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Smallpox: A Bioterrorism Threat?

Sharon A. Sanders, RN

Susan Walters Schmid, BA, MA, PhD (candidate)

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Following the anthrax illnesses and deaths near the end of 2001, infectious diseases such as anthrax and smallpox have become a major focus of the Centers for Disease Control and Prevention (CDC) and local public health departments. The United States is thought to be at risk for a smallpox bioterrorism attack. Because of this concern, in 2002 the federal government announced a program to vaccinate 450,000 volunteer healthcare workers using its stores of current vaccine. The first civilians to receive the vaccine would be frontline public health workers who would be responsible for implementing a surveillance and containment program in the event of an outbreak.

In November 2002 many healthcare professionals, including nurses, received information about the Smallpox Healthcare Team the federal government was proposing to protect the public from a smallpox bioterrorism attack. Employers such as hospitals and public health departments gave their first-responder employees informational packets from their state and local public health departments about smallpox and the vaccination program.

Most of the information was from the Centers for Disease Control and Prevention (CDC). Healthcare workers were asked to read it and decide if they wished to participate in the vaccination program purely on a voluntary basis. Emergency department staff, including nurses and doctors, were first priority to be vaccinated. The vaccinated medical workers were expected to care for patients if an outbreak occurred and to participate in vaccinating the general public for prevention if necessary. Nurses were officially made aware of a disease they thought had been eradicated.

In our infectious disease classes, we nurses learned about variola (smallpox) along with varicella (chicken pox), rubeola (measles), and rubella (German measles). Many of us who are older remember receiving a vaccination on our arm or thigh. We were told little about how to care for the red, ugly, itchy sore, only to leave it alone and not to scratch the itch.

Those of us who were adults before the mid-1970s may have received repeat vaccinations prior to entering school, or before traveling, or upon entering the military. Some of you may have received four or more vaccinations. Those under 30 years of age will have had no vaccination.

Since the 9/11 attack, bioterrorism has been added to our body of clinical information, especially in emergency departments (EDs). Teaching aides have appeared on education bulletin boards; one such is flashcards called "Bioterrorism Quick Reference," which give descriptions of diseases that could be used for bioterrorism.

The early signs and symptoms for many of these diseases are flu-like, and they can be highly contagious during the period before a definitive diagnosis is made. This puts healthcare workers—especially those who see patients early in their illness—at high risk for contracting an infectious disease.

Whether to become part of the Smallpox Healthcare Team was a difficult decision for many of us. Some individuals were concerned about the safety and effectiveness of the vaccine. Many others were not confident the government would be totally honest during a time of perceived or real threat to our national security.

We were to care for people who had an illness producing over 30% mortality and highly contagious to those not vaccinated. Volunteers would be vaccinated, but not their families. In the packet of information, the Advisory Committee on Immunization Practices (ACIP) gave the following job description for volunteers.

The healthcare workers would be vaccinated and trained to provide in-room medical care for the first few smallpox patients requiring hospital admission and to evaluate and manage patients who present to the ED with suspected smallpox. For the first 7 to 10 days after patients with smallpox were identified, this team would be hospital-based and provide care 24 hours a day, in 8 to 12 hour shifts.

The job description made the decision easy for many individuals. Having to be available for 24-hour care would be a hardship for many nurses. Being away from family members would be difficult, especially during the chaos of a public health emergency. In addition to the problems of caring for the sick, we would be working under conditions most of us have never experienced.

If there is a bioterrorism attack, it is almost certain that the police and military will be closely involved with the hospital to protect the general public from further exposure. Many healthcare workers could not volunteer; they were to be excluded because of specific medical conditions such as eczema, pregnancy, or allergy to some antibiotics.

In December 2002 the President ordered all military personnel to be vaccinated and expected to start vaccinating healthcare volunteers as soon as mid-January 2003. The general population was to be offered the vaccine by 2004 or earlier, depending on when enough doses became available.

Since the program was announced there has been ongoing discussion among state and local public healthcare providers, hospital administrators, unions representing healthcare workers, and indeed the entire medical community about the need for healthcare professionals to be vaccinated against smallpox. Many healthcare workers, hospitals, and public health departments refused to participate in the program.

They had questions about the safety of the vaccine, about liability, about patient exposure from vaccinated workers, about worker compensation for lost time due to vaccine reactions, and about the cost and losses to other public health needs when funds are diverted to smallpox.

Because of the many concerns and questions, few civilian healthcare workers volunteered to have the smallpox vaccination. According to the CDC, during January 24–December 31, 2003, smallpox vaccine was administered to 39,213 civilian healthcare and public health workers. Five hundred thousand military personnel were vaccinated.

As the vaccinations were given, a new concern developed that had not been mentioned in the earlier precautions. Serious cardiac problems arose, such as myocarditis or pericarditis, myocardial infarction, and cardiac death. The number of individuals with these adverse reactions was small and possibly not related to the vaccine, but there were now new guidelines for smallpox vaccinations.

In 2003 the CDC announced that smallpox vaccination is recommended for military personnel and civilian first responders without contraindications who are identified as part of terrorism preparedness and first-response teams. New screening guidelines were instituted to minimize potential ischemic risks by excluding persons with known cardiac disease or three or more cardiac risk factors. Although this study casts doubt, said the CDC, on the causal link between death caused by cardiac adverse events and smallpox vaccination, in the absence of a smallpox outbreak all potential volunteers should be screened for risk factors, and those at high risk for adverse reactions to vaccination should be excluded (CDC, 2003).

Some healthcare workers did volunteer for the program, and it is thought that with the current group of vaccinated healthcare workers and the larger number of vaccinated military personnel we will have sufficient numbers to begin care of infected individuals and launch public vaccinations in the event of a terrorist attack using smallpox.

There is still concern about how well-coordinated our public health response will be and how prepared we are as a medical community to identify smallpox as rapidly as needed to prevent a widespread dissemination of the disease before containment and public vaccinations can start.

Over the millennia, health practitioners have put their own health and safety at risk to care for the sick and dying during many contagious-disease epidemics. During this time of threat, our generation of healthcare workers has once more been asked to put our professional skills and our bodies at the frontlines to protect the general population.

Making the choice to be part of this team was not easy, but some of us did put our fear and skepticism aside and volunteered. Others had health or other reasons for not volunteering, but we all know learning about the disease is one way to prepare for a healthcare crisis.

THE DISEASE

Smallpox is an infectious disease caused by the variola virus. It is marked by fever and a distinctive progressive skin rash. The name smallpox is derived from the Latin word for "spotted" and refers to the raised bumps that appear on the face and body of an infected person. There is no specific treatment for smallpox, and the only prevention is vaccination.

Smallpox lesions on the face and trunk of a young girl. Photo courtesy of CDC.

Smallpox is an orthopoxvirus and is classified as a Category A agent by the CDC. Other Category A agents are anthrax, plague, botulism, tularemia, and viral hemorrhagic fevers. Category A agents are believed to pose the greatest potential threat for adverse public health impact and have a moderate to high potential for large-scale dissemination. The public is generally aware of category A agents, and broad-based public health preparedness efforts are necessary.

There are two clinical forms of smallpox: variola major and variola minor. Variola major is the most common and severe form of smallpox. It produces an extensive rash and high fever. There are four types of variola major smallpox:

• Ordinary: the most frequent type, accounting for 90% or more of cases
• Modified: mild, and occurring in previously vaccinated persons
• Flat: rare, very severe, and usually fatal
• Hemorrhagic: rare, very severe, and usually fatal

Historically, variola major has an overall fatality rate of about 30%. Variola minor is a less common presentation of smallpox, and a much less severe disease, with death rates historically of 1% or less.

