AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Smallpox is an acute contagious disease caused by the variola virus (Poxvirus variolae), a member of the Poxviridae family of the genus Orthopoxvirus. Virologists have speculated that it evolved from an African rodent poxvirus 10 millennia ago. Because of the absence of an animal vector, communities had to reach a critical population (estimated at 200,000 around 3000 BC) before endemic smallpox could be established. The name is derived from the Latin word for "spotted" and refers to the raised bumps on the face and body of the patient. Poxviridae are linear double-stranded DNA viruses that replicate in the cytoplasm. Poxviridae consist of 2 families: Chordopoxvirinae, which infect vertebrates, and Entomopoxvirinae, which infect insects. Vaccinia virus, monkeypox virus, and cowpox virus are other viruses within the Orthopoxvirus genus that infect humans.

The two classic varieties of smallpox are variola major and variola minor, each of which confers immunity against the other. Variola major is the more severe and common form of smallpox. It causes more extensive rash and fever. Variola major smallpox has 4 subtypes, as follows:

• Ordinary smallpox - The most common form, which accounts for 90% or more of cases
• Modified smallpox - A mild form that develops in previously vaccinated persons
• Flat smallpox (malignant smallpox) - A severe variety in which lesions do not project above the skin surface
• Hemorrhagic smallpox (fulminant smallpox) - A rare, very severe, highly fatal variety of the disease in which hemorrhages develop in the skin and mucous membranes

Variola minor is less common and much less virulent and was previously found mainly in South Africa, South America, Europe, and Australia.

Variola sine eruptione (variola sine exanthemata) is another less common form. In addition, a pharyngeal form develops in immunized individuals; this form presents with a spotty enanthem over the soft palate, uvula, and pharynx. An influenzalike form exists but rarely results in a rash. Both of these forms are relatively mild, usually affect individuals who have been previously immunized, and do not cause mortality. A pulmonary form characterized by severe symptoms, cyanosis, and bilateral infiltrates has been described in individuals with little or no immunity. The mortality rate is undetermined.

During the first half of the 20th century, all outbreaks of smallpox in Asia and most in Africa were due to variola major. The case fatality rate was 20% or more in unvaccinated persons. Variola minor carried a case fatality rate of 1% or less and was endemic in some countries in Europe, North America, South America, and many parts of Africa.

Smallpox outbreaks have occurred sporadically for thousands of years, but, after a successful global vaccination program, the disease has now been eradicated. The last case of smallpox in the United States was reported in 1949. The last naturally occurring case in the world was seen in Somalia in 1977. After the disease was eliminated from the world, routine smallpox vaccination was stopped because prevention was no longer necessary. The long-term consequence of eradication is that much of the world's population is now unvaccinated and at risk for infection.

Pathophysiology

Smallpox is a double-stranded, 135- to 375-kilobase (kb) DNA virus that replicates in the cytoplasm of the host cell and forms B-type inclusion bodies (Guarnieri bodies), unlike herpes viruses, which replicate in the nucleus. The orthopoxviruses are among the largest and most complex of all viruses. The virion is brick-shaped with a diameter of approximately 200 nm.

The virus is transmitted mainly through the airborne route and adheres via droplet spread of viral particles onto the mucosal surfaces of the oropharyngeal and respiratory tract. This transmission occurs through close personal contact (eg, face-to-face within 6 ft, household contact) for extended periods. Respiratory spread over long distances (eg, from one hospital floor to another) has been reported. Exposure to clothing or blankets contaminated with infected material can also result in disease.

Smallpox has a lower transmission rate than measles, pertussis, and influenza. Transmission through casual and limited contact has been reported in military personnel. Although rare, airborne (ie, suspended viral particles) and fomite transmission can occur. Humans are the only natural hosts of variola; nonhuman animals and insects do not carry the variola virus. Pregnant women tend to develop hemorrhagic disease, but intrauterine infection occurs in even the mildest maternal infections, resulting in premature delivery and high fetal and neonatal mortality rates.

