INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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.

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 afterward.

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.

Although the variola virus was believed to infect only humans, infection has recently 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 was previously 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 deep-seated 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

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

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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.

• 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.
  • 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 unvaccinated 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 95-100% mortality rate in unvaccinated patients.
  • Alastrim, or variola minor, presents with lesions like those in 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 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.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Acute leukemia
Allergic dermatitis
Bullous pemphigoid
Chickenpox
Disseminated herpes zoster
Disseminated herpes simplex
Drug reactions
Drug eruptions
Ehrlichiosis
Erythema multiforme major (including Stevens-Johnson syndrome)
Gram-negative septicemia
Hand-foot-and-mouth disease
Meningococcemia
Measles
Monkeypox (endemic in some areas of Africa)
Hemorrhagic varicella
Rocky Mountain spotted fever
Secondary syphilis
Vaccinia

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• The CDC has made available an algorithm that has worked well to guide clinical and public health responses to suspected smallpox cases. The poster is available from the CDC, and the CDC's Web site contains an interactive version of the algorithm and laboratory protocol (see Evaluate a Rash Illness Suspicious for Smallpox).
• Perform a viral swab of the pharynx in patients in whom smallpox is suspected, or swab a freshly opened pustule, if available. Otherwise, open a lesion with a scalpel and obtain a culture.
• The following are recommended rapid tests (all providing test results within hours) for assessing smallpox infection, in increasing order of reliability:
• • Electron microscopy - May be useful to differentiate herpes viruses and poxviruses
  • Tzanck smear - Not specific for varicella because it detects all alphaherpesviruses
  • VZV direct fluorescent antibody (DFA) assay - Agent specific, simple, and commercially available (However, reliability requires careful collection and prompt processing of specimens.)
  • Real-time PCR testing - Most sensitive and specific rapid assay for detection of VZV (now available to all state health departments and Laboratory Response Network [LRN] laboratories)
• Serologic testing is not useful for rapid diagnostic purposes.
• Send the swab samples in a Vacutainer tube with the rubber stopper taped. Double seal the tube, and inform the receiving laboratory and courier of the potential biohazard. Prior to collection of samples or shipment, the CDC or the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) should be consulted directly, as should local public health authorities. In addition to individual state laws concerning highly infectious agents, specific federal laws apply to the shipping of such pathogens across state lines.

Imaging Studies

• No imaging studies assist in making the diagnosis of variola infection.

Procedures

• Include a lumbar puncture in the workup for hemorrhagic variola to exclude meningococcemia.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Prehospital Care

No prehospital care is indicated except to stabilize the patient. Strict blood, body fluid, and droplet protection are required for all personnel involved with treating or transporting patients with known or suspected smallpox. All EMS personnel exposed to the patient require quarantine and vaccination.

Emergency Department Care

In the emergency department, containment of the diseases is the single most important intervention in patients in whom variola infection is suggested.

• Immediate contact and droplet isolation of the patient is required.
• The patient and any individual who came into contact with the patient up to 17 days prior to the illness (including the treating physician and nursing staff) should remain in isolation until a definite diagnosis is made. Presently, this requires sending a viral culture to the CDC in Atlanta, Ga.
• Notify the local health authorities immediately.
• The most likely scenario of a variola outbreak is from a terrorist attack. Given the highly infective nature of the organism (not taking into account a genetically altered virus), researchers estimate that 1 infected patient can subsequently infect 20 new contacts during the infectious stage of the illness.
• The presentation of a clinically apparent case implies that a larger population has probably been infected.
• Because of the medicolegal and social implications of quarantine and isolation for a minimum of 17 days, coordinated involvement on the federal, state, and local levels is mandatory. In practicality, a strict quarantine of a large segment of the population is probably not possible.

