Bioterrorism Update: Smallpox

Once thought to be totally eradicated, smallpox is again raising fear and new concerns–this time in regard to its potential as a weapon of mass destruction.

By Mark Graber, MD

Dr. Graber is associate professor of emergency medicine and family medicine at the University of Iowa College of Medicine in Iowa City and a member of the Emergency Medicine editorial board.

What is the history of smallpox? Has it been used as a biological weapon in the past?

Smallpox, or variola, is caused by a DNA orthopoxvirus and has been plaguing mankind for at least 3000 years. The first documented epidemic of smallpox occurred during the Egyptian-Hittite war in 1350 B.C. An inspection of the lesions on the mummy of Ramses V, the Egyptian pharaoh who died in 1143 B.C. at the age of 35, reveals that he may have died from smallpox.

The first use of smallpox as a biological weapon, albeit inadvertently, occurred when Spanish conquerors led by Cortez introduced smallpox in 1520 during their assault on the Aztec capital city of Tenochtitlan in Mexico. In the years that followed, almost 90% of the population of the New World was killed by smallpox. The disease was used deliberately as a biological weapon during the French and Indian war in 1754 by the English, who distributed tainted blankets to Native Americans; the mortality reached 50% in many tribes. Smallpox was also used by the American government during its wars with Native Americans.

After an extremely successful and unprecedented worldwide vaccination program was conducted throughout the 1960s and 1970s, smallpox was almost completely eliminated. The last case of wild smallpox occurred in Somalia in 1977. Since then, however, several small epidemics related to laboratory exposure have occurred. One of the reasons the program was so effective is that humans are the only hosts; animal reservoirs of smallpox do not exist.

Today, only Russian laboratories and the Centers for Disease Control and Prevention (CDC) in Atlanta are officially known to have samples of the smallpox virus. In recent years, however, concern has been mounting over the possibility and likelihood of other nations and perhaps terrorist groups possessing or obtaining their own supplies of the virus.

What is the clinical course of smallpox?

The disease begins with asymptomatic viremia about four days after a person is infected. Within 7 to 17 days after the initial infection, high fever will develop, along with prostration, malaise, headache, and backache. Severe abdominal pain and, occasionally, delirium may also appear. These symptoms are then followed by a macular rash that becomes vesicular in one to two days and then pustular. The rash generally develops first on the feet and hands and moves centrally, in a pattern opposite to that associated with varicella, or chicken pox. Unlike the lesions of that disease, all smallpox lesions develop at the same rate.

Among unvaccinated populations, the fatality rate is reported to be about 30%, but this figure includes populations in developing countries who suffer from malnourishment and poor medical care. Mortality among healthy adults and older children in developed countries is likely to be lower. Death usually occurs as a result of toxemia accompanied by circulating immune complexes and pulmonary edema. Platelet levels may be depleted, and hemorrhage may be noted during the perimortem period. A second strain of the virus causes variola minor, a less severe form of smallpox, which is associated with a mortality of about 1%.

There are two clinical forms of smallpox that are difficult to recognize. The first is hemorrhagic smallpox, which can occur in anyone but especially in pregnant women and is uniformly fatal. The hemorrhagic form has a shorter incubation period and is accompanied by severe headache, abdominal pain, and high fever, followed by petechiae and generalized mucosal bleeding. Death occurs rapidly, within five to six days after the rash appears.

Malignant smallpox, the second variant of the disease, is usually fatal. In this form, confluent lesions develop and remain flaccid. Diffuse erythroderma will also appear (described as having a reddish crepe rubber appearance) and occasionally hemorrhage into the skin. In patients who survive this disease, these lesions heal without scarring.

How does smallpox spread and what makes it an ideal biological weapon?

Unlike inhalational anthrax, in which human-to-human spread is unknown, smallpox is readily transmitted from person to person. Smallpox spreads by aerosolized droplets produced by coughing or sneezing or by contact with an infected person. Smallpox can also result from contact with fomites, such as contaminated bedding and clothing. In aerosolized form, the smallpox virus is stable and could potentially spread through a city's population, even among asymptomatic persons. However, the virus is difficult to produce in amounts sufficient for aerosolization, and it is not completely resistant to drying and sunlight.

Smallpox is an ideal weapon because almost everybody today is vulnerable to infection. Smallpox vaccination remains effective for about 10 years after immunization, but as 12 years have passed since the last immunizations were given in 1989 (to U.S. military personnel), no population today is immune. Fortunately, as a weapon, smallpox does have at least one drawback: any attacker will be exposing both his native population and the target population to the virus.

How is the diagnosis of smallpox established, and how are specimens collected?

The diagnosis of smallpox is clinical. As noted above, all of the lesions of smallpox progress at the same rate of development, unlike those of chicken pox, in which lesions appear at different times. In its early stages, smallpox may be confused with chicken pox, erythema multiforme with bullae, or allergic contact dermatitis. The vesicle fluid should be tested for varicella virus; a negative finding is strongly suggestive of smallpox.