Implantation of just a few virions into the oropharynx or respiratory tracts can cause infection. The virus infects macrophages during the first 72 hours of the incubation phase. The virus migrates and multiplies in the regional lymph nodes, resulting in asymptomatic viremia by the fourth day. The virus multiplies in the spleen, bone marrow, and lymph nodes, resulting in a symptomatic secondary viremia (ie, fever, toxemia) by the eighth day. Finally, the virus re-enters the blood in leukocytes, producing fever and toxemia, and then passes from leukocytes to adjacent cells in small blood vessels of the dermis and beneath the oropharyngeal mucosa, leading to the initial onset of the enanthem and exanthem, at which point (approximately day 14) the patient becomes infectious.

The spleen, lymph nodes, kidneys, liver, bone marrow, and other viscera may also contain large amounts of virus. Incubation periods are typically 10-12 days but can range from 7-17 days. Intrauterine infections rarely occur and usually have shorter incubation periods. Patients exposed through routes other than the person-to-person respiratory route also have shorter incubation periods. Prior immunization, vaccinia immune globulin (VIG), and, possibly, antiviral chemotherapy may extend the incubation period.

Patients with smallpox are sometimes contagious upon the onset of fever (prodromal phase) but are most contagious upon rash onset. Infected persons are contagious until the last smallpox scab separates. The highest intensity of viral shedding is during the first 10 days of the rash. Infection rates among close contacts of infected persons have been reported to be between 37 and 88%. Survivors of natural infection acquire lifelong immunity.

Frequency

United States

The last outbreak of smallpox in the United States was in 1947, when 12 cases were reported in New York City. In the United States, routine vaccination of the civilian population ended in 1972 and in 1990 for the US military.

The most current statistics indicate that approximately 41% of the resident US population is younger than 30 years, most of whom have not been vaccinated against smallpox. The immune status of those who were vaccinated 30 or more years ago has not been satisfactorily established, but some evidence shows residual immunity. Reports from the late 19th century indicate that vaccination 20-30 years previously may not protect against infection but often prevents death. No conclusive studies have shown whether people with residual immunity can transmit smallpox to nonvaccinated individuals.

International

The last endemic case of variola major was reported in Bangladesh in 1975; the last endemic case of variola minor was reported in Somalia in 1977. In 1979, a laboratory accident in Birmingham, England, resulted in a single case of the disease. Smallpox is authorized to be kept for research purposes only at 2 World Health Organization reference laboratories. One is the US Centers for Disease Control and Prevention (CDC) in Atlanta, Ga, and the other is the State Research Centre of Virology and Biotechnology, also known as the VECTOR Institute, in Koltsovo, Russia. Routine smallpox vaccinations was stopped in 1972 and smallpox was declared eradicated in 1980 after a worldwide vaccination program. In 2002, The Washington Post reported that the Central Intelligence Agency identified possible clandestine smallpox virus stocks in 4 other nations.

Mortality/Morbidity

Variola major infection carries an overall fatality rate of approximately 30% (range, 15-50%) in an unvaccinated population and 3% in a vaccinated population. However, flat smallpox carries a 45.4% mortality rate in patients with discrete lesions who have been immunized. Unimmunized patients with confluent disease have a 99.3% mortality rate. Patients with hemorrhagic smallpox have a mortality rate of more than 96%, regardless of immunization status. Variola minor infection is a less common type of smallpox and a much less severe disease, with a death rate of 1% or less.

Age

Age distribution mirrors that of the general population, although residual immunity from previous vaccination could potentially decrease disease in the older population.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• The incubation period ranges from 7-17 days but is usually 10-12 days. During the incubation period, patients are not contagious.
• The initial symptoms of smallpox include fever, malaise, head and body aches, and, rarely, vomiting. The fever ranges from 38.8-40°C (101-104°F).
• In this prodromal phase, patients are usually too ill to perform normal activities of daily living. The phase may last 2-3 days but may last as long as 5 days.