HISTORY

Smallpox has been present throughout human history. It has traveled with its human hosts as the population spread out over the earth. The mummified body of Pharaoh Ramses V (who ruled Egypt for four years and died in 1157 B.C. at the age of 35) exhibits a pustular rash, which is thought to be the earliest physical evidence of smallpox.

Smallpox was carried by traders from Egypt to India during the first millennium B.C. From India it spread to China in the first century A.D. and then was seen in Japan in the sixth century A.D. In the eleventh and twelfth centuries, the Crusades brought Europeans in large numbers to the East and the disease spread westward upon their return home.

Smallpox arrived in the New World with the European explorers, who were looking for new territories and wealth. The native populations, which had no previous exposure or immunity, were especially susceptible to the disease. Smallpox was a major factor in conquering and decimating the Aztecs and Incas in the sixteenth century.

The native populations of North America and the aborigines of Australia met the same fate in the seventeenth and eighteenth centuries when Europeans came to their territories. By the early 1950s, it is estimated that there were about 50 million cases of smallpox occurring worldwide each year.

Vaccination against smallpox was first attempted in the tenth century in India and China, and was further developed and perfected by English physician Edward Jenner in the late 1700s. In 1796 Jenner discovered that inoculation with cowpox gave immunity to smallpox. By 1801 over 100,000 persons in England had been vaccinated.

In 1980 the World Health Assembly declared smallpox eradicated worldwide. The United States ended its general vaccination program in 1972 and only a few lab workers and some military personnel were vaccinated after that time.

In the United States the younger generations have no immunity and the older population, vaccinated over 30 years ago, is thought to have little or no immunity. This leaves our nation as susceptible to the disease as the early Egyptians, the Aztecs, or the Australian aborigines.

SMALLPOX ERADICATION PROGRAM

The eradication of smallpox from the earth is one of the greatest accomplishments in human history. The methods that were used, and the lessons learned from the eradication program, are still relevant in planning a response to an intentional release of the virus. D.A. Henderson, MD, MPH, Former Director Global Smallpox Eradication Program for WHO

For centuries, smallpox stalked the world with impunity, causing unmeasured suffering, death, and blindness. It existed as an endemic infection wherever concentrations of population were sufficient to sustain transmission.

The impact of smallpox on history and human affairs was profound. At the end of the eighteenth century in Europe, an estimated 400,000 people were dying annually from smallpox, and survivors accounted for one-third of all cases of blindness.

During the eighteenth century alone, five reigning European monarchs died of smallpox, and the Austrian Hapsburg line of succession shifted four times in four generations. With the start of vaccinations in 1796, and subsequent improvements in production and distribution of the vaccine in the nineteenth century, the incidence of smallpox in industrialized countries diminished markedly.

Most of Europe became smallpox-free in the early twentieth century, and transmission was stopped throughout Europe and North America soon after World War II. But it is estimated that in the early 1950s there were still about 50 million cases of smallpox occurring worldwide each year.

In 1950 the Pan American Sanitary Organization, the predecessor to the Pan American Health Organization, undertook a hemisphere-wide eradication program, and by 1967 had eliminated smallpox from all countries of the Americas except Brazil. The first proposal for global eradication of smallpox was made to the World Health Assembly by the USSR in 1958.

The proposal outlined a worldwide vaccination program to be completed in a three- to five-year period. Some progress was made during the next seven years, but overall results were disappointing. In 1966 the World Health Assembly intensified the eradication program by providing a special budget of $2.4 million per year specifically for smallpox eradication.

During 1967, the year the Intensified Global Eradication (IGE) program began, an estimated 10 to 15 million smallpox cases occurred in thirty-one countries in which the disease was endemic. More than 1 billion people lived in these endemic areas. A major reservoir was Africa, where most countries south of the Sahara were infected. A second major reservoir was in Asia, extending from Bangladesh through India, Nepal, Pakistan, and Afghanistan. The third was the Indonesian archipelago, and the fourth was Brazil, which comprises half of South America.

The initial program was based on a two-fold strategy: (1) mass vaccination campaigns in each country using vaccine of ensured potency and stability that would reach at least 80% of the population; (2) development of surveillance programs to detect and contain cases and outbreaks. Of the two strategies, the second—case detection and containment—proved to be the more successful.

Despite these early successes, the IGE program had to surmount numerous problems, including lack of organization and discipline in national health services, epidemic smallpox among refugees fleeing areas stricken by civil war and famine, shortages of funds and vaccine, and a host of other problems posed by difficult terrain, climate, and varying cultural beliefs. In addition, it was soon learned that even when 80% of the population was vaccinated smallpox often persisted.

SURVEILLANCE AND CONTAINMENT

Soon after the eradication program began, it became apparent that by isolating people with smallpox and vaccinating their contacts, outbreaks could be more rapidly contained than was previously thought. This strategy was called surveillance and containment, and it became the key element in the global eradication program.

Surveillance and containment proved effective even in areas where vaccination coverage was low. Special surveillance teams were recruited and trained. They visited each health unit in an area to ensure that each week it submitted a report indicating the number of cases seen.

When cases were reported the teams worked with local health staff to discover additional cases and to contain the outbreaks. They visited schools and public places to inquire about rumors of smallpox. A special WHO smallpox recognition card was printed and distributed to help in the search. Although setbacks occurred, the surveillance and containment strategy was an enormous success. Using it, the last case of smallpox in Brazil was reported in 1971, and Indonesia's last case occurred in 1972.

India, Pakistan, and Bangladesh (with a population at that time of more than 700 million persons) proved to be a particular challenge. But with intensive house to house searches and strict containment, the last case of variola major occurred in Bangladesh in October 1975. By the end of 1975 smallpox persisted only in the Horn of Africa. In the region where there was frequent civil war and famine, the problem of refugees made the task of eradication even more difficult.

With the interruption of smallpox transmission in Asia, more resources were made available in Africa, including more staff and transportation. However, just as it seemed that the last outbreaks had been controlled, nomads in Somalia disseminated the disease throughout the southern part of that country. Thus an intensive surveillance, containment, and vaccination program was undertaken in the spring and summer of 1977 in Somalia. As a result of this effort, on October 26, 1977 the world saw its last case of smallpox—a hospital cook named Ali Maow Maalin in Merka, Somalia.

Searches for additional cases continued in Africa for more than two years, during which time thousands of rash illnesses were investigated. None proved to be smallpox. Although two cases of smallpox occurred in England in 1978 as a result of a laboratory accident, smallpox had been eradicated from the world.

Two years later, on December 9, 1979, the World Health Organization (WHO) officially certified that smallpox had been eradicated. In 1980 the World Health Assembly recommended that all countries cease vaccination. The World Health Organization also recommended that all laboratories either destroy their remaining stocks of variola virus or transfer them to one of two WHO reference laboratories—the Institute of Viral Preparations in Moscow, or the Centers for Disease Control and Prevention in Atlanta.

All international laboratories were believed to have complied with this request. However, in 1993 the former deputy director of the Soviet Union's civilian bioweapons program reported that his government had produced large quantities of variola virus for use as a biologic weapon.

With the break-up of the Soviet Union, and consequent unemployment of many scientists, there is concern that both the virus and the expertise to produce it may have become available to other governments or terrorist groups. The deliberate reintroduction of smallpox as an epidemic disease would be an international crime of unprecedented proportions. Although this has not occurred, it is now considered to be a possibility.

It is critical that physicians and other frontline healthcare providers be familiar with the disease and maintain vigilance for suspected cases. It is also critical that a public health response plan be in place should a case occur. Such plans are now under development. The global eradication of smallpox ranks as one of the greatest triumphs in medicine. The strategies used successfully in the original eradication program will be used again should the need arise.

