eMedicine Specialties > Emergency Medicine > Warfare - Chemical, Biological, Radiological, Nuclear and Explosives

CBRNE - Smallpox

Author: Christopher J Hogan, MD, Assistant Professor, Department of Emergency Medicine, Medical College of Virginia/Virginia Commonwealth University Hospital
Coauthor(s): Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Chair, Department of Emergency Medicine, Director of Medical Toxicology - Allegheny General Hospital, Associate Professor, Department of Emergency Medicine, Drexel University College of Medicine
Contributor Information and Disclosures

Updated: Jun 12, 2009

Introduction

Background

Smallpox (variola) represents both the zenith and nadir of human achievement. It is the only disease that has been 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 infection, which once caused high mortality rates, has occurred since October 26, 1977. (The last naturally occurring case involved an unvaccinated hospital cook in Somalia.) Smallpox officially was declared eradicated by the World Health Organization (WHO) in 1980. Smallpox also represents one of the most devastating potential biological weapons ever conceived.

A child with variola is shown below.

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) unsuccessfully tried to weaken Native American forces during the French and Indian War by giving them smallpox-contaminated blankets and goods.¹ Whether because of 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. The WHO Committee on Orthopoxvirus Infections has proposed multiple dates for destruction of the remaining viral stocks, only to be pushed back under pressure from various factions.

Various sources from the former Soviet Union allege that the Russian 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 strains that are more virulent. Since the fall of the Soviet Union, concern exists that this expertise may be used 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. Vaccination of the general population in the United States ceased after 1980, and vaccination in military personnel was discontinued in 1989. Currently, the populace in the United States is considered immuno-naive to the variola virus. Forty-two percent of the US population was never vaccinated, and an estimated 53% of the US population has received the smallpox vaccine.²

Two vaccination programs were started in the aftermath of the 9/11 attacks, one a military program that inoculated 730,580 persons, and a voluntary vaccination for health care workers that ultimately inoculated 37,901 individuals. Vaccinated individuals theoretically retain immunity for approximately 10 years, although the duration has never been fully evaluated. Because of the ease of production and aerosolization of the virus (only 10-100 virus particles are needed for infection), smallpox is a potential biological weapon.

Pathophysiology

Variola is a member of the Orthopoxvirus genus, of which cowpox, monkeypox, orf, and molluscum contagiosum are also members. Poxviruses are the largest animal viruses, larger than some bacteria. They have a large genome, composed of 200 kilobase (kb) 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.

A boy with monkeypox is shown in the images below.

Frequency

United States

No recent case of systemic smallpox has been reported in the United States. Since vaccination commenced, isolated cases of vaccinia virus illnesses from vaccine recipients and their close contacts have occurred. Since the 2001 terrorist attacks, vigilance for smallpox cases has heightened, given the high potential for its use as a weapon of mass destruction. From January 2002 through June 2004, the CDC received 43 consultations regarding suspected smallpox cases. Ultimately, most of those persons with suspected variola were diagnosed with varicella (53% of all the suspected variola cases).

International

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

Mortality/Morbidity

Variola major, or smallpox, has an overall mortality rate 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. The malignant and hemorrhagic forms of smallpox are not caused by unique variola strains but are thought to be due to host factors such as a deficient cellular immune response to the virus.

• Pregnant women have a heightened morbidity rate to variola. In one study prior to virus eradication, the morbidity rate was 27% in vaccinated patients and 61% in unvaccinated patients versus a nonpregnant control morbidity rate of 6% (vaccinated) and 35% (unvaccinated).
• The hemorrhagic variety of variola also carried a higher mortality rate 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 and 192 died. Pregnant women are more likely to develop this variant. Scientists who manufacture biological weapons might attempt to elucidate the mechanisms that lead to the development of hemorrhagic smallpox in victims, which would serve to maximize the terror impact of their weapons.
• 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 develops in people with some intact immune response who were previously vaccinated. In a vaccinated population, this version would constitute approximately 15%.

Race

No racial predilection exists.

Sex

With the exception of pregnant women, males and females are infected in equal proportions.

Age

No age predilection exists, although mortality is higher in the extremes of age. In people who are unvaccinated, the distribution of illness mirrors that of the age distribution of the population. However, in India, prior to eradication, 70% of infections were in children younger than 14 years.