Physical

• The initial cutaneous lesions of smallpox appear as small red spots on the face, in the mouth and pharynx, and on the forearms. Initially, smallpox lesions are small papules but change into vesicles and pustules within 1-2 days. The rash is typically described as centrifugal. The initial lesions are shotty and do not disappear with pressure.
• These spots develop into sores that break open and spread large amounts of the virus into the mouth and throat. The patient becomes most contagious at this time.
• Around the time the sores in the mouth break down, a rash appears on the skin, starting on the face, spreading to the arms and legs, and progressing to the hands and feet. Usually, the rash spreads to all parts of the body within 24 hours. As the rash appears, the fever reduces and the patient may start to feel better.
• By the third day of the rash, it turns into raised papules.
• By the fourth day, the papules fill with a thick opaque fluid and often have a depression in the center that resembles an umbilicus (bellybutton), which is a major distinguishing characteristic of smallpox. At this time, the fever often rises again and remains high until scabs form over the papules.
• The papules become pustules. The pustules are sharply raised and are usually round and firm to the touch, as if a small round object is present under the skin. The pustules begin to form a crust and then scab.
• By the end of the second week after the rash appears, most of the sores have formed scabs. The scabs begin to separate, leaving marks on the skin that eventually become pitted scars. Most scabs separate by the third week after the rash appears.
• The person is contagious until all of the scabs are gone.
• The smallpox rash has a centrifugal distribution, with more lesions on the arms and legs than on the trunk. Rash on the palms and soles is common. As a comparison, a chickenpox rash has a centripetal distribution, with more lesions on the trunk and with fewer or no lesions on the palms and soles.
• Most patients report severe headaches and spinal pain. Few patients develop neuropsychiatric symptoms (hallucinations, delirium, depression and psychosis, manic depression). Autopsies of patients with smallpox have demonstrated perivenular demyelination.
• Ten to 20% of patients with smallpox develop ophthalmic complications (variola residua). Conjunctivitis is most common, appearing 5 days after rash onset. Some patients develop painful pustules and bulbar conjunctivitis. During epidemics, corneal ulceration was common (complicated by bacterial superinfection and perforation).
• Two to 5% of children develop osteomyelitis (osteomyelitis variolosa) due to viral invasion of the bone rather than to secondary infection. Radiographic surveys in children have found rates as high as 20%.

Causes

• The variola virus causes all forms of smallpox.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Monkeypox
Acne
Chickenpox (varicella-zoster virus)
Drug eruptions
Generalized vaccinia and eczema vaccinatum
Insect bites
Viral hemorrhagic fevers (may be confused with hemorrhagic smallpox)

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Smallpox infection may be confirmed based on the presence of brick-shaped virions viewed with electron microscopy examination of vesicular or pustular fluid or scabs.
• • Although smallpox and all other viruses in the Orthopoxvirus genus exhibit identically appearing brick-shaped virions, the clinical aspects of these diseases generally suffice for distinguishing cowpox and vaccinia from smallpox.
  • Monkeypox virions may also be indistinguishable from smallpox virions, but naturally occurring monkeypox is typically limited to tropical rain forest areas of Africa.
• Variola virus can be detected with electron microscopy, virus culture from live cells, or DNA analysis using polymerase chain reaction (PCR).
• • Cell culture is seldom used because it is not as effective as the other methods and because it requires the use of live virus, which, in turn, requires the use of a biosafety level 4 (BSL-4) laboratory.
  • PCR and electron microscopy can be used to examine inactivated samples and therefore do not require such high levels of isolation and can be performed in local laboratories.
  • Electron microscopy can help identify the virus as a member of the Orthopoxvirus genus, but it cannot help determine the exact species.
  • PCR can be used to identify the species (variola) and can even distinguish minor genetic variations in the different strains. PCR is a relatively new technology and has been used to identify variola only twice previously, and never in a clinical situation. PCR can amplify small and specific lengths of DNA and can accurately differentiate variola virus DNA from other species in the genus. The sensitivity is 5-10 copies of DNA. PCR can be useful to distinguish between chickenpox and smallpox.
• Smallpox skin specimen should be collected with precautions in place.
• • Gloves should be worn during collection. Fluid from lesions can be harvested on a cotton swab; prior to shipping specimens, state and local health department laboratories should be contacted for specific instructions.
  • The CDC recommends the following procedures for handling specimens obtained from a patient thought to be infected with the smallpox virus:
  • • Specimens should be collected by someone who has recently been vaccinated (or who is vaccinated that day) and who wears gloves and a mask.
    • To obtain vesicular or pustular fluid, the lesions may need to be opened with the blunt edge of a scalpel. The fluid can then be harvested on a cotton swab. Scabs can be picked off with forceps.
    • Specimens should be deposited in a Vacutainer tube. The tube should be sealed with adhesive tape at the juncture of the stopper and the tube. This tube, in turn, should be enclosed in a second durable and watertight container.
    • State or local health department laboratories should be contacted immediately for proper specimen shipping protocols.
• Laboratory examination should be performed only in designated BSL-4 laboratories. Once established that an epidemic is caused by the smallpox virus, clinically similar cases would not require further laboratory testing.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

No known treatment is effective. Medical management of smallpox is mainly supportive.