SMALLPOX AND BIOTERRORISM

Because routine childhood vaccination in the United States stopped in 1971, people less than 30 years old are susceptible to smallpox and, if exposed, will exhibit classic or atypical presentations. Individuals over 30 years old may have been vaccinated during childhood or as adolescents or adults for travel or occupational reasons, and their susceptibility is related to the length of time since vaccination.

Vaccination of healthcare workers and persons traveling overseas continued until the late 1970s and some military personnel were vaccinated until 1990. Epidemiologic studies have shown that an increased level of protection against smallpox persists for less than 5 years after primary vaccination and substantial but waning immunity can persist for more than 10 years.

Antibody levels after revaccination can remain high longer, conferring a greater period of immunity than occurs after primary vaccination alone. Although it is assumed that adults more than 30 years old in the United States have little or no immunity to smallpox, there is evidence that vaccination during infancy results in long-term reduction in mortality. Therefore, it is possible that if smallpox virus were introduced into the U.S. population, some vaccinated adults—especially those who have received two or more doses of smallpox vaccine—may develop modified smallpox following exposure and that mortality would be markedly lower than for unvaccinated individuals.

The potential of smallpox as a biologic weapon is most dramatically illustrated by two European smallpox outbreaks in the 1970s. The first occurred in Meschede, Germany, in 1970. This outbreak illustrated that smallpox virus in an aerosol suspension can spread widely and infect at very low doses. Another outbreak occurred in Yugoslavia in February 1972. Despite routine vaccination in Yugoslavia, the first case in the 1972 outbreak resulted in 11 others; those 11, on average, each infected 13 more.

Other outbreaks in Europe from 1958 on showed that such explosive spread was not unusual during the seasonal period of high transmission—that is, from December through April. We can only speculate on the rapidity of the spread of the smallpox virus in a population where no one younger than 25 years of age has ever been vaccinated and older people have little remaining immunity.

The Dark Winter: A Smallpox Exercise

To illustrate how smallpox might behave as a biologic weapon, a collaborative exercise was conducted in June 2001 by four organizations—the Center for Strategic and International Studies (CSIS), Johns Hopkins Center for Civilian Biodefense Studies, Analytic Services Inc. (ANSER), Services Institute for Homeland Security, and the Oklahoma National Memorial Institute.

A fictional scenario called The Dark Winter depicted a covert smallpox attack on the United States. The exercise was conducted during three mock National Security Council (NSC) meetings starting December 9, 2001. Two presumptions were made—a death rate of 30% and the presumption that each infected person will infect more than 10 others. The useable U.S. stockpile of smallpox vaccine was 12 million doses.

In this fictional scenario, the first smallpox cases were reported in Oklahoma, with 20 cases confirmed and 14 unconfirmed. There were reports of unconfirmed cases in Georgia and Pennsylvania. The initial exposure was presumed to have occurred on or about December 1, 2001, based on the 7–17 days incubation period.

By December 22, 2001, 13 days into the epidemic, a total of 16,000 smallpox cases had been reported in 25 states (14,000 within the previous 24 hours) and 1000 people had died. Ten other countries reported cases of smallpox thought to have been caused by international travelers from the United States.

The Johns Hopkins Center for Civilian Biodefense Studies issued a mock announcement two weeks into the epidemic, stating "Vaccine supplies are depleted and new vaccine will not be ready for at least four weeks. States have restricted nonessential travel. Food shortages are growing in some places, and the national economy is suffering. Residents have fled and are fleeing cities where new cases emerge. Canada and Mexico have closed their borders to the United States. The public demands mandatory isolation of smallpox victims and their contacts, but identifying contacts has become logistically impossible."

The summary described a worst-case scenario based on the presumed high contact rate, noting that by the third generation "there could be 300,000 new cases of smallpox with 100,000 deaths, and that the fourth generation of cases could conceivably comprise as many as 3,000,000 cases of smallpox and lead to as many as 1,000,000 deaths."

The Dark Winter scenario demonstrates how rapidly smallpox could spread. The exercise also shows how unprepared we are to contain the disease and also underscores that there are not enough doses available to vaccinate the general population and healthcare workers.

Many researchers who have reviewed this exercise feel the numbers in the scenario are probably high because they were based on the outbreaks in Germany in 1970 and Yugoslavia in 1972, both with high person-to-person contact. It is thought today that the rate of person-to-person infections would be 1:1 or 1:2.

SMALLPOX TRANSMISSION

Natural transmission of smallpox in a population is relatively slow. There is an interval of 2 to 3 weeks between each generation of cases. Smallpox generally spreads less widely and less rapidly than varicella or measles. This is probably because transmission of variola virus doesn' t usually occur until the onset of a rash and generally requires direct and fairly prolonged face-to-face contact to spread from one person to another.

Human-to-human transmission normally occurs by inhalation of large virus-containing airborne droplets of saliva from an infected person. Virus transmission occurs as the fever peaks and coincides with the onset of the skin rash. The rash occurs about 2 to 4 days after the onset of fever, which begins 10 to 14 days following the initial infection (range, 7–19 days).

Infectious virus particles are released by the sloughing of oropharyngeal lesions, which continues for about a week. Patients are most infectious during this time. Transmissibility of the virus via large airborne droplets decreases during the later stages of the disease as sloughing of the oropharyngeal lesions slows.

Smallpox also can be spread through direct contact with infected bodily 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. Humans are the only natural hosts of variola. Smallpox is not known to be transmitted by insects or animals.

Transmission via contact with material from the smallpox pustules or crusted scabs can also occur. Scabs are much less infectious than respiratory secretions, presumably due to binding of the virions in the fibrin matrix of the scab. During the smallpox era, the disease had secondary household or close-contact infection rates up to 80%. Because of the current lack of natural or vaccine-induced immunity, it is difficult to predict the attack rates in today' s population.

After the smallpox virus is introduced into the respiratory tract or skin via percutaneous inoculation, it remains localized and replicates for up to three days. The viral dissemination in the body involves a primary viremia in which the virus moves to the lymph nodes, spleen, and sometimes bone marrow. The virus replicates in the lymphoid organs then migrates to the bloodstream, producing a secondary viremia followed by fever and toxemia.

The secondary viremia carries the virus to the basal layer of the oropharyngeal region and epidermis by the 10th to 14th day after the initial infection. Just after the fever peaks, the development of oropharyngeal lesions (called enanthem or eruptive lesions on the surface of a mucous membrane) begins, and is soon followed by the development of skin lesions (called exanthem or skin eruptions).

Lesions occur first on the mucous membranes of the mouth, tongue, pharynx, larynx, and upper part of the esophagus. Transmission by large-particle airborne droplets is maximal at the time of the appearance of skin lesions.

The disease can be spread by these large-particle airborne droplets until the skin scabs fall off, however, droplet transmissibility decreases significantly after the second week of disease as the oral lesions of the enanthem heal and viral titers in the saliva decrease. The infected person is contagious until the last smallpox scab falls off.

At the time of rash onset, most patients are already confined to bed because of the high fever and toxemia associated with the prodromal stage of the illness. Prodromal pertains to the early symptoms that mark the onset of disease.

Because people with severe prodromal illness may seek medical attention, hospitals could be a source of infection because of transmission from unrecognized hospitalized individuals. Implementation of appropriate isolation measures for patients with rash and fever would limit this type of transmission.

Secondary cases of smallpox are usually limited to those who come in contact with the infected person in the household or hospital. During the global eradication program, it was possible to interrupt the chain of transmission of smallpox by isolating smallpox patients in a setting in which they had contact only with adequately vaccinated people.

This limited the next potential generation of cases to people who had already been exposed, such as household and other close contacts. Contacts were identified and immediately vaccinated. Contacts who became ill were also isolated to establish a barrier to further transmission. This strategy was found to be effective even if community vaccination levels were low.