Consultations

Consult the infectious disease service early since it may help determine the diagnosis. As mentioned previously, contact the state, federal, and local health authorities.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Once the disease is fully manifested, medical treatment of variola is supportive care. Vaccinations and postexposure interventions are the mainstays of treatment. The various vaccines available and being tested are divided into generations based on their method of manufacturing and degree of virus attenuation. First-generation vaccines are composed of vaccinia virus derived from calf lymph or chicken embryos, have little attenuation, and represent the majority of the vaccine stockpile. Second-generation vaccines are viruses taken from first-generation vaccines that are then sterilely tissue-cultured with the aim of decreasing adverse outcomes. Lastly, third-generation vaccines use replication-deficient viruses that are highly attenuated, again with the aim of decreasing side effects and adverse outcomes.

Drug Category: Vaccine

The vaccinia (smallpox) vaccine and vaccinia immune globulin (VIG) are available only through the CDC and state and federal health agencies. Dryvax, and now ACAM200, are the only vaccines available, although vaccines from other countries may be made available in a smallpox outbreak.³ One hundred million doses of the Wyeth Laboratory vaccine (New York Board of Health virus grown on scarified calves) exist in the United States. This stock was diluted in 2002, and the current stock is approximately 1000 million doses.⁴ Fifty to one-hundred million additional doses are estimated to exist worldwide. Almost 750,000 doses of this vaccine have been used to vaccinate the US military. When the vaccine was made available to first-line health care individuals, 38,000 received the vaccine.

One large-scale producer of a cell-cultured smallpox vaccine (Acambis) received US Food and Drug Administration (FDA) approval on August 31, 2007, for active immunization for those determined to be at high risk for smallpox infection. It is a single-dose vaccine that is the primary smallpox vaccine for use in the Strategic National Stockpile, with 192.5 million doses produced. Although believed to have less potential for adverse outcomes, ACAM2000 has been found to have similar rates of side effects such as myopericarditis.

Also under development is a modified vaccinia virus Ankara (MVA), which may be suitable as a new smallpox vaccine. Because it uses an attenuated virus, it can theoretically be used in those with contraindications to a first- or second-generation vaccine. When given prior to administration of Dryvax, it was shown to increase the immune response to vaccination while decreasing the severity of the lesion formation.⁵ Although this attenuated strain was used in Europe in the 1960s, it has never been field tested against an actual smallpox epidemic, unlike the first-generation vaccines (thus, its effectiveness in protecting against infection was never evaluated).

Persons exposed to variola (meaning all household or other face-to-face contacts after onset of fever) within a few days were found to experience attenuated illness if vaccinated within 4 days. Researchers estimate that, of the previously vaccinated population, only approximately 20% still have effective immunity. Those who were not revaccinated within 3 years (eg, laboratory workers) should be vaccinated again.⁴ From the most recent military vaccination campaign, postvaccinial encephalitis or encephalomyelitis has been reported to occur at an incidence of 1 case per 300,000 vaccinations, and myopericarditis has been found in a significantly higher number of patients.^{6, 4, 7}

Drug Category: Blood products

Immune globulins bind to the virus particle, stimulate an immune response, and offer transient protection while the host immune system develops antibodies. A new VIG is being developed. The IV route is anticipated to be the preferred method of administration, and new dosage recommendations (eg, lower dose than the current IM product) are expected. The new VIG contains low-aggregated protein levels, allowing IV or IM administration.

Drug Category: Immune globulins

Indicated for passive immunity. VIG is the only drug available for amelioration of some vaccinia-related complications. VIG is produced from pooled human sera taken from vaccinia-immunized individuals and is available only from the CDC. VIG has been effective when administered early in cases of vaccinia necrosum and eczema vaccinatum. VIG has not been effective in cases of encephalopathy. The use of VIG for generalized vaccinia reactions is usually not necessary. Recently, VIGIV has been FDA approved.

Drug Category: Antivirals

In vitro studies demonstrated cidofovir to inhibit poxvirus replication and cell lysis.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Supportive care is the primary intervention for a clinically evident infection. This includes hydration therapy for fluid loss through fever and skin barrier breakdown. Antibiotics may be needed for secondary skin infections. Maintain respiratory and contact isolation for 17 days or until the scabs fall off.

Further Outpatient Care

• Plastic surgery consultation may be necessary for skin disfiguration.

In/Out Patient Meds

• No medications are required other than those previously mentioned (see Medication).

Transfer

• Make any transfer with full respiratory and contact isolation.