• Supportive care in symptomatic patients consists of the following:
• • The patient should be isolated (see Isolation) until all scabs have fallen off (about 3-4 wk after rash onset) to prevent transmission of the smallpox (variola) virus to nonimmune persons.
  • The fluid and electrolyte balance should be monitored and maintained to avoid dehydration.
  • Medications are given for fever and pain.
  • Good nutritional support is maintained.
  • Skin care should be instituted.
  • Complications should be monitored for and treated.
  • Unless the diagnosis of smallpox is confirmed in a laboratory, patients should receive smallpox vaccination if they will be isolated with other patients with confirmed or suspected smallpox to prevent accidental transmission.
• Treatment for patients with possible or known exposure to smallpox consists of the following:
• • The smallpox vaccine is the only known way to prevent smallpox in an exposed person. If given within 4 days of viral exposure, the vaccine can prevent or significantly lessen the severity of smallpox symptoms. Vaccination 4-7 days after exposure may offer some protection from the disease and may lessen its severity.
  • Isolate patients possibly infected with smallpox virus in negative-pressure rooms and vaccinate within the first 4 days after exposure.
  • Supportive and symptomatic treatment (eg, hydration, nutrition) should be provided.
  • Vaccination does not protect patients with smallpox who have already developed a rash.
• New drugs are under investigation; one of these drugs is cidofovir, which has shown good results in the laboratory (see Medication).
• Isolation recommendations by the CDC are as follows:
• • In an outbreak, patients with confirmed or suspected smallpox may be isolated in several ways. The goal of isolation is to prevent transmission of smallpox from an infected patient to nonimmune individuals while maintaining an appropriate care and comfort level for the patient. Medical personnel should consult with public health officials to determine the most appropriate method for isolation of patients with smallpox.
  • If a patient with confirmed or suspected smallpox requires hospital care, the following steps must be taken while the patient is hospitalized:
  • • The patient should be kept in strict airborne and contact isolation in a room with negative air pressure (and individual high-efficiency particulate air [HEPA]–filtered ventilation exhaust, if available). This room should have private shower and bathroom facilities and not share ventilation with any other part of the hospital.
    • Unvaccinated personnel who enter and leave the isolation room should wear protective clothing, including gowns, masks (properly fitted N95 respirator masks), gloves, protective eyewear, and surgical booties. Recently successfully vaccinated personnel should exercise contact precautions (eg, gowns, gloves) and should wear a surgical mask and eye protection, as indicated, for procedures in which contact with body fluids is possible.
    • All protective clothing should be removed and placed into biohazard waste disposal containers before leaving the isolation room and re-entering other areas of the hospital.
    • All infectious waste and contaminated protective clothing should be disposed of or sterilized in an appropriate manner (incineration for disposable materials; autoclaving, ethylene oxide decontamination, or laundering in hot water and bleach for reusable equipment or clothing). Public health officials should be consulted for specific waste disposal and decontamination guidelines.
    • Personnel entering the isolation room or handling infectious waste or clinical specimens from the patient should be vaccinated or have documented successful recent smallpox vaccinations (within 3 y). Public health officials should be contacted for vaccination requests.
    • Steps should be taken to confirm or to rule out the diagnosis of smallpox. Public health officials should be consulted for assistance with the laboratory diagnosis.
  • Nonhospital isolation: Public health officials should be consulted before nonhospital isolation is initiated. Patients with confirmed or suspected smallpox who do not require hospital care may be isolated in nonhospital facilities that do not share ventilation systems with other facilities. These facilities should have appropriate climate control capabilities (heating and air conditioning), running water, and bathroom facilities. If patients with suspected or confirmed smallpox are isolated together, all patients should receive smallpox vaccination to prevent accidental transmission due to misdiagnosis. All persons entering these facilities must have documented successful recent smallpox vaccinations (within 3 y).

