pressure room

  3. Supportive care: fluids, fever reduction, pain management, and wound care

  4. Ventilator assistance as needed

  5. Antibiotics for pneumonia and/or secondary skin infections

  6. Smallpox vaccination

Ordinary smallpox, semi-confluent or confluent lesions should be treated like extensive skin burns in a critical care unit. Flat and hemorrhagic smallpox should be treated like shock, including fluid resuscitation and cardiopulmonary support in a critical care unit.

Optimal Therapeutic Approach for this Disease

There is no specific medical or surgical treatment for smallpox. Supportive medical management is described in the treatment options section.

Patient Management

There is no specific medical or surgical treatment for smallpox. Supportive medical management is described above.

Management of Contacts

Management of contacts, such as family members and health care providers, requires post-exposure prophylaxis. The most important action in post-exposure prophylaxis is urgent smallpox vaccination. Smallpox vaccination within 3 days of exposure will completely prevent or significantly modify smallpox in most people. Vaccination 4 to 7 days after exposure likely offers some protection from disease or may modify the severity of the disease.

Dryvax (Wyeth, Inc) is the smallpox vaccine licensed and used most commonly in the United States. A newer vaccine called ACAM2000 (Acambis, Inc.), licensed in 2007, is not available to the US public but is used in the military and kept in the national stockpile.

Dermatologists will not typically administer smallpox vaccine. “Ring” vaccination may be considered by public health officials, a technique whereby those in contact with the direct contacts of a smallpox patient receive smallpox vaccination. This ensures that the vaccine is given to persons who were, or could have been, exposed to an infected person. Ring vaccination was an effective strategy in eradicating smallpox.

Anyone in contact with a smallpox patient but who chooses not receive the vaccine should be considered for isolation for at least 18 days. Vaccinia immune globulin (VIG) and certain anti-virals such as cidofovir and ribavirin, discussed below, are NOT approved for post-exposure prophylaxis, but experimental data in orthopoxvirus animal models suggest possible benefit. Human dosing guidelines are not established.

Unusual Clinical Scenarios to Consider in Patient Management

There is no US Food and Drug Administration (US FDA) approved antiviral drug for the treatment of smallpox, vaccinia or other orthopoxviruses. Currently available drugs under study for orthopoxvirus infections include the following:

Cidofovir (Vistide®), an antiviral compound that shows some activity against orthopoxviruses in laboratory animal models, suggesting a possible benefit in smallpox, either treatment or post-exposure prophylaxis. Cidofovir, approved for cytomegalovirus (CMV) retinitis in HIV patients, is administered intravenously and often causes serious renal toxicity. More information:

Ribavirin, approved for use in respiratory syncytial virus (RSV), has broad antiviral activity. It shows some activity against orthopoxviruses in laboratory animal models, suggesting a possible benefit in smallpox treatment, as well as smallpox post-exposure prophylaxis.

Imatinib mesylate (Gleevec®; STI571), an approved cancer treatment, limits the release of enveloped extracellular virions and protects mice from a lethal challenge with vaccinia. Gleevec® and related compounds are under study by the US CDC for use against smallpox and monkeypox.

For the three drugs discussed above, the safety profile, tolerability, effective dose, timing, and length of administration for use in human orthopoxvirus infections are unknown. Insufficient information exists on which to base recommendations for any of the compounds to treat orthopoxvirus infections, including smallpox, and post-vaccination complications.

The US CDC website (smallpox page) contains the most up-to-date information on treatment options for smallpox:

Experimental (unlicensed) drugs for orthopoxvirus infections:

Tecovirimat (ST-246) is a novel antiviral that inhibits the egress of orthopoxviruses by disrupting the production of an important viral envelope protein (p37). It has been reported to be 100% active against vaccinia virus or other orthopoxviruses in vitro and in laboratory animals. Tecovirimat, given orphan drug status by US FDA, is being developed by SIGA Technologies, Inc., under license from ViroPharma, Inc., for use in humans.

Dermatologists will not typically administer smallpox vaccination but may encounter smallpox post-vaccination complications, such as eczema vaccinatum and generalized vaccinia. Be alert for a history of recent vaccination in patient or household contact. DFA or a Tzanck smear can be done to assess for varicella-zoster and herpes viruses.

Vaccinia immunoglobulin (VIG) an isotonic solution of pooled immunoglobulin fractions of plasma from persons vaccinated for smallpox., is the only product available for treatment of complications of orthopox infection. VIG is administered intravenously or intramuscularly (IM). The usual dose for an average person is about 0.6 mL/kg IM (40 mL given IM over a 24- to 36-hour period). In severe eczema vaccinatum and progressive vaccinia, higher doses (1 to 10 mL/kg) may be used.

The US CDC maintains VIG in limited quantities and should be contacted to discuss potential use (1-800-CDC-INFO or 1-800-232-4636, 24 hours/day, 365 days/year). VIG has NO role or value in treating or preventing smallpox.

What is the Evidence?

Breman, JG, Henderson, DA. "Diagnosis and management of smallpox". N Engl J Med. vol. 346. 2002. pp. 1300-8.

(A useful review of the clinical aspects of smallpox)

Moore, ZS, Seward, JF, Lane, JM. "Smallpox". Lancet. vol. 367. 2006. pp. 425-35.

(A useful review of smallpox, basic science and clinical aspects)

Di Giulio, DB, Eckburg, PB. "Human monkeypox: an emerging zoonosis". Lancet Infect Dis. vol. 4. 2004. pp. 15-25.

(Describes the emergence of monkeypox)

Boyd, DA, Sperling, LC, Norton, SA. "Eczema herpeticum and clinical criteria for investigating smallpox". Emerg Infect Dis. vol. 15. 2009. pp. 1102-4.

(Describes a case of eczema herpeticum fulfilling smallpox criteria for high risk, but ruled out by Tzanck smear and DFA test results)

Duraffour, S, Andrei, G, Snoeck, R. "Tecovirimat, a p37 envelope protein inhibitor for the treatment of smallpox infection". Drugs. vol. 13. 2010. pp. 181-91.

(Describes the mode of action of Tecovirimat® [ST 246], a promising antiviral that may be useful in smallpox)

Reeves, PM, Bommarius, B, Lebeis, S, McNulty, S, Christensen, J, Swimm, A. "Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases". Nat Med. vol. 11. 2005. pp. 731-9.

(Describes mode of action of abl1 tyrosinase inhibitors, such as Gleevec®, a cancer drug that may be useful for treating orthopox viruses, including smallpox)

Dropulic, LK, Cohen, JI. "Update on new antivirals under development for the treatment of double-stranded DNA virus infections". Clin Pharmacol Ther. vol. 88. 2010. pp. 610-9.

(Describes most promising drugs under study for treating orthopoxviruses, including smallpox)

Ligon, BL. "Monkeypox: a review of the history and emergence in the Western hemisphere". Semin Pediatr Infect Dis. vol. 15. 2004. pp. 280-7.

(This paper describes monekypox emergence in the Western hemisphere.)

Nafziger, SD. "Smallpox". Crit Care Clin. vol. 21. 2005. pp. vii-46.

(Reviews smallpox treatment in critical care setting)

Handley, L, Buller, RM, Frey, SE, Bellone, C, Parker, S. "The new ACAM2000 vaccine and other therapies to control orthopoxvirus outbreaks and bioterror attacks". Expert Rev Vaccines. vol. 8. 2009. pp. 841-50.

(Describes next generation of orthopox vaccines, including ACAM2000 for smallpox)
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Lung Cancer Regimens Drugs
Other Cancers Regimens
Rare Cancers Regimens
Skin Cancer Regimens Drugs