American College of Physicians: Internal Medicine — Doctors for Adults ®



From the May ACP Observer, copyright 2004 by the American College of Physicians.

While the world was officially declared free of smallpox in 1980, the United States, Russia and possibly other countries or groups have access to smallpox cultures. As a result, bioterrorism through the release of smallpox is possible.

Former Soviet Union officials, for example, have testified that their government successfully produced large quantities of smallpox virus that was adapted for use in bombs and missiles. Even more chilling, aerosol release of the smallpox virus would disseminate the disease widely. The virus is very stable in an aerosol form, and only a relatively small dose is needed to infect large numbers of people.

Smallpox would pose a significant threat to civilian populations because of its case-fatality rate of 30% and up. In addition, there is no effective treatment for the viral disease.

The U.S. population would be particularly susceptible to smallpox because people under age 30 have not been routinely vaccinated for the disease. Older individuals might also lack protection even if they had been vaccinated, because immunity to smallpox wanes over time.

Clinical presentation and diagnosis

Smallpox is diagnosed based on clinical grounds and then confirmed by laboratory tests conducted at the CDC or other high-containment laboratories.

A single suspected case of smallpox constitutes an international health emergency. National officials and local and state health authorities must be notified immediately. There are four principal presentations of smallpox based upon the nature and evolution of the lesions: ordinary, modified, flat and hemorrhagic. In addition, variola sine eruptione (smallpox without rash) is a febrile syndrome occurring during the incubation period in vaccinated individuals exposed to smallpox.

Ordinary smallpox occurs in over 90% of unvaccinated individuals exposed to smallpox. It initially presents with a febrile prodrome characterized by severe headache and backache, and sometimes vomiting. The fever is usually high, from 101 F (38.3 C) to 104 F (40 C), lasts two to four days, and is often associated with prostration. The ordinary smallpox rash first appears as an oral enanthem characterized as minute red spots in the mouth and pharynx that enlarge and then quickly erode.

The smallpox rash starts on the face, spreads to the extremities and often is less intense on the trunk.

These lesions release large amounts of virus into the saliva at about the time the skin rash appears. The exanthem first appears as a few macules on the face (especially the forehead), followed by the proximal extremities, distal extremities and then the trunk.

The macules evolve into vesicles by the second or third day. The vesicles become distended with fluid that first appears opalescent then becoming opaque and turbid. The distended vesicles often have a central depression or dimple that may persist into the pustular stage. Umbilication is seldom seen in other vesicular or pustular illness and is an important distinguishing feature of smallpox. By the sixth or seventh day all the vesicles become pustules and each individual lesion reaches it maximum size during this stage.

The pustules are sharply raised, round, very firm and deeply embedded into the skin. On palpating the skin, these lesions feel like a bead or a hard pea. By the end of the second week the pustules crust over, and by the third week the crusts fall off, leaving characteristic pitted scars.

Smallpox lesions occur in crops on each body area. As a result, on any one part of the body, the smallpox lesions are all in the same stage of development: macules, papules or vesicles, pustules, or scabs.

The distribution of the rash is centrifugal; it is most dense on the face; more dense on the extremities than on the trunk; and more dense on the proximal than the distal extremities. The palms and soles are involved in most cases.

Smallpox lesions appear on the palms of the hand and the soles of the feet—a key difference from lesions caused by chickenpox.

In general, the extent of the rash parallels the clinical severity. In some cases the concentration of the lesions on the face or extremities can be so dense that the rash becomes confluent. These individuals tend to have a higher mortality rate as compared to those with a sparse exanthem.

Modified smallpox occurs in previously vaccinated individuals. The prodrome is usually less severe as compared to ordinary smallpox and the skin lesions tend to evolve more rapidly, may be more superficial, and may not develop at the same rate and thus fail to show the uniformity of skin lesions typical of ordinary smallpox. Modified smallpox can easily be confused with chickenpox.

Flat (malignant) smallpox is characterized by lesions that remain flat and fail to form raised vesicles or pustules. The prodrome is very severe, the lesions evolve very slowly, are soft and velvety to touch, and do not umbilicate. In a large series of smallpox cases in India, the vast majority of flat smallpox occurred in children and was almost universally fatal.