Consultations

Infectious disease specialists and public health officials should be consulted.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Currently, no medications are approved to treat smallpox. Certain medications, including topical idoxuridine and cidofovir, can be used under investigational new drug (IND) protocol for the management of smallpox. Secondary bacterial infections of the skin can be treated with semisynthetic penicillins (nafcillin, oxacillin, dicloxacillin, cloxacillin) or first-generation cephalosporins (eg, cefazolin, cephalexin) or clindamycin. Ampicillin/sulbactam or amoxicillin/clavulanate can also be used. A history of prior adverse reactions or hypersensitivity is the primary contraindication.

Drug Category: Investigational antiviral agents

Cidofovir is currently approved for the treatment of cytomegalovirus (CMV) infections but not smallpox. Animal models support the potential usefulness of this agent in smallpox. Given immediately after exposure, cidofovir has shown some benefit in the prevention of vaccinia, monkeypox, and cowpox. Pulmonary viral levels and pneumonitis were also reduced in animal models of cowpox.

Drug Category: Ophthalmic antiviral agents

Idoxuridine is approved for treatment of CMV retinitis. In the event of ocular involvement with smallpox, it may be given, but its efficacy is undocumented.

Drug Category: Live virus vaccines

Primary immunization as soon as possible after exposure or at first sign of infection is indicated for prevention and management of smallpox. Currently, US military personnel, US Department of Defense civilian employees, and health care professionals are recommended candidates to receive the vaccination because they will likely be at highest risk in case of a biological attack (eg, bioterrorism). The first vaccination was performed in 1796 by Edward Jenner, using material scraped from a cowpox blister on a maid after Jenner observed that other maids infected with cowpox rarely developed smallpox. He inoculated the child with scrapings from a patient with smallpox, and he noted that the child did not develop smallpox. Immunization was ceased in 1972 in the United States and in 1980 worldwide, after the disease was declared eradicated.

Drug Category: Immune globulins

These agents are indicated for passive immunity. VIG is the only drug available for amelioration of some vaccinia-related complications. VIG is produced from pooled human sera taken from vaccinia-immunized individuals and is available only from the CDC. VIG has been effective when administered early in cases of vaccinia necrosum and eczema vaccinatum. VIG has not been effective in cases of encephalopathy. The use of VIG for generalized vaccinia reactions is usually not necessary. Recently, intravenous VIG (VIGIV) has been FDA-approved.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention

• Vaccination: One of the best ways to prevent smallpox is through vaccination. Vaccine given to individuals before exposure to smallpox can completely protect them. Vaccination within 3 days after exposure prevents or greatly lessens the severity of smallpox in most people. Vaccination 4-7 days after exposure likely offers some protection from disease or may decrease the severity of disease. Vaccination does not protect patients with smallpox who have already developed a rash.
• • Vaccinated persons normally exhibit an accelerated immune response. Thus, whenever possible, assigning those who have previously been vaccinated to duties involving close patient contact is prudent.
  • Persons with known or possible exposure to smallpox should be vaccinated if the exposure has occurred within 3 days unless the patient has specific contraindications for which the risks of immunization are considered even greater than the dangers associated with contracting smallpox.
• Vaccinia immune globulin (VIG): This is indicated when the vaccination is contraindicated.
• Hospital infection control: Whenever possible, patients should be cared for at home in the event of a large smallpox outbreak. However, in the event of an outbreak with only a few cases or when patients cannot be cared for at home, hospital admission is advisable.
• • Individuals with smallpox should be placed in isolation in rooms under negative pressure that are equipped with high-efficiency particulate air (HEPA) filtration.
  • All persons caring for patients with smallpox should be vaccinated, except those with contraindications to the vaccine, who should be furloughed. Ideally, all health care workers caring for patients with smallpox should be vaccinated; however, this may not be possible in the event of an epidemic because a large number of persons are required for the delivery of care.
  • Patients should be isolated under strict airborne and contact precautions, and the number of personnel in contact with them should be limited, as should the caregivers in contact with other patients who do not have smallpox.
  • Wear appropriate protective equipment when in contact with persons who may be infected.
  • Properly dispose of all protective equipment (ie, in biohazard bags) before leaving the anteroom.
  • Avoid transporting the patient through the hospital (eg, use in-room portable radiograph equipment); if transporting the patient is unavoidable, have the patient wear a surgical mask and the health care worker a mask with an N-95 respirator.
  • If smallpox infection is confirmed, place contacts under fever surveillance for 18 days after their last contact with the infected patient.
  • Contacts or a supervisor should monitor the patient’s temperature twice daily. If the patient’s temperature is higher than 38.1°C (100.5°F), public health authorities should be notified immediately.
  • The vaccine should be administered to all persons who had contact with a patient confirmed to have smallpox. Additionally, the vaccine should be administered to personnel without contraindications who will be involved in the future evaluation or care of patients possibly infected, if not already a contact.
  • Do not reuse equipment or the room for other patients unless it has been properly decontaminated.
  • The CDC recommends that authorities should consider designating specific hospitals for smallpox care and that all persons isolated for smallpox should be vaccinated.