SMALLPOX INFECTION: RASH TO RESOLUTION

The characteristic feature of smallpox is the skin rash. Initially, the capillaries in the dermal papillae dilate, followed by swelling of the endothelium and infiltration of lymphocytes and histiocytes (macrophages present in connective tissue).

Polymorphonuclear leukocytes enter skin vesicles from the dermis to produce the pustular lesions. The pustular fluid eventually dries up as the disease disappears and the lesions become filled with granular tissue, which forms scabs consisting of degenerated epithelial cells and leukocytes.

Virus particles can be present in large numbers in the scabs but are generally not highly infectious because they are enclosed within the hard, dry scab. Lesion scars or pockmarks are sequelae caused mainly by destruction of infected sebaceous glands and are most prominent on the face.

Cell-mediated immunity most likely plays the primary role in the recovery from smallpox infection. Antibodies play a secondary role in recovery, though they play a primary role in protecting against re-infection. The presence of viral neutralizing antibodies is considered a marker of immunity.

Small hemorrhages may occur in the heart and liver, but generally vital organs are not damaged enough to cause death. Death results from a profound toxemia leading to respiratory and/or heart failure.

Ordinary-type smallpox rash development through consecutive stages. Courtesy World Health Organization.

Incubation Period (not contagious)

Exposure to the virus begins an incubation period during which people do not have any symptoms and may feel fine. The incubation period averages about 12 to 14 days but can range from 7 to 17 days and during this time the infected person is not contagious.

Initial Symptoms—Prodromal Phase (may be contagious)

Following the incubation period, the infected person enters the prodromal phase lasting 2 to 4 days. Smallpox may be contagious during the prodromal phase, but is most infectious during the first 7 to 10 days following rash onset. The first symptoms of smallpox include fever, malaise, head and body aches, and sometimes vomiting. The fever is usually high, 101° to 104 °F. At this time, people are usually too sick to carry on their normal activities.

Smallpox infection, day 2. Photo courtesy World Health Organization.

The rash appears 2 to 4 days after the patient first becomes ill with fever. On the first day of rash a few raised spots called papules appear. They are usually seen first on the face and subsequently on the body and extremities. On the right side of the above picture, a few small papules may be seen. Unless it is known that the patient has been exposed to the virus, or was in contact with a smallpox case two weeks earlier, we may not suspect the diagnosis at this time.

Smallpox infection, day 4. Photo courtesy World Health Organization.

Early Rash (highly contagious)

Following the prodromal phase an early rash appears that lasts about 4 days. During the early rash phase the patient is at the most contagious phase of the infection. A rash emerges, first as small red spots on the tongue and in the mouth. These spots develop into sores that break open and spread large amounts of the virus into the mouth and throat. At this time, the person becomes contagious.

Around the time the sores in the mouth break down, a rash appears on the skin, starting on the face and spreading to the arms and legs and then to the hands and feet. Usually the rash spreads to all parts of the body within 24 hours. As the rash appears, the fever usually falls and the person may start to feel better.

By the third day of the early rash phase, the rash becomes raised bumps. By the fourth day, the bumps fill with a thick, opaque fluid and often have a depression in the center that looks like a bellybutton. (This is a major distinguishing characteristic of smallpox.) Fever often will rise again at this time and remain high until scabs form over the bumps.

On day 7, the rash is definitely pustular. Note that the pocks, although varying somewhat in size, all resemble each other in appearance. The rash is now so characteristic that there should be no mistake in diagnosis.

Smallpox infection, day 7. Photo courtesy World Health Organization.

During days 8 and 9, the pustules increase somewhat in size. They are firm to the touch and deeply embedded in the skin.

Smallpox infection, days 8 and 9. Photo courtesy World Health Organization.

Pustular Rash (still contagious)

Following the early rash phase a pustular rash appears that lasts about 5 days. The infected person is still contagious during this phase. The raised bumps become pustules; they are sharply raised, usually round and firm to the touch, as if there is a small round object under the skin. People often say the bumps feel like BB pellets embedded in the skin.

Pustules and Scabs (still contagious)

Following the pustular rash phase, pustules and scabs appear that last about 5 days. The person remains contagious during this phase. 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 scabbed over.

Resolving Scabs (still contagious)

Following the appearance of pustules and scabs, the scabs begin to resolve over about 6 days. The person is still contagious during this phase. The scabs begin to fall off; leaving marks on the skin that will eventually become pitted scars. Most scabs will have fallen off three weeks after the rash appears. The person is contagious to others until all of the scabs have fallen off.

Gradually the pustules dry up and dark scabs form. The scabs begin to appear between 10 and 14 days after the rash first develops. The scabs contain live smallpox virus. Until all scabs have fallen off, the patient may infect others.

Pustules are drying up and dark scabs are forming. Photo courtesy World Health Organization.

By day 20 the scabs have come off and light-colored or depigmented areas are observed. Over a period of many weeks the skin gradually returns to its normal appearance. However, scars that will last for life may remain on the face. Such scars are an indication of previous infection with smallpox.

By day 20 the scabs had fallen off. Photo courtesy World Health Organization.

Scabs Resolved (no longer contagious)

When all of the scabs have resolved and fallen off the person is no longer contagious.

CLINICAL FEATURES OF SMALLPOX

Smallpox is characterized by both an enanthem, with lesions in the mucous membranes of the mouth and on the posterior pharynx, and an exanthem (skin eruptions or rash). Lesions on each area of the body are at the same stage of development, are deeply embedded in the skin, and are more densely concentrated on the face and extremities.

Constitutional symptoms prior to onset of rash (exanthem) include fever (100%), which generally occurs about 1 to 3 days before rash onset, headache (90%), backache (90%), chills (60%), and vomiting (50%). Less common symptoms include pharyngitis and severe abdominal pain.

Ordinary Smallpox

The hallmark of the ordinary (or classic) type of smallpox is a generalized vesiculopustular rash with lesions found more densely on the face and extremities (centrifugal), including the palms and soles. All lesions on any one part of the body are at a similar stage of development and are approximately the same size. The rash progresses from sparse macules on day 1, to papules on days 2, vesicles on days 3 to 4, pustules on days 5 to approximately 12, and scabs on days 13 to 18 for a total duration of 2 to 3 weeks.

Modified Smallpox

A rash that progresses through the stages more rapidly and has fewer lesions characterizes modified smallpox, which occurs more commonly among previously vaccinated persons. Infection via cutaneous inoculation also has a shorter course with appearance of one or several vesicles at the site of inoculation after about 3 days.

Asymptomatic cases are very uncommon and their role in transmission is unclear but likely to be minimal. In 5% to 10% of smallpox patients, more rapidly progressive, malignant disease develops, which is almost always fatal within 5 to 7 days. In such patients, the lesions are so densely confluent that the skin looks like crepe rubber; some patients exhibit bleeding into the skin and intestinal tract.

Smallpox vs. Chickenpox

The disease most commonly confused with smallpox is chickenpox (varicella), and during the first 2 to 3 days of rash it may be all but impossible to distinguish between the two. However, all smallpox lesions develop at the same pace and, on any part of the body, appear identical.

Chickenpox lesions are much more superficial and develop in crops. Papules, vesicles, pustules, and scabs can be seen adjacent to each other. Moreover, the rash in chickenpox is more dense over the trunk (the reverse of smallpox), and chickenpox lesions are almost never found on the palms or soles.

A typical smallpox rash distribution. Note that the rash is concentrated on the face and distal extremities. Courtesy of the World Health Organization.

A chickenpox rash distribution, which is more superficial than smallpox. Note that the rash is concentrated on the trunk. Courtesy of the World Health Organization.