Deterrence/Prevention

• In a variola outbreak, the high rate of spread can be reduced by identification of the disease (a high index of suspicion is needed) and rapid containment.
• The most likely scenario of a variola outbreak is from a terrorist attack.
• Given the highly infective nature of the organism (not taking into account a genetically altered virus), researchers estimate that 1 infected patient could infect as many as 20 new contacts during the infectious stage of the illness. However, based upon historical data, 5-6 close friends or family members was the norm.

Complications

• Complications associated with high morbidity and mortality rates that can be reduced are secondary skin infections and dehydration.

Prognosis

• Smallpox is one of the most communicable of infectious diseases. Studies have shown that approximately 30% of susceptible contacts became infected. Only measles and influenza have a consistently higher attack rate.
• In general, variola has a mortality rate of 30% in the unvaccinated population.
• Pregnant women have a heightened morbidity to variola. The morbidity rate is 27% in vaccinated patients and 61% in unvaccinated patients versus a nonpregnant control morbidity rate of 6% (vaccinated) and 35% (unvaccinated).

Patient Education

• Heightened awareness of the manifestations of this disease may help reduce the population exposed in an outbreak through early diagnosis and preventive medicine, public health initiatives, or both.
• For excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education articles Biological Warfare, Smallpox, Personal Protective Equipment, and Molluscum Contagiosum.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Failing to notify the local, state, or federal health authorities and discharging a patient with this disease back into the general population are the gravest potential errors. The state health authorities are also the source of vaccine for both the patient and exposed health care workers.
• • Involvement of the state and local authorities gives the clinician the needed support to quarantine individuals and their contacts in the event of an outbreak.
  • This quarantine also involves the healthcare staff and EMS personnel.
  • The presentation of a clinically apparent case implies that a larger population has been infected. Because of the medicolegal and social implications of isolation and quarantine, coordinated involvement on the federal, state, and local levels is mandatory.

Special Concerns

• The pediatric population is particularly susceptible to death from variola because of their relatively immature immune system, although children in a naive population have the highest mortality rate.
• When treating smallpox, give special care to patients with HIV; pregnant women; patients with eczema, leukemia, or malignancy that requires chemotherapy; and patients with hereditary immune disorders, all of whom should be given VIG instead of the vaccination.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Thomas W McGovern, MD, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Characteristic skin lesion of variola on the arms and legs of an adolescent. Photo used with permission from the World Health Organization (WHO).
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Media file 2:  Small child with pustular lesions of variola. Photo used with permission of the World Health Organization (WHO).
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Media file 3:  Infant with advanced lesions of variola. Photo used with permission of the World Health Organization (WHO).
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Media file 4:  Unvaccinated infant with centrifugally distributed umbilicated pustules on day 3 of ordinary form of variola major strains of smallpox. 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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Media file 5:  Unvaccinated infant with centrifugally distributed umbilicated pustules on day 5 of ordinary form of variola major strains of smallpox. 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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Media file 6:  Unvaccinated infant with centrifugally distributed umbilicated pustules on day 7 of ordinary form of variola major strains of smallpox. 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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Media file 7:  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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Media file 8:  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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Media file 9:  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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Media file 10:  Adult with variola major with hundreds of pustular lesions distributed centrifugally. Fitzsimmons Army Medical Center slide file.
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Media file 11:  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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Media file 12:  Boy with monkeypox in Democratic Republic of the Congo in 1996. Note the centrifugal distribution as was typical of smallpox. Courtesy of William Clemm.
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Media file 13:  Boy with monkeypox in Democratic Republic of the Congo in 1996. Note synchronicity of lesions as was typical of smallpox. Courtesy of William Clemm.
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Media file 14:  Bioterrorist Agents. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/bioterrorism.html.
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REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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6. Weiss MM, Weiss PD, Mathisen G, Guze P. Rethinking smallpox. Clin Infect Dis. Dec 1 2004;39(11):1668-73. [Medline].
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8. Abramowicz M, ed. Drugs and vaccines against biological weapons. Med Lett Drugs Ther. Feb 12 1999;41(1046):15-6. [Medline].
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Article Last Updated: Dec 20, 2007