Complications

• Skin
• • Formation of furuncles and/or abscesses secondary to bacterial infection
  • Sepsis
  • Pockmarks
• Eyes
• • Blepharitis
  • Conjunctivitis
  • Corneal ulceration 
• Joints and bones
• • Arthritis
  • Osteomyelitis variolosa
  • Symmetrical elbow joint involvement 
• Respiratory system
• • Pulmonary edema
  • Pneumonitis
• Central nervous system - Encephalitis (1 in 500 cases)
• Other - Dehydration

Prognosis

• The mortality rate in untreated patients is 30% or higher. The more severe hemorrhagic and malignant forms are usually fatal.

Patient Education

• Isolation
• Barrier protection - Gown, mask, gloves
• Cremation of corpses
• Isolation of contacts if fever or rash develops
• Surveillance of all face-to-face contacts
• For excellent patient education resources, visit eMedicine's patient education article Smallpox.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Persons with known cardiac disease (eg, previous myocardial infarction, angina, congestive heart failure, cardiomyopathy) should not be vaccinated. Myocardial infarctions and angina without myocardial infarction have been reported following smallpox vaccinations. The association between smallpox vaccination and these cardiac events is not clear.
• Pregnant women who receive the smallpox vaccine are at risk of fetal vaccinia, which usually results in stillbirth or death of the infant. Pregnant women should not be vaccinated, and women should be advised against becoming pregnant for 4 weeks after vaccination.

Special Concerns

• Bioterrorism: Based on the following CDC criteria, smallpox is a high-priority (category A) agent for bioterrorism:
• • Easily disseminated or transmitted from person to person
  • High mortality rate and potential for significant public health effect
  • Probable instigator of panic and social disruption
  • Special actions required for public health preparedness

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Smallpox virion. Courtesy of US Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Photo

Media file 2:  After exposure to the smallpox virus, a symptom-free incubation period follows. It normally lasts 10-12 days, but it may vary from 7-17 days. Smallpox begins with fever, headache, and severe backache. A rash appears after 2-4 days and progresses through characteristic stages of papules, vesicles, pustules, and, finally, scabs. The scabs desquamate at the end of the third or fourth week. Courtesy of the World Health Organization.
	View Full Size Image
Media type:  Graph

Media file 3:  Smallpox rash at days 3, 5, and 7 of evolution. Lesions are denser on the face and extremities than on the trunk. They also appear on the palms of the hand and have a similar appearance. Courtesy of the World Health Organization.
	View Full Size Image
Media type:  Photo

Media file 4:  Flat-type smallpox on day 6 of the rash. Courtesy of the US Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Photo

Media file 5:  This smallpox patient survived toxemia to succumb to secondary tissue damage days after this photo was taken. Courtesy of the US Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Photo

Media file 6:  Smallpox vaccination with bifurcated needle. Reconstituted vaccine is held between the prongs of the needle and injected subcutaneously by multiple punctures; 15 rapid strokes, at right angles to the skin over the deltoid muscle, are made within a 5-mm area. Courtesy of the World Health Organization.
	View Full Size Image
Media type:  Photo

Media file 7:  Smallpox vaccination. Evolving primary vaccination appearance. Courtesy of the US Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Photo

Media file 8:  Typical temperature chart of a patient with smallpox infection (from Henderson, 1999).
	View Full Size Image
Media type:  Graph