CLINICAL FEATURES: COMPARING SMALLPOX WITH CHICKENPOX

	Smallpox	Varicella (chickenpox)
Major distinguishing features	Febrile prodrome: temperature >102 and systemic symptoms (prostration, severe headache, backache, abdominal pain, or vomiting) 1–4 days before rash onset	No or mild prodrome before rash onset
	Lesions are deep, firm, well-circumscribed pustules; may be confluent or umbilicated	Lesions typically superficial vesicles
Other distinguishing features	Rash concentrated on face and distal extremities (centrifugal)	Rash concentrated on trunk and proximal extremities (± face, scalp)
	Rash in same stage of evolution on any one part of the body	Rash appears in crops so lesions are in different stages of evolution (papules, vesicles, crusts) on any one part of the body
	First lesions on oral mucosa/palate (enanthem); followed by exanthem (rash) on face or forearm	First lesions on trunk (occasionally face)
	Lesions on palms and soles (seen in >50%)	Lesions very uncommon on palms and soles
	Lesions may itch at scabbing stage	Lesions generally intensely itchy
	Lesions evolve from papule pustule in days	Lesions generally evolve from macules to papules to vesicles to crusts in <24 hours
	Illness lasts 14–21 days	Illness lasts 4–7 days

Epidemiologic features of chickenpox (varicella) that should be useful in distinguishing it from smallpox include:

• Most cases of chickenpox occur in children. Only 5% of adults 20 to 29 years of age are susceptible and only 1% of adults 30 to 39 years are susceptible.
• Varicella in adults is uncommon. However, adults from tropical climates are more likely to be susceptible than their U.S. counterparts. Although varicella cases have declined dramatically in areas where moderate to high vaccine coverage has been achieved in the United States, varicella cases have declined in all age groups.
• Approximately 90% of cases are still occurring among children <15 years.
• Chickenpox has an expected case fatality rate of 2 to 3 per 100,000 cases, much lower than smallpox.
• Chickenpox has a secondary attack rate among susceptible household contacts, approximately 80% (range, 65% to 90%), higher than smallpox.

Another disease commonly confused with smallpox is herpes zoster. In herpes zoster, lesions are usually localized to 1 or 2 dermatomes, but they can become generalized, especially among immunocompromised persons.

The lesions in localized herpes zoster are painful and could likely be differentiated from smallpox based on their appearance. Other diagnoses with similar presentation include drug eruptions, erythema multiforme, impetigo, disseminated herpes simplex, enteroviral infections associated with a vesicular rash, and others.

The CDC provides an online tool entitled Evaluate a Rash Illness Suspicious for Smallpox, which may be used for rash evaluation when there is no release or circulation of smallpox. This tool is located on the CDC website at http://www.bt.cdc.gov/agent/smallpox/diagnosis/riskalgorithm/.

THE SMALLPOX VACCINE

Smallpox spreads most readily during the cool, dry winter months but can be transmitted in any climate and in any part of the world. The only weapons against the disease are vaccination and patient isolation. Vaccination before exposure or within 2 to 3 days after exposure affords almost complete protection against disease.

Vaccination as late as 4 to 5 days after exposure may protect against death. Because smallpox can be transmitted from the time of the earliest appearance of rash, early detection of cases, and prompt vaccination of all contacts is critical.

VACCINIA

The vaccinia virus, the virus in the smallpox vaccine, is another "pox"-type virus. Vaccinia is related to smallpox, but is milder. The smallpox vaccine helps the body develop immunity to smallpox. The vaccine does not contain the smallpox (variola) virus and cannot give you smallpox.

Components of a smallpox vaccination kit including the diluent, a vial of Dryvax smallpox vaccine, and a bifurcated needle. Vaccinia (smallpox) vaccine, derived from calf lymph, and currently licensed in the United States, is a lyophilized, live-virus preparation of infectious vaccinia virus; it does not contain variola virus.

The vaccinia virus may cause rash, fever, and head and body aches. In certain groups of people, complications from the vaccinia virus can be severe. Vaccinia is spread by touching a vaccination site before it has healed or by touching bandages or clothing that have been contaminated with live virus from the smallpox vaccination site; in this way, vaccinia can spread to other parts of the body or to other individuals. This is called inadvertent inoculation. In the past, spreading to other parts of the vaccine recipients' bodies was the more common form of inadvertent inoculation.

Smallpox Vaccine Safety

The smallpox vaccine is the best protection you can get if you are exposed to the smallpox virus. Anyone directly exposed to smallpox, regardless of health status, should be offered the smallpox vaccine because the risks associated with smallpox disease are far greater than those posed by the vaccine.

Live Virus Vaccine

A "live virus" vaccine is a vaccine that contains a "living" virus that is able to give and produce immunity, usually without causing illness. Because the virus in the smallpox vaccine is live, it can be transmitted to other parts of the body or to other people. When using a live-virus vaccine, the vaccination site must be closely monitored and care taken to prevent inadvertent inoculation.

For most people with healthy immune systems, live-virus vaccines are effective and safe. Sometimes a person getting a live vaccine experiences mild symptoms associated with the virus in the vaccine. Other live-virus vaccines include measles, mumps, rubella, and chickenpox.

Length of Protection

Smallpox vaccination provides full immunity for 3 to 5 years and decreasing immunity thereafter. If a person is vaccinated again later, immunity lasts even longer. Historically, the vaccine has been effective in preventing smallpox infection in 95% of those vaccinated.

In addition, the vaccine was proven to prevent or substantially lessen infection when given within a few days of exposure. It is important to note, however, that at the time when the smallpox vaccine was used to eradicate the disease, testing was not as advanced or precise as it is today, so there may still be things to learn about the vaccine and its effectiveness and length of protection.

Receiving the Vaccine

The smallpox vaccine is not given with a hypodermic needle. As most people have experienced it, it is not a shot. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution.

When removed, the needle retains a droplet of the vaccine. The needle is used to prick the skin 15 times in a few seconds. The pricking is not deep, but it will cause a sore spot and one or two droplets of blood to form. The vaccine usually is given in the upper arm.

A close-up of the tip of a bifurcated needle used to vaccinate individuals containing some vaccine solution. Photo courtesy CDC/James Gathany, 2002.

A CDC clinician demonstrating the use of a bifurcated needle during the 2002 Smallpox Vaccinator Workshop. Photo courtesy CDC/James Gathany, 2002.

If the vaccination is successful, a red and itchy bump develops at the vaccine site in 3 or 4 days. In the first week, the bump becomes a large blister, fills with pus, and begins to drain. During the second week, the blister begins to dry up and a scab forms. The scab falls off in the third week, leaving a small scar. People who are being vaccinated for the first time have a stronger reaction than those who are being revaccinated.

Photographs of normal vaccination site at intervals over a two-week period. During a primary response, a person never before exposed to the vaccinia virus is vaccinated, stimulating the T cell population to expand and mount a sound antibody response to a secondary inoculation to the smallpox virus. Photo courtesy CDC/Arthur E. Kaye, 1969.

Recognition of Expected Vaccine Reactions

Successful vaccination (called a take) is normally associated with tenderness, redness, swelling, and a lesion at the vaccination site. Primary vaccination may also be associated with fever for a few days and enlarged, tender lymph nodes in the axilla of the vaccinated arm. These symptoms are more common in persons receiving their first dose of vaccine (15% to 20%) than in persons being revaccinated (0% to 10%).

Side Effects of the Vaccinia Vaccine

There are side effects and risks associated with the smallpox vaccine. Most people experience normal, usually mild, reactions that include a sore arm, fever, and body aches. However, some people experience reactions ranging from serious to life-threatening.

People most likely to have serious side effects are:

• Those who have had, even once, skin conditions (especially eczema or atopic dermatitis) and
• Those with weakened immune systems—who have received a transplant, are HIV-positive, are receiving treatment for cancer, or are currently taking medications (like steroids) that suppress the immune system.