Hemorrhagic smallpox is a rare, severe form that is accompanied by extensive bleeding into the skin, mucous membranes and gastrointestinal tract. In India, the majority of cases were found in adults, with pregnant women at highest risk.

Differential diagnosis

Absence of a high, incapacitating fever prior to the rash makes smallpox very unlikely. For most physicians, the diagnostic task will be to distinguish chickenpox from smallpox. Although the chickenpox rash resembles that of smallpox, the former is more superficial, more delicate in appearance and less sharply circumscribed.

The distribution of the lesions also differs. Chickenpox lesions rarely develop on the palms and soles, as is the case with smallpox. Chickenpox lesions begin on the trunk and then spread to the face and extremities, with most lesions concentrated on the trunk or equally distributed between trunk and extremities. In contrast, the smallpox rash starts on the face, spreads to the extremities and often spares or is less intense on the trunk.

In addition, the lesions of smallpox rash evolve at the same rate and are at the same stage of development on any given part of the body. New varicella lesions, by contrast, appear in crops every few days, and lesions at different stages of maturation (i.e., vesicles, pustules and scabs) appear at the same time on the same part of the body. Varicella lesions also rapidly evolve, often developing from macules to crusting vesicles within 24 hours, whereas each stage of the smallpox rash persists for two to three days.

The ACP Bioterrorism Resource Center has descriptions and clinical images of smallpox and its mimics.


Because smallpox is caused by the variola virus, there are no known antiviral drugs that can effectively treat it.

Vaccinia immune globulin does not effectively treat active smallpox infection. Routine care is supportive and includes nutritional, hemodynamic and volume support, as well as prevention and treatment of secondary bacterial infections with antibiotics.

Post-exposure containment

The incubation period for smallpox is between seven and 17 days. Patients are most infectious with the onset of oral lesions because the main means of transmission is via saliva droplets.

Prolonged and direct face-to-face contact is usually required to spread smallpox from one person to another. Smallpox can also be spread through direct contact with infected bodily fluids or contaminated objects such as bedding or pieces of clothing.

Smallpox is infrequently spread by virus carried in the air in enclosed settings such as buildings, buses and trains. An infected person is contagious until the last smallpox scab falls off. Humans are the only natural hosts of variola.

Immediately isolate all patients that are at high or moderate risk for smallpox. Because of the potential for widespread aerosol dissemination of smallpox virus, patients should be isolated in the home or other nonhospital facility whenever possible. Primary and secondary contacts of smallpox patients do not need to be isolated unless they develop symptoms of the disease.

Vaccination and close monitoring of primary and secondary contacts of patients are effective containment measures and should be implemented by public health officials. The vaccinia vaccine lessens the severity of smallpox or prevents it altogether if it is administered within seven days of exposure. (See "Smallpox vaccine.")

The vaccinia vaccine should be considered for people who have previously been vaccinated, because immunity begins to wane three to five years after the vaccine is given. People who have been directly exposed to the smallpox virus should get the vaccine regardless of their health status.


Smallpox vaccine

To facilitate preparedness and response, the Advisory Committee on Immunization Practices (ACIP) recommends vaccination only for persons designated by public health authorities as necessary to conduct investigation and follow-up of initial smallpox cases who would have direct patient contact.

ACIP recommends that each state and territory establish and maintain >1 smallpox response team. ACIP and the Healthcare Infection Control Practices Advisory Committee (HICPAC) recommend that each acute-care hospital identify health care workers who can be vaccinated and trained to provide direct medical care for the first smallpox patients requiring hospital admission and to evaluate and manage patients who are suspected of having smallpox.

When feasible, the first-stage vaccination program should include previously vaccinated health care personnel to decrease the potential for adverse events. Additionally, persons administering smallpox vaccine in this pre-event vaccination program should be vaccinated.