Media file 9:  US Centers for Disease Control and Prevention Pocket Reference Guide for smallpox vaccine adverse events. Available at: http://www.bt.cdc.gov/training/smallpoxvaccine/reactions/SmallpoxVaccinationGuide.pdf. Courtesy of the US Centers for Disease Control and Prevention.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• ARF BM, Moyer RW. Entomopoxvirus B. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:914-8.
• Alibek K, Handelman S. Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World - Told from Inside by the Man Who Ran It. New York, NY: Random House; 1999.
• Aylward B, Hennessey KA, Zagaria N, et al. When is a disease eradicable? 100 years of lessons learned. Am J Public Health. Oct 2000;90(10):1515-20.
• Bergoin M. Entomopoxvirus A. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:911-3.
• Brauner SC, Pavan-Langston D. Smallpox, vaccinia, and the eye. Int Ophthalmol Clin. 2006;46(2):11-25.
• Bray M, Martinez M, Smee DF, et al. Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. J Infect Dis. Jan 2000;181(1):10-9. [Medline].
• Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. Apr 25 2002;346(17):1300-8. [Medline].
• Breman JG, Arita I, Fenner F. Preventing the return of smallpox. N Engl J Med. Jan 30 2003;348(5):463-6.
• Bugert JJ, Melquiot N. Molluscipoxvirus. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:880-4.
• Centers for Disease Control and Prevention, National Immunization Program. Smallpox: What Every Clinician Should Know [video online]. Available at: http://www.cdc.gov/nip/ed/smallpox-trg/clinician-should-know/default.htm. Atlanta, Ga: Centers for Disease Control and Prevention;. Apr 2003. [Full Text].
• Centers for Disease Control and Prevention. Emergency Preparedness and Response. Smallpox. Available at: http://www.bt.cdc.gov/agent/smallpox/index.asp. Atlanta, Ga: Centers for Disease Control and Prevenion;. 2004. [Full Text].
• Centers for Disease Control and Prevention (2002). Smallpox vaccine overview. Available at: http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp. [Full Text].
• Cleri DJ, Villota FJ, Porwancher RB. Smallpox, bioterrorism, and the neurologist. Arch Neurol. Apr 2003;60(4):489-94.
• Cleri DJ, Porwancher RB, Ricketti AJ, et al. Smallpox as a bioterrorist weapon: myth or menace?. Infect Dis Clin North Am. Jun 2006;20(2):329-57, ix.
• Cleri DJ, Ricketti AJ, Villota FJ, et al. Smallpox, monkeypox, other pox diseases and vaccination. Infect Dis Pract Clin. 2005;29:396-406.
• De Clercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. Jul 2002;55(1):1-13.
• Department of Defense. MILVAX. Department of Defense Smallpox Vaccination Program. Available at: http://smallpox.mil/. Arlington, Va: Department of Defense; 2004. [Full Text].
• Eichner M. Case isolation and contact tracing can prevent the spread of smallpox. Am J Epidemiol. Jul 15 2003;158(2):118-28.
• Espy MJ, Cockerill III FR, Meyer RF, et al. Detection of smallpox virus DNA by LightCycler PCR. J Clin Microbiol. Jun 2002;40(6):1985-8.
• Essani K, Bejcek BE, Paulose M. Yatapoxvirus. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:907-10.
• Federici BA. Entomopoxvirus C. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:919-21.
• Fenner F, Henderson DA, Arita I, et al. Smallpox and Its Eradication. In: Communicable Disease Surveillance and Response. Available at: http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html. Geneva, Switzerland: World Health Organization; 1988:. 1460. [Full Text].
• Frey SE, Newman FK, Cruz J, et al. Dose-related effects of smallpox vaccine. N Engl J Med. Apr 25 2002;346(17):1275-80. [Medline].
• Gross CP, Sepkowitz KA. The myth of the medical breakthrough: smallpox, vaccination, and Jenner reconsidered. Int J Infect Dis. Jul-Sep 1998;3(1):54-60.
• Henderson DA. The looming threat of bioterrorism. Science. Feb 26 1999;283(5406):1279-82. [Medline].
• Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. Jun 9 1999;281(22):2127-37. [Medline].
• Immunization Practices Advisory Committee (ACIP). Vaccinia (smallpox) vaccine. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep. Dec 13 1991;40(RR-14):1-10.