Smallpox Vaccine and Heart Problems

Careful monitoring of smallpox vaccinations given over recent months has suggested that the vaccine may cause heart inflammation (myocarditis), inflammation of the membrane covering the heart (pericarditis), and/or a combination of these two problems (myopericarditis).

The CDC reported that as of March 21, 2003 there were 25,645 volunteers vaccinated against smallpox in the United States and its territories. This does not include an unknown number of military personnel who also have been vaccinated. Of the 25,645 civilians who received the smallpox vaccine, 7 experienced heart problems and 3 died after receiving the vaccine. Two of those who died were healthcare workers in Maryland and Florida and the third was a 55-year-old National Guardsman. It is not known at this time if the smallpox vaccination caused these adverse events.

The military has given thousands of troops the smallpox vaccine. A few cases of heart inflammation have been reported in members of the military receiving the vaccine for the first time. No such cases occurred in people who had been vaccinated before. According to the Department of Defense, none of the cases have been severe and all of the individuals have recovered.

On March 27, 2003, the CDC added a temporary medical deferral to the smallpox vaccination program for persons who have been diagnosed with heart disease. The CDC is recommending that persons with known cardiac disease—such as cardiomyopathy, previous heart attack, history of angina, or other evidence of coronary artery disease—be temporarily deferred from receiving the smallpox vaccination.

The presence of these conditions in a close contact is not a reason to defer vaccination. On March 30, 2003, former director of California Department of Health Services Diana M. Bonta ordered California counties to suspend all smallpox immunizations until the CDC updates its recommendations about who should and who should not receive smallpox inoculations.

The CDC provides state health departments with simple questions about heart problems to use in screening people volunteering for smallpox vaccination. These may be temporary exclusions and may change as more information is gathered.

In 2005 the CDC made available an algorithm developed by the Department of Defense for evaluating possible postvaccine heart problems. Called Algorithm for Evaluating Suspected Vaccinia Vaccination (Smallpox Vaccination) Pericarditis-Myocarditis, it may be downloaded from the CDC website (see References at the end of this course for complete information).

Smallpox Vaccine Contraindications

Some people are at greater risk for serious side effects from the smallpox vaccine. Individuals who have any of the following conditions, or live with someone who does, should not get the smallpox vaccine unless they have been exposed to the smallpox virus. People who have been directly exposed to the smallpox virus should get the vaccine, regardless of their health status.

In addition, individuals should not get the smallpox vaccine if they:

• Are allergic to the vaccine or any of its ingredients (eg, allergic to polymixin B, streptomycin, tetracycline, and neomycin).
• Are less than 18 years of age.
• Have a moderate or severe short-term illness. (These people should wait until they are completely recovered to get the vaccine.)
• Are currently breastfeeding.

Pregnant women should not get the vaccine because of the risk it poses to the fetus. Also, individuals under 18 years of age and those allergic to the vaccine or any of its components should not receive the vaccine.

In the past, about 1,000 people for every 1 million people vaccinated for the first time experienced reactions that, while not life-threatening, were serious. These reactions included:

• Erythema multiforme: a toxic or allergic reaction at the site of the vaccination.
• Inadvertent inoculation: spread of the vaccinia virus to other parts of the body and to other individuals.
• Generalized vaccinia: spread of the vaccinia virus to other parts of the body through the blood.

These types of reactions may require medical attention. In the past, between 14 and 52 people out of every 1 million people vaccinated for the first time experienced potentially life-threatening reactions to the vaccine.

Based on experience, it is estimated that 1 or 2 people in 1 million people who receive the vaccine may die as a result. Careful screening of potential vaccine recipients is essential to ensure that those at increased risk do not receive the vaccine.

Serious Adverse Reactions

Smallpox vaccination is associated with some risk for adverse reactions that are life threatening; the two most serious are postvaccine encephalitis and progressive vaccinia.

POSTVACCINE ENCEPHALITIS

• Occurs at a rate of 3 per million primary vaccinees.
• Forty percent of the cases are fatal.
• Some patients are left with permanent neurologic damage.

PROGRESSIVE VACCINIA

• Occurs among those who are immunosuppressed because of a congenital defect, malignancy, radiation therapy, or AIDS.
• The vaccinia virus simply continues to grow, and unless these patients are treated with vaccinia immune globulin, they may not recover.
• Pustular material from the vaccination site may be transferred to other parts of the body, sometimes with serious results.

This child manifested a generally distributed maculopapular rash after receiving a primary smallpox vaccination. Generalized vaccinia is the result of the systemic spread of smallpox virions from the vaccination site. Despite the lesions, it is usually a benign complication of a primary vaccination that is self-limited, except in some immunosuppressed individuals. Photo courtesy CDC/Arthur E. Kaye, 1969.

DIAGNOSIS AND TREATMENT

There are three clinical forms of smallpox that can occur in unvaccinated individuals; ordinary, flat, and hemorrhagic. An additional form, modified-type, is seen most often in individuals with previous vaccinations.

Ordinary Smallpox (most common form)

An early, vigorous cellular immune response in immune-competent persons inhibits most virus growth. However, some virus survives the host immune defenses and produces ordinary smallpox, the most common form, in which characteristic skin lesions appear in a discrete centrifugal rash. The disease progresses in the usual pattern beginning with the prodromal phase when the fever, rash, and other symptoms appear and ending through the resolution of the scabs when the person is no longer infective.

Flat-Type or Malignant Smallpox (rare)

A deficient cellular immune response to variola virus is believed to be associated with a very rare manifestation of smallpox called flat-type smallpox. This form of disease is characterized by intense toxemia and occurs more frequently in children.

Skin lesions develop slowly, become confluent, and remain flat and soft, never progressing to the pustular stage. Lesions have been described as "velvety" to the touch and sections of the skin may slough off. The majority of flat-type smallpox cases are fatal but, if the patient survives, the lesions gradually disappear without forming scabs.

Hemorrhagic Smallpox (rare)

In persons with a highly compromised immune response, there is extensive multiplication of the virus in the spleen and bone marrow to produce a rare condition known as hemorrhagic smallpox. Megakaryocyte destruction in the bone marrow is believed to lead to defective blood coagulation.

The rare hemorrhagic-type smallpox is associated with petechiae in the skin and bleeding from the conjunctiva and mucous membranes. A high level of viremia is maintained in this type of smallpox as opposed to the other clinical forms of the disease.

Hemorrhagic-type illness begins with severe prodromal symptoms that include high fever, severe headache, and abdominal pain after a shortened incubation period. Soon after onset of illness, a dusky erythema develops, which is followed by petechiae and skin and mucosal hemorrhages.

Death usually occurs by the 5th or 6th day of rash, often before lesions more characteristic for smallpox rash develop. The two forms of hemorrhagic-type smallpox, early and late, are differentiated by the occurrence of hemorrhages after the appearance of the rash in the late form.

Hemorrhagic-type smallpox occurs among all ages and in both sexes but is more common in adults. Pregnant women also seem to be more susceptible to developing this form of smallpox than other adults.

Modified-Type Smallpox (previously vaccinated individuals)

This form of smallpox most often occurs in previously vaccinated individuals. The modification of this form of smallpox relates to the character and development of the rash, with more rapid progression and resolution. In general, the prodromal stage may still consist of severe headache, backache, and fever, and the duration may not be shortened.

Once the skin lesions appear, however, they generally evolve more quickly, with crusting completed within 10 days. The lesions may be fewer in number and are more superficial than those seen in ordinary-type smallpox. Fever during the evolution of the rash is usually absent during this modified clinical course.