Clinical

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 high fever (102-105°F), myalgias (particularly backache), and headache.
  • 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 shed, 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 can easily 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. These lesions contain a high viral load and are infectious.

Physical

Currently, the clinical diagnosis of smallpox is based on several criteria.² The major criteria are (1) a febrile prodrome 1-4 days before rash onset; (2) the classic smallpox lesions (ie, deep-seated, firm, round, well-circumscribed lesions); and (3) lesions that are at the same stage of development.

The minor criteria include (1) a centrifugal distribution of lesions, with the first lesions on the oral mucosa or palate, face, or forearms; (2) a toxic or moribund appearance; (3) the slow evolution of lesions of 1-2 days per stage; and (4) lesions that appear on the palms and soles.

A child with lesions of the variola strain is shown in the images below.

• 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 centrally from the limbs.
  • Lesions favor ventral surfaces and progress through stages of macule, papule, vesicle, papules (often umbilicated, like molluscum contagiosum), and crusts. Unlike in varicella, in which 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. Pustular lesions are shown in the image below.
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    Adult with variola major with hundreds of pustular lesions distributed centrifugally. Fitzsimmons Army Medical Center slide file.

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    Adult with variola major with hundreds of pustular lesions distributed centrifugally. Fitzsimmons Army Medical Center slide file.

  • 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, shown in the image below, accounts for 3% of infections and has an exceptionally high mortality rate (94% in unvaccinated patients). Death usually ensues before the hemorrhagic macules can progress to papules.
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    Hemorrhagic-type variola major lesions. Death usually ensued before typical pustules developed. Reprinted with permission from Herrlich A, Mayr A, Munz E, et al: Die pocken; Erreger, Epidemiologic und klinisches Bild. 2nd ed. Stuttgart, Germany: Thieme; 1967. In: Fenner F, Henderson DA, Arita I, et al: Smallpox and its eradication. Geneva, Switzerland: World Health Organization; 1988: 10-14, 35-36.

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    Hemorrhagic-type variola major lesions. Death usually ensued before typical pustules developed. Reprinted with permission from Herrlich A, Mayr A, Munz E, et al: Die pocken; Erreger, Epidemiologic und klinisches Bild. 2nd ed. Stuttgart, Germany: Thieme; 1967. In: Fenner F, Henderson DA, Arita I, et al: Smallpox and its eradication. Geneva, Switzerland: World Health Organization; 1988: 10-14, 35-36.

  • Soft or velvety skin lesions are present in flat smallpox, which has a 95-100% mortality rate in unvaccinated patients.
  • Alastrim, or variola minor, shown in the images below, presents with lesions like those in variola major except that they are less numerous and more diminutive.
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    Ordinary form of variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from Fenner F, Henderson DA, Arita I, et al: Smallpox and its eradication. Geneva, Switzerland: World Health Organization; 1988: 10-14, 35-36; photographs by Arita.

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    Ordinary form of variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from Fenner F, Henderson DA, Arita I, et al: Smallpox and its eradication. Geneva, Switzerland: World Health Organization; 1988: 10-14, 35-36; photographs by Arita.

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    Ordinary form of variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from Fenner F, Henderson DA, Arita I, et al: Smallpox and its eradication. Geneva, Switzerland: World Health Organization; 1988: 10-14, 35-36; photographs by Arita.

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    Ordinary form of variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from Fenner F, Henderson DA, Arita I, et al: Smallpox and its eradication. Geneva, Switzerland: World Health Organization; 1988: 10-14, 35-36; photographs by Arita.

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    Ordinary form of variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from Fenner F, Henderson DA, Arita I, et al: Smallpox and its eradication. Geneva, Switzerland: World Health Organization; 1988: 10-14, 35-36; photographs by Arita.

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    Ordinary form of variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from Fenner F, Henderson DA, Arita I, et al: Smallpox and its eradication. Geneva, Switzerland: World Health Organization; 1988: 10-14, 35-36; photographs by Arita.

  • 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 mainly humans (and some primates in laboratory experiments), and no animal or arthropod vectors exist.
• The laboratories in the world known to house the smallpox virus are the CDC in Atlanta, Ga; the Russian State Research Center of Virology and Biotechnology in Koltsovo; and the Institute of Viral Preparations in Moscow, Russia.

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