INTRODUCTION	Section 2 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Background: Smallpox (variola) represents both the zenith and nadir of human achievement. It is the only disease eradicated through a concerted and extensive effort that transcended political and ideologic boundaries. Because of these efforts, not one documented naturally occurring case of this once high-mortality infection has occurred since October 26, 1977. (The last case was an unvaccinated hospital cook in Somalia.) Smallpox officially was declared eradicated by the World Health Organization (WHO) in 1980. It also represents one of the most devastating potential biological weapons ever conceived.

For centuries, smallpox affected political and social agendas. Epidemics plagued Europe and Asia until Edward Jenner developed a vaccine in 1796; he subcutaneously inoculated patients with the milder cowpox virus. The viral illness incidence of infection in Europe steadily declined from that point onward.

In the Americas, smallpox decimated the native population, who never had been exposed to variola, when it followed closely behind the European explorers in the 1600s. The British forces at Fort Pitt (Pittsburgh, PA) purposefully gave smallpox-contaminated blankets and goods to Native Americans during the French and Indian Wars in an attempt to weaken resistance to colonial expansion. Whether due to this or through natural spread, the subsequent epidemic carried a mortality rate of 50% among native tribes.

Farr first accurately predicted variola infection rates in the 1830s. Once the disease and its method of spread were understood better, smallpox vaccination became mandatory in developed countries in the early 1900s. The development of the vaccinia virus and its subsequent vaccine enabled aggressive immunization by the WHO, which led to variola eradication in 1977.

The variola virus no longer exists outside of a few laboratories around the world. The official virus repositories are at the Centers for Disease Control and Prevention (CDC) in Atlanta, GA, and the Institute of Viral Preparations in Moscow, Russia. Viral stocks also exist at the Russian State Research Center of Virology and Biotechnology in Koltsovo. Multiple dates for destruction of the remaining viral stocks have been proposed by the WHO Committee on Orthopoxvirus Infections, only to be pushed back under pressure from various factions, including the US government.

Various sources from the Soviet Union allege that the military had pursued and currently pursues an active biological warfare program. For instance, the Russian government confirmed a suspected outbreak from an accidental release of aerosolized anthrax near a military microbiology laboratory in 1992. In 1980, the Soviet Union commenced large-scale production of the smallpox virus and genetic recombination of more virulent strains. Since the fall of the Soviet Union, concern exists that this expertise may be employed in other countries. The extent of smallpox stockpiles in other countries is unknown but may be significant since the collapse of the Soviet Union.

Variola, prior to eradication, carried a mortality rate of 30% in unvaccinated persons. Researchers estimate that vaccinated individuals retain immunity for approximately 10 years, although the duration never has been evaluated fully. Vaccination of the general population in the United States ceased after 1980, and vaccination in military personnel was discontinued in 1989. Therefore, the current populace in the United States is considered immuno-naïve to the variola virus. Forty-two percent of the US population is younger than 30 years and never was vaccinated. The ease of production and aerosolization of the virus is well documented. Researchers estimate that only 10-100 virus particles are needed for infection; thus, smallpox is a potential biological weapon of staggering lethality.

Pathophysiology: Variola is a member of the Orthopoxvirus genus, of which cowpox, monkeypox, orf, and molluscum contagiosum also are members. Poxviruses are the largest animal viruses visible with a light microscope and are larger than some bacteria. They have the largest genome, comprised of 200 kilobase double-stranded DNA enclosed in a double membrane layer. Poxviruses are the only viruses that can replicate in cell cytoplasm without the need of a nucleus. Although it was believed that the variola virus infected only humans, infection recently has been elicited in cra-eating macaques when exposed to large amounts of injected and aerosolized virus, thus potentially providing an in vivo source of research that previously was unavailable.

The virus is acquired from inhalation, although virus particles can remain viable on fomites (clothing, bedding, surfaces) for approximately 1 week. The virus initially replicates in respiratory tract epithelial cells. From there, a massive asymptomatic viremia ensues, resulting in focal infection of the skin, intestines, lungs, kidneys, and brain. The multiplication in the skin epithelial cells first leads to a rash, progressing into pustules approximately 14 days after inoculation. A cell-mediated immune response is responsible for pustule formation, as immunocompromised rabbits do not produce these characteristic lesions. Patients who survive an initial infection often have severely deformed skin from the pustules and subsequent granulation tissue formation.

Frequency:
 

• Internationally: Since the last wild documented case in 1977, only 2 deaths from smallpox have been reported (1978 in Birmingham, England), one from a laboratory worker who infected her mother and the second from a photographer with an office next to the lab space where the accidental exposure to the virus occurred.

