The first symptoms of smallpox usually appear 12 to 14 days after you're infected. During the incubation period of seven to 17 days, you look and feel healthy and can't infect others.

Following the incubation period, a sudden onset of flu-like signs and symptoms occurs. These include:

• Fever
• Overall discomfort (malaise)
• Headache
• Severe fatigue (prostration)
• Severe back pain
• Sometimes vomiting, diarrhea or both

A few days later, the characteristic smallpox rash appears as flat, red spots (lesions). Within a day or two, many of these lesions turn into small blisters filled with clear fluid (vesicles) and later, with pus (pustules). The rash appears first on your face, hands and forearms, and later on your trunk. It's usually most noticeable on the palms of your hands and the soles of your feet. Lesions also develop in the mucous membranes of your nose and mouth. The distribution of lesions is a hallmark of smallpox and a primary way of diagnosing the disease.

When the pustules erupt, the skin doesn't break, but actually separates from its underlying layers. The pain can be excruciating. Scabs begin to form eight to nine days later and eventually fall off, leaving deep, pitted scars. All lesions in a given area progress at the same rate through these stages. People who don't recover usually die during the second week of illness.

Smallpox vs. chickenpox
In the past, smallpox was sometimes confused with chickenpox, a childhood infection that's seldom deadly. Yet chickenpox differs from smallpox in several important ways:

• Severity and location of lesions. Chickenpox lesions are much more superficial than are those of smallpox and occur primarily on the trunk, rather than on the face, arms and hands.
• Types of lesions. You'll often see a combination of scabs, vesicles and pustules in someone with chickenpox. In smallpox, all of the lesions in a given area are at the same stage.
• Timing of transmission. A person infected with chickenpox can unknowingly transmit the virus to others before symptoms develop. But smallpox becomes infectious only when signs and symptoms appear and remains contagious until scabs fall from the pustules. Smallpox is most contagious after the fever starts and during the first week of the rash. You're less likely to become infected if you're exposed to someone in the later stages of the disease.

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The variola virus causes smallpox. Once you're infected, the virus replicates inside your cells — first in the lymph nodes and then in your spleen and bone marrow. Eventually, the virus settles in the blood vessels in your skin and the mucous membranes of your nose and throat. When the lesions in your mouth slough off, large amounts of virus are released into your saliva. This is when you're most likely to transmit the disease to others.

How smallpox spreads
Smallpox usually requires fairly prolonged face-to-face contact to spread. It's most often transmitted in air droplets when an infected person coughs, sneezes or talks. In rare instances, airborne virus may spread further, possibly through the ventilation system in a building, infecting people in other rooms or on other floors. Smallpox can also spread through contact with contaminated clothing and bedding, although the risk of infection from these sources is slight.

Types of smallpox
Two main forms of smallpox exist:

• Variola minor. This is a milder form of the disease and causes a less serious illness. It's fatal in less than 1 percent of people who contract it.
• Variola major. By contrast, this form of the disease kills one-third of the people it infects.

Variola major smallpox is further divided into five subtypes:

• Ordinary smallpox. This is the most frequently occurring type, accounting for more than 70 percent of all smallpox cases.
• Modified smallpox. This milder form of the disease occurs in people who have been vaccinated against smallpox in the past.
• Variola sine eruptione. People with this form of the disease develop fever but no rash.
• Hemorrhagic smallpox. This rare form is characterized by a red, pinpoint rash and bleeding in the skin and mucous membranes. In some cases, hemorrhagic smallpox may destroy the entire skin surface and all mucous membranes. Hemorrhagic smallpox is almost always fatal within three to four days.
• Flat smallpox. This rare form, which occurs mainly in children, also is often fatal. The early signs and symptoms are similar to other forms of the disease, but the lesions are flat and never become filled with pus. Eventually, the skin takes on a rubbery appearance. Bleeding in the skin and intestinal tract also may occur.

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Although most people who get smallpox survive, variola major is fatal in about 30 percent of people who contract it. Almost no one survives the hemorrhagic and flat forms of the disease. People who recover from smallpox usually have severe scars, especially on the face, arms and legs. In some cases, smallpox may cause blindness.