To collect specimens for laboratory diagnosis, vesicles should be opened and fluid collected with a cotton swab. Swabs should be placed in a sealed Vacutainer, placed in a waterproof, unbreakable container, and clearly labeled as a biohazard. Ideally, specimens should be collected by a vaccinated staff member and in accordance with the appropriate precautions discussed below. The laboratory must be notified, as specimens must be processed under biosafety level 4 conditions. Currently in the U.S., only the CDC and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) are capable of testing for smallpox virus. Electron microscopy cannot differentiate between variola, vaccinia, cowpox, or monkeypox viruses. New polymerase chain reaction techniques that can rapidly diagnose smallpox may become available soon.

What is the isolation procedure for patients with suspected smallpox and how long do they remain infectious?

Immediate isolation, preferably at home, is necessary for all patients who have or may have the disease. The USAMRIID recommends isolation at home so that in the event of an epidemic fewer people will be exposed and medical facilities and resources will not be overwhelmed. The CDC's Hospital Infection Control Practices Advisory Committee has devised the Recommendations for Isolation Precautions in Hospitals (available at http://www.cdc.gov/ncidod/hip/isolat/isopart2.htm), which deal with the prevention of droplet and airborne transmission.

Patients do not become infectious until a rash appears. After that point they remain infectious until all scabs have separated, usually in about two to three weeks. In the event of a large exposure, a quarantine of all exposed persons may not be practical. In this case, exposed patients should be instructed to check their temperature several times a day. A temperature of greater than 38°C (101°F) should be considered a sign that active smallpox is imminent; only patients with such a temperature should then be quarantined.

How is smallpox treated?

The disease itself has no cure; supportive care, while keeping the infected patient isolated, is all that is available. Antibiotic therapy is helpful against bacterial infection, which usually invades the lesions of smallpox and may eventually become lethal if untreated. Cidofovir, an antiviral agent used to treat cytomegalovirus infection, may be active against smallpox virus, but obviously, no studies involving that or any other treatment have been conducted.

Who should be immunized?

Immunization should be attempted for anyone potentially exposed to smallpox. Immunization can prevent or mitigate smallpox when given within four days of exposure–obviously, the sooner the better. The vaccine for smallpox is derived from the vaccinia virus.

Eczema and pregnancy are relative contraindications to vaccination against smallpox. The only absolute contraindications to vaccination are a suppressed immune system and HIV infection; vaccination of patients with these disorders may lead to disseminated vaccinia. Because smallpox may be especially devastating to such patients, however, vaccination may still be prudent if they have definitely been exposed to the disease. In such cases, they should begin prophylactic therapy, if possible, with vaccinia immune globulin (VIG), 0.3 ml/kg.

The complications of vaccination include postimmunization encephalitis, which occurs in 1 in every 300,000 people who are vaccinated and is fatal in 25% of those cases. Eczema vaccinatum, a disseminated infection that occurs among persons with eczema, is another complication, as is generalized vaccinia (usually self-limited); localized spreading from the immunization site to other sites of the body, such as the eye; and, in patients with suppressed immune systems, progressive vaccinia (vaccinia necrosum), which is a severe local reaction in which lesions spread throughout an affected extremity and even to bone and other organs.

Because of the risk of adverse effects associated with smallpox vaccination, it is unlikely that vaccination of the general public will be recommended in the absence of a known exposure. Although the vaccine is currently available in very limited supplies (about 15 million doses), the production of about 300 million doses has been planned to begin soon. The earliest projected availability of the vaccine is in late 2002.

Eczema vaccinatum and progressive vaccinia can be treated with VIG, given intramuscularly in a dosage of 0.6 ml/kg of body weight divided over 24 to 36 hours and repeated in two to three days, if necessary. This therapy is not useful for treating encephalitis and is contraindicated for vaccinia keratitis. The drug is available through the CDC, but supplies are limited.

What are the decontamination techniques used to prevent the spread of smallpox?

All laundry, bedding, and other items handled by infected persons should be autoclaved or washed in hot water with bleach. Standard hospital antiviral surface cleaners are adequate for sanitizing counters, floors, and other surfaces. These steps are crucial, as viable virus has been found in scabs that have been stored for up to 13 years. If possible, the bodies of deceased patients should be cremated to prevent the spread of the disease to funeral home personnel. Some have suggested that exhumed bodies could be a source of ongoing infection, but evidence of such a form of transmission has not been documented.

What should clinicians do if they suspect a case of smallpox?

Smallpox should be considered a public health emergency. Clinicians who suspect smallpox should contact their local health department immediately, as well as their hospital infection control officer. The local health department will then contact the state public health department and the CDC.

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