Laboratory Diagnosis

The usual preliminary method of diagnosis of orthopoxvirus infections such as smallpox is by observing the characteristic brick-shaped virions in negatively stained preparations of vesiculopustular fluid or homogenates of scab material viewed by electron microscopy. Species diagnosis was formerly made by observation of the morphology of pocks on the chorioallantoic membrane (CAM) 3 days after infection of 12-day-old chick embryos.

Now, however, a variety of relatively rapid identification methods are available at the CDC for genus and species identification. Orthopoxviruses are very closely related, thus specific identification can be accomplished using hyperimmune antiserum against any species within the genus, most commonly vaccinia virus.

Treatment

Medical management of a patient with smallpox is mainly supportive and consists of:

• Isolation of the patient to prevent transmission of the variola virus to nonimmune persons
• Monitoring and maintaining fluid and electrolyte balance
• Monitoring for, and treatment of, complications

In addition, unless the diagnosis of smallpox is laboratory-confirmed, patients should receive a smallpox vaccination if they will be isolated with other confirmed or suspected smallpox cases. Vaccination of suspected cases of smallpox is done to prevent the accidental transmission of smallpox virus to any suspected smallpox patients who have been misdiagnosed as smallpox cases.

Isolation

In a smallpox outbreak, isolation of confirmed or suspected smallpox patients may be accomplished by several methods, depending upon certain circumstances (eg, number of patients, severity of illness, availability of resources). Ultimately, the goal of isolation is to prevent transmission of smallpox from an infectious patient (from the time the rash appears until all of the scabs have separated, about 3 to 4 weeks) to nonimmune individuals while maintaining an appropriate care and comfort level for the patient.

All potential methods of isolation must be considered with these goals in mind. Several potential methods for patient isolation are outlined below. Medical personnel need to consult with public health officials to determine the most appropriate method for isolation of smallpox patients.

Hospital Isolation

If a confirmed or suspected smallpox patient requires hospital care, the following steps must be taken while the patient is hospitalized:

• Place the patient under strict respiratory and contact isolation in a room with negative air pressure (and individual HEPA-filtered ventilation exhaust, if available). This room should have private shower/bathroom facilities and not share ventilation with any other part of the hospital.
• Use protective clothing including: gowns, masks (properly fitted N95 respirator masks), gloves, protective eyewear, and surgical booties, which should be worn by unvaccinated personnel who enter and leave the isolation room.
• Recently successfully vaccinated personnel should exercise contact precautions (eg, gowns, gloves) and should wear a surgical mask and eye protection as indicated for procedures where contact with body fluids may occur.
• Removal and disposal of all protective clothing into biohazard waste disposal containers should be done 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(s) should be vaccinated or have documented successful recent smallpox vaccinations (within 3 years).
• Steps should be taken to confirm or rule out the diagnosis of smallpox. Public health officials should be consulted for assistance with the laboratory diagnosis.

Non-Hospital Isolation

Public health officials should be consulted before non-hospital isolation is initiated. Confirmed or suspected smallpox patients who do not require hospital care may be isolated in non-hospital facilities that do not share ventilation systems with other facilities.

These facilities should have appropriate climate control capabilities (heating/air conditioning), running water, and bathroom facilities. If suspected and confirmed smallpox patients are isolated together, all patients should receive a smallpox vaccination to prevent accidental transmission because of misdiagnosis. All persons entering these facilities must have documented successful recent smallpox vaccinations (within 3 years).

Fluid and Electrolyte Balance

During the vesicular and pustular stages of smallpox, patients may experience significant fluid losses and become hypovolemic or develop shock. Fluid loss can result from:

• Fever
• Nausea and vomiting
• Decreased fluid intake due to swallowing discomfort from pharyngeal lesions
• Body fluid shifts from the vascular bed into the subcutaneous tissue
• Massive skin desquamation in patients with extensive confluent lesions
• Electrolyte and protein loss

Fluid and electrolyte balance should be monitored in hospitalized patients with appropriate oral or intravenous correction of imbalances. Patients with less severe disease who do not require hospitalization should be encouraged to maintain good oral intake of fluids and be educated on the signs and symptoms of hypovolemia and dehydration. Patients should be counseled to seek medical attention if hypovolemia/dehydration occurs.

Skin Care

The skin should be kept clean and efforts should be made to avoid rupturing vesicles or pustules. No salves or ointments should be applied. In general, scab lesions should be allowed to heal and separate on their own.

All scabs should separate by 3 to 4 weeks, however, lesions on the palms and soles may persist longer than 3 to 4 weeks unless artificially removed. Bacterial superinfection of lesions may occur and should be treated with appropriate antibiotics.

MONITORING AND TREATMENT OF COMPLICATIONS

Several complications may occur during the course of a smallpox infection, including hemorrhages, secondary bacterial infections, corneal ulceration and/or keratitis, arthritis or "osteomyelitis variolosa," respiratory, gastrointestinal and genitourinary symptoms, and encephalitis.

Hemorrhage

Minor hemorrhagic manifestations such as subconjunctival hemorrhages are common occurrences with smallpox infection. If the subconjuctival hemorrhages are isolated and are not accompanied by evidence of coagulopathy or active bleeding such as decreasing hemoglobin, hematocrit or platelets, no specific therapy is needed.

If signs of more extensive hemorrhage are present, such as mucosal bleeding, bleeding into smallpox lesions, ecchymoses, hematemesis, or hematuria, the patient should be evaluated for disseminated intravascular coagulation (DIC) and treated appropriately. Hemorrhagic complications may indicate a more severe form of the disease called hemorrhagic smallpox, which has a poor prognosis. Also, because of a high, sustained viremia coupled with mucosal hemorrhaging during their course of illness, these patients are highly infectious.

Secondary Bacterial Infections

Bacterial superinfections can include abscesses of skin lesions, pneumonia, osteomyelitis, joint infections, and septicemia. Laboratory diagnostics such as gram stain, culture, and antibiotic-susceptibility testing should be performed to help guide antibiotic therapy.

Corneal Ulceration and/or Keratitis

These complications occur more frequently in hemorrhagic-type smallpox but are occasionally seen in ordinary-type smallpox. Corneal ulcerations can appear around the second week of illness and begin at the corneal margins.

Ulcers can heal rapidly, leaving a minor opacity or, on occasion, may cause severe corneal scarring. Keratitis and corneal ulceration is far more common in malnourished individuals. Topical idoxuridine has been used but its efficacy is undocumented.

Gastrointestinal Symptoms

Nausea and vomiting can occur in the earlier stages of smallpox, especially in the prodromal period before rash development, and should be treated symptomatically. Diarrhea may occasionally occur and should also be treated symptomatically as needed.

Acute dilation of the stomach occurs rarely and is more common in infants. In some severe cases (especially flat-type), extensive viral infection of the intestinal mucosa occurs with sloughing of the mucosal membrane. Most of these cases are fatal.

Arthritis or Osteomyelitis Variolosa

Arthritis or osteomyelitis variolosa (OV) usually occurs after the 15th day and is accompanied by a brief recurrence of fever during the scabbing stage. The elbow is the most commonly affected joint and symmetrical, bilateral involvement was frequently seen. This complication is most commonly caused by viral infection of the metaphyses of growing bones. Most cases resolve without permanent deformity.

Respiratory Symptoms

Viral bronchitis and pneumonitis can be common complications of severe smallpox and are considered part of the normal disease syndrome. Treatment is symptomatic, with measures to treat hypoxemia with supplemental oxygen and/or intubation/ventilation as indicated. Secondary bacterial pneumonia can occur and should be treated with appropriate antibiotics as guided by laboratory diagnostics (gram stain, culture, antibiotic susceptibility testing, etc.).