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Even a single confirmed case of smallpox would be considered an international health emergency. Based on symptoms and appearance of the rash, the Centers for Disease Control and Prevention (CDC) or a CDC Laboratory Response Network-designated variola testing laboratory can do definitive testing using a tissue sample taken from one of the lesions on the skin of the infected person.

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No cure for smallpox exists. The smallpox vaccine can prevent or lessen the severity of the disease for some people if given within four days of infection. But vaccination doesn't help once signs and symptoms develop. For now, the best that doctors can offer people with symptomatic smallpox is supportive therapy and antibiotics to treat secondary bacterial infections.

Apart from immediate vaccination, isolation of the infected person is the only way to manage the disease. Unfortunately, isolation can only contain the spread of the virus, not eradicate it.

Because of the bioterrorism threat, new treatments are under investigation. One of these, cidofovir, has shown promise in laboratory studies.

©1998-2009 Mayo Foundation for Medical Education and Research (MFMER). Terms of use.

Smallpox vaccine
In 1967, the World Health Organization (WHO) launched a global immunization campaign to eradicate smallpox. The WHO's efforts were remarkably effective, and the last naturally occurring case of smallpox was reported in 1977. In 1980, smallpox vaccinations were discontinued worldwide.

The vaccine today
The United States currently has enough smallpox vaccine to vaccinate all Americans. The CDC has provided public health officials with a contingency plan to quickly inoculate every American should the need arise.

Such a decision would not be undertaken lightly because the smallpox vaccine also has the small but real potential to cause serious harm. Unlike many other vaccines, the smallpox vaccine contains a live vaccina virus — a pox-type virus related to smallpox, but milder than smallpox. The vaccine can't cause smallpox, but because it's live, care must be taken of the vaccination site to keep the virus from spreading. Touching the vaccination site before it's healed, or touching bandages or clothing contaminated with the virus, can cause it to spread to other parts of your body or to other people.

Experts in virology say the vaccine causes a fatal complication in about 1 of every 1 million people who receive it. That means that if the entire American population were to be vaccinated, 300 people would be expected to die of complications from the vaccine. Many others who are vaccinated might develop painful sores and severe scars, and others would likely have residual brain damage from encephalitis — a potentially fatal brain inflammation.

Who should not receive the vaccination
Because of the risk of severe and sometimes fatal reactions, the CDC and WHO recommend that the general public not be vaccinated. But because military personnel and some health care workers continue to be vaccinated, it's important to know who should not receive the vaccine.

You should not receive the smallpox vaccine if you:

• Have certain skin conditions. This includes eczema, a history of eczema or other chronic skin conditions, or sharing a household with someone with eczema, a history of eczema or skin conditions such as impetigo.
• Are pregnant. The vaccine is not known to cause birth defects, but in rare cases it may cause infection of the fetus, leading to stillbirth or death soon after delivery.
• Have impaired immunity. You shouldn't have a vaccination if you have a disease or are undergoing treatment that suppresses your immune system. This includes people with cancer, people with organ transplants, and those undergoing radiation therapy or treatment with drugs that suppress the immune system.
• Have AIDS or are HIV-positive. The human immunodeficiency virus (HIV) wasn't identified before the end of routine smallpox vaccination, so it's not known what effect the vaccine might have on people with the disease. Currently, the CDC recommends that HIV-positive people not be vaccinated.
• Are allergic to any of the ingredients in the vaccine. This includes the antibiotics polymyxin B sulfate, streptomycin sulfate, chlortetracycline hydrochloride and neomycin sulfate.
• Have underlying heart disease. You also shouldn't be vaccinated if you have three or more known risk factors for heart disease, including high blood pressure, diabetes, high cholesterol and smoking, or a parent or sibling of someone with heart disease.

If you were vaccinated before 1972
Many people may have never been vaccinated against smallpox. Others received the vaccine more than 25 years ago. It's not known how long immunity lasts, although it's likely the vaccine is most effective for about three to five years, with immunity decreasing after that. Partial immunity may last much longer. People who are revaccinated appear to have increased immunity, although one recent study indicates that recent or multiple vaccinations aren't essential for maintaining antibodies that protect against the disease.

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