To avoid serious adverse reactions to the smallpox vaccine, which contains a live vaccinia virus that can be spread to others, persons who have the following conditions, or who live with persons who have the following conditions, should not receive the smallpox vaccine except in an epidemic setting:

  • Persons with current or past diagnosis of eczema or atopic dermatitis.
  • Persons with active acute or chronic disruptive skin conditions including burns, impetigo, chickenpox, contact dermatitis, shingles, herpes, severe acne or psoriasis.
  • Persons who are immunosuppressed because of conditions such as HIV/AIDS, solid organ or stem cell transplants, malignancy, leukemia, lymphoma, agammaglobulinemia, autoimmune disease or receiving immunosuppressant drugs (including inhaled steroids).
  • Persons allergic to the vaccine or any of its ingredients (it may contain polymyxin B sulfate, streptomycin sulfate, chlortetracycline hydrochloride, neomycin sulfate).
  • Persons with conjunctival inflammation.
  • Infants younger than 12 months.
  • Women who are pregnant or plan to get pregnant.
  • Women who are breastfeeding.
  • Persons with a moderate to severe short-term illness.
  • Persons with known cardiac disease such as previous myocardial infarction, angina, congestive heart failure, or cardiomyopathy.

This last recommendation follows reports of cardiac events following smallpox vaccinations, including myocardial infarctions and angina without myocardial infarction. It is unclear if there is any association between smallpox vaccination and these cardiac events. Experts are exploring these issues in depth, and this exclusion may be removed as more information becomes available.

To prevent the spread of vaccinia from vaccinated patients, advise vaccinees and/or guardians to do the following until a scab has formed:

  • Keep the vaccination site covered.
  • Do not touch, scratch or rub the vaccination site.
  • Avoid person-to-person contact with susceptible persons.
  • Avoid touching, rubbing or otherwise performing any maneuvers that might transfer the vaccinia virus to the eye or surrounding skin.
  • Discard the vaccination site covering carefully and enclose it in a sealed plastic bag.
  • After handling the vaccination site covering, thoroughly wash hands.
  • More information on normal and adverse reactions to the smallpox vaccine and how to manage them is online.


CDC criteria for assessing smallpox risk

The CDC has developed criteria that can be used to evaluate suspected smallpox cases and to categorize them into high, moderate or low risk using major and minor smallpox criteria.

Major smallpox criteria

  1. Febrile prodrome (fever > 101 F, 38.3 C) 1-4 days before rash onset and at least one of the following systemic complaints: prostration, headache, backache, chills, vomiting or abdominal pain.
  2. Rash lesions are deep in the skin, firm or hard to the touch, round and well circumscribed, and may become umbilicated or confluent.
  3. On any one part of the body, all the lesions are in the same stage of development.

Minor smallpox criteria

  1. The distribution of the rash is centrifugal (i.e., greatest concentration of the lesions on the face and distal extremities with relative sparing of the trunk.
  2. The first lesions of the rash appear on the oral mucosa or palate, or on the face or forearms.
  3. The patient appears toxic or moribund.
  4. Lesions progress slowly (i.e., individual lesions evolved from macules to papules to pustules; each stage lasting 1-2 days).
  5. Lesions on the palms or soles.

A person is considered high risk for smallpox if he or she fulfills all three major criteria. Persons are considered at moderate risk if they have a febrile prodrome and either one other major criterion or > 4 minor criteria. Any person who does not have a febrile prodrome is considered low risk, as are persons who have a febrile prodrome and less than 4 minor criteria.

All high risk patients require contact precautions and respiratory isolation. These patients should be immediately reported to the local and/or state health authorities. Consultation with infectious disease or dermatology specialists is strongly recommended. If high risk status is confirmed, the case must be reported to the CDC and arrangements will be made for laboratory testing for smallpox virus.

Moderate risk patients should be isolated and urgently evaluated with help from infectious disease or dermatology specialists. The most important laboratory procedure for moderate risk patients is rapid diagnostic testing for varicella zoster virus. Low risk patients can be clinically managed as indicated. Smallpox testing is not indicated for individuals who do not meet the CDC case definition.

Smallpox infection can be rapidly confirmed in high-containment laboratories by electron microscopic examination of vesicular or pustular fluid or scabs.

Specimens should be collected by someone who has recently been vaccinated and is wearing gloves, a gown, protective eyewear and an N95 mask or HEPA-filtered respirator.

Proper precautions must be taken with specimens. They should be put in a vacutainer tube that is sealed with adhesive tape at the juncture of the stopper and tube. This tube must be enclosed in a second durable, watertight container.

A case investigation worksheet and a poster that includes the rash illness algorithm and information on differential diagnosis are available the CDC Web site.


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