Pulmonary edema is common in the more severe forms of smallpox, hemorrhagic and flat-type, and should be treated with careful monitoring of oxygenation, fluid status, blood pressure (with supplemental oxygen), and diuretics administered as needed. Patients with cough during the first week of disease may transmit disease more readily than patients without a cough because this is the period when oral secretions contain the largest amount of virus. Patients who develop a cough later in the course of disease (after day 10), when viral counts in secretions are lower, are not as infectious as those who develop coughs earlier.

Encephalitis

This complication occurs in about 1 out of every 500 cases of smallpox. It usually appears between the 6th and 10th day of illness when the rash is still in the papular or vesicular stage. During the smallpox era, this complication was a minor contributor to the case-fatality rate of classical smallpox (variola major), the most common form of smallpox. Although sometimes slow, recovery was usually complete.

Genitourinary Symptoms

Orchitis (infected testicles) is usually unilateral. Hematuria (blood in the urine) can be present in hemorrhagic-type smallpox if bleeding into the pelvis of the kidney occurs.

PUBLIC HEALTH ISSUES

Smallpox Response Plan

A smallpox response plan was first put in place in the United States in the early 1970s. Until recently, the plan only considered an importation of smallpox and provided guidance for actions to be taken by a State Health Officer in the event of a suspected case.

In 1999 efforts were begun to update the response plan in the context of an intentional release of smallpox virus as an act of terrorism. Following the anthrax attacks in 2001, the plan was revised to provide detailed information on surveillance and response to a smallpox virus release.

The smallpox response plan will change as resources and capabilities change and additional needs are identified. The current plan is intended to assist with local and state response planning by identifying actions that must be taken in the event of a suspected smallpox case.

Key Elements of Preparedness

The key elements of preparedness for a smallpox response are:

• Surveillance and diagnosis to achieve the early detection of an introduced case
• Isolation of the case or cases
• Identification and vaccination of the contacts of the case or cases

The CDC has published a series of six guides that give detailed information on critical aspects of the plan (http://www.bt.cdc.gov/agent/smallpox/response-plan/index.asp).

Guide A contains surveillance, contact tracing, and epidemiologic investigation guidelines. This includes pre-event rash surveillance, information on differential diagnosis; case definitions; and contact identification, tracing, and surveillance. In addition, there are data collection forms to support these activities.

Guide B contains details on smallpox vaccine and vaccination. This includes strategies; indications and contraindications to vaccination; and reconstitution, administration, and storage of the vaccine. It also describes recognition and surveillance of vaccine adverse events, guidelines for the use of vaccinia immune globulin, and contingencies for resterilization and reuse of needles if needed.

Guide C contains isolation guidelines for both confirmed and suspected cases. It also describes the isolation of the febrile contacts of patients who may be developing smallpox. The issue of quarantine—that is, isolation of people before they become ill—is also discussed.

Guide D details methods for proper specimen collection and transport.

Guide E includes the communication plan and activities. In the event of a smallpox outbreak, communications will be critical. This guide details strategies for communicating with the media, the public, and with providers.

Guide F describes decontamination guidelines for reusable medical equipment; medical waste; clothing, bedding, and linens; facilities and rooms; and vehicles used for transportation of patients.

Several annexes to the plan contain details of other issues likely to be encountered, including the general care of smallpox patients, vaccination clinic procedures, and vaccine adverse event reporting. There are also a variety of forms and checklists to assist in preparing for and responding to a smallpox outbreak.

The response plan will always remain a living document that will be updated periodically as resources and capacities change. It is an excellent starting point for response planning on all levels of public health. The underlying concepts included in the plan will remain even if the strategies for implementing the concepts may require adaptation.

CASE INVESTIGATION AND CONTACT IDENTIFICATION

Although smallpox is considered most infectious during the first 7 to 10 days of the rash, some individuals may not notice the first lesions. Ulcerated lesions in the oropharynx occur and the person may be highly infectious during this time period, which may immediately precede or coincide with onset of the exanthem.

Contact identification is the most urgent task when investigating smallpox cases because vaccination of close contacts as soon as possible following exposure, preferably within 3 to 4 days, may prevent or modify disease spread. This was the successful strategy used for the global eradication of smallpox.

Much of the epidemiologic investigation can be performed in conjunction with identification and evaluation of potential smallpox cases. However, because time is of the essence, adequate personnel must be available to collect and analyze data that would allow the rapid identification of persons who have had close contact with the smallpox-infected patient since date of onset of fever.

Since smallpox is a contagious disease, once a case is confirmed, the highest priorities for public health officials are to reduce risk of ongoing transmission by immediately identifying and vaccinating close contacts of patients and isolating the infected patients. Public health officials must identify the most likely source of initial exposure (within 24 hours of the first confirmation of smallpox).

This may require extensive trace-back capabilities if the initial recognition and confirmation of smallpox occurred later than the first generation of disease in the outbreak. To the extent possible, the population at risk should be identified. At-risk persons should be placed under surveillance and public health officials should consider offering smallpox vaccine to the exposed population and to their household contacts.

The age distribution of cases would be expected to mimic the age distribution of the population due to virtual nonexistent population immunity. Identify any unexpected epidemiologic features of the outbreak (eg, unusual presentation, morbidity, mortality, incubation period, transmission, and affected population) and evaluate the characteristics and extent of the outbreak to develop the most effective containment strategies.

During the smallpox era, the seasonal transmission of disease was highest during winter and early spring. Public health officials should review the epidemiologic features of smallpox. There is an expected case fatality rate of up to 30% with smallpox. The case fatality rate may be higher because of:

• Lack of natural immunity
• A high percentage of non-vaccinated persons in the U.S. population
• Waning immunity against smallpox in previously vaccinated persons
• A larger immunocompromised population when compared to the smallpox era

It may be lower because of:

• Better intensive-care and medical treatment options than 30 years ago
• Partial immunity among the adult population

AUTHOR COMMENTS

As a healthcare professional currently working in a small community hospital ED my co-workers and I were recently asked to volunteer to be vaccinated for smallpox and be part of the Smallpox Response Team in our local community. Our area has a small population base and we feel isolated and insulated from the problems of big-city life. But, in reality, we are within 1 to 3 hours of several large metropolitan areas and are situated on an interstate highway.

This location makes us more vulnerable to outside threats than many of us would like to believe. My initial response was "Why not? It could happen. I already had several vaccination scars and I don't remember any problems when I received the vaccinations. I am a nurse and this is what we do—we take care of people when they are sick, and even contagious."

After discussion with family, friends, and co-workers, my certainty wavered and the decision became less clear. Everyone I worked with had an opinion—mostly against taking the vaccine. I vacillated back and forth. Finally the decision was made for me when the local public health department balked at participating and my employers (at the corporate level) decided not to participate due to concerns of their own.

Many of you reading this have been conflicted about taking the vaccine. None of us want to expose ourselves and our families, patients, and co-workers to a potentially dangerous and possibly unnecessary treatment. I finally made my personal decision when I heard about the cardiac problems that were happening post vaccination. I have risk factors for cardiac disease and decided to not take the chance except in the event of an imminent threat.

Many nurses decided the personal risk was too great and decided against vaccination. Are we being naive and politically ignorant when we think a smallpox attack cannot happen in our country? Are we overly confident that, if it happens, smallpox will be easily identified and contained by vaccinating the people exposed, thus preventing a widespread contagious event?

Those questions may not be fully answered unless we are exposed to an actual attack from smallpox. We may wish to go back to the time when we thought smallpox was gone, but as healthcare providers we must be educated and vigilant to protect ourselves, our families, and our country from the presumed threat. Understanding smallpox and being able to recognize and treat it are important steps in the fight against the possible resurgence of a disease, believed to be eradicated, which has killed millions of people over the history of human civilization.

Posted June 22, 2007

Expires July 1, 2009

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