Mortality/Morbidity: Variola major, or smallpox, has a mortality of 30%. Variola minor, or alastrim, is a milder form of the virus, carrying a mortality rate of 1%. Four types of variola presentations exist: classic, hemorrhagic, malignant, and modified. Classic smallpox was believed to be the most communicable disease—approximately 30% of susceptible contacts became infected.

• Pregnant women have a heightened morbidity to variola. In one study prior to virus eradication, morbidity was 27% in vaccinated patients and 61% in unvaccinated patients versus a nonpregnant control morbidity of 6% (vaccinated) and 35% (unvaccinated).

   

• The hemorrhagic variety of variola also carried a higher mortality and led to death more quickly. Patients often died before the pustular lesions formed, but this variety is recognizable by the hemorrhagic lesions that erupt in the mucosal and cutaneous membranes. Comprehensive studies documenting almost 7000 cases of variola found 200 patients had this form of the disease; 192 died. Pregnant women are more likely to contract this version. Biological warfare design probably would employ this variety for an optimal number of deaths per unit of agent dispersed.

• Prior to eradication, the malignant or flat form of variola affected 6% of the population and evolved more slowly than the classic presentation. Lesions were not pustular; instead they consisted of a flattened macule, often described as feeling velvety. The mortality rate for this form approaches 100%.

• The modified variety of smallpox essentially consists of those previously vaccinated with some intact immune response. In a vaccinated population, this version would constitute approximately 15%.

Race: No racial predilection exists.

Sex: With the exception of pregnant patients, males and females are infected in equal proportions.

	CLINICAL	Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History:

• Incubation periods for the major types of variola infection range from 7-17 days.

• An asymptomatic viremia occurs 72-96 hours after infection.

• At the end of the incubation period, a second viremia results in the onset of clinical symptoms such as fever, myalgias, headache, rigors, and, particularly, backache.

• Rigors and vomiting are present in more than one half of patients.

• Delirium occurs in 15% of the infected population.

• This prodrome lasts 2-4 days, and during this time, viremia is present and patients are most infectious.

• A rash appears 48-72 hours after the prodrome and progresses from macules to characteristic papules. During the period of mucosal lesions (just after appearance of the rash), the virus is highly contagious because the mucosal membranes lack a keratinized layer. As these cells slough, virus particles are released, coughed, or sneezed into the outside environment.

• Virus titers in saliva are highest the first week of infection, but infectivity can last up to 3 weeks (until the scabs fall off). Live virus can be cultured from scabs.

• Early in the course of the disease, the rash and macules easily can be mistaken for varicella, given the coincidence of fever and myalgias. The macules give way to papules, and finally, the characteristic pustules form, although this can take up to 2 weeks from exposure. The distribution and character of these lesions are the sine qua non of variola. The contents of these lesions contain a high viral load and are infectious.

Physical:

• In 10% of patients, a fleeting erythematous exanthem can be seen in fair-skinned patients before the typical cutaneous manifestations occur.

• Lesions occur first in the oral mucosa, spreading to the face, then to the forearms and hands, and finally to the lower limbs and trunk. This is in distinction to the rash from varicella, which progresses from the limbs centrally.

• Lesions favor ventral surfaces and progress through stages of macule, papule, vesicle, papules (often umbilicated, like molluscum contagiosum), and crusts. Unlike in varicella, where lesions in different stages are present, the exanthem of variola is synchronous, with numerous monomorphic lesions.

• The rash settles centrifugally, sparing the axillae, palms, soles, and antecubital areas. Crusts detach after 2-4 weeks, leaving depressed, hypopigmented scars.

• Lesions are concentrated on the hands, face, feet, and calves.

• While the description above fits ordinary cases of smallpox (variola major), other presentations may occur.

• Hemorrhagic smallpox accounts for 3% of infections and has an exceptionally high mortality rate (94% in vaccinated patients). Death usually ensues before the hemorrhagic macules can progress to papules.

• Soft or velvety skin lesions are present in "flat smallpox," which has a 66% mortality rate in vaccinated patients.

• Alastrim, or variola minor, presents with lesions like variola major except that they are less numerous and more diminutive.

• Variola may be seen without an eruption in 30-50% of vaccinated contacts of patients with smallpox. Patients develop a mild prodrome followed by conjunctivitis without skin changes.

Causes:

• The variola virus is the only known cause of smallpox. The disease affects only humans, and no animal or arthropod vectors or carriers exist.

• Only two laboratories in the world are known to house smallpox virus: the CDC in Atlanta, GA, and the Russian State Research Center of Virology and Biotechnology in Koltsovo.