• Inglesby TV, Henderson DA, Bartlett JG, et al. Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. May 12 1999;281(18):1735-45. [Medline].
• Johnson RT. Postinfectious demyelinated diseases. In: Viral Infection of the Nervous System. Williams & Wilkins;1981:765-73.
• Kerr PJ, McFadden G. Leporipoxvirus. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:873-9.
• Kitching RP. Capripoxvirus. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:869-72.
• Lawler JV, Burgess TH. Smallpox. In: Roy MJ, ed. Physician's Guide To Terrorist Attack. Totowa, NJ:. Humana Press;2003:197-220.
• LeDuc JW, Jahrling PB. Strengthening national preparedness for smallpox: an update. Emerg Infect Dis. Jan-Feb 2001;7(1):155-7.
• Letai AG. Smallpox and smallpox vaccination. N Engl J Med. May 8 2003;348(19):1920-5; author reply 1920-5.
• Meltzer MI, Damon I, LeDuc JW, Millar JD. Modeling potential responses to smallpox as a bioterrorist weapon. Emerg Infect Dis. Nov-Dec 2001;7(6):959-69.
• Mercer A, Fleming S. Parapoxvirus. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:896-901.
• Moss B, Senkevich TG. Orthopoxvirus. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:885-95.
• Ness TL, Moyer RW. Suipoxvirus. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:902-6.
• Preston R. The Demon in the Freezer: A True Story. New York, NY: Random House; 2002.
• Redfield RR, Wright DC, James WD, et al. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med. Mar 12 1987;316(11):673-6. [Medline].
• Reeder MM, Palmer PES. Smallpox osteomyelitis (osteomyelitis variolosa). In: The Radiology of Tropical Medicine With Epidemiological, Pathological and Clinical Correlation. Baltimore:. Williams & Wilkins;1981:765-73.
• Ropp SL, Esposito JJ, Loparev VN, Palumbo GJ. Poxviruses infecting humans. In: Murray PR, ed. Manual of Clinical Microbiology. Washington, DC: American Society of Microbiology. 1999;1137-44.
• Ropp SL, Jin Q, Knight JC, et al. PCR strategy for identification and differentiation of small pox and other orthopoxviruses. J Clin Microbiol. Aug 1995;33(8):2069-76.
• Ryabchikova E, Sokunova E, Kononova J, Guskov A. Studies of Variola Virus Replication in Cell Cultures and Chick Embryo Chorion-allantois Membrane. In: Price R, ed. ASA Newsletter. Available at: http://www.asanltr.com/newsletter/02-3/articles/023a.htm. Aberdeen, Md: Applied Science and Analysis; 2002:. Article 023a. [Full Text].
• Skinner MA, Laidlaw SM, Boulanger D. Avipoxvirus. In: Tidona CA, Darai G, eds. The Springer Index of Viruses. Berlin:. Springer-Verlag;2002:864-8.
• Smee DF, Bailey KW, Sidwell RW. Treatment of lethal vaccinia virus respiratory infections in mice with cidofovir. Antivir Chem Chemother. Jan 2001;12(1):71-6.
• Smee DF, Bailey KW, Wong MH, et al. Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice. Antiviral Res. Oct 2001;52(1):55-62.
• Stearn EW, Stearn AE. The Effect of Smallpox on the Destiny of the Amerindian. Boston, Mass: Bruce Humphries; 1945.
• Torres Cantero AM. Is smallpox "in" again?. J Epidemiol Community Health. Apr 2004;58(4):279.
• Tudor V, Strati I. The clinical picture. In: Smallpox: Cholera. Tunbridge Wells, Kent:. Abacus Press;1977:34-71.
• U.S. Bureau of the Census. Statistical Abstract of the United States: 1999. 119th ed. Washington, DC: Bureau of the Census; 1999.
• US Army Center for Health Promotion and Preventive Medicine. Current issues in Smallpox. Available at: http://chppm-www.apgea.army.mil/risk/current.aspx. [Full Text].
• US Army Medical Research Institute of Infectious Diseases. Smallpox. In: Kortpeter M, Christopher G, Cieslak T, et al, eds. USAMRIID's Medical Management of Biological Casualties. Available at: http://www.usamriid.army.mil/education/bluebook.html. 4th ed. Fort Detrick, Md: Operational Medicine Department; 2001:. 44-8. [Full Text].
• World Health Organization. WHO Fact Sheet on Smallpox. In: Communicable Disease Surveillance and Response. Available at: http://www.who.int/emc/diseases/smallpox/factsheet.html. Geneva, Switzerland;. Oct 2001. [Full Text].

Article Last Updated: Jan